Effect of Selumetinib and MK-2206 Vs Oxaliplatin and Fluorouracil In
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1 PRIVILEGED COMMUNICATION Activated August 15, 2012 2 FOR INVESTIGATIONAL USE ONLY 3 4 5 SWOG 6 7 8 RANDOMIZED PHASE II CLINICAL TRIAL OF AZD6244 HYDROGEN SULFATE (NSC-748727) AND 9 MK-2206 (NSC-749607) VS MFOLFOX IN PATIENTS WITH METASTATIC PANCREATIC CANCER 10 AFTER PRIOR CHEMOTHERAPY 11 12 NCT # 01658943 13 14 15 PARTICIPANTS: ALL SWOG GROUP MEMBER, CCOP, AND AFFILIATE MEDICAL ONCOLOGISTS; 16 CTSU 17 18 19 STUDY CHAIRS: AGENTS: 20 21 Vincent Chung, M.D. (Medical Oncology) NCI Supplied: 22 City of Hope National Medical Center AZD6244 hydrogen sulfate (NSC-748727) 23 1500 E. Duarte Road (IND-111587) 24 Duarte, CA 91010 MK-2206 (NSC-749607) (IND-111587) 25 Pager: 626-423-5526 Commercially Available: 26 Phone: 626-471-9200 5-Fluorouracil (5-FU) (NSC-19893) 27 FAX: 626-301-8233 Oxaliplatin (Eloxatin®) (NSC-226046) 28 E-mail: [email protected] 29 30 Philip A. Philip, M.D., Ph.D. (Medical Oncology) 31 Karmanos Cancer Institute 32 Hematology/Oncology 33 4100 John R. 4HWCRC 34 Detroit, MI 48201 35 Pager: 313-745-5111 36 Phone: 313-576-8746 37 Fax: 313-576-8729 38 E-mail: [email protected] 39 40 ECOG STUDY CHAIRS: BIOSTATISTICIANS: 41 42 Dana Backlund Cardin, M.D. Shannon McDonough, M.S. 43 Phone: 615/322-4967 Katherine A. Guthrie, Ph.D. 44 E-mail: [email protected] SWOG Statistical Center 45 Fred Hutchinson Cancer Research Center 46 1100 Fairview Avenue N, M3-C102 47 PO Box 19024 48 Seattle, WA 98109-1024 49 Phone: 206/667-4623 50 FAX: 206/667-4408 51 E-mail: [email protected] 52 E-mail: [email protected] 53 54 55
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56 TABLE OF CONTENTS 57 58 Page 59 SCHEMA ...... 5 60 1.0 OBJECTIVES ...... 6 61 1.1 Primary Objective ...... 6 62 1.2 Secondary Objective ...... 6 63 1.3 Other Objectives ...... 6 64 2.0 BACKGROUND ...... 6 65 3.0 DRUG INFORMATION ...... 10 66 3.1 AZD6244 hydrogen sulfate (selumetinib, ARRY-142886) (NSC # 748727) ...... 67 (IND-111587) ...... 10 68 3.2 5-Fluorouracil (5-FU) (NSC-19893) ...... 16 69 3.3 MK-2206 (NSC-749607) (IND-111587) ...... 19 70 3.4 Oxaliplatin (Eloxatin®) (NSC-266046) ...... 25 71 4.0 STAGING CRITERIA ...... 31 72 5.0 ELIGIBILITY CRITERIA ...... 32 73 5.1 Disease Related Criteria ...... 32 74 5.2 Prior/Concurrent Therapy Criteria ...... 33 75 5.3 Clinical/Laboratory Criteria ...... 33 76 5.4 Specimen Submission Criteria ...... 34 77 5.5 Regulatory Criteria ...... 34 78 6.0 STRATIFICATION FACTORS ...... 35 79 7.0 TREATMENT PLAN ...... 35 80 7.1 Arm 1: mFOLFOX ...... 35 81 7.2 Arm 2: Combination of MK-2206 and AZD6244 Hydrogen Sulfate ...... 36 82 7.3 Supportive Care Guidelines ...... 36 83 7.4 Investigational Drug ...... 38 84 7.5 Criteria for Removal from Protocol Treatment ...... 38 85 7.6 Discontinuation of Treatment ...... 38 86 7.7 Follow-Up Period ...... 38 87 8.0 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS ...... 38 88 8.1 NCI Common Terminology Criteria for Adverse Events ...... 38 89 8.2 Dose Modifications ...... 38 90 8.3 Dose Delay/Modification for FOLFOX ...... 39 91 8.4 Dose Delay/Modification for MK-2206 and AZD6244 Hydrogen Sulfate ...... 43 92 8.5 Dose Modification Contacts ...... 45 93 8.6 Adverse Event Reporting ...... 45 94 9.0 STUDY CALENDAR ...... 46 95 10.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ...... 48 96 10.1 Measurability of Lesions...... 48 97 10.2 Objective Status ...... 49 98 10.3 Best Response ...... 50 99 10.4 Performance Status ...... 51 100 10.5 Progression-Free Survival ...... 51 101 10.6 Overall Survival ...... 51 102 11.0 STATISTICAL CONSIDERATIONS ...... 52 103 11.1 Accrual Goals ...... 52 104 11.2 Primary Chemotherapy Objective ...... 52 105 11.3 Adverse Events Monitoring ...... 52 106 11.4 Eligible Patients ...... 52 107 11.5 Data and Safety Monitoring Committee ...... 53 108 12.0 DISCIPLINE REVIEW ...... 53 109 13.0 REGISTRATION GUIDELINES ...... 53 110 13.1 Registration Timing ...... 53 111 13.2 Investigator/Site Registration ...... 53
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112 13.3 OPEN Registration Requirements ...... 54 113 13.4 Registration Procedures...... 55 114 13.5 Exceptions to SWOG registration policies will not be permitted ...... 56 115 14.0 DATA SUBMISSION SCHEDULE ...... 56 116 14.1 Data Submission Requirement ...... 56 117 14.2 Master Forms ...... 56 118 14.3 Data Submission Procedures ...... 56 119 14.4 Data Submission Overview and Timepoints ...... 57 120 15.0 SPECIAL INSTRUCTIONS...... 58 121 16.0 ETHICAL AND REGULATORY CONSIDERATIONS ...... 58 122 16.1 Adverse Event Reporting Requirements ...... 61 123 17.0 BIBLIOGRAPHY ...... 66 124 18.0 APPENDIX ...... 68 125 18.1 Determination of Expedited Adverse Event Reporting Requirements ...... 69 126 18.2 Intake Calendar ...... 71 127 18.3 Medications Known to Prolong the QT Interval and/or Induce Torsades de Pointes ..... 72 128 18.4 CYP3A4/5 and CYP1A2 Prohibited Medications ...... 76 129 18.5 New York Heart Association Classifications ...... 77 130
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131 To submit site registration For patient Submit study data directly to the Lead documents: enrollments: Cooperative Group unless otherwise specified in the protocol:
CTSU Regulatory Office Please refer to the Online Data Submission: Institutions 1818 Market Street, patient enrollment participating through the CTSU are required to Suite 1100 section for instructions submit and amend their data electronically via Philadelphia, PA 19103 on using the OPEN Online Data Submission. Access the SWOG system. Workbench using your CTSU userid and Phone: 1-866-651-CTSU password at the following url: Fax: 215-569-0206 https://crawb.crab.org/TXWB/ctsulogon.aspx.
Exceptions: Data items that are not available for online submission (operative and pathology reports, patient completed forms, scan reports, etc.) may be submitted by fax at 800-892-4007. Do not submit data or forms to CTSU Data Operations. Do not copy the CTSU on data submissions.
The study protocol and all related forms and documents must be downloaded from the protocol- specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Sites must use the current form version and adhere to the instructions and submission schedule outlined in the protocol.
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement.
For patient eligibility questions contact the SWOG Data Operations Center by phone or email: Phone: 206/652-2267; E-mail: [email protected] And: For treatment or toxicity related questions contact the Study PI of the Coordinating Group. For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help Desk by phone or e-mail: CTSU General Information Line – 1-888-823-5923, or [email protected]. All calls and correspondence will be triaged to the appropriate CTSU representative. For detailed information on the regulatory and monitoring procedures for CTSU sites please review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website https://www.ctsu.org
The CTSU Web site is located at https://www.ctsu.org 132 133 134 135
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136 137 138 SCHEMA 139 140 141 Registration 142 143 144 145 146 147 148 Randomization 149 150 151 152 153 154 Arm 1 Arm 2 155 156 mFOLFOX MK-2206 157 AZD6244 hydrogen sulfate 158 159 160 161 162 PROGRESSION, 163 164 SYMPTOMATIC DETERIORATION, 165 DEATH 166 167 168 169 170 171 172 OFF TREATMENT 173 174 175 176
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177 1.0 OBJECTIVES 178 179 1.1 Primary Objective 180 181 a. To assess overall survival in patients with metastatic pancreatic cancer treated 182 with the combination of AZD6244 hydrogen sulfate and MK-2206 compared to 183 those treated with mFOLFOX. 184 185 1.2 Secondary Objective 186 187 a. To assess the frequency and severity of toxicity associated with the combination 188 of AZD6244 hydrogen sulfate and MK-2206 compared to those with mFOLFOX 189 in this patient population. 190 191 1.3 Other Objectives 192 193 a. To assess progression free survival (PFS) in patients with metastatic pancreatic 194 cancer treated with the combination of AZD6244 hydrogen sulfate and MK-2206 195 compared to those treated with mFOLFOX. 196 197 b. To assess objective tumor response in the subset of patients with measurable 198 disease (confirmed and unconfirmed complete and partial response) in patients 199 with metastatic pancreatic cancer treated with the combination of AZD6244 200 hydrogen sulfate and MK-2206 compared to those treated with mFOLFOX. 201 202 c. To bank tissue and blood for future translational medicine studies. 203 204 205 2.0 BACKGROUND 206 207 Metastatic pancreatic adenocarcinoma remains resistant to cytotoxic treatment, and median 208 overall survival is only 6 months. Even with the recent advances in targeted therapies, 209 researchers still have not found an effective treatment for this disease. Erlotinib in combination 210 with gemcitabine is approved for Stage IV pancreatic cancer patients; however, there is only a 2 211 week median survival benefit as well as a very modest increase in 1 year survival from 17% to 212 24%. (1) Nonetheless, this was the first targeted agent to show a statistically significant survival 213 benefit in pancreatic cancer. At ASCO 2010, the FOLFIRINOX data was presented which 214 showed an improvement in survival over gemcitabine albeit with increased toxicities. (2) The 215 applicability of FOLFIRINOX is therefore limited to a population of patients with a good 216 performance status, younger age, near normal liver function and a willingness to undergo an 217 aggressive therapy for metastatic disease. For this reason, the majority of patients with 218 metastatic disease will still be treated with gemcitabine in the front line setting. 219 220 After failure on gemcitabine, treatment options are extremely limited. NCCN guidelines for 221 salvage therapy include clinical trials, fluoropyrimidine based therapy (with or without oxaliplatin) 222 or best supportive care depending on performance status and organ function. The best study to 223 show a survival benefit with second line treatment was the CONKO-3 trial presented at ASCO 224 2008. (3) This showed that adding oxaliplatin to folinic acid and 5-fluorouracil extended survival 225 in gemcitabine refractory pancreatic cancer. Overall survival doubled from 13 weeks with folinic 226 acid and 5-fluorouracil to 26 weeks with the oxaliplatin containing regimen. Progression free 227 survival also improved from 9 weeks to 13 weeks. (4) With the development of novel, oral 228 targeted therapy, there is an urgent need to understand the signaling pathways driving cancer 229 growth. Being able to target these important pathways will hopefully improve the survival of 230 patients and quality of life with oral rather than IV cytotoxic therapy. 231 232 KRas and AKT in pancreas cancer: The Ras pathway is important in signal transduction from 233 cell surface receptors to the nucleus leading to cell growth, angiogenesis and survival. KRas 234 mutations are one of the earliest genetic alterations with most pancreatic adenocarcinomas being 235 KRas mutant. Mutations of the KRas gene lead to inactivation of the GTPase and therefore
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236 persistent activation of downstream signaling pathways. Ras signaling also activates the 237 PI3K/AKT pathway which is likely a driver for uncontrolled cell growth and cell survival. By 238 preventing the release of cytochrome c from the mitochondria as well as inactivating proapoptotic 239 factors such as BAD and procaspace-9, activated AKT leads to cell survival. Also by inactivating 240 FOXO transcription factor, the genes critical for apoptosis are repressed. As expected, AKT has 241 been shown to play a key role in chemoresistance in multiple cancers including pancreatic 242 adenocarcinoma. (5,6) AKT activation has been reported in 30-70% of pancreas tumors making 243 it a rational target in this disease. (7,8) 244 245 MK-2206: MK-2206 is the first allosteric AKT inhibitor in clinical development. Since it does not 246 bind to AKT’s active site, it does not compete with either ATP or peptide substrate binding. At 247 nanomolar concentrations, MK-2206 effectively inhibited all three isoforms of AKT. In the Phase I 248 study, safety and tolerability of MK-2206 was assessed at 30, 60, 90 mg, and 75 mg every other 249 day. Pharmacokinetic studies as well as correlative studies looking at phosphorylated Akt (pAkt) 250 were performed. Dose escalation occurred in 19 patients (8 female/11 male) and no dose limiting 251 toxicities (DLT) were observed at 30 and 60 mg. Common drug-related AEs included skin 252 (47.1%), gastrointestinal (41.2%), and general disorders (29.4%). Four of seven patients 253 experienced DLTs (CTCAE Grade 3/4 skin rash and CTCAE Grade 3 mucositis) at the 90 mg 254 dose. The protocol was amended to explore the 75 mg dose however, 2/3 patients experienced 255 DLT of rash. The maximum tolerated dose (MTD) of MK-2206 was determined to be 60 mg QOD 256 and pharmacokinetic analysis showed dose proportional AUC0-48hr and Cmax up to 60 mg with a 257 median Tmax of 6 hours. The mean t1/2 ranged from 63 to 76 hours. Decreases in whole blood 258 pAkt was observed at all dose levels. Observed clinical activity included: central tumor necrosis, 259 decreased ascites and peripheral edema, reduction in index lesions, normalization of LFTs, and 260 decreased CA-125. Stable disease at the two month evaluation was observed in 6 patients (1 261 patient at 30 mg and 5 patients at 60 mg). (9) Four healthy volunteers complained of transient 262 eye discomfort, dryness or visual blurring but ophthalmologic exam did not reveal any 263 abnormalities. (10) Overall, MK-2206 was well tolerated. 264 265 AZD-6244: AZD6244 (ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of 266 MEK 1/2. Preclinical studies with AZD-6244 showed higher sensitivity to MEK inhibition in cell 267 lines with BRAF and RAS mutations. (11) The Phase I study conducted at Roswell Park Cancer 268 Institute, enrolled patients initially in the dose escalation phase, part A. Once the maximum- 269 tolerated dose (MTD) was determined, patients were stratified by cancer type (melanoma versus 270 other) and randomly assigned to receive the MTD or 50% MTD. The MTD dose of 200 mg bid 271 had significant rash in part B of the study therefore the dose was reduced to 50% MTD (100 mg 272 bid) which was well tolerated. Pharmacokinetics were less than dose proportional, with a median 273 half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood 274 mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK 275 phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki- 276 67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. 277 Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 278 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Since a majority of 279 pancreatic cancers have KRAS mutations, MEK inhibition may be an important component of 280 multi-targeted therapy in this disease. 281 282 Targeting MEK and AKT/PI3K: Recently, there has been interest in targeting both the PI3K/AKT 283 and MEK pathways which may be beneficial in KRAS and BRAF mutant tumors. Research done 284 by the MD Anderson group on non-small cell lung cancer showed that targeting the MEK pathway 285 alone was not effective due to activation of AKT. Therefore, inhibition of both pathways would be 286 synergistic leading to increased cell apoptosis. Multiple cell lines were tested and differing ratios 287 of drug concentration lead to increased synergy. The combination of AZD6244 and MK-2206 at 288 8:1, 4:1 and 2:1 were synergistic while the 1:8 was only additive or even antagonistic is some cell 289 lines (Figures below). Two KRAS mutant cells, A549 and H157, were selected for further testing 290 in vivo. In the following figure, treatment with the combination resulted in a significant reduction in 291 tumor volume and improved the survival of the mice. Additional correlative studies were 292 293
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294 performed looking for on target effect. Immunohistochemistry using p-ERK and p-AKT antibodies 295 showed absence of the protein after treatment. A TUNEL assay was performed and significant 296 number of cells underwent apoptosis with combination treatment. (12) 297 298 At AACR 2011, Dr. Bendall presented early data from their Phase I clinical trial of GDC-0973 299 (MEK 1 / 2 inhibitor) and GDC-0941 (PI3K inhibitor). (13) Twenty seven patients were enrolled at 300 escalating doses and the regimen was well tolerated with mild toxicities. The most common 301 toxicities included diarrhea (90%, all Grade 1-2), fatigue (61%: Grade 1-2 50% and Grade 3 302 11%), nausea (61%, all Grade 1-2), rash (50%: Grade 1-2 45% and Grade 3 5%), vomiting (33%, 303 all Grade 1-2, decreased appetite (17%, all Grade 1-2) and dysgeusia (17%, all Grade 1-2). 304 Administration of the two drugs together did not alter the pharmacokinetics of either drug. 305 Several patients had decrease in tumor size including one patient with melanoma, one with 306 prostate cancer and two with NSCLC. Dr. Tolcher presented his Phase I clinical trial of MK-2206 307 and AZD6244 in patients with advanced or metastatic solid tumors at the 2011 ASCO meeting. 308 (14) In this trial, patients were treated with MK-2206 either every other day or weekly in 309 combination with AZD6244 continuous dosing once or twice per day. Thirty-three patients were 310 treated at five dose levels and Grade 3 macular skin rash occurred in 2 of 3 patients at MK2-206 311 45 mg QOD and AZD6244 75 mg BID. The recommended Phase II dosing is MK-2206 at 90 mg 312 Q week in combination with AZD6244 75 mg QD. The toxicities limiting further dose escalation 313 were skin rash, diarrhea, stomatitis and ocular events. 314 315 Study Rationale: A major reason for the repeated failure of single targeted agents is that solid 316 tumors (including pancreatic cancer) are genetically complex with respect to gene mutations with 317 many redundant pathways. Current research is looking at blocking multiple signaling pathways to 318 slow cancer growth and enhance apoptosis. Previous research has focused on finding an 319 oncogene that the cancer is addicted to drive growth. In pancreatic cancer, blocking AKT alone is 320 unlikely to be sufficient. However, preclinical work targeting the PI3K/AKT with the MEK/ERK 321 pathways significantly enhanced cytotoxicity. (15) Recently published, pancreatic cancer cell 322 lines harboring KRas mutations were shown to be more sensitive to therapy that blocked both 323 pathways. Apoptosis increased with combination treatment through activation of FOXO 324 transcription factors. (16) FOXO is important in modulating both cell cycle and apoptosis during 325 tumorigenesis. The regulation of FOXO target genes is multifactorial, and therefore other 326 transcription factors and post-translation regulatory events will influence the final level of protein 327 expression. 328 329 Despite introduction of FOLFIRINOX, only 20% of patients with metastatic disease are able to 330 receive this regimen. The experience thus far has not supported the use of single agent targeted 331 therapies in this disease. A multitargeted approach offers a better opportunity for more effective 332 control of cell proliferation and induction of apoptosis. This will also be one of the earliest studies 333 in pancreatic cancer whereby a noncytotoxic regimen is being tested. The combination of 334 AZD6244 and MK-2206 is potentially a promising treatment for pancreatic cancer patients. In Dr. 335 Tolcher’s Phase I clinical trial presented at ASCO 2011, there were 2 confirmed partial responses 336 observed in a KRAS mutant low-grade serous ovarian cancer and a KRAS mutant non-small cell 337 lung cancer. Four patients were observed to have stable disease with two of them being 338 pancreas cancer patients. One patient was KRAS mutant and another was wild-type. This 339 noncytotoxic approach to cancer therapy appears promising especially for patients with KRAS or 340 BRAF mutant tumors. This study could lay the foundation for further noncytotoxic studies in this 341 deadly disease. It will also add to knowledge on the biology of this disease and has the potential 342 of testing this combination in earlier stages of the disease and in the frontline therapy of patients 343 with metastatic disease. Blood and tissue samples will be collected for potential future correlative 344 studies.
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345 346 347 348 349 350 351 352 353 354 355 356
357
358 359 (12)
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360 This randomized Phase II clinical trial is designed to minimize selection bias. Currently, majority 361 of patients with metastatic pancreatic cancer still receive gemcitabine as first line therapy. 362 Patients who fail gemcitabine and are in favorable performance status are frequently offered 363 treatment with FOLFOX. Therefore, mFOLFOX has been chosen as the control arm of this 364 randomized Phase II study. We have removed the bolus 5-fluorouracil to decrease issues with 365 neutropenia and thrombocytopenia that commonly occurs after gemcitabine treatment. The 366 CONKO-3 trial showed that adding oxaliplatin to folinic acid and 5-fluorouracil doubled overall 367 survival from 13 weeks to 26 weeks but this schedule of dosing is not commonly used in the 368 United States. 369 370 Inclusion of Women and Minorities 371 372 This study was designed to include women and minorities, but was not designed to measure 373 differences of intervention effects. The anticipated accrual in the ethnicity/race and sex 374 categories is shown in the table below. 375 Ethnic Category Females Males Total Hispanic or Latino 4 5 9 Not Hispanic or Latino 63 61 124 Total Ethnic 67 66 133 Racial Category American Indian or Alaskan Native 0 0 0 Asian 3 2 5 Black or African American 10 9 19 Native Hawaiian or other Pacific Islander 0 0 0 White 54 55 109 Racial Category: Total of all Subjects 67 66 133 376 377 378 3.0 DRUG INFORMATION 379 380 Investigator’s Brochures 381 382 For information regarding Investigator’s Brochures, please refer to SWOG Policy 15. 383 384 For this study, 5-fluorouracil and oxaliplatin are commercially available; therefore, Investigator 385 Brochures are not applicable to this/these drugs. Information about commercial drugs is publicly 386 available in the prescribing information and other resources. 387 388 For this study, AZD6244 hydrogen sulfate and MK-2206 are investigational and are being 389 provided under an IND held by the National Cancer Institute. The Investigator Brochures may be 390 obtained by contacting the NCI’s Pharmaceutical Management Branch (PMB) at 240/276-6575. 391 392 3.1 AZD6244 hydrogen sulfate (selumetinib, ARRY-142886) (NSC # 748727) (IND-111587) 393 394 a. PHARMACOLOGY 395 396 Mechanism of action: AZD6244 is a selective non-competitive inhibitor of mitogen 397 activated protein kinase (MEK) 1 and 2. Activated MEK phosphorylates its only 398 known substrates, ERK (extracellular signal related kinase) 1 and 2. 399 Phosphorylated ERK (pERK) dimerizes and translocates to the nucleus where it 400 is involved in functions including the regulation of meiosis, mitosis, and 401 postmitotic functions in differentiated cells.
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402 b. PHARMACOKINETICS 403 404 1. Absorption: oral bioavailability of the hydrogen sulfate capsule 405 formulation after a 5mg/kg dose was found to be 56%. Single dose 406 studies showed a tmax occurrence at 1.5 hours post dose. A food effect 407 study showed significant reductions in AUC when administered with a 408 high fat meal. AZD 6244 is therefore recommended to be taken on an 409 empty stomach (i.e. 2 hours after or 1 hour prior to a meal). 410 411 2. Distribution: AZD 6244 is widely distributed throughout the body, 412 however tissue concentration has been found to be lower than blood. 413 The agent is predominately associated with the plasma compartment in 414 distribution studies with a protein binding of 98.4%. Minimal CNS 415 penetration has been observed, and steady state volume of distribution 416 has ranged from 87-126 L 417 418 3. Metabolism: Both Phase 1 and 2 metabolism occur with AZD 6244 with 419 the majority of metabolites detected as glucuronide conjugates. Phase 1 420 metabolism included N-demethylation, oxidative defluorination, and loss 421 of the side chain to form amide and acid metabolites. Inhibition studies 422 indicated that CYP 1A2 was the enzyme primarily responsible for the 423 formation of the N-desmethyl metabolite. CYP 2C19 and 3A4 also 424 metabolized AZD6244. Preliminary investigation in vitro using human 425 hepatocytes indicated that AZD6244 was a weak inducer of CYPs 3A, 426 1A and 2C9. 427 428 4. Elimination: In all species studied fecal excretion was found to be the 429 primary route of elimination. Organ studies confirmed that biliary 430 elimination is the primary route of excretion. The mean t 1/2 of AZD 6244 431 has ranged from 9-13 hours, with clearance reported at 12-23 L/hr. 432 433 c. ADVERSE EFFECTS 434 435 1. Human data: 436 437 Comprehensive Adverse Events and Potential Risks list (CAEPR) 438 for Selumetinib (AZD6244 Hydrogen sulfate [NSC 748727]) 439 440 The Comprehensive Adverse Event and Potential Risks list (CAEPR) 441 provides a single list of reported and/or potential adverse events (AE) 442 associated with an agent using a uniform presentation of events by body 443 system. In addition to the comprehensive list, a subset, the Specific 444 Protocol Exceptions to Expedited Reporting (SPEER), appears in a 445 separate column and is identified with bold and italicized text. This 446 subset of AEs (SPEER) is a list of events that are protocol specific 447 exceptions to expedited reporting to NCI via CTEP-AERS (except as 448 noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event 449 Reporting Requirements' 450 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ 451 aeguidelines.pdf for further clarification. Frequency is provided based on 452 665 patients. Below is the CAEPR for Selumetinib (AZD6244). 453 454 NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 455 in parentheses next to the AE in the SPEER. If this CAEPR is part of a 456 combination protocol using multiple investigational agents and has an AE 457 listed on different SPEERs, use the lower of the grades to determine if 458 expedited reporting is required. 459
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460 Version 2.4, February 26, 2013 461 462
463 Specific Protocol 464 Adverse Events with Possible Exceptions to 465 Relationship to Selumetinib (AZD6244) Expedited Reporting 466 (CTCAE 4.0 Term) (SPEER) 467 [n= 665] 468 (formerly known as 469 ASAEL) Less Likely Rare but Serious 470 Likely (>20%) 471 (<=20%) (<3%) 472 BLOOD AND LYMPHATIC SYSTEM DISORDERS 473 Anemia Anemia (Gr 3) 474 Febrile 475 2 476 neutropenia CARDIAC DISORDERS 477 478 Left ventricular Left ventricular systolic systolic dysfunction 479 dysfunction (Gr 2) 480 GASTROINTESTINAL DISORDERS 481 Abdominal pain Abdominal pain (Gr 482 2) Constipation Constipation 483 (Gr 2) 484 Diarrhea3 Diarrhea3 (Gr 3) 485 Dry mouth 486 Mucositis oral Mucositis oral (Gr 2) Nausea Nausea (Gr 3) 487 Vomiting Vomiting (Gr 2) 488 GENERAL DISORDERS AND ADMINISTRATION SITE 489 CONDITIONS Edema face Edema face 490 (Gr 2) 491 Edema limbs Edema limbs (Gr 2) 492 Fatigue Fatigue (Gr 2) 493 Fever Fever (Gr 2) INVESTIGATIONS 494 Alanine Alanine 495 aminotransferase aminotransferase 496 increased increased (Gr 3) 497 Alkaline 498 phosphatase 499 increased Aspartate Aspartate 500 aminotransferase aminotransferase 501 increased increased 502 (Gr 3) Platelet count 503 decreased 504
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505 506 507 METABOLISM AND NUTRITION DISORDERS 508 Anorexia Anorexia (Gr 2) 509 Hypoalbuminemia 510 Hypomagnesemia 511 NERVOUS SYSTEM DISORDERS 512 Dizziness 513 Headache Headache (Gr 2) 514 PSYCHIATRIC DISORDERS 515 Insomnia 516 RESPIRATORY, THORACIC AND MEDIASTINAL 517 DISORDERS 518 Cough Cough (Gr 2) 519 Dyspnea Dyspnea (Gr 2) 520 521 SKIN AND SUBCUTANEOUS TISSUE DISORDERS 522 Dry skin Dry skin (Gr 2) 523 Pruritus 524 Rash acneiform Rash acneiform (Gr 525 3) 526 Rash maculo- Rash maculo-papular 527 papular (Gr 2) 528 VASCULAR DISORDERS 529 Hypertension 530 531 1 This table will be updated as the toxicity profile of the agent is revised. 532 Updates will be distributed to all Principal Investigators at the time of 533 revision. The current version can be obtained by contacting 534 [email protected] . Your name, the name of the investigator, 535 the protocol and the agent should be included in the e-mail. 536 2 Febrile neutropenia/neutropenic infection has been observed primarily 537 in trials combining Selumetinib (AZD6244) and docetaxel. 538 3 SBE-CD (Captisol®, vehicle) in the mix and drink formulation is known 539 to cause soft stools and/or diarrhea in rats and dogs; however, it is 540 possible that some of these findings might be related to exacerbation 541 of the vehicle effect by Selumetinib (AZD6244). 542 4 Infection includes all 75 sites of infection under the INFECTIONS AND 543 INFESTATIONS SOC. 544 545 Also reported on Selumetinib (AZD6244) trials but with the 546 relationship to Selumetinib (AZD6244) still undetermined: 547 BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and 548 lymphatic system disorders - Other (hemorrhagic anemia) 549 CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - 550 Other (Takatsubo cardiomyopathy syndrome); Chest pain - cardiac; 551 Heart failure; Palpitations; Right ventricular dysfunction; Sinus 552 bradycardia 553 EYE DISORDERS - Blurred vision; Extraocular muscle paresis; Eye 554 disorders - Other (bilateral macular edema); Eye disorders - Other (black 555 haze in line of vision); Eye disorders - Other (elevated intraocular 556 pressure); Flashing lights; Glaucoma; Retinopathy 557 GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; 558 Colitis; Dyspepsia; Esophagitis; Flatulence; Gastric hemorrhage; 559 Gastroesophageal reflux disease; Ileal stenosis 560
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561 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 562 Flu like symptoms; Non-cardiac chest pain 563 HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary 564 disorders - Other (cholangitis) 565 INFECTIONS AND INFESTATIONS – Infection 566 INVESTIGATIONS - CPK increased; Creatinine increased; 567 Electrocardiogram QT corrected interval prolonged; Neutrophil count 568 decreased; Weight gain 569 METABOLISM AND NUTRITION DISORDERS - Dehydration; 570 Hypokalemia; Hyponatremia 571 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 572 Arthralgia; Back pain; Generalized muscle weakness; Musculoskeletal 573 and connective tissue disorder - Other (joint swelling); Musculoskeletal 574 and connective tissue disorder - Other (rhabdomyolysis); Myalgia; 575 Myositis; Pain in extremity 576 NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Depressed 577 level of consciousness; Dysgeusia; Dysphasia; Ischemia 578 cerebrovascular; Leukoencephalopathy; Memory impairment; Nervous 579 system disorders - Other (numbness); Nervous system disorders - Other 580 (spinal cord compression); Oculomotor nerve disorder; Peripheral 581 sensory neuropathy; Reversible posterior leukoencephalopathy 582 syndrome; Seizure 583 PSYCHIATRIC DISORDERS - Confusion; Depression 584 RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria 585 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult 586 respiratory distress syndrome; Epistaxis; Hypoxia; Pharyngolaryngeal 587 pain; Pleural effusion; Pneumonitis; Sore throat; Voice alteration 588 SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Pain of 589 skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; 590 Scalp pain; Skin and subcutaneous tissue disorders - Other (angular 591 cheilitis, unilateral); Skin and subcutaneous tissue disorders - Other (skin 592 fissures) 593 VASCULAR DISORDERS - Hypotension; Thromboembolic event 594 595 Note: Selumetinib (AZD6244) in combination with other agents could 596 cause an exacerbation of any adverse event currently known to be 597 caused by the other agent, or the combination may result in events never 598 previously associated with either agent. 599 600 A case of Stevens Johnson Syndrome has been reported with the 601 combination of MK-2206 and AZD6244 which included severe mucositis 602 and systemic toxicity consisting of lethargy, fever and abdominal pain. 603 The relationship of this syndrome to the combination is still 604 undetermined. 605 606 2. Pregnancy and Lactation: Preclinical reproductive toxicology data 607 indicate that AZD6244 hydrogen sulfate can have adverse effects on 608 embryofoetal development and survival at dose levels that do not induce 609 maternal toxicity. In addition, in the genotoxicity study package there was 610 a positive mouse micronucleus test. It is not known whether AZD6244 611 hydrogen sulfate or its metabolites are excreted into human milk or 612 secreted in human semen. Therefore, AZD6244 hydrogen sulfate should 613 not be administered to pregnant or breast-feeding women and 614 conception while on treatment must be avoided. Female patients of 615 childbearing potential should use acceptable methods of contraception 616 for 16 weeks after completing the study drug to avoid pregnancy and/or 617 potential adverse events on the developing embryo. Male patients with 618 sexual partners who are pregnant or who could become pregnant (i.e., 619
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620 women of child-bearing potential) should use acceptable methods of 621 contraception for 16 weeks after completing the study to avoid 622 pregnancy and/or potential adverse effects on the developing embryo. 623 Acceptable methods of contraception include implants, injectables, 624 combined oral contraceptives (which must all be combined with barrier 625 methods of contraception as any interaction with AZD6244 hydrogen 626 sulfate is unknown), some IUDs and vasectomised partner. 627 628 3. Drug Interactions: No formal drug interaction studies have been done. In 629 combination studies no interaction was noted between AZD6244 630 hydrogen sulfate and docetaxel, dacarbazine, or MK-2206 631 632 d. DOSING & ADMINISTRATION 633 634 1. Dosing – See Treatment Plan 635 636 2. AZD6244 hydrogen sulfate should be taking on an empty stomach at 637 least 2 hours after a meal or 1 hour before. Chemo or Radiation therapy 638 other than that specified in the protocol is prohibited. Laxatives, agents 639 known to prolong the QTc interval, and potent CYP 3A4 inducers or 640 inhibitors should be avoided. 641 642 e. STORAGE AND STABILITY 643 644 1. AZD6244 or N-desmethyl AZD6244 showed no evidence of mutagenic or 645 clastogenic potential in vitro. Nevertheless as this agent is still under 646 investigation precautions for handling hazardous substances should 647 taken. 648 649 2. The capsules should remain in their original packaging until use. For 650 additional stability information refer to the investigational product label. 651 Store the AZD6244 hydrogen sulfate capsules at room temperature 652 (20˚C-25˚C). Stability studies are still ongoing. 653 654 f. HOW SUPPLIED 655 656 1. AZD6244 hydrogen sulfate will be supplied as capsules of 25 mg for oral 657 administration. AZD6244 hydrogen sulfate capsules are supplied in white 658 high density polyethylene (HDPE) bottles with foil-lined, induction-sealed, 659 child-resistant closures. Each bottle contains 60 capsules. Each capsule 660 contains a dispersion of AZD6244 hydrogen sulfate in d-α-tocopheryl 661 polyethylene glycol 1,000 succinate (TPGS; a water soluble form of 662 vitamin E). 663 664 2. AZD6244 hydrogen sulfate will be supplied by the NCI through PMB 665 666 3. Drug Handling and Accountability 667 668 NCI supplied agents may be requested by the Principal Investigator (or 669 their authorized designee) at each participating institution. Pharmaceutical 670 Management Branch (PMB) policy requires that agent be shipped directly 671 to the institution where the patient is to be treated. PMB does not permit 672 the transfer of agents between institutions (unless prior approval from PMB 673 is obtained.) The CTEP assigned protocol number must be used for 674 ordering all CTEP supplied investigational agents. The responsible 675 investigator at each participating institution must be registered with 676
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677 CTEP, DCTD through an annual submission of FDA form 1572 678 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator 679 Data Form (IDF), and Financial Disclosure Form (FDF). If there are 680 several participating investigators at one institution, CTEP supplied 681 investigational agents for the study should be ordered under the name of 682 one lead investigator at that institution. 683 684 Active CTEP-registered investigators and investigator-designated 685 shipping designees and ordering designees can submit agent requests 686 through the PMB Online Agent Order Processing (OAOP) application < 687 https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx >. Access to 688 OAOP requires the establishment of a CTEP Identity and Access 689 Management (IAM) account < https://eapps-ctep.nci.nih.gov/iam/ > and 690 the maintenance of an “active” account status and a “current” password. 691 For questions about drug orders, transfers, returns, or accountability, 692 call 240/276-6575 Monday through Friday between 8:30 am and 4:30 pm 693 (ET) or email [email protected] anytime. 694 695 4. Drug return and/or disposition instruction (include forms if needed) 696 697 Agent Inventory Records - The investigator, or a responsible party 698 designated by the investigator, must maintain a careful record of the 699 inventory and disposition of all agents received from DCTD using the NCI 700 Drug Accountability Record Form (DARF). (See the NCI Investigator’s 701 Handbook for Procedures for Drug Accountability and Storage.) 702 703 3.2 5-Fluorouracil (5-FU) (NSC-19893) 704 705 Please refer to the FDA approved package insert for complete information. 706 707 a. Description 708 709 1. 5-FU is a fluorinated pyrimidine, which has been modified from the 710 naturally occurring product uracil by the addition of a fluoride at position 711 5. 712 713 2. Molecular Formula: C4H3FN2O2 714 715 3. Molecular Weight: 130.1g/mol 716 717 b. Pharmacology 718 719 Mechanism of Action: 5-FU’s primary mode of action is the inhibition of 720 thymidylate synthase which is necessary for both the synthesis and repair of 721 DNA. The agent exhibits activity in different phases of the cell cycle based on 722 mode of administration. After bolus exposure of 5-FU S-phase cytotoxicity is 723 noted. After 24 hours of continuous intravenous infusion G-1 phase cytotoxicity 724 has been demonstrated. 725 726 c. Pharmacokinetics 727 728 1. Absorption: Oral 5-FU is incompletely absorbed from the GI tract with 729 highly variable rates of bioavailability reported between 0 and 80%. 730 Topical absorption is also minimal with only 2.4% of active drug being 731 absorbed from the 5% commercial cream.
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732 733 2. Distribution: 5-Fluorouracil has wide ranging distribution to both tissue 734 and extracellular fluid. Volume of distribution has been reported between 735 13-27 liters after IV bolus administration. 736 737 3. Metabolism: The metabolism of 5-FU is well known and occurs primarily 738 in the liver via non-linear kinetics. The rate limiting step of hepatic 739 breakdown is the conversion of 5-fluorouracil to 5-6 dihydrofluorouracil 740 via dihydropyrimidine dehydrogenase (DPD). Patients with known DPD 741 deficiency should not be given 5-FU. 742 743 4. Elimination: the elimination half life of 5-FU after IV bolus administration 744 has been reported to occur within 6-22 minutes. Small amounts of 745 unchanged 5-FU are eliminated via the kidney and biliary systems. 746 747 d. Adverse Effects 748 749 1. Human: 750 • CNS: confusion, disorientation, euphoria, nystagmus, headache, 751 encephalopathy, and periphereal neuropathy 752 • Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, and 753 photophobia, excessive nasal discharge, reddening of the eyes, 754 blurring of the vision 755 • Gastrointestinal: stomatitis, esophagopharyngitis, nausea, vomiting, 756 anorexia, diarrhea, gastrointestinal ulceration and bleeding 757 • Cardiovascular: cardiomyopathy, ischemic chest pain, myocardial 758 ischemia, diaphoresis, thrombophlebitis, electrocardiogram changes. 759 • Dermatologic: maculopapular rash, alopecia, dry skin, fissuring, 760 hand-foot syndrome, nail changes, rash, photosensitivity and vein 761 pigmentation. onycholisis, dystrophy, pain and thickening of the nail 762 bed, transverse striations, half and half nail changes, loss of nail, 763 paronychial inflammation, and hyperpigmentation 764 • Hematologic: leucopenia, agranulocytosis, anemia, epistaxis, 765 pancytopenia, and thrombocytopenia 766 • Immunologic: allergic reactions, anaphylaxis 767 768 2. Pregnancy and lactation: 5-FU is classified as pregnancy category D. 769 Teratogenic effects have been demonstrated in animals, however no well 770 controlled studies in humans have been performed. In addition, no 771 adequate data is available on the use of 5-FU while breast feeding. 772 Women are advised to use formula if remaining on treatment. 773 774 3. Drug interactions: 775 DRUG CLASS EXAMPLES OUTCOME Blood thinning NSAIDS, platelet Increased risk of hemorrhage agents inhibitors, salicylates, strontium-89 chloride, thrombolytics, warfarin Antifolates Dapsone, trimethoprim, Increased antifolate toxicity pyrimethamine Hydantoins Phenytoin, Altered levels of hydantoin fosphenytoin, ethotoin serum levels monitor closely Growth factors G-CSF, GM-CSF, PEG- Increased bone marrow G-CSF suppression if used outside of recommended timelines
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DRUG CLASS EXAMPLES OUTCOME Vaccines Any live vaccine ie. Potential for infection with live rotavirus virus Cardiac Digoxin Altered absorption due to GI glycosides toxicity. Monitor levels closely Cytochrome p450 Ramelteon, bosentan, Increased levels of co- 2C9 metabolized administered agent use agents alternative if possible ------Dipyridamole Inhibition of DPD function and increased 5-FU toxicity nitroimidazoles Metronidazole, Increased 5-FU levels and Tinidazole toxicity ------Tamoxifen Increased risk of thromboembolism 776 777 e. Administration (Dosing): See treatment plan (Section 7.1) 778 779 f. Storage/Stability 780 781 1. Compatibility: Store unopened vials at room temperature and protect 782 from light. May be diluted in NS or D5W. 783 784 2. 5-FU is a cytotoxic drug and appropriate procedures for handling, 785 preparing and administering the drug should be followed. 786 787 3. When diluted in NS or D5W to a concentration of 1.5 mg/ml in either 788 glass or polyvinyl chloride containers 5-FU is stable for 8 weeks at room 789 temperature. (17) In ethylene vinyl chloride pumps, 5-FU 10 mg/ml in NS 790 or D5W is stable for 28 days at 4—35 degrees C. 791 792 g. How Supplied 793 794 1. 5-FU is available as an IV solution for injection. The concentration is 50 795 mg/ml 796 797 2. 5-FU is commercially available and should be purchased by a third party. 798 This drug will not be supplied by the NCI. 799 800 3. Drug accountability will not be required for 5-FU as it is commercially 801 available. 802 803 804 805
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806 807 3.3 MK-2206 (NSC-749607) (IND-111587) 808 809 a. PHARMACOLOGY 810 811 Mechanism of Action: MK-2206 is a highly selective non-ATP competitive allosteric 812 inhibitor of Akt 1 and 2. The PI3K-Akt pathway is activated downstream of EGFR, 813 HER2, IGF1R, and cMet, and is a suspected driver of tumor progression in most 814 cancers. The following has been implicated in Akt activation: 1) mutations of 815 receptor tyrosine kinases, PI3K, and Ras, 2) inactivation of the tumor suppressor 816 gene PTEN, 3) amplification or mutation of Akt itself. It has been discovered that the 817 Akt pathway plays a key role in rendering cells resistant to chemotherapy, and as 818 expected studies have shown that Akt inhibition is synergistic with chemotherapy. 819 In addition, it is believed that because Akt inhibitors target pathways downstream of 820 the most common mutations they will have broader utility and provide less 821 resistance in the clinic. 822 823 b. PHARMACOKINETICS 824 825 1. Absorption: MK-2206 dosed once weekly has a median tmax of 4-6 hours. 826 Bioavailability of the agent was variable across species with dogs showing 827 the best absorption at 86% of the dose. 828 829 2. Distribution: MK-2206 has displayed a high volume of distribution across 830 species with an average Vdss 9-11 L/kg. The agent has been found to 831 distribute to most tissues excluding the central nervous system. The agent 832 has also exhibited a high plasma protein binding of over 90%. 833 834 3. Metabolism: The primary pathway for MK-2206 metabolism appears to be 835 direct glucuronidation in rats. Less than 5% was shown to be excreted 836 unchanged in the urine. In contrast, dog metabolism has shown a greater 837 number of pathways involved in metabolism including oxidation, 838 glucuronidation, direct glucuronidation, and formation of carbamoyl 839
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840 glucuronide. In addition, a greater amount of unchanged drug has been 841 found (30%) during dog metabolism studies. At clinically relevant doses, 842 MK-2206 has shown little propensity to act on the Cytochrome P450 843 pathway, however it does appear to be both a p-glycoprotein substrate and 844 inhibitor. 845 846 4. Elimination: The mean renal clearance of MK-2206 is approximately 76.6 847 ml/min. t ½ has been reported at approximately 70 hours. 848 849 c. ADVERSE EFFECTS 850 851 1. Human data: 852 853 Comprehensive Adverse Events and Potential Risks list (CAEPR) 854 for MK-2206 (NSC 749607) 855 856 The Comprehensive Adverse Event and Potential Risks list (CAEPR) 857 provides a single list of reported and/or potential adverse events (AE) 858 associated with an agent using a uniform presentation of events by body 859 system. In addition to the comprehensive list, a subset, the Agent 860 Specific Adverse Event List (ASAEL), appears in a separate column and 861 is identified with bold and italicized text. This subset of AEs (ASAEL) 862 contains events that are considered 'expected' for expedited reporting 863 purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse Event 864 Reporting Requirements' 865 http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/adve 866 rse_events.htm for further clarification. The CAEPR does not provide 867 frequency data; refer to the Investigator's Brochure for this information. 868 Below is the CAEPR for MK-2206. 869 870 Frequency is provided based on 193 patients. Below is the CAEPR for 871 MK-2206. 872 873 NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 874 in parentheses next to the AE in the SPEER. If this CAEPR is part of a 875 combination protocol using multiple investigational agents and has an AE 876 listed on different SPEERs, use the lower of the grades to determine if 877 expedited reporting is required. 878 Version 2.1, March 22, 2013 879
Specific Protocol Adverse Events with Possible Exceptions to Expedited Relationship to MK-2206 Reporting (SPEER) (CTCAE 4.0 Term)
[n= 193] (formerly known as
ASAEL) Less Likely Rare but Serious Likely (>20%) (<=20%) (<3%) BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia CARDIAC DISORDERS Sinus Sinus bradycardia (Gr 2) bradycardia
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880 GASTROINTESTINAL DISORDERS Constipation Diarrhea Diarrhea (Gr 2) Mucositis oral Mucositis oral (Gr 2) Nausea Nausea (Gr 2) Vomiting Vomiting (Gr 2) GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Fatigue (Gr 2) Fever Fever (Gr 2) IMMUNE SYSTEM DISORDERS Allergic reaction INVESTIGATIONS Alanine aminotransferase increased Alkaline phosphatase increased Creatinine increased INVESTIGATIONS (contd.) Electrocardiogram Electrocardiogram QT QT corrected corrected interval interval prolonged prolonged (Gr 2) Hemoglobin increased Investigations - Investigations - Other Other (eosinophilia) (Gr 2) (eosinophilia) Investigations - Other (insulin c- peptide increased) Lymphocyte count decreased Neutrophil count decreased Platelet count decreased White blood cell White blood cell decreased decreased (Gr 2) METABOLISM AND NUTRITION DISORDERS Anorexia Anorexia (Gr 2) Hyperglycemia Hyperglycemia (Gr 2) Hypokalemia Hyponatremia
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881 NERVOUS SYSTEM DISORDERS Dysgeusia Headache Headache (Gr 2) SKIN AND SUBCUTANEOUS TISSUE DISORDERS Dry skin Dry skin (Gr 2) Pruritus Pruritus (Gr 2) Rash maculo- Rash maculo-papular papular (Gr 3) 882 883 1 This table will be updated as the toxicity profile of the agent is revised. 884 Updates will be distributed to all Principal Investigators at the time of 885 revision. The current version can be obtained by contacting 886 [email protected]. Your name, the name of the investigator, 887 the protocol and the agent should be included in the e-mail. 888 Also reported on MK-2206 trials but with the relationship to MK- 889 2206 still undetermined: 890 CARDIAC DISORDERS - Atrioventricular block complete; Palpitations 891 EAR AND LABYRINTH DISORDERS - Vertigo 892 ENDOCRINE DISORDERS - Hypothyroidism 893 EYE DISORDERS - Blurred vision; Conjunctivitis; Dry eye; Extraocular 894 muscle paresis; Eye disorders - Other (blepharitis); Eye disorders - Other 895 (eye swelling); Eye disorders - Other (foreign body sensation in eyes); 896 Eye disorders - Other (iritis); Eye disorders - Other (mydriasis); Eye 897 disorders - Other (visual acuity reduced); Eye pain; Floaters; Keratitis; 898 Photophobia; Retinal detachment; Uveitis 899 GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal 900 pain; Ascites; Cheilitis; Dry mouth; Dyspepsia; Dysphagia; Gastritis; Lip 901 pain; Oral pain; Toothache 902 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 903 Chills; Edema face; Edema limbs; Flu like symptoms; General disorders 904 and administration site conditions - Other (throat tightness); Injection site 905 reaction; Irritability; Localized edema; Non-cardiac chest pain; Pain 906 INFECTIONS AND INFESTATIONS - Infections and infestations - Other 907 (herpetic vesicular rash [due to herpes zoster infection]); Infections and 908 infestations - Other (oral herpes); Nail infection; Paronychia; Rhinitis 909 infective; Sepsis; Skin infection; Urinary tract infection 910 INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall 911 INVESTIGATIONS - Activated partial thromboplastin time prolonged; 912 Aspartate aminotransferase increased; Blood bilirubin increased; INR 913 increased; Investigations - Other (blood LDH increased); Investigations - 914 Other (hyperinsulinemia); Investigations - Other (glucose urine present); 915 Lipase increased; Serum amylase increased; Weight gain; Weight loss 916 METABOLISM AND NUTRITION DISORDERS - Dehydration; 917 Hypercalcemia; Hyperkalemia; Hypermagnesemia; Hypoalbuminemia; 918 Hypocalcemia; Hypomagnesemia; Hypophosphatemia 919 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 920 Arthralgia; Back pain; Bone pain; Generalized muscle weakness; 921 Myalgia; Neck pain; Pain in extremity 922 NERVOUS SYSTEM DISORDERS - Akathisia; Dizziness; Lethargy; 923 Presyncope; Reversible posterior leukoencephalopathy syndrome; 924 Seizure 925 PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; 926 Insomnia
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927 RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; 928 Renal and urinary disorders - Other (renal tubular necrosis); Urinary 929 incontinence; Urinary tract pain 930 REPRODUCTIVE SYSTEM AND BREAST DISORDERS - 931 Gynecomastia; Reproductive system and breast disorders - Other 932 (genital hemorrhage); Vaginal hemorrhage 933 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 934 Bronchial obstruction; Cough; Dyspnea; Hypoxia; Pneumonitis; 935 Pulmonary edema; Respiratory, thoracic and mediastinal disorders - 936 Other (oropharyngeal pain); Sore throat 937 SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; 938 Erythema multiforme; Hyperhidrosis; Palmar-plantar erythrodysesthesia 939 syndrome; Photosensitivity; Purpura; Rash acneiform; Skin and 940 subcutaneous tissue disorders - Other (skin discoloration); Skin and 941 subcutaneous tissue disorders - Other (skin irritation); Urticaria 942 VASCULAR DISORDERS - Hematoma; Hypertension; Hypotension; 943 Thromboembolic event 944 Note: MK-2206 in combination with other agents could cause an 945 exacerbation of any adverse event currently known to be caused by the 946 other agent, or the combination may result in events never previously 947 associated with either agent. 948 949 A case of Stevens Johnson Syndrome has been reported with the 950 combination of MK-2206 and AZD6244 which included severe mucositis 951 and systemic toxicity consisting of lethargy, fever and abdominal pain. 952 The relationship of this syndrome to the combination is still 953 undetermined. 954 955 2. Pregnancy and Lactation: No developmental and reproductive toxicity 956 studies have been conducted to date with MK-2206. 957 958 3. Drug Interactions: MK-2206 is expected to have little Cytochrome P450 959 interaction. The agent has been found to be both an inhibitor and 960 substrate to p glycoprotein. 961 962 d. DOSING & ADMINISTRATION 963 964 1. Dosing-See Treatment Plan 965 966 2. MK-2206 should be taken 2 hours before or after food. In acute overdose, 967 use activated charcoal to reduce the absorption of MK-2206. If additional 968 measures are needed, consider emptying the stomach. Administer specific 969 medical therapy as clinically appropriate 970 971 e. STORAGE & STABILITY 972 973 1. Compatibility information: NA 974 975 2. Handling: The genotoxic potential of MK-2206 was evaluated in 3 in vitro 976 studies. MK-2206 was neither genotoxic nor mutagenic. While polyploidy 977 (endoreduplication) was seen in the in vitro chromosome aberration 978 assay in CHO cells, this was not considered to indicate a potential for 979 aneuploidy, as confirmed by a negative in vitro assay for induction of 980 micronuclei in CHO cells. These results indicate that administration of 981 MK-2206 is not associated with an increased risk of genetic toxicity. This 982 agent is still considered investigational and so proper procedures for 983 handling cytotoxic agents should be used. 984 985 3. Store intact bottles at room temperature, not to exceed 30ºC. Shelf life 986 studies of MK-2206 are ongoing
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987 f. HOW SUPPLIED 988 989 1. MK-2206 tablets are available as 5-mg and 25-mg tablets that are film 990 coated, packaged in HDPE bottles. The pharmaceutical collaborator does 991 not have stability data to support repackaging MK-2206 tablets in any 992 container other than what is provided. The 5-mg and 25-mg bottles contain 993 10 and 20 tablets, respectively. When inventory allows, the 5 mg and 25 994 mg bottles also contain 30 tablets each. The white film (Opadry® 995 20A18273) coating consists of hydroxypropyl cellulose, hydroxypropyl 996 methylcellulose and titanium dioxide. Inactive ingredients consist of 997 microcrystalline cellulose (Avicel PH102®), calcium phosphate dibasic 998 anhydrous (ATAB®), croscarmellose sodium, and magnesium stearate. 999 1000 2. MK-2206 is an investigational agent supplied to investigators by the 1001 Division of Cancer Treatment and Diagnosis (DCTD), NCI. MK-2206 is 1002 provided to the NCI under a Clinical Trials Agreement between Merck & 1003 Co. and the NCI Division of Cancer Treatment and Diagnostic (DCTD). 1004 1005 3. Drug Ordering: MK-2206 may be requested by the Principal Investigator 1006 (or their authorized designee) at each participating institution. 1007 Pharmaceutical Management Branch (PMB) policy requires that drug be 1008 shipped directly to the institution where the patient is to be treated. PMB 1009 does not permit the transfer of agents between institutions (unless prior 1010 approval from the PMB is obtained). The CTEP assigned protocol 1011 number (S1115) must be used for ordering all CTEP supplied 1012 investigational agents. The responsible investigator at each participating 1013 institution must be registered with CTEP, DCTD, through an annual 1014 submission of FDA form 1572, Supplemental Investigator Data Form 1015 (IDF), Financial Disclosure Form (FDF) and a Curriculum Vitae (CV). If 1016 there are several participating investigators at one institution, CTEP 1017 supplied investigational agents for the study should be ordered under the 1018 name of one lead investigator at that institution. 1019 1020 Active CTEP-registered investigators and investigator-designated 1021 shipping designees and ordering designees can submit agent requests 1022 through the PMB Online Agent Order Processing (OAOP) application 1023 (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP 1024 requires the establishment of a CTEP Identity and Access Management 1025 (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance 1026 of an “active” account status and a “current” password. 1027 For questions about drug orders, transfers, returns, or accountability, call 1028 240/276-6575 Monday through Friday between 8:30 am and 4:30 pm 1029 (ET) or email [email protected] anytime. 1030 1031 4. Drug Accountability: The investigator, or a responsible party designated 1032 by the investigator, must maintain a careful record of the receipt, 1033 disposition, and return of all drugs received from the PMB using the Drug 1034 Accountability Record Form available on the NCI home page 1035 (http://ctep.cancer.gov). 1036 1037 5. Drug Returns: All unused drug supplies should be returned to the PMB. 1038 When it is necessary to return study drug (e.g., sealed vials remaining 1039 when expired vials are recalled by the PMB), investigators should return 1040 the study drug to the PMB using the NCI Return Agent Form available on 1041 the NCI home page (http://ctep.cancer.gov). 1042 1043 a. Agent Inventory Records - The investigator, or a responsible party 1044 designated by the investigator, must maintain a careful record of 1045 the inventory and disposition of all agents received from DCTD 1046
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1047 using the NCI Drug Accountability Record Form (DARF). (See the 1048 NCI Investigator’s Handbook for Procedures for Drug 1049 Accountability and Storage.) 1050 1051 b. Drug expiration: if packaging does not have an expiration date, 1052 check with drug ordering designee and/or PI at site to confirm 1053 receipt of ongoing stability testing letter from NCI when internal 1054 drug audits are being performed on a quarterly basis. If 1055 packaging has expiration date, indicate drug expiration date on 1056 the DARF under Manufacturer and Lot # and use the drug lots 1057 with shorter expiration date first. 1058 1059 6. Questions about drug orders, transfers, returns or accountability should 1060 be addressed to the PMB by calling 240/276-6575 Monday through 1061 Friday between 8:30 am and 4:30 pm Eastern Time. 1062 1063 3.4 Oxaliplatin (Eloxatin®) (NSC-266046) 1064 1065 Please refer to the FDA approved package insert for complete information. 1066 1067 a. Description 1068 1069 1. Oxaliplatin is a third generation platinum analog. Oxaliplatin contains a 1070 bulky carrier ligand, 1,2-diaminocyclohexane (DACH), not present in 1071 either cisplatin or carboplatin. 1072 1073 2. Molecular Formula: C8H14N2O4Pt 1074 1075 3. Molecular Weight: 397.3 g/mol 1076 1077 b. Pharmacology 1078 1079 Mechanism of Action: Oxaliplatin is a non-cell cycle specific, alkylating 1080 antineoplastic agent that inhibits DNA synthesis through the formation of 1081 Crosslinks between the N7 positions of two adjacent guanines (GG), adjacent 1082 adenine-guanines (AG), and guanines separated by an intervening nucleotide 1083 (GNG). These crosslinks inhibit DNA replication and transcription. 1084 1085 c. Pharmacokinetics 1086 1087 1. Absorption: NA 1088 1089 2. Distribution: oxaliplatin has a protein binding of 70-95% with longer in 1090 vitro exposure leading to higher protein binding rates. In addition, it has 1091 been demonstrated approximately 37% of platinum is taken up by 1092 erythrocytes. Steady state volume of distribution is approximately 35L. 1093 1094 3. Metabolism: Oxaliplatin is rapidly metabolized in plasma primarily by 1095 biotransformation. No unchanged oxaliplatin is found 2 hours after 1096 administration. Oxaliplatin demonstrates no cytochrome P450 1097 metabolism. 17 known metabolites of oxaliplatin have been identified, 1098 monochloro DACH platinum, dichloro DACH platinum, and mono and 1099 diaquo DACH platinum, are cytotoxic. 1100 1101 4. Elimination: Platinum is predominately excreted through the kidney with 1102 a clearance of 9-17 L/hour. Elimination kinetics are triphasic with alpha, 1103 beta, and gamma half-lives of approximately .3, 15.5, and 321 hours 1104 respectively. A very small (2%) amount of platinum is excreted in the 1105 feces.
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1106 d. Adverse Effects: 1107 1108 Refer to package insert or manufacturer website for the most complete and up to 1109 date information on contraindications, warnings and precautions, and adverse 1110 reactions. 1111
Adverse Events with Possible Relationship to Oxaliplatin (CTCAE 4.0 Term) [n= 1141]
Likely (>20%) Less Likely (<=20%) Rare but Serious (<3%) BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia Disseminated intravascular coagulation BLOOD AND LYMPHATIC SYSTEM DISORDERS (contd.) Febrile neutropenia Hemolysis Thrombotic thrombocytopenic purpura CARDIAC DISORDERS Atrial fibrillation Atrial flutter Paroxysmal atrial tachycardia Sinus bradycardia Sinus tachycardia Supraventricular tachycardia Ventricular arrhythmia Ventricular fibrillation Ventricular tachycardia EAR AND LABYRINTH DISORDERS Hearing impaired Middle ear inflammation EYE DISORDERS Conjunctivitis Dry eye Eye disorders - Other (amaurosis fugax) Eye disorders - Other (cold-induced transient visual abnormalities) Eyelid function disorder Papilledema GASTROINTESTINAL DISORDERS Abdominal pain Ascites Colitis Constipation Diarrhea Dry mouth Dyspepsia Dysphagia Enterocolitis
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GASTROINTESTINAL DISORDERS (contd.) Esophagitis Flatulence Gastritis Gastrointestinal disorders – Other (pneumatosis intestinalis) Gastrointestinal hemorrhage2 Gastrointestinal necrosis3 Gastrointestinal ulcer4 Ileus Mucositis oral Nausea Pancreatitis Small intestinal obstruction Vomiting GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Chills Edema face Edema limbs Fatigue Fever Gait disturbance General disorders and administration site conditions - Other (Hepato-renal syndrome) Injection site reaction Non-cardiac chest pain HEPATOBILIARY DISORDERS Cholecystitis Hepatic failure Hepatobiliary disorders - Other (hepatic enlargement) Hepatobiliary disorders - Other (veno-occlusive liver disease) IMMUNE SYSTEM DISORDERS Allergic reaction INFECTIONS AND INFESTATIONS Infection5 INVESTIGATIONS Activated partial thromboplastin time prolonged Alanine aminotransferase increased Alkaline phosphatase increased Aspartate aminotransferase increased Blood bilirubin increased Creatinine increased GGT increased INR increased
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INVESTIGATIONS (contd.) Lymphocyte count decreased Neutrophil count decreased Platelet count decreased Weight gain Weight loss White blood cell decreased METABOLISM AND NUTRITION DISORDERS Acidosis Anorexia Dehydration Hyperglycemia Hyperuricemia Hypoalbuminemia Hypocalcemia Hypoglycemia Hypokalemia Hypomagnesemia Hyponatremia Hypophosphatemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia Back pain Bone pain Myalgia Trismus NERVOUS SYSTEM DISORDERS Ataxia Depressed level of consciousness Dizziness Dysgeusia Dysphasia Extrapyramidal disorder Headache Intracranial hemorrhage Ischemia cerebrovascular Nerve disorder6 Nervous system disorders - Other (multiple cranial nerve palsies) Peripheral motor neuropathy Peripheral sensory neuropathy Seizure PSYCHIATRIC DISORDERS Anxiety Confusion Depression Insomnia
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RENAL AND URINARY DISORDERS Acute kidney injury Hematuria Renal hemorrhage Urinary frequency Urinary retention REPRODUCTIVE SYSTEM AND BREAST DISORDERS Hematosalpinx Ovarian hemorrhage REPRODUCTIVE SYSTEM AND BREAST DISORDERS (contd.)
Prostatic hemorrhage Spermatic cord hemorrhage
Testicular hemorrhage Uterine hemorrhage Vaginal hemorrhage RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Adult respiratory distress syndrome Allergic rhinitis Bronchopulmonary hemorrhage
Bronchospasm Cough Dyspnea Hiccups Pneumonitis Pulmonary fibrosis Sinus disorder Voice alteration SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia Dry skin Hyperhidrosis Palmar-plantar erythrodysesthesia syndrome
Pruritus Rash maculo-papular Urticaria VASCULAR DISORDERS Flushing Hot flashes Hypertension Hypotension Phlebitis Thromboembolic event Vascular disorders - Other (hemorrhage with thrombocytopenia)
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1112 1113 1 This table will be updated as the toxicity profile of the agent is revised. 1114 2 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, 1115 Colonic hemorrhage, Doudenal hemorrhage, Esophageal hemorrhage, 1116 Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 1117 hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal 1118 hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, 1119 Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, 1120 and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 1121 DISORDERS SOC. 1122 3 Gastrointestinal necrosis includes Anal necrosis, Esophageal necrosis, 1123 Gastric necrosis, Pancreatic necrosis, Peritoneal necrosis, and Rectal 1124 necrosis under the GASTROINTESTINAL DISORDERS SOC. 1125 4 Gastrointestinal ulcer includes Anal ulcer, Colonic ulcer, Duodenal ulcer, 1126 Esophageal ulcer, Gastric ulcer, Ileal ulcer, Jejunal ulcer, Rectal ulcer, and 1127 Small intestine ulcer under the GASTROINTESTINAL DISORDERS SOC. 1128 5 Infection includes all 75 sites of infection under the INFECTIONS AND 1129 INFESTATIONS SOC. 1130 6 Nerve disorder includes Abducens nerve disorder, Accessory nerve disorder, 1131 Acoustic nerve disorder NOS, Facial nerve disorder, Glossopharyngeal nerve 1132 disorder, Hypoglossal nerve disorder, IVth nerve disorder, Oculomotor nerve 1133 disorder, Olfactory nerve disorder, Trigeminal nerve disorder, and Vagus 1134 nerve disorder under the NERVOUS SYSTEM DISORDERS SOC. 1135 7 Gastrointestinal perforation includes Colonic perforation, Duodenal 1136 perforation, Esophageal perforation, Gastric perforation, Ileal perforation, 1137 Jejunal perforation, Rectal perforation, and Small intestinal perforation under 1138 the GASTROINTESTINAL DISORDERS SOC. 1139 1140 Also reported on oxaliplatin trials but with the relationship to oxaliplatin 1141 still undetermined: 1142 1143 CARDIAC DISORDERS - Heart failure; Left ventricular systolic dysfunction; 1144 Myocardial infarction; Pericardial effusion 1145 EYE DISORDERS - Eye pain 1146 GASTROINTESTINAL DISORDERS – Gastrointestinal perforation7 1147 INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury to 1148 superior vena cava; Vascular access complication 1149 INVESTIGATIONS - Cardiac troponin I increased; Lipase increased; Serum 1150 amylase increased 1151 METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Tumor lysis 1152 syndrome 1153 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 1154 Generalized muscle weakness 1155 NERVOUS SYSTEM DISORDERS - Syncope 1156 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hypoxia 1157 VASCULAR DISORDERS - Visceral arterial ischemia 1158 1159 Note: Oxaliplatin in combination with other agents could cause an exacerbation 1160 of any adverse event currently known to be caused by the other agent, or the 1161 combination may result in events never previously associated with either agent. 1162 1163 1. Pregnancy and Lactation: Oxaliplatin may cause fetal harm when 1164 administered to a pregnant woman (FDA pregnancy risk category D). In 1165 animal studies, oxaliplatin at doses less than one-tenth the 1166 recommended human dose based on body surface area caused 1167 developmental mortality and adversely affected fetal growth (decreased 1168 fetal weight, delayed ossification). If this drug is used during pregnancy 1169
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1170 2. or if the patient becomes pregnant while taking this drug, the patient 1171 should be counseled regarding the potential risks to the fetus. Females 1172 of childbearing potential should avoid becoming pregnant while receiving 1173 treatment with oxaliplatin. It is unknown whether oxaliplatin is excreted in 1174 breast milk. Therefore alternative means to feeding, or delaying 1175 treatment should be considered. 1176 3. Drug Interactions: 1177 Drug Examples Outcome Class Blood NSAIDS, platelet inhibitors, Increased risk of thinning salicylates, strontium-89 chloride, hemorrhage agents thrombolytics, warfarin Growth G-CSF, GM-CSF, PEG-G-CSF Increased bone marrow factors suppression if used outside of recommended timelines Vaccines Any live vaccine ie. rotavirus Potential for infection with live virus ------Zalcitabine Increased risk of neuropathy 1178 1179 e. Administration (Dosing): See treatment plan (Section 7.1) 1180 1181 f. Storage/Stability 1182 1183 1. Compatibility: Oxaliplatin is incompatible in a solution with alkaline 1184 medications or diluents (such as basic solutions of 5-FU) and must not 1185 be mixed with these or administered simultaneously through the same 1186 infusion line. The infusion line should be flushed with D5W prior to 1187 administration of any concomitant medications. Only D5W is acceptable 1188 for dilution. Aluminum needles or iv sets should not be used as 1189 degradation of platinum may occur. 1190 1191 2. Special Handling: oxaliplatin is a cytotoxic drug and appropriate 1192 procedures for handling, preparing and administering the drug should be 1193 followed. 1194 1195 3. Store the intact vials at controlled room temperature. Excursions 1196 permitted to 15°C to 30°C (59°F to 86°F), not exceeding 30°C. 1197 Reconstituted solution: in 5% Dextrose or Water for Injection in the 1198 original vial, the solution may be stored for up to 48 hours between 2°C 1199 to 8° C (36°F-46°F). Infusion solution: after dilution in 5% Dextrose in 1200 Water, the shelf life is 24 hours at 2°C to 8°C (36°F-46°F). 1201 1202 g. How Supplied 1203 1204 1. Oxaliplatin is commercially available, and should therefore be purchased 1205 by a third party. This drug will not be supplied by the NCI. 1206 1207 2. Drug accountability will not be required for oxaliplatin as it is 1208 commercially available. 1209 1210 1211 4.0 STAGING CRITERIA 1212 1213 Staging criteria are not applicable for this study.
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1214 1215 5.0 ELIGIBILITY CRITERIA 1216 1217 Each of the criteria in the following section must be met in order for a patient to be considered eligible for 1218 registration. Use the spaces provided to confirm a patient's eligibility. For each criterion requiring test 1219 results and dates, please record this information on the Onstudy Form and submit via Medidata Rave® 1220 (see Section 14.0). Any potential eligibility issues should be addressed to the Data Operations Center in 1221 Seattle at 206/652-2267 prior to registration. 1222 1223 In calculating days of tests and measurements, the day a test or measurement is done is considered Day 1224 0. Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28. This 1225 allows for efficient patient scheduling without exceeding the guidelines. If Day 28 or 42 falls on a 1226 weekend or holiday, the limit may be extended to the next working day. 1227 1228 SWOG Patient No. 1229 1230 Patient's Initials (L, F, M) 1231 1232 5.1 Disease Related Criteria 1233 1234 a. Patients must have histologically or cytologically confirmed diagnosis of 1235 pancreatic adenocarcinoma. Patients with endocrine or neuroendocrine tumors, 1236 lymphoma of the pancreas, or ampullary cancer are not eligible. 1237 1238 b. Patients must have distant metastatic disease. Patients with macroscopic 1239 residual disease post-resection as the only site of disease are not eligible. 1240 Patient must not have clinically significant ascites (defined as requiring 1241 paracentesis) or have brain metastases. 1242 1243 c. Patients must have received one line, and no more than one line, of prior 1244 gemcitabine-based chemotherapy for advanced/metastatic pancreatic cancer 1245 and must have documentation of metastatic disease progression while on this 1246 treatment. Documented disease progression must occur within 42 days of the 1247 last treatment. 1248 1249 OR 1250 1251 For patients who received one line of gemcitabine-based chemotherapy for 1252 treatment in the adjuvant setting, recurrence to a metastatic site must be 1253 documented by imaging studies within 6 months of completing chemotherapy. 1254 Chemoradiation as part of adjuvant treatment is acceptable. If the patient 1255 received one line of adjuvant gemcitabine-based treatment and had disease 1256 recurrence after 6 months of completing chemotherapy, patients will only be 1257 eligible after failing one additional line of gemcitabine-based chemotherapy used 1258 to treat the metastatic disease. 1259 1260 d. Patient must have measurable and/or non-measurable disease (see Section 1261 10.0). X-rays, scans or physical examinations for assessment of measurable 1262 disease must have been completed within 28 days prior to registration. X-rays, 1263 scans or other tests for assessment of non-measurable disease must have been 1264 completed within 42 days prior to registration. All disease must be assessed and 1265 documented on the Baseline Tumor Assessment Form.
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1266 SWOG Patient No. 1267 1268 Patient's Initials (L, F, M) 1269 1270 5.2 Prior/Concurrent Therapy Criteria 1271 1272 a. Patients must have completed systemic therapy at least 14 days prior to 1273 registration, any surgical procedure must have been performed at least 14 days 1274 prior to registration, and radiation therapy must be completed at least 7 days 1275 prior to registration. Patients must have recovered to ≤ Grade 1 from any of the 1276 effects of prior therapies or procedures. 1277 1278 b. Patients must not plan to receive concurrent chemotherapy, radiotherapy, agents 1279 known to prolong QTc interval (Appendix 18.3, Table 1), or agents known to be 1280 strong inducers or inhibitors of CYP3A4/5 or CYP1A2 (see Appendix 18.4 for a 1281 list of prohibited agents). 1282 1283 c. Patient must not have received prior treatment with FOLFIRINOX, FOLFOX, 1284 oxliplatin-based chemotherapy, MEK inhibitors, PI3K inhibitors, or AKT inhibitors. 1285 1286 5.3 Clinical/Laboratory Criteria 1287 1288 a. Patient must have a Zubrod performance status of 0-1 (see Section 10.4). 1289 1290 b. Patient must have adequate hematologic function as evidenced by all of the 1291 following within 14 days prior to registration: leukocytes ≥ 3,000/mcL; ANC ≥ 1292 1,500/mcL; platelets ≥ 100,000/mcL; hemoglobin ≥ 9.0 g/dL. 1293 1294 c. Patients must have adequate kidney function as evidenced by at least ONE of 1295 the following: 1296 1297 • Serum creatinine ≤ 1.5 mg/dl within 14 days prior to registration. 1298 1299 • Calculated creatinine clearance ≥ 60 ml/min. The serum creatinine value 1300 used in the calculation must have been obtained within 14 days prior to 1301 registration. 1302 1303 Calculated creatinine clearance = (140 – age) x wt (kg) x [0.85 (if female)] 1304 72 x creatinine (mg/dl) 1305 1306 d. Patients must have adequate hepatic function as evidenced by all of the following 1307 within 14 days prior to registration: total bilirubin ≤ 1.5 x Institutional Upper Limit 1308 of Normal (IULN); AST and ALT both ≤ 2.5 x IULN. 1309 1310 e. Patients must have an albumin level ≥ 3.0 g/dL within 14 days prior to 1311 registration. 1312 1313 f. Patients must have an International Normalized Ratio (INR) ≤ 1.5 x IULN within 1314 14 days prior to registration. 1315 1316 g. Patients must have an ECG within 14 days prior to registration. Patients must 1317 have QTcF (by Fridericia’s calculation) ≤ 450 msec (male) or ≤ 470 msec 1318 (female). 1319 1320 h. Patients with baseline neuropathy must be ≤ Grade 1 according to CTCAE v4.0.
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1321 SWOG Patient No. 1322 1323 Patient's Initials (L, F, M) 1324 1325 5.3 Clinical/Laboratory Criteria (contd.) 1326 1327 i. Patients must not have uncontrolled diarrhea or active infection requiring 1328 antibiotics and be fully recovered from any previous serious infections within 7 1329 days prior to registration. 1330 1331 j. Patients must be able to swallow tablets and capsules. 1332 1333 k. Patients with diabetes must be well controlled with fasting glucose ≤ Grade 1 1334 according to CTCAE v4.0 within 14 days prior to registration. 1335 1336 l. Patients with history of congestive heart failure must have an ejection fraction ≥ 1337 55% within 14 days prior to registration. 1338 1339 m. Patients must not have any of the following: uncontrolled hypertension; acute 1340 coronary syndrome within 6 months prior to registration; poorly controlled angina; 1341 New York Heart Association Class II-IV heart failure (see Appendix 18.5); prior or 1342 current cardiomyopathy; atrial fibrillation; or severe valvular heart disease. 1343 1344 n. Patients must not have a current or past history of central serous retinopathy, 1345 retinal vein occlusion, retinal detachment, or have uncontrolled glaucoma 1346 (irrespective of IOP). 1347 1348 o. No prior malignancy is allowed except for the following: adequately treated basal 1349 cell or squamous cell skin cancer, in situ cervical cancer, adequately treated 1350 Stage I or II cancer from which the patient is currently in complete remission, or 1351 any other cancer from which the patient has been disease free for five years. 1352 1353 p. Patients must not be pregnant or nursing due to unknown fetal and infant risks. 1354 Women/men of reproductive potential must have agreed to use an effective 1355 contraceptive method during the study plus at least 16 weeks after last dose. A 1356 woman is considered to be of "reproductive potential" if she has had menses at 1357 any time in the preceding 12 consecutive months. In addition to routine 1358 contraceptive methods, "effective contraception" also includes heterosexual 1359 celibacy and surgery intended to prevent pregnancy (or with a side-effect of 1360 pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or 1361 bilateral tubal ligation. However, if at any point a previously celibate patient 1362 chooses to become heterosexually active during the time period for use of 1363 contraceptive measures outlined in the protocol, he/she is responsible for 1364 beginning contraceptive measures. 1365 1366 q. Prestudy history and physical must be obtained within 28 days prior to 1367 registration. 1368 1369 5.4 Specimen Submission Criteria 1370 1371 a. Sites must seek additional patient consent for the future use of specimens as 1372 described in Section 15.0. 1373 1374 5.5 Regulatory Criteria 1375 1376 a. All patients or their legally authorized representative must be informed of the 1377 investigational nature of this study and must sign and give written informed 1378 consent in accordance with institutional and federal guidelines. 1379 1380 b. As part of the OPEN registration process (see Section 13.3 for OPEN access 1381 instructions) the treating institution's identity is provided in order to ensure that 1382 the current (within 365 days) date of institutional review board approval for this 1383 study has been entered into the system.
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1384 6.0 STRATIFICATION FACTORS 1385 1386 Patients will be stratified according to: 1387 1388 a. Duration of prior systemic therapy line (≤ 4 months vs. > 4 months) 1389 1390 b. Presence of liver metastasis (yes vs. no) 1391 1392 1393 7.0 TREATMENT PLAN 1394 1395 For treatment or dose modification questions, please contact Vincent Chung, M.D. (626) 423- 1396 5526 or Philip Philip, M.D., Ph.D. (313) 745-5111. For dosing principles or questions, please 1397 consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org 1398 (then click on "Policies and Manuals" under the "Visitors" menu and choose Policy 38). 1399 1400 7.1 Arm 1: mFOLFOX 1401 1402 a. Pre-Medication 1403 1404 Antiemetics may be given at the discretion of the treating physician. 1405 1406 Sample Regimen 1407 1408 Agent Dose Route Schedule* 1409 1410 Ondansetron 24 mg By mouth 30 minutes prior to mFOLFOX 1411 1412 Decadron 10 mg IV 30 minutes prior to mFOLFOX 1413 1414 b. Treatment 1415 1416 Agent Dose Route Day Schedule* 1417 1418 Oxaliplatin 85 mg/m2 IV over 1 & 15 1419 2 hours 1420 1421 5-FU 2,400 mg/m2 IV over 1-2 & Given following 1422 46-48 hrs 15-16 completion of 1423 of oxaliplatin 1424 1425 * Note: One cycle = 28 days 1426 1427
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1428 7.2 Arm 2: Combination of MK-2206 and AZD6244 Hydrogen Sulfate 1429 1430 a. Antiemetics may be given at the discretion of the treating investigator. 1431 1432 b. Treatment 1433 1434 Agent Dose Route Day Schedule* 1435 1436 MK-2206 135 mg PO 1, 8, 15, 22 Should be taken with 1437 AZD6244 hydrogen 1438 sulfate on an empty 1439 stomach 2 hours before 1440 or after a meal.** 1441 1442 AZD6244 100 mg PO Daily Should be taken on an 1443 hydrogen sulfate empty stomach 2 hours 1444 before or after a meal. 1445 1446 * Note: One cycle = 28 days regardless of dose delays 1447 ** If the patient experiences significant GI toxicities, patient may take MK-2206 1448 first followed by AZD6244 hydrogen sulfate 30 minutes later. 1449 1450 c. Drug compliance for Arm 2 will be recorded by patients in the Intake Calendar 1451 (see Appendix 18.2). Institutional CRAs will review and ascertain patient 1452 adherence with protocol therapy at the end of treatment for each cycle. Calendar 1453 should be kept in the patient's clinic chart. Note that the Intake Calendar is 1454 provided only as a tool for tracking compliance. Sites may utilize institutional pill 1455 diaries or other source documentation in place of the Intake Calendar at the 1456 discretion of the treating physician. 1457 1458 7.3 Supportive Care Guidelines 1459 1460 a. Both Arms 1461 1462 1. Erythropoeitin and myeloid colony stimulating factors (GCSF, GMCSF, 1463 pegGCSF) may be used in accordance with ASCO guidelines 1464 (http://jop.ascopubs.org/cgi/content/full/2/4/196). 1465 1466 2. Loperamide: For symptoms of diarrhea and/or abdominal cramping that 1467 occur at any time during a treatment cycle, patients will be instructed to 1468 begin taking loperamide. Loperamide should be started at the earliest 1469 sign of (1) a poorly formed or loose stool or (2) the occurrence of 1 to 2 1470 more bowel movements than usual in 1 day or (3) an increase in stool 1471 volume or liquidity. Loperamide should be taken in the following manner: 1472 4 mg at the first onset of diarrhea, then 2 mg every 2 hours around the 1473 clock until diarrhea-free for at least 12 hours. Patients may take 1474 loperamide 4 mg every 4 hours during the night. The maximum daily 1475 dose of loperamide is 16 mg/day. Patients should be advised to obtain 1476 loperamide at the initial treatment visit so that they have sufficient supply 1477 on hand in case antidiarrheal support is required. Additional antidiarrheal 1478 measures may be used at the discretion of the treating physician. 1479 Patients may be instructed to increase fluid intake to help maintain fluid 1480 and electrolyte balance during episodes of diarrhea. 1481 1482 Clostridium difficile colitis should be excluded with a stool toxin titer in the 1483 event of severe or treatment-refractory diarrhea. 1484
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1485 b. Arm 2 1486 1487 Patients should receive full supportive care, including antiemetics, antibiotics, 1488 transfusions of blood and blood products, etc. when appropriate. Whenever any 1489 medications are administered, the reason(s) for treatment, dosage and date of 1490 treatment must be recorded on the case report forms. 1491 1492 1. Antiemetic therapy 1493 1494 Routine premedication for nausea is not necessary, but symptomatic 1495 patients should be treated with standard antinausea/antiemetic therapy 1496 as necessary. If the patient vomits after taking the tablets, the dose is 1497 replaced only if the tablets can actually be seen and counted. 1498 1499 2. Skin toxicity 1500 1501 Treat as appropriate. Agents to consider: minocycline, topical 1502 tetracycline or clindamycin, topical silver sulfadiazine, topical steroids, 1503 diphenhydramine, oral prednisone (short course). 1504 1505 3. Hyperglycemia Management (MK-2206) 1506 1507 Asymptomatic hyperglycemia (Grade 1-2) has been noted in the Phase I 1508 study of MK-2206. Grade 3 hyperglycemic events (> 250 mg/dL) should 1509 lead to consultation with and endocrinologist or other specialist. In this 1510 study, subjects will be monitored with fasting blood sugars evaluated 1511 every 2 weeks. If elevations of fasting blood sugar are seen, a dietary 1512 consultation and a low carbohydrate diet can be considered. Appropriate 1513 therapy will usually involve oral antihyperglycemic agents, since the 1514 inhibition of glucose transports into the cell by AKT/mTOR inhibitors may 1515 render insulin ineffective. The goal of therapy is to keep fasting glucose 1516 < 150 mg/dL, random blood glucose levels < 180 mg/dL, and hemoglobin 1517 A1C < 8%. 1518 1519 4. Visual Changes (AZD6244 hydrogen sulfate) 1520 1521 Blurred vision has been noted in the Phase I clinical trial. If clinically 1522 significant visual changes occur, the patient should be referred to an 1523 ophthalmologist for further evaluation. 1524 1525 5. Sun Exposure (AZD6244 hydrogen sulfate) 1526 1527 Patients should avoid excessive sun exposure and use adequate 1528 sunscreen protection if sun exposure if anticipated. 1529 1530 6. Vitamin E (AZD6244 hydrogen sulfate) 1531 1532 Patients should not take vitamin E supplements or multivitamin 1533 supplements which provide a total daily dose in excess of 100% of the 1534 recommended daily allowance for vitamin E. High doses of vitamin E have 1535 been reported to potentiate the anticoagulant activity of coumarins such as 1536 warfarin. Patients who are taking coumarin anticoagulants should increase 1537 the frequency of assessment of anticoagulation, such as INR 1538 measurements, upon initiation of dosing with AZD6244 hydrogen sulfate. 1539
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1540 7.4 Investigational Drug 1541 1542 Because this study contains an investigational drug for which CTEP holds the IND, it falls 1543 under CTEP requirements for full reporting. This involves required submission of cycle- 1544 specific toxicity and dose information (see Section 14.4, the S1115 Treatment Form, and 1545 the S1115 Adverse Event Form.). A cycle is defined as 28 days. 1546 1547 7.5 Criteria for Removal from Protocol Treatment 1548 1549 a. Progression of disease or symptomatic deterioration (as defined in Section 10.2). 1550 1551 b. Unacceptable toxicity. 1552 1553 c. Treatment delay for any reason > 4 weeks. 1554 1555 d. The patient may withdraw from the study at any time for any reason. 1556 1557 7.6 Discontinuation of Treatment 1558 1559 All reasons for discontinuation of treatment must be documented in the Off Treatment 1560 Notice. 1561 1562 7.7 Follow-Up Period 1563 1564 All patients will be followed until death or 3 years after registration, whichever occurs first. 1565 1566 1567 8.0 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 1568 1569 8.1 NCI Common Terminology Criteria for Adverse Events 1570 1571 This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 1572 Version 4.0 for toxicity and Serious Adverse Event reporting. A copy of the CTCAE 1573 Version 4.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov). All 1574 appropriated treatment areas should have access to a copy of the CTCAE Version 4.0. 1575 1576 8.2 Dose Modifications 1577 1578 a. General Considerations 1579 1580 1. No dose re-escalations are permitted. If the patient experiences toxicity 1581 requiring a dose reduction, the dose will remain lowered for subsequent 1582 cycles. 1583 1584 2. Where several toxicities with different grades or severity occur at the 1585 same time, the dose modification applied should be the greatest 1586 reduction applicable. 1587 1588 3. For toxicities that are considered by the investigator to be unlikely to 1589 develop into serious or life-threatening events (e.g., alopecia, altered 1590 taste, etc.), treatment will be continued at the same dose without 1591 reduction or interruption. In addition, no dose reductions or interruptions 1592 will be required for anemia (non-hemolytic) as it can be satisfactorily 1593 managed by transfusions. 1594 1595 4. The maximum dose delay for any reason is 4 weeks. 1596 1597 5. Dose omitted during a cycle will not be made up.
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1598 8.3 Dose Delay/Modification for FOLFOX 1599 1600 a. Dose Levels for Treatment Modifications 1601 1602 Agent Starting Dose Level -1 Level -2* 1603 1604 Oxaliplatin 85 mg/m2 65 mg/m2 50 mg/m2 1605 1606 5-Fluorouracil 2,400 mg/m2 2,000 mg/m2 1,600 mg/m2 1607 infusion 1608 1609 * Patient must be removed from the specified agent if further reduction is 1610 indicated beyond the -2 level. 1611 1612 When, at the beginning of a treatment cycle, treatment delay related to 1613 either oxaliplatin or 5-FU treatment alone is indicated, all treatment 1614 should be delayed. Treatment should only be restarted when the 1615 requirements for restarting both oxaliplatin and 5-FU are met. 1616 1617 b. Neutrophil Count or White Blood Cell Decreased 1618 1619 Toxicity Grade Dose Modification 1620 1621 Oxaliplatin 5-FU 1622 1623 2 Hold treatment. Hold treatment. 1624 Check weekly. Check weekly. 1625 When resolves to When resolves to 1626 ≤ Grade 1, continue ≤ Grade 1, continue 1627 at same dose level. at same dose level. 1628 1629 3 - 4 Hold treatment. Hold treatment. 1630 Check weekly. Check weekly. 1631 When resolves to When resolves to 1632 ≤ Grade 1, continue ≤ Grade 1, continue 1633 at next lowest dose level. at next lowest dose level. 1634 1635 Febrile Hold treatment. Hold treatment. 1636 neutropenia Check weekly. Check weekly. 1637 When resolves to When resolves to ≤ Grade 1638 ≤ Grade 1 continue at 1 continue at next lowest 1639 next lowest dose level. dose level. 1640 1641
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1642 c. Platelet Count Decreased 1643 1644 Toxicity Grade Dose Modification 1645 1646 Oxaliplatin 5-FU 1647 1648 2 Hold treatment. Hold treatment. 1649 Check weekly. Check weekly. 1650 When resolved to ≤ When resolved to ≤ 1651 Grade 1 continue at Grade 1 continue at 1652 same dose level. same dose level. 1653 1654 3 - 4 Hold treatment. Hold treatment. 1655 Check weekly. Check weekly. 1656 When resolved to ≤ When resolved to ≤ 1657 Grade 1 continue at Grade 1 continue at 1658 next lowest dose level. next lowest dose level. 1659 1660 1661 d. Diarrhea* 1662 1663 Toxicity Grade Dose Modification 1664 1665 Oxaliplatin 5-FU 1666 1667 2 - 3 Hold treatment. Hold treatment. 1668 Check weekly. Check weekly. 1669 When resolves to When resolves to 1670 ≤ Grade 1, continue ≤ Grade 1, continue at 1671 at same dose level. next lowest dose level 1672 1673 4 Hold treatment. Hold treatment. 1674 Check weekly. Check weekly. 1675 When resolves to When resolves to 1676 ≤ Grade 1, continue at ≤ Grade 1, continue at 1677 next lowest dose level. next lowest dose level 1678 1679 * Despite optimal use of antidiarrheals. 1680 1681 e. Mucositis 1682 1683 Toxicity Grade Dose Modification 1684 1685 Oxaliplatin 5-FU 1686 1687 2 Hold treatment. Hold treatment. 1688 Check weekly. Check weekly. 1689 When resolves to When resolves to 1690 ≤ Grade 1, continue ≤ Grade 1, continue 1691 at same dose level. at same dose level. 1692 1693 3 - 4 Hold treatment. Hold treatment. 1694 Check weekly. Check weekly. 1695 When resolves to When resolves to 1696 ≤ Grade 1, continue ≤ Grade 1, continue at 1697 at same dose level. next lowest dose level. 1698 1699
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1700 f. Allergic Reactions 1701 1702 Toxicity Grade* Dose Modification 1703 1704 Oxaliplatin 5-FU 1705 1706 3 - 4 Discontinue oxaliplatin No dose modification 1707 1708 * For Grade 1 or 2 acute allergic reactions, pre-medication 30 minutes prior to 1709 oxaliplatin administration is recommended with dexamethasone 20 mg IV, 1710 diphenhydramine 50 mg IV, and one of the following: ranitidine 50 mg IV or 1711 famotidine 20 mg IV. If an allergic reaction persists into the next cycle, 1712 administer 50 mg dexamethasone PO 12 hours and 6 hours prior to 1713 administration of oxaliplatin. 1714 1715 g. Palmar-plantar Erythrodysesthesia Syndrome 1716 1717 Toxicity Grade Dose Modification 1718 1719 Oxaliplatin 5-FU 1720 1721 3 - 4 No dose modification Hold treatment. 1722 Check weekly. 1723 When resolves to 1724 ≤ Grade 1, continue at 1725 next lowest dose level. 1726 1727 1728 h. Cough, Dyspnea, Hypoxia or Pneumonitis 1729 1730 Toxicity Grade Dose Modification 1731 1732 Oxaliplatin 5-FU 1733 1734 3 - 4 Hold treatment until interstitial No dose modification 1735 lung disease is ruled out, then 1736 resume treatment at same 1737 dose level. 1738 1739 1740 i. Hemolytic Uremic Syndrome (HUS) 1741 1742 Recommended evaluation of suspected hemolytic uremic syndrome: Evaluation 1743 should include CBC differential, platelets, PT, PTT, fibrinogen, FDP (Fibrin 1744 degradation products), Anti thrombin III, Von Willebrand factor, anti-nuclear 1745 antibody, rheumatoid factor, Compliment Cascade C3, C4, and CH50, anti- 1746 platelet antibodies, platelet-associated IgG and circulating immune complexes. 1747 Renal evaluation should include creatinine, BUN and urinalysis with microscopic 1748 examination. Other laboratory and hematological evaluations as appropriate 1749 should also be obtained, including peripheral blood smear and free hemoglobin. 1750 1751 Toxicity Grade Dose Modification 1752 1753 Oxaliplatin 5-FU 1754 1755 3 - 4 Discontinue oxaliplatin No dose modification 1756 1757
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1758 j. Paresthesia or Peripheral Sensory Neuropathy – Dose modifications for 1759 oxaliplatin only 1760 1761 Toxicity Duration of Toxicity Persistent between 1762 1 - 7 days > 7 days cycles 1763 1764 1 No dose No dose No dose 1765 modification modification modification 1766 1767 2 No dose No dose Next lowest dose 1768 modification modification level for oxaliplatin 1769 1770 3 Next lowest Next lowest Discontinue 1771 dose level dose level 1772 for oxaliplatin for oxaliplatin 1773 1774 Peripheral Discontinue Discontinue Discontinue 1775 Sensory 1776 Neuropathy Grade 4 1777 1778 1779 k. Laryngopharyngeal Dysesthesia (loss of sensation of breathing without any 1780 objective evidence of respiratory distress) 1781 1782 Toxicity Dose Modification 1783 1784 Oxaliplatin 5-FU 1785 1786 2-4 Hold oxaliplatin and evaluate Administration must be 1787 patient's oxygen saturation via a postponed until the end 1788 pulse oximeter. If normal, of oxaliplatin infusion. 1789 reassurance 1790 such as an anxiolytic agent or 1791 benzodiazepine should be 1792 considered. The patient should be 1793 observed in the clinic until the episode 1794 has resolved. The oxaliplatin infusion 1795 may then be continued at 1/3 the rate.* 1796 1797 * Because this syndrome may be associated with the rapidity of oxaliplatin 1798 infusion, subsequent doses of oxaliplatin should be administered as 6-hour 1799 infusions (instead of the normal 2-hour infusion). 1800
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1801 l. Other Non-Hematologic Toxicities 1802 1803 Note: Alopecia, fatigue, anorexia, viral infections, hyperglycemia, diarrhea 1804 controlled by medication, and nausea or vomiting that can be controlled by 1805 antiemetics do not require dose modifications. 1806 1807 Toxicity Grade Dose Modification 1808 1809 Oxaliplatin 5-FU 1810 1811 2 Hold treatment. Hold treatment. 1812 Check weekly. Check weekly. 1813 When resolves to When resolves to 1814 ≤ Grade 1, continue ≤ Grade 1, continue 1815 at same dose level. at same dose level. 1816 1817 3 Hold treatment. Hold treatment. 1818 Check weekly. Check weekly. 1819 When resolves to When resolves to 1820 ≤ Grade 1, continue ≤ Grade 1, continue at 1821 at same dose level. next lowest dose level. 1822 1823 4 Hold treatment. Hold treatment. 1824 Check weekly. Check weekly. 1825 When resolves to When resolves to 1826 ≤ Grade 1, continue at ≤ Grade 1, continue at 1827 next lowest dose level. next lowest dose level. 1828 1829 1830 8.4 Dose Delay/Modification for MK-2206 and AZD6244 Hydrogen Sulfate 1831 1832 a. Dose levels: 1833 1834 MK-2206 1835 Dose Tablet Count to achieve dose Starting Dose 135 mg q week 25 mg tabs x 5 + 5 mg tabs x 2 First dose reduction 100 mg q week 25 mg tabs x 4 Second dose reduction* 75 mg q week 25 mg tabs x 3 1836 1837 AZD6244 hydrogen sulfate 1838 Dose Capsule Count to achieve dose Starting Dose 100 mg Daily 25 mg capsules x 4 First dose reduction 75 mg Daily 25 mg capsules x 3 Second dose reduction* 50 mg Daily 25 mg capsules x 2 1839 * If more than two dose reductions are indicated, patient must be removed from 1840 protocol treatment. 1841 1842 When, at the beginning of a treatment cycle, treatment delay related to MK-2206 1843 or AZD6244 hydrogen sulfate treatment alone is indicated, all treatment should 1844 be delayed. Treatment should only be restarted when the requirements for both 1845 MK-2206 and AZD6244 hydrogen sulfate are met.
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1846 1847 b. Diarrhea 1848 1849 Grade Dose Modification 1850 1851 2 None. If unacceptable to patient or medically concerning, 1852 then hold both drugs until recovery to ≤ Grade 1. Restart at 1853 same dose.* 1854 1855 ≥ 3 Hold until recovery to ≤ Grade 1, then reduce dose one level. 1856 (despite 1857 optimal 1858 use of loperamide) 1859 1860 * If dose has been previously held for Grade 2 toxicity and Grade 2 symptoms 1861 recur, OR if the patient finds the symptoms unacceptable, hold dose of both 1862 drugs until recovery to ≤ Grade 1 and then reduce both drugs dose one level. 1863 1864 c. Rash 1865 1866 Grade Dose Modification 1867 1868 2 None. If unacceptable to patient or medically concerning, 1869 then hold both drugs until recovery to ≤ Grade 1. Restart at 1870 same dose.* 1871 1872 ≥ 3 Hold both drugs until recovery to ≤ Grade 1, then reduce 1873 dose of both drugs one level. 1874 1875 * If dose has been previously held for Grade 2 toxicity and Grade 2 symptoms 1876 recur, OR if the patient finds the symptoms unacceptable, hold dose of both 1877 drugs until recovery to ≤ Grade 1 and then reduce dose of both drugs one 1878 level. 1879
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1880 d. Other Non-Hematological 1881 1882 If non-hematological laboratory values are elevated at baseline, then no dose 1883 reductions are necessary, unless values increase by at least two grades, are 1884 deemed drug related, and are of clinical significance. 1885 1886 Grade Dose Modification 1887 1888 2 None. If unacceptable to patient or medically 1889 concerning, then hold both drugs until recovery to ≤ 1890 Grade 1. Restart both drugs at same dose.* 1891 1892 Grade 3 or Hold both drugs until recovery to ≤ Grade 1, then reduce 1893 prolonged/ dose of both drugs one level. 1894 Clinically significant 1895 Grade 2 1896 1897 Grade 4 Permanently remove patient from protocol treatment. 1898 1899 * If dose has been previously held for Grade 2 toxicity and Grade 2 symptoms 1900 recur, OR if the patient finds the symptoms unacceptable, hold dose of both 1901 drugs until recovery to ≤ Grade 1 and then reduce dose of both drugs one 1902 level. 1903 1904 e. Hematological 1905 1906 Grade Dose Modification 1907 1908 2 None. If unacceptable to patient or medically 1909 concerning, then hold both drugs until recovery to ≤ 1910 Grade 1. Restart at same dose.* 1911 1912 Grade ≥ 3 Hold until recovery to ≤ Grade 1, then reduce dose of 1913 or prolonged/ both drugs one level. 1914 Clinically significant 1915 Grade 2 1916 1917 * If dose has been previously held for Grade 2 toxicity and Grade 2 symptoms 1918 recur, OR if the patient finds the symptoms unacceptable, hold dose of both 1919 drugs until recovery to ≤ Grade 1 and then reduce dose of both drugs one 1920 level. 1921 1922 8.5 Dose Modification Contacts 1923 1924 For treatment or dose modification questions, please contact Vincent Chung, M.D. 626/ 1925 423-5526 or Philip Philip, M.D., Ph.D. 313/745-5111. 1926 1927 8.6 Adverse Event Reporting 1928 1929 Toxicities (including suspected reactions) that meet the expedited reporting criteria as 1930 outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 1931 Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 1932
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1933 9.0 STUDY CALENDAR 1934 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Ω % REQUIRED Follow-up Follow-up STUDIES PRE Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Prior After To Progression STUDY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Progression PHYSICAL ∑ History and Physical Exam X ~ X X X X X X X X X X X Weight and Performance Status X X X X X X X X X X X Disease Assessment X X X Toxicity Notation X X X X X X X X X X Baseline Abnormalities Assessment X
LABORATORY ∑ CBC/Differential/Platelets X X X X X X X X X Serum Creatinine or Calculated Creatinine Clearance X X X X X X X X X AST/ALT X X X X X X X X X PT/INR X Blood Sugar ∏ X ф X X X X X X X X X X Comprehensive metabolic panel * X X X X X X X X
SPECIMEN SUBMISSION £ Paraffin-embedded tissue X Blood sample X X†
SCANS ∑ CT scan or MRI for disease assessment ≠ X X X ECG X Study Calendar continued on next page.
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TREATMENT ∑ Oxaliplatin (Arm 1) δ X X X X X X X X 5-FU (Arm 1) α X X X X X X X X MK-2206 (Arm 2) Ұ X X X X X X X X X X X X X X X X AZD6244 hydrogen sulfate (Arm 2) β X X X X X X X X X X X X X X X X 1935 1936 ∑ Protocol treatment and parameters will continue at these intervals until progression of disease or until patient has met any of the guidelines in Section 1937 7.5. 1938 £ Optional submission for patients. See Section 15.0 for additional information. 1939 δ To be given on Day 1 and 15 of each cycle. See Section 7.3. 1940 α To be given Days 1-2 and 15-16 of each cycle. See Section 7.3. 1941 Ұ To be given on Day 1, 8, 15, and 22 of each cycle. See Section 7.3. 1942 β Every day. See Section 7.3. 1943 Ω After off treatment prior to disease progression, scans for disease assessment and physical assessments (with lab tests performed at the discretion of 1944 the treating investigator) should take place every 8 weeks until progression. 1945 % After off treatment following disease progression, physical assessments (with lab tests performed at the discretion of the treating investigator) should 1946 take place once every 6 months for three years from the time of registration. 1947 ≠ Scans are to be performed every 8 weeks while on treatment and off treatment until progression. 1948 * Include the following labs: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, LDH, phosphorus, potassium, total 1949 protein, and sodium. 1950 ∏ Patients on Arm 2 must have a fasting blood sugar tested for the duration of the study. Patients on either Arm with elevated blood sugar must be 1951 managed with oral hypoglycemics. Finger-stick testing may be performed during Weeks 2 and 4 for patients on Arm 1. 1952 ф Prestudy blood sugar must be fasting for all patients. 1953 † Submission requested for patients on Arm 2 only on Day 15. 1954 ~ Prestudy history and physical exam must be obtained within 28 days prior to registration. 1955
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1956 10.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 1957 1958 This study will use the RECIST 1.1 guidelines. (18) 1959 1960 10.1 Measurability of Lesions 1961 1962 a. Measurable disease 1963 1964 Measurable disease is defined differently for lymph nodes compared with other 1965 disease and will be addressed in a separate section below. 1966 1967 1) Lesions that can be accurately measured in at least one dimension (longest 1968 diameter to be recorded) as ≥ 2.0 cm by chest x-ray, by ≥ 1.0 cm with CT or 1969 MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All tumor 1970 measurements must be recorded in decimal fractions of centimeters (or 1971 millimeters). 1972 1973 The defined measurability of lesions on CT scan is based on the assumption 1974 that CT slice thickness is 0.5 cm or less. If CT scans have slice thickness 1975 greater than 0.5 cm, the minimum size for a measurable lesion should be 1976 twice the slice thickness. 1977 1978 2) Malignant lymph nodes are to be considered pathologically enlarged and 1979 measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 1980 perpendicular to the long axis of the lymph node) when assessed by scan 1981 (CT scan slice recommended being no greater than 0.5 cm). 1982 1983 b. Non-measurable disease. All other lesions (or sites of disease), including small 1984 lesions (longest diameter <1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 1985 1.5 cm short axis), are considered non-measurable disease. Bone lesions, 1986 leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 1987 cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 1988 followed by CT or MRI), are considered as non-measurable as are previously 1989 radiated lesions that have not progressed. 1990 1991 c. Notes on measurability: 1992 1993 1. For CT and MRIs, the same type of scanner should be used and the 1994 image acquisition protocol should be followed as closely as possible to 1995 prior scans. Body scans should by performed with breath-hold scanning 1996 techniques, if possible. 1997 1998 2. PET-CT: At present, the low dose or attenuation correction CT portion of 1999 a PET-CT is not always of optimal diagnostic CT quality for use with 2000 RECIST measurements. However, if the site can document that the CT 2001 performed as part of a PET-CT is of identical diagnostic quality to a 2002 diagnostic CT, then the CT portion of the PET-CT can be used for 2003 RECIST measurements and can be used interchangeably with 2004 conventional CT. 2005 2006 3. Ultrasound: Ultrasound is not useful in assessment of lesion size and 2007 should not be used as a method of measurement. 2008 2009 4. Cystic lesions that meet the criteria for radiographically defined simple 2010 cysts should not be considered as malignant lesions (neither measurable 2011 nor non-measurable) since they are, by definition simple cysts.
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2012 5. If a target lesion becomes very small some radiologists indicate that it is 2013 too small to measure. If the lesion is actually still present, a default 2014 measurement of 0.5cm should be applied. If the radiologist believes the 2015 lesion has gone, a default measurement of 0.0cm should be recorded. 2016 2017 10.2 Objective Status 2018 2019 Objective Status is to be recorded at each evaluation. All measurable lesions up to a 2020 maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 2021 should be identified as target lesions at baseline. All other lesions (or sites of disease) 2022 including any measurable lesions over and above the 5 target lesions should be identified 2023 as non-target lesions. Measurements must be provided for target measurable lesions, 2024 while presence or absence must be noted for non-target measurable and non- 2025 measurable disease. 2026 2027 For studies that use disease progression as an endpoint, whole body scanning at specific 2028 intervals is necessary to determine that progression is NOT present outside of the 2029 “target” areas. Therefore, in these studies it is not acceptable to image only the “target” 2030 areas of the body in follow-up scans. For study-specific imaging requirements, see the 2031 Study Calendar in Section 9.0. 2032 2033 a. Complete Response (CR): Complete disappearance of all target and non-target 2034 lesions (with the exception of lymph nodes mentioned below). No new lesions. 2035 No disease related symptoms. Any lymph nodes (whether target or non-target) 2036 must have reduction in short axis to < 1.0 cm. All disease must be assessed 2037 using the same technique as baseline. 2038 2039 b. Partial Response (PR): Applies only to patients with at least one measurable 2040 lesion. Greater than or equal to 30% decrease under baseline of the sum of 2041 appropriate diameters of all target measurable lesions. No unequivocal 2042 progression of non-measurable disease. No new lesions. All target measurable 2043 lesions must be assessed using the same techniques as baseline. 2044 2045 c. Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration. 2046 All target measurable lesions must be assessed using the same techniques as 2047 baseline. 2048 2049 d. Progression: One or more of the following must occur: 20% increase in the sum 2050 of appropriate diameters of target measurable lesions over smallest sum 2051 observed (over baseline if no decrease during therapy) using the same 2052 techniques as baseline, as well as an absolute increase of at least 0.5 cm. 2053 Unequivocal progression of non-measurable disease in the opinion of the treating 2054 physician (an explanation must be provided). Appearance of any new 2055 lesion/site. Death due to disease without prior documentation of progression and 2056 without symptomatic deterioration (see Section 10.2e). 2057 2058 Notes regarding new lesions: FDG-PET imaging can complement regular scans 2059 in identifying new lesions according to the following algorithm. 2060 2061 1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is 2062 a sign of progression based on a new lesion. 2063 2064 2. No FDG-PET at baseline and a positive FDG-PET at follow-up 2065 corresponding to a potential new site of disease must have a 2066 confirmation by anatomical assessment (e.g. CT, MRI, x-ray) as new site 2067 of disease to be considered progressive disease. In such a case, the 2068 date of progressive disease will be the date of the initial abnormal FDG- 2069 PET.
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2070 e. Symptomatic deterioration: Global deterioration of health status requiring 2071 discontinuation of treatment without objective evidence of progression. Efforts 2072 should be made to obtain objective evidence of progression after discontinuation. 2073 2074 f. Assessment inadequate, objective status unknown. Progression or 2075 symptomatic deterioration has not been documented, and one or more target 2076 measurable lesions have not been assessed or inconsistent assessment 2077 methods were used. 2078 2079 g. Objective status notes: 2080 2081 1. Non-measurable and non-target measurable disease do not affect 2082 Objective Status in determination of CR (must be absent--a patient who 2083 otherwise has a CR, but who has non-measurable or non-target 2084 measurable disease present or not assessed, will be classified as having 2085 a PR). However, non-measurable and non-target lesions are included in 2086 determination of progression (if new sites of disease develop or if 2087 unequivocal progression occurs in the opinion of the treating physician). 2088 2089 2. An objective status of PR or stable cannot follow one of CR. Stable can 2090 follow PR only in the rare case that tumor increases too little to qualify as 2091 progression, but enough that a previously documented 30% decrease no 2092 longer holds. 2093 2094 3. In cases for which initial flare reaction is possible (hypercalcemia, 2095 increased bone pain, erythema of skin lesions), objective status is not 2096 progression unless either symptoms persist beyond 4 weeks or there is 2097 additional evidence of progression. 2098 2099 4. Lesions that appear to increase in size due to presence of necrotic tissue 2100 will not be considered to have progressed. 2101 2102 5. For bone disease documented on bone scan only, increased uptake 2103 does not constitute unequivocal progression. However, increase in the 2104 soft tissue component of a lesion as measured by CT or MRI would 2105 constitute progression. 2106 2107 6. Appearance of new pleural effusions does not constitute unequivocal 2108 progression unless cytologically proven of neoplastic origin, since some 2109 effusions are a toxicity related to therapy or other medical conditions. 2110 Increase in the size of an existing effusion does not constitute 2111 unequivocal progression, since the fluid status of the patient could alter 2112 the size of the effusion. 2113 2114 7. If CR determination depends on a lesion for which the status is unclear 2115 by the required tests, it is recommended the residual lesion be 2116 investigated with biopsy or fine needle aspirate. 2117 2118 10.3 Best Response 2119 2120 This is calculated from the sequence of objective statuses. 2121 2122 a. CR: Two or more objective statuses of CR a minimum of four weeks apart 2123 documented before progression or symptomatic deterioration. 2124 2125 b. PR: Two or more objective statuses of PR or better a minimum of four weeks 2126 apart documented before progression or symptomatic deterioration, but not 2127 qualifying as CR.
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2128 c. Unconfirmed CR: One objective status of CR documented before progression or 2129 symptomatic deterioration but not qualifying as CR or PR. 2130 2131 d. Unconfirmed PR: One objective status of PR documented before progression or 2132 symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 2133 2134 e. Stable/no response: At least one objective status of stable/no response 2135 documented at least 6 weeks after registration and before progression or 2136 symptomatic deterioration, but not qualifying as anything else above. 2137 2138 f. Increasing disease: Objective status of progression within 12 weeks of 2139 registration, not qualifying as anything else above. 2140 2141 g. Symptomatic deterioration: Objective status of symptomatic deterioration within 2142 12 weeks of registration, not qualifying as anything else above. 2143 2144 h. Inadequate assessment, response unknown: Progression or symptomatic 2145 deterioration greater than 12 weeks after registration and no other response 2146 category applies. 2147 2148 10.4 Performance Status 2149 2150 Patients will be graded according to the Zubrod Performance Status Scale. 2151 2152 POINT DESCRIPTION 2153 2154 0 Fully active, able to carry on all pre-disease performance without 2155 restriction. 2156 2157 1 Restricted in physically strenuous activity but ambulatory and 2158 able to carry out work of a light or sedentary nature, e.g., light 2159 housework, office work. 2160 2161 2 Ambulatory and capable of self-care but unable to carry out any 2162 work activities; up and about more than 50% of waking hours. 2163 2164 3 Capable of limited self-care, confined to bed or chair more than 2165 50% of waking hours. 2166 2167 4 Completely disabled; cannot carry on any self-care; totally 2168 confined to bed or chair. 2169 2170 10.5 Progression-Free Survival 2171 2172 From date of registration to date of first documentation of progression or symptomatic 2173 deterioration (as defined in above), or death due to any cause. Patients last known to be 2174 alive and progression free are censored at date of last contact. 2175 2176 10.6 Overall Survival 2177 2178 From date of registration to date of death due to any cause. Patients last known to be 2179 alive are censored at date of last contact. 2180
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2181 2182 11.0 STATISTICAL CONSIDERATIONS 2183 2184 11.1 Accrual Goals 2185 2186 The accrual rate is estimated to be 5 per month. Since SWOG has not had any recent 2187 accrual experience for studies in second line pancreatic cancer, we use the accrual rate 2188 of the most recent SWOG randomized Phase II trial in first line metastatic pancreatic 2189 cancer S0727 to estimate the accrual rate for this study. S0727 accrued approximately 2190 10 per month. We conservatively estimate accrual of 5 per month to this second line trial 2191 since SWOG has historically had high success in accruing to trials in pancreatic cancer. 2192 2193 11.2 Primary Chemotherapy Objective 2194 2195 The primary endpoint of this study is overall survival (OS). Based on previous studies, 2196 median OS in the control group is approximately 6 months. Assuming a one-sided type 1 2197 error of 10%, 80% power, approximately 2 years of accrual and 1.5 years of follow-up, 2198 120 eligible patients will be accrued to detect an improvement in median survival from 6 2199 to 9 months (corresponding to a 1.5 hazard ratio). Accounting for the possibility of a 10% 2200 ineligibility rate, the study will accrue approximately 133 patients to achieve 120 eligible 2201 patients. This sample size would also have approximately 83% power to detect a 1.5 2202 hazard ratio for progression-free survival (PFS) which corresponds to an improvement 2203 from median of 2 months to median of 3 months. 2204 2205 11.3 Adverse Events Monitoring 2206 2207 This trial will employ careful adverse event monitoring for the first 20 patients randomized 2208 to the experimental arm since there is limited pre-existing data for this specific 2209 combination under study. This monitoring will involve the Study Chair, Study Statistician, 2210 Disease Committee Chair, and SWOG GI Executive Officer, in conjunction with the 2211 SWOG DSMC and CTEP if there are any causes for concern. Adverse event data will be 2212 reviewed for Serious Adverse Event rates, with discussions of protocol modification or 2213 early closure if required. Should accrual become too rapid, consideration will be given to 2214 a temporary closure until the adverse event profile of these early patients can be fully 2215 assessed. Any toxicity with an occurrence rate of at least 14% is highly likely (95% 2216 chance) to be seen at least once in these 20 patients. If the study remains open to full 2217 accrual, we will continually monitor adverse events on a regular basis in addition to the 2218 monitoring and interim analysis described below. 2219 2220 An interim analysis of the primary endpoint will be performed with the intent of testing the 2221 alternative hypothesis (e.g., terminate early if a 1.5 hazard ratio is deemed to be highly 2222 unlikely [p<.05, which would provide a 35% chance of rejecting the alternative hypothesis 2223 and stopping early]) once 34% of the expected events in the control arm have been 2224 observed which will occur at approximately 15 months. The final analysis will be done 2225 approximately 1.5 months after closure to accrual, at which time we will have 2226 approximately 115 deaths and 120 PFS events. The differences in OS between the two 2227 study arms will be evaluated using the log-rank test. The secondary endpoint, PFS will 2228 be analyzed in a similar manner. For patients with measurable disease, response will be 2229 compared using the chi square test. 2230 2231 11.4 Eligible Patients 2232 2233 With 60 eligible patients per arm, we will be able to estimate the probability of any 2234 individual event to within 13% in each arm. Any toxicity with an occurrence rate of at 2235 least 5% is highly likely (95% chance) to be seen at least once per arm. 2236
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2237 11.5 Data and Safety Monitoring Committee 2238 2239 A Data and Safety Monitoring Committee will oversee the conduct of this trial. A majority 2240 of the voting members of the DSMC are from outside of SWOG, and at least one outside 2241 member is a patient advocate, and one is a statistician. The Group Statistician (or 2242 designee), two representatives from the Cancer Therapy Evaluation Program (CTEP) 2243 (one physician and one statistician) and one representative of the Division of Cancer 2244 Prevention (DCP) are non-voting members. The members of this Committee will receive 2245 confidential reports every 6 months from the Southwest Oncology Group Statistical 2246 Center, and will meet at the Group’s bi-annual meetings or hold conference calls 2247 necessary. They will receive additional reports, if needed, for assessment of Adverse 2248 Events, or other study related matters. The Committee will be responsible for decisions 2249 regarding possible termination and/or early reporting of the study, and any major study 2250 amendments. 2251 2252 In addition to the above DSMC review, toxicity and accrual monitoring are done routinely 2253 by the Study Chair, study Statistician and the Disease Committee Chair. Endpoint 2254 monitoring is done by the study Statistician and Study Chair. Accrual reports are 2255 generated weekly, and formal toxicity reports are generated every 6 months. In addition, 2256 the Statistical Center, Adverse Event Coordinator at the Operations Office, SAE 2257 Physician Reviewer, and Study Chair monitor toxicities on an ongoing basis. 2258 2259 2260 12.0 DISCIPLINE REVIEW 2261 2262 Discipline review is not applicable to this study. 2263 2264 2265 13.0 REGISTRATION GUIDELINES 2266 2267 13.1 Registration Timing 2268 2269 Patients must be registered prior to initiation of treatment (no more than seven working 2270 days prior to planned start of treatment). 2271 2272 2273 13.2 Investigator/Site Registration 2274 2275 This study is supported by the NCI Cancer Trials Support Unit (CTSU). 2276 2277 Prior to the recruitment of a patient for this study, investigators must be registered 2278 members of a Cooperative Group. Each investigator must have an NCI investigator 2279 number and must maintain an “active” investigator registration status through the annual 2280 submission of a complete investigator registration packet (FDA Form 1572 with original 2281 signature, current CV, Supplemental Investigator Data Form with signature and Financial 2282 Disclosure Form with original signature) to the Pharmaceutical Management Branch, 2283 CTEP, DCTD, NCI. These forms are available on the CTSU Web site (enter credentials 2284 at https://www.ctsu.org; then click on the Register tab) or by calling the PMB at 240/276- 2285 6575 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 2286 2287 Each investigator or group of investigators at a clinic site must obtain IRB approval for 2288 this protocol and submit IRB approval and supporting documentation to the CTSU 2289 Regulatory Office before they can enroll patients. Study centers can check the status of 2290 their registration packets by querying the Regulatory Support System (RSS) site 2291 registration status page of the CTSU member web site by entering credentials at 2292 https://www.ctsu.org. 2293
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2294 Requirements for site registration: 2295 2296 • CTSU IRB Certification 2297 • CTSU IRB/Regulatory Approval Transmittal Sheet 2298 2299 13.3 OPEN Registration Requirements 2300 2301 The individual registering the patient must have completed the appropriate SWOG 2302 Registration Worksheet. The completed form must be referred to during the registration 2303 but should not be submitted as part of the patient data. 2304 2305 Oncology Patient Enrollment Network (OPEN) will also ask additional questions that are 2306 not present on the SWOG Registration Worksheet. The individual registering the patient 2307 must be prepared to provide answers to the following questions: 2308 2309 a. Institution CTEP ID 2310 2311 b. Protocol Number 2312 2313 c. Registration Step 2314 2315 d. Treating Investigator 2316 2317 e. Cooperative Group Credit 2318 2319 f. Credit Investigator 2320 2321 g. Patient Initials 2322 2323 h. Patient’s Date of Birth 2324 2325 i. Patient SSN (SSN is desired, but optional. Do not enter invalid numbers.) 2326 2327 j. Country of Residence 2328 2329 k. ZIP Code 2330 2331 l. Gender (select one): 2332 • Female Gender 2333 • Male Gender 2334 2335 m. Ethnicity (select one): 2336 • Hispanic or Latino 2337 • Not Hispanic or Latino 2338 • Unknown 2339 2340 n. Method of Payment (select one): 2341 • Private Insurance 2342 • Medicare 2343 • Medicare and Private Insurance 2344 • Medicaid 2345 • Medicaid and Medicare 2346 • Military or Veterans Sponsored NOS 2347 • Military Sponsored (Including Champus & Tricare) 2348 • Veterans Sponsored 2349 • Self Pay (No Insurance) 2350
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2351 • No Means of Payment (No Insurance) 2352 • Other 2353 • Unknown 2354 2355 o. Race (select all that apply): 2356 • American Indian or Alaska Native 2357 • Asian 2358 • Black or African American 2359 • Native Hawaiian or other Pacific Islander 2360 • White 2361 • Unknown 2362 2363 13.4 Registration Procedures 2364 2365 a. All site staff (SWOG and CTSU Sites) will use OPEN to enroll patients to this 2366 study. OPEN is a web-based application and can be accessed at 2367 https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 2368 website at https://www.ctsu.org, or from the OPEN Patient Registration link on 2369 the SWOG CRA Workbench. 2370 2371 b. Prior to accessing OPEN site staff should verify the following: 2372 2373 • All eligibility criteria have been met within the protocol stated timeframes 2374 and the affirmation of eligibility on the Registration Worksheet has been 2375 signed by the registering investigator or another investigator 2376 designate. Site staff should refer to Section 5.0 to verify eligibility. 2377 2378 • All patients have signed an appropriate consent form and HIPAA 2379 authorization form (if applicable). 2380 2381 • The study site is listed as “approved” in the CTSU RSS. 2382 2383 c. Access requirements for OPEN: 2384 2385 • Site staff will need to be registered with CTEP and have a valid and 2386 active CTEP-IAM account. This is the same account (user ID and 2387 password) used for the CTSU members' web site. 2388 2389 • To perform registrations, the site user must have been assigned the 2390 'Registrar' role on the SWOG or CTSU roster: 2391 2392 1. If you are a SWOG member, to perform registrations on SWOG 2393 protocols you must have an equivalent 'Registrar' role on the SWOG 2394 roster. Role assignments are handled through SWOG. 2395 2396 2. If you are not a SWOG member, to perform registrations on SWOG 2397 protocols you must have the role of Registrar on the CTSU roster. 2398 Site and/or Data Administrators can manage CTSU roster roles via 2399 the new Site Roles maintenance feature under RSS on the CTSU 2400 members' web site. This will allow them to assign staff the 2401 "Registrar" role. 2402 2403 Note: The OPEN system will provide the site with a printable confirmation of 2404 registration and treatment information. Please print this confirmation for your 2405 records. 2406 2407
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2408 d. Further instructional information is provided on the OPEN tab of the CTSU 2409 members’ side of the CTSU website at https://www.ctsu.org or at 2410 https://open.ctsu.org. For any additional questions contact the CTSU Help Desk 2411 at 1-888-823-5923 or [email protected]. 2412 2413 13.5 Exceptions to SWOG registration policies will not be permitted 2414 2415 a. Patients must meet all eligibility requirements. 2416 2417 b. Institutions must be identified as approved for registration. 2418 2419 c. Registrations may not be cancelled. 2420 2421 d. Late registrations (after initiation of treatment) will not be accepted. 2422 2423 2424 14.0 DATA SUBMISSION SCHEDULE 2425 2426 14.1 Data Submission Requirement 2427 2428 Data must be submitted according to the protocol requirements for ALL patients 2429 registered, whether or not assigned treatment is administered, including patients deemed 2430 to be ineligible. Patients for whom documentation is inadequate to determine eligibility 2431 will generally be deemed ineligible. 2432 2433 14.2 Master Forms 2434 2435 Master forms can be found on the protocol abstract page on the SWOG website 2436 (www.swog.org) and (with the exception of the sample consent form and the Registration 2437 Worksheet) must be submitted on-line via the Web; see Section 14.3a for details. 2438 2439 14.3 Data Submission Procedures 2440 2441 a. SWOG institutions must submit data electronically via the Web using Medidata 2442 Rave® at the following url: 2443 2444 https://login.imedidata.com/selectlogin 2445 2446 1. If prompted, select the ‘CTEP-IAM IdP’ link. 2447 2. Enter your valid and active CTEP-IAM userid and password. This is the 2448 same account used for the CTSU members’ web site and OPEN. 2449 2450 b. You may also access Rave® via the SWOG CRA Workbench. Go to the SWOG 2451 web site (http://swog.org) and logon to the Members Area using your SWOG 2452 Roster ID Number and password. After you have logged on, click on 2453 Workbenches, then CRA Workbench to access the home page for the CRA 2454 Workbench and follow the link to Rave® provided in the left-hand navigation 2455 panel. 2456 2457 To access the CRA Workbench the following must be done (in order): 2458 2459 1. You are entered into the SWOG Roster and issued a SWOG Roster ID 2460 Number, 2461 2. You are associated as an investigator or CRA/RN at the institution where 2462 the patient is being treated or followed, 2463 3. Your Web User Administrator has added you as a web user and has 2464 given you the appropriate system permissions to view data for that 2465 institution.
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2466 For assistance with points 1 and 2 call the Operations Office at 210/614-8808. 2467 For point 3, contact your local Web User Administrator (refer to the "Who is my 2468 Web User Administrator?" function on the swog.org Members logon page). 2469 2470 For difficulties with the CRA Workbench, please email 2471 [email protected]. 2472 2473 c. Institutions participating through the Cancer Trials Support Unit (CTSU) please refer 2474 to the CTSU Participation Table on Page 1a. 2475 2476 14.4 Data Submission Overview and Timepoints 2477 2478 a. WITHIN 7 DAYS OF REGISTRATION: 2479 2480 1. S1115 Onstudy Form 2481 2482 2. Baseline Tumor Assessment Form 2483 2484 3. S1115 Baseline Abnormalities Form 2485 2486 4. Submit pathology report 2487 2488 5. Submit radiology reports from all scans performed to assess disease at 2489 baseline. 2490 2491 b. WITHIN 28 DAYS OF REGISTRATION: 2492 2493 Materials for banking of specimens (including pathology report) as described in 2494 Section 15.0 2495 (http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp). 2496 2497 c. WITHIN 14 DAYS AFTER EVERY CYCLE OF TREATMENT: 2498 2499 1. S1115 Treatment Form 2500 2501 2. S1115 Adverse Event Form 2502 2503 d. WITHIN 14 DAYS AFTER EVERY DISEASE ASSESSMENT (INCLUDING 2504 BOTH ON TREATMENT AND OFF TREATMENT PRIOR TO DISEASE 2505 PROGRESSION): 2506 2507 1. Follow-Up Tumor Assessment Form 2508 2509 2. Radiology reports from all scans used to assess disease. 2510 2511 e. WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 2512 2513 1. Follow-Up Tumor Assessment Form 2514 2515 2. Radiology Reports 2516 2517 3. Follow-Up Form documenting date, site and method for determining 2518 progression/relapse – if patient is already off treatment. 2519 2520 4. Off Treatment Notice – if patient is still on treatment 2521
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2522 f. WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT: 2523 2524 Submit the Off Treatment Notice and final on treatment S1115 Treatment Form. 2525 2526 g. ONCE OFF ALL PROTOCOL TREATMENT, EVERY 8 WEEKS UNTIL 2527 PROGRESSION, THEN EVERY SIX MONTHS, FOR UP TO THREE YEARS 2528 FROM THE DATE OF REGISTRATION: 2529 2530 Submit the Follow-Up Form 2531 2532 h. WITHIN 30 DAYS OF DISCONTINUATION OF TREATMENT AND 2533 RESOLUTION OF TOXICITIES: 2534 2535 S1115 Adverse Event Form 2536 2537 i. WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 2538 2539 Submit the Notice of Death and final S1115 Treatment Form, S1115 Adverse 2540 Event Form and Follow-Up Tumor Assessment Form (if the patient was still on 2541 protocol treatment) or Follow-Up Form (if the patient was off protocol treatment) 2542 documenting death information. 2543 2544 2545 15.0 SPECIAL INSTRUCTIONS 2546 2547 Specimens for Banking 2548 2549 Specimens for banking (submitted to the SWOG Specimen Repository – Solid Tissue, Myeloma 2550 and Lymphoma Division, Lab #201) (optional for patient): 2551 2552 a. With patient’s consent, specimens must be submitted within 28 days of registration (see 2553 Section 9.0): 2554 2555 1. Tumor block or twenty 10-micron unstained tumor sections (FFPE) (from primary 2556 or metastatic site) per the instructions in the link below. 2557 2558 2. Approximately 10 ml of blood will be obtained after registration (prior to treatment 2559 and, for patients on Arm 2, on Day 15) in a purple top (EDTA) tube and stored on 2560 ice. Shipment should occur on the same day as collection or the next day by 2561 overnight delivery Monday through Thursday (no holidays). Fresh blood may 2562 also be shipped on Friday overnight for Saturday delivery. 2563 2564 Specimen collection and submission instructions can be accessed on the SWOG solid 2565 tumor website 2566 (http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp). 2567 2568 b. Specimen collection kits are not being provided for this submission. Sites will use 2569 institutional supplies. 2570 2571 2572 16.0 ETHICAL AND REGULATORY CONSIDERATIONS 2573 2574 The following must be observed to comply with Food and Drug Administration regulations for the 2575 conduct and monitoring of clinical investigations; they also represent sound research practice: 2576
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2577 Informed Consent 2578 2579 The principles of informed consent are described by Federal Regulatory Guidelines (Federal 2580 Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 2581 Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They 2582 must be followed to comply with FDA regulations for the conduct and monitoring of clinical 2583 investigations. 2584 2585 Institutional Review 2586 2587 This study must be approved by an appropriate institutional review committee as defined by 2588 Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 2589 and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code 2590 of Federal Regulations 45 CFR 46). 2591 2592 Drug Accountability 2593 2594 An investigator is required to maintain adequate records of the disposition of investigational drugs 2595 according to procedures and requirements governing the use of investigational new drugs as 2596 described in the Code of Federal Regulations 21 CFR 312. 2597 2598 Publication and Industry Contact 2599 2600 The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 2601 a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 2602 (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 2603 Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the 2604 “Intellectual Property Option to Collaborator” 2605 (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 2606 terms of award, apply to the use of the Agent(s) in this study: 2607 2608 1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 2609 Agent(s) be transferred or licensed to any party not participating in the clinical study. 2610 Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 2611 shall be maintained as such by the investigators. The protocol documents for studies 2612 utilizing Agents contain confidential information and should not be shared or distributed 2613 without the permission of the NCI. If a copy of this protocol is requested by a patient or 2614 patient’s family member participating on the study, the individual should sign a 2615 confidentiality agreement. A suitable model agreement can be downloaded from: 2616 http://ctep.cancer.gov. 2617 2618 2. For a clinical protocol where there is an investigational Agent used in combination with 2619 (an)other Agent(s), each the subject of different Collaborative Agreements, the access to 2620 and use of data by each Collaborator shall be as follows (data pertaining to such 2621 combination use shall hereinafter be referred to as "Multi-Party Data”): 2622 2623 a. NCI will provide all Collaborators with prior written notice regarding the existence 2624 and nature of any agreements governing their collaboration with NCI, the design 2625 of the proposed combination protocol, and the existence of any obligations that 2626 would tend to restrict NCI's participation in the proposed combination protocol. 2627 2628 b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 2629 clinical trial by any other Collaborator solely to the extent necessary to allow said 2630 other Collaborator to develop, obtain regulatory approval or commercialize its 2631 own Agent. 2632
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2633 c. Any Collaborator having the right to use the Multi-Party Data from these trials 2634 must agree in writing prior to the commencement of the trials that it will use the 2635 Multi-Party Data solely for development, regulatory approval, and 2636 commercialization of its own Agent. 2637 2638 3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 2639 Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 2640 appropriate and unless additional disclosure is required by law or court order as 2641 described in the IP Option to Collaborator 2642 (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all 2643 Clinical Data and Results and Raw Data will be collected, used and disclosed consistent 2644 with all applicable federal statutes and regulations for the protection of human subjects, 2645 including, if applicable, the Standards for Privacy of Individually Identifiable Health 2646 Information set forth in 45 C.F.R. Part 164. 2647 2648 4. When a Collaborator wishes to initiate a data request, the request should first be sent to 2649 the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 2650 Group studies, or PI for other studies) of Collaborator's wish to contact them. 2651 2652 5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 2653 guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 2654 DMC for this clinical trial. 2655 2656 6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 2657 the Group office for Cooperative Group studies or by the principal investigator for non- 2658 Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 2659 and comment prior to submission for publication. Collaborator(s) will have 30 days from 2660 the date of receipt for review. Collaborator shall have the right to request that publication 2661 be delayed for up to an additional 30 days in order to ensure that Collaborator’s 2662 confidential and proprietary data, in addition to Collaborator(s)’s intellectual property 2663 rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to 2664 Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 2665 days prior to submission, but in any case, prior to presentation at the meeting or 2666 publication in the proceedings. Press releases and other media presentations must also 2667 be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press 2668 release/ media presentation should be sent to: 2669 2670 Email: [email protected] 2671 2672 The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 2673 manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 2674 proprietary information. 2675 2676 Monitoring 2677 2678 This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 2679 Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are 2680 due January 31, April 30, July 31 and October 31. 2681 2682 Confidentiality 2683 2684 Please note that the information contained in this protocol is considered confidential and should 2685 not be used or shared beyond the purposes of completing protocol requirements until or unless 2686 additional permission is obtained. 2687
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2688 16.1 Adverse Event Reporting Requirements 2689 2690 a. Purpose 2691 2692 Adverse event data collection and reporting, which are required as part of every 2693 clinical trial, are done to ensure the safety of patients enrolled in the studies as 2694 well as those who will enroll in future studies using similar agents. Adverse 2695 events are reported in a routine manner at scheduled times during a trial. 2696 (Directions for routine reporting are provided in Section 14.0.) Additionally, 2697 certain adverse events must be reported in an expedited manner to allow for 2698 more timely monitoring of patient safety and care. The following guidelines 2699 describe expedited adverse event reporting for this protocol. See also Appendix 2700 18.1 for general and background information about expedited reporting. 2701 2702 b. Reporting method 2703 2704 This study requires that expedited adverse event reporting use CTEP’s Adverse 2705 Event Reporting System (CTEP-AERS). The NCI’s guidelines for CTEP-AERS 2706 can be found at 2707 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events. 2708 htm. 2709 2710 c. When to report an event in an expedited manner 2711 2712 Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP- 2713 AERS. When the adverse event requires expedited reporting, submit the report 2714 within the number of calendar days of learning of the event, as specified in Table 2715 16.1 or 16.2, as applicable. 2716 2717 In the rare event when internet connectivity is disrupted a 24-hour notification is 2718 made to NCI by telephone at 301-897-7497. An electronic report MUST be 2719 submitted immediately upon re-establishment of internet connection. Please 2720 note that all paper CTEP-AERS forms have been removed from the CTEP 2721 website and will NO LONGER be accepted. 2722 2723 Any supporting documentation requested by CTEP should be submitted in 2724 accordance with instructions provided by the CTEP-AERS system. 2725 2726 d. Other recipients of adverse event reports 2727 2728 The SWOG Operations Office will forward reports and documentation to the 2729 appropriate regulatory agencies and drug companies as required. 2730 2731 Adverse events determined to be reportable to the Institutional Review Board 2732 responsible for oversight of the patient must be reported according to local policy 2733 and procedures. 2734 2735 e. Expedited reporting for investigational agents 2736 2737 Expedited reporting is required if the patient has received at least one dose of the 2738 investigational agent(s) as part of the trial. Reporting requirements are provided 2739 in Table 16.1. The investigational agents used in Arm 2 of this study are 2740 AZD6244 hydrogen sulfate and MK-2206. If there is any question about the 2741 reportability of an adverse event or if on-line CTEP-AERS cannot be used, 2742 please telephone or email the SAE Specialist at the Operations Office, 210/614- 2743 8808 or [email protected], before preparing the report. 2744
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2745 Table 16.1: Late Phase 2 and Phase 3 studies: Expedited Reporting Requirements for Adverse 2746 Events that Occur on Studies under a CTEP IND within 30 Days1 of the Last Dose of the 2747 Investigational Agent1 AZD6244 hydrogen sulfate or MK-2206 in this Study (Arm 2) 2748 FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes: 1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS within the timeframes detailed in the table below. Grade 1 Grade 2 Grade 4 & 5 Hospitalization Grade 3 Timeframes Timeframes Timeframes Timeframes Resulting in Hospitalization 10 Calendar Days ≥ 24 hrs 24-Hour 5 Calendar Not resulting in Days Hospitalization Not required 10 Calendar Days ≥ 24 hrs
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR or Section 16.1f. Expedited AE reporting timelines are defined as: o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24- hour report.
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE.
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:
Expedited 24-hour notification followed by complete report within 5 calendar days for: • All Grade 4, and Grade 5 AEs Expedited 10 calendar day reports for: • Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization • Grade 3 adverse events
May 5, 2011
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2749 f. Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 2750 Requirements for Phase 2 and 3 Trials Utilizing an Agent under a CTEP- 2751 IND: 2752 2753 1) Submission of the on-line CTEP-AERS report plus any necessary 2754 amendments generally completes the reporting requirements. In 2755 addition, you may be asked to submit supporting clinical data to the 2756 SWOG Operations Offices in order to complete the evaluation of the 2757 event. If requested, the supporting data should be sent within 5 2758 calendar days by fax to 210-614-0006. Supporting clinical data 2759 submitted should include: 2760 • Printed copy of the first page of the CTEP-AERS Report. 2761 • Copies of clinical source documentation of the event. 2762 • If applicable, and they have not yet been submitted to the SWOG 2763 Data Operations Center copies of Off Treatment Notice and/or 2764 Notice of Death. 2765 2766 2) The adverse events listed below also require expedited monitoring for 2767 this trial: 2768 • Retinal vein occlusion or blindness 2769 2770 3) For study arm 2, the adverse events listed below do not require 2771 expedited reporting via CTEP-AERS: 2772 • Grade 4 myelosuppression 2773 2774 g. Expedited reporting for commercial agents 2775 2776 Commercial reporting requirements are provided in Table 16.2. The commercial 2777 agent(s) used in arm 1 of this study are 5-fluorouracil and oxaliplatin. If there is 2778 any question about the reportability of an adverse event, please telephone or 2779 email the SAE Program at the Operations Office, 210-614-8808 or 2780 [email protected], before preparing the report. 2781 2782 2783 2784
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2785 Table 16.2. Late Phase 2 and Phase 3 studies: Expedited reporting 2786 requirements for adverse events experienced by patients on study arm 1 2787 (FOLFOX) who have received only the commercial drugs listed in Section 2788 16.1g above within 30 days of the last administration of the commercial 2789 agents. 2790
a Attribution Grade 4 Grade 5 Unexpected Expected Unexpected Expected Unrelated CTEP- CTEP-
or Unlikely AERS AERS Possible, CTEP- CTEP- Probable, CTEP-AERS AERS AERS Definite CTEP-AERS: Indicates an expedited report is to be submitted via NCI CTEP-AERS within 10 calendar days of learning of the eventb. a This includes all deaths within 30 days of the last dose of treatment with a commercial agent(s), regardless of attribution. Any death that occurs more than 30 days after the last dose of treatment with a commercial agent(s) and is attributed (possibly, probably, or definitely) to the agent(s) and is not due to cancer recurrence must be reported according to the instructions above.
b Submission of the on-line CTEP-AERS report plus any necessary amendments generally completes the reporting requirements. You may, however, be asked to submit supporting clinical data to the Operations Office in order to complete the evaluation of the event. If requested, the specified data should be sent within 5 calendar days by fax to 210-614-0006. 2791 2792 h. Reporting Secondary Malignancies, including AML/ALL/MDS 2793 2794 1. A secondary malignancy is a cancer caused by treatment for a previous 2795 malignancy (e.g., treatment with investigational agent/intervention, 2796 radiation or chemotherapy). A secondary malignancy is not considered a 2797 metastasis of the initial neoplasm. 2798 2799 CTEP requires all secondary malignancies that occur following treatment 2800 with an agent under an NCI IND to be reported via CTEP-AERS. Three 2801 options are available to describe the event. 2802 2803 • Leukemia secondary to oncology chemotherapy (e.g., Acute 2804 Myelocytic Leukemia [AML]) 2805 • Myelodysplastic syndrome (MDS) 2806 • Treatment-related secondary malignancy 2807 2808 Any malignancy possibly related to cancer treatment (including 2809 AML/MDS) should also be reported via the routine reporting mechanisms 2810 outlined in each protocol. 2811 2812 Second Malignancy: A second malignancy is one unrelated to the 2813 treatment of a prior malignancy (and is NOT a metastasis from the initial 2814 malignancy). Second malignancies require ONLY routine reporting via 2815 CDUS unless otherwise specified. 2816 2817 For more information see: 2818 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ 2819 aeguidelines.pdf. 2820
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2821 2. Supporting documentation should be submitted to CTEP in accordance 2822 with instructions provided by the CTEP-AERS system. A copy of the 2823 report and the following supporting documentation must also be 2824 submitted to SWOG Operations Office within 30 days: 2825 2826 • a copy of the pathology report confirming the AML/ALL /MDS 2827 diagnosis 2828 • (if available) a copy of the cytogenetics report 2829 2830 SWOG 2831 ATTN: SAE Program 2832 4201 Medical Drive, Suite 250 2833 San Antonio, Texas 78229 2834 2835 NOTE: If a patient has been enrolled in more than one NCI-sponsored 2836 study, the report must be submitted for the most recent trial. 2837 2838 i. Reporting Pregnancy, Fetal Death, and Death Neonatal 2839 2840 1. Pregnancy Study participants who become pregnant while on study; that 2841 pregnancy should be reported in an expedited manner via CTEP-AERS 2842 as Grade 3 “Pregnancy, puerperium and perinatal conditions – 2843 Other (pregnancy)” under the Pregnancy, puerperium and perinatal 2844 conditions SOC. 2845 2846 Additionally, the pregnancy outcome for patients on study should be 2847 reported via CTEP-AERS at the time the outcome becomes known, 2848 accompanied by the same Pregnancy Report Form used for the initial 2849 report. 2850 2851 2. Fetal Death Fetal Death defined in CTCAE as “A disorder characterized 2852 by death in utero; failure of the product of conception to show evidence 2853 of respiration, heartbeat, or definite movement of a voluntary muscle 2854 after expulsion from the uterus, without possibility of resuscitation” 2855 should be reported expeditiously as Grade 4 “pregnancy, puerperium 2856 and perinatal conditions – Other (pregnancy loss)” under the 2857 Pregnancy, puerperium and perinatal conditions SOC. 2858 2859 3. Death Neonatal Neonatal death, defined in CTCAE as “A disorder 2860 characterized by cessation of life occurring during the first 28 days of life” 2861 that is felt by the investigator to be at least possibly due to the 2862 investigational agent/intervention should be reported expeditiously. 2863 2864 A neonatal death should be reported expeditiously as Grade 4 “General 2865 disorders and administration – Other (neonatal loss)” under the 2866 General disorders and administration SOC. 2867 2868 Fetal death and neonatal death should NOT be reported as a Grade 5 event. If 2869 reported as such, the CTEP-AERS interprets this as a death of the patient being 2870 treated. 2871 2872 NOTE: When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 2873 or “Neonatal loss”, the Pregnancy Information Form should also be completed 2874 and faxed with any additional medical information to 301-230-0159. The 2875 potential risk of exposure of the fetus to the investigational agent(s) or 2876 chemotherapy agent(s) should be documented in the “Description of Event” 2877 section of the CTEP-AERS report. 2878 2879 The Pregnancy Information Form is available at: 2880 http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm
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2881 17.0 BIBLIOGRAPHY 2882 2883 1. Moore MJ, Goldstein D, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in 2884 patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of 2885 Canada Clinical Trials Group. JCO 25:1960-66, 2007. 2886 2887 2. Conroy T, Desseigne F, et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic 2888 Cancer. New England J of Med 364:1817-1825, 2011. 2889 2890 3. Pelzer U, et al. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final 2891 results of the CONKO 003 study. JCO 26 supp, abstr 4508, 2008. 2892 2893 4. Pelzer U, Schwaner I, et al. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5- 2894 fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: A phase III- 2895 study from the German CONKO-study group. European J of Cancer 47:1676-1681, 2011. 2896 2897 5. Shankar S, Chen Q, Srivastava R. Inhibition of PI3K/AKT and MEK/ERK pathways act 2898 synergistically to enhance antiangiogenic effects of EGCG through activation of FOXO 2899 transcription factor. J of Mol Signaling 3:1-7, 2008. 2900 2901 6. Roy SK, Srivastava R, Shankar S. Inhibition of PI3K/AKT and MAPK/ERK pathways causes 2902 activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic 2903 cancer. J of Mol Signaling 5:1-13, 2010. 2904 2905 7. Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene 2906 24:7455-64, 2005. 2907 2908 8. Cheng JQ, et al. The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 2909 24:7482-92, 2005. 2910 2911 9. Tolcher AW, et al. A phase I study of MK-2206, an oral potent allosteric Akt inhibitor (Akti), in 2912 patients (pts) with advanced solid tumor (ST). J. Clin. Oncol. 27:15s, (suppl; abstr 3503), 2009. 2913 2914 10. Investigator’s Brochure (2008). “MK-2206” 2915 2916 11. Davies BR, et al. AZD-6244, a potent inhibitor of mitogen-activated protein kinase/ extracellular 2917 signal regulated kinase kinase ½ kinase: mechanism of action in vivo, PK/PD relationship and 2918 potential for combination in preclinical models. Mol Cancer Ther 6: 2209-2219, 2007. 2919 2920 12. Meng J, Dai B, Fang B, et al. Combination treatment with MEK and AKT inhibitors is more 2921 effective than each drug alone in human non-small cell lung cancer in vitro and in vivo. PLOS 2922 One 5 :1-10, 2010. 2923 2924 13. Bendall J. et al. Phase I clinical trial of GDC-0973 (MEK 1 / 2 inhibitor) and GDC-0941 (PI3K 2925 inhibitor).AACR 102nd Annual Meeting, Abstract LB-89, 2011. 2926 2927 14. Tolcher AW, et al. A phase I dose-escalation study of oral MK-2206 (allosteric AKT inhibitor) with 2928 oral selumetinib (AZD6244; MEK inhibitor) in patients with advanced or metastatic solid tumors. J 2929 Clin Oncol 29 (suppl; abstr 3004), 2011. 2930 2931 15. Bertotti A. et al. Only a Subset of MET-Activated Pathways are Required to Sustain Oncogene 2932 Addiction. Science Signaling 100: 1-15, 2009. 2933 2934 16. Roy SK, Srivastava R, and Shankar S. Inhibition of PI3K/AKT and MAPK/ERK pathways causes 2935 activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic 2936 cancer. J of Mol Signaling 5: 1-13, 2010.
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2937 17. Biondi L, Narin JG. Stability of 5-fluorouracil and flucytosine in parenteral solutions. Can J Hosp 2938 Pharm 39:60-4, 1986. 2939 2940 18. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 2941 Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij. New 2942 response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2943 45: 228-247, 2009. 2944 2945 2946
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2947 18.0 APPENDIX 2948 2949 18.1 Determination of Expedited Adverse Event Reporting Requirements 2950 2951 18.2 Intake Calendar 2952 2953 18.3 Medications Known to Prolong the QT Interval and/or Induce Torsades de Pointes 2954 2955 18.4 CYP3A4/5 and CYP1A2 Prohibited Medications 2956 2957 18.5 New York Heart Association Classifications 2958 2959 2960 2961
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2962 18.1 Determination of Expedited Adverse Event Reporting Requirements 2963 2964 Adverse event data collection and reporting, which are required as part of every clinical 2965 trial, are done to ensure the safety of patients enrolled in the studies as well as those who 2966 will enroll in future studies using similar agents. Adverse events are reported in a routine 2967 manner at scheduled times during a trial. (Directions for routine reporting are provided in 2968 Section 14.0.) Additionally, certain adverse events must be reported in an expedited 2969 manner to allow for more timely monitoring of patient safety and care. Expedited adverse 2970 event reporting principles and general guidelines follow; specific guidelines for expedited 2971 adverse event reporting on this protocol are found in Section 16.1. 2972 2973 All serious adverse events determined to be reportable to the Institutional Review Board 2974 responsible for the oversight of the patient must be reported according to local policy and 2975 procedures. Documentation of this reporting should be maintained for possible 2976 inspection during quality assurance audits. 2977 2978 Steps to determine if an adverse event is to be reported in an expedited manner 2979 (This includes all events that occur while on treatment or within 30 days of the last dose 2980 of protocol treatment.) 2981 2982 Step 1: Determine whether the patient has received an investigational agent, commercial 2983 agent, or a combination of investigational and commercial agents. 2984 2985 An investigational agent is a protocol drug administered under an Investigational New 2986 Drug Submission (IND). In some instances, the investigational agent may be available 2987 commercially, but is actually being tested for indications not included in the approved 2988 package label. 2989 2990 Commercial agents are those agents not provided under an IND but obtained instead 2991 from a commercial source. The NCI, rather than a commercial distributor, may on some 2992 occasions distribute commercial agents for a trial. 2993 When a study includes both investigational and commercial agents, the following rules 2994 apply. 2995 • Concurrent administration: When an investigational agent(s) is used in 2996 combination with a commercial agent(s), the combination is considered to be 2997 investigational and expedited reporting of adverse events would follow the 2998 guidelines for investigational agents. 2999 • Sequential administration: When a study includes an investigational agent(s) 3000 and a commercial agent(s) on the same study arm with sequential administration 3001 all expedited reporting of adverse events should follow the guidelines for the type 3002 of agent being given. For example, if the patient begins the study on the 3003 investigational agent(s), then all expedited reporting of adverse events should 3004 follow guidelines for the investigational agent(s). Once the patient begins 3005 receiving the commercial agent(s) then all expedited reporting of adverse events 3006 should follow the guidelines for commercial agent(s). 3007 3008 Step 2: Identify the type of event using the NCI Common Terminology Criteria for 3009 Adverse Events (CTCAE). The CTCAE provides descriptive terminology and a grading 3010 scale for each adverse event listed. A copy of the CTCAE can be downloaded from the 3011 CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI 3012 has an Index to the CTCAE that provides help for classifying and locating terms. 3013 3014 Step 3: Grade the event using the NCI CTCAE version specified in the protocol for 3015 reporting serious adverse events. 3016
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3017 Step 4: Determine if the adverse event is Expected or an Exception to Expedited 3018 Reporting. Expected events are those that have been previously identified as resulting 3019 from administration of the agent and are listed in one of the following: 3020 3021 • The current NCI SPEER (Specific Protocol Exceptions to Expedited Reporting) 3022 for treatments using agents provided under an NCI-held IND, or an equivalent 3023 listing for treatments using agents provided under a Non-CTEP-held IND; located 3024 in Section 3.0 of the protocol. 3025 • For treatments using commercial agents, the current CAEPR (Comprehensive 3026 Adverse Event and Potential Risks), ASAEL (Agent Specific Adverse Event List), 3027 or other list of expected toxicities located in Section 3.0 of the protocol, or the 3028 drug package insert. 3029 • Exception to Expedited reporting located in Section 16.1f of the protocol. 3030 3031 An adverse event is considered unexpected, for expedited reporting purposes only, 3032 when either the type of event or the severity of the event is not listed in one of the areas 3033 outlined above. 3034 3035 Step 5: Determine whether the adverse event involved hospitalization or a prolongation 3036 of hospitalization (≥ 24 hours). 3037 3038 Step 6: Additionally, for commercial drugs, determine whether the adverse event is 3039 related to the protocol therapy. Attribution categories are as follows: Unrelated, Unlikely, 3040 Possible, Probable, and Definite. Consult the appropriate table for expedited reporting 3041 criteria for commercial agent(s). 3042 3043 NOTE: Any event that occurs more than 30 days after the last dose of study agent and 3044 is attributed (possible, probable, or definite) to the study agent(s) must be reported 3045 according to the instructions above and as outlined in the appropriate table in Section 3046 16.1.
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3047 18.2 Intake Calendar 3048 3049 SWOG Patient ID______Patient Initials (L, F, M) ______SWOG Study #______3050 3051 Institution/Affiliate ______Physician ______3052 3053 Instructions for the participant: 3054 3055 This is a monthly calendar on which you are to record the number of tablets/pills/capsules you 3056 take each day. Be sure you have enough calendars to last until your next appointment. If you 3057 develop any side effects from the tablets/pills/capsules, mark this on the calendar on the day 3058 you note the effect. Bring your calendars with you each time you have an appointment. 3059 3060 If you have questions contact: ______Telephone: ______3061 3062 Your next appointment is: ______3063 3064 Special instructions: 3065 3066 3067 3068 Month: Year: 3069 Sunday Monday Tuesday Wednesday Thursday Friday Saturday
3070 Patient Signature:
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3071 18.3 Medications Known to Prolong the QT Interval and/or Induce Torsades de Pointes 3072 3073 It has been recognized for a number of years that certain prescription medications can 3074 prolong the QT/QTc interval and cause a form of acquired Long QT syndrome, known as 3075 drug induced LQTS. The drugs that prolong the QT interval and/or have a risk of inducing 3076 Torsade de Pointes (TdP) are listed below. We have divided these into two groups based 3077 on their known or perceived risk of causing TdP: 3078 3079 Table 1. Drugs That are Generally Accepted by Authorities to Have a Risk of Causing 3080 Torsades de Pointes 3081 3082 Concomitant use of these drugs (Table 1) is not allowed during the study or within 2 3083 weeks prior to registration (at least four weeks for Levomethadyl). These drugs 3084 should also be avoided for up to 4 weeks following discontinuation of study 3085 treatment: Drug (Generic Names) Drug Class (Clinical Usage) Comments Albuterol (by parenteral Bronchodilator (asthma) Inhaled Albuterol at normal administration) doses acceptable Amiodarone Anti-arrhythmic (heart F>M, TdP Cases in Literature rhythm) Arsenic trioxide Anti-cancer (leukaemia) TdP Cases in Literature Bepridil Anti-anginal (heart pain) F>M Chlorpromazine Anti-psychotic/antiemetic TdP Cases in Literature (schizophrenia/nausea) Chloroquine Anti-malaria (malaria infection) Cisapride GI stimulant (stimulates GI Open Prescription Restricted motility) F>M Disopyramide Anti-arrhythmic (heart F>M rhythm) Dofetilide Anti-arrhythmic (heart rhythm) Domperidone Anti-nausea (nausea) Droperidol Sedative/hypnotic TdP Cases in Literature (anaesthesia adjunct) Erythromycin Antibiotic/GI stimulant F>M (infection/GI motility) Halofantrine Anti-malarial (malaria F>M infection) Haloperidol Anti-psychotic (schizophrenia, agitation) Ibutilide Anti-arrhythmic (heart F>M rhythm) Levomethadyl Opiate agonist (narcotic dependence) Mesoridazine Anti-psychotic (schizophrenia) Methadone Opiate agonist (pain control/ F>M narcotic dependence) Pentamidine Anti-infective (pneumocystis F>M pneumonia) Pimozide Anti-psychotic (Tourette's F>M, TdP Cases in Literature tics) Procainamide Anti-arrhythmic (heart rhythm)
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3086 Quinidine Anti-arrhythmic (abnormal F>M heart rhythm) Salbutamol (by parenteral Bronchodilator (asthma) Inhaled salbutamol at normal administration) doses acceptable Sotalol Anti-arrhythmic (heart F>M rhythm) Sparfloxacin Antibiotic (bacterial infection) Thioridazine Anti-psychotic (schizophrenia) 3087 3088 Table 2. Drugs That in Some Reports May be Associated With Torsades de Pointes 3089 But at This Time Lack Substantial Evidence of Causing Torsades de Pointes 3090 3091 These drugs (Table 2) will be allowed during the study, at the discretion of the 3092 Investigator, if considered absolutely necessary. In such cases, the patient must be 3093 closely monitored, including regular checks of QTc and electrolytes. 3094 Drug (Generic Names) Drug Class (Clinical Comments Usage) Alfuzocin Alpha 1-blocker (Benign prostatic hyperplasia) Amantadine Dopaminergic/Anti- viral/Anti-infective (Parkinson’s disease) Amitriptyline Tricyclic anti-depressant (depression) Amoxapine Tricyclic anti-depressant (depression) Azithromycin Antibiotic (bacterial infection) Citalopram Anti-depressant (depression) Clarithromycin Antibiotic (bacterial TdP Cases in Literature infection) Clomipramine Tricyclic antidepressant (depression) Chloral hydrate Sedative (sedation/insomnia) Clozapine Anti-psychotic (schizophrenia) Desipramine Tricyclic anti-depressant TdP Cases in Literature (depression) Dolastron Anti-nausea (nausea and vomiting) Doxepin Anti-depressant TdP Cases in Literature (depression) Felbamate Anti-convulsant (seizures) Flecainide Anti-arrhythmic (heart Association not clear rhythm) Fluconazole Anti-fungal (fungal infection) Fluoxetine Anti-depressant Association not clear (depression) Foscarnet Antiviral (HIV infection)
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3095 Fosphenytoin Anticonvulsant (seizures) Galantamine Cholinesterase inhibitor ((Alzheimer's Disease) Gatifloxacin Antibiotic (bacterial infection) Gemifloxacin Antibiotic (bacterial infection) Granisetron Anti-nausea (nausea and vomiting) Imipramine Anti-depressant TdP Cases in Literature (depression, pain, other) Indapamide Diuretic (stimulates urine TdP Cases in Literature, & salt loss) QT in animals Isradipine Anti-hypertensive (high blood pressure) Itraconazole Anti-fungal (fungal infection) Lapatinib Anti-cancer (breast cancer) Levofloxacin Antibiotic (bacterial Association not clear infection) Lithium Anti-mania (bipolar disorder) Mexilitine Anti-arrhythmic (abnormal heart rhythm) Moexipril/HCTZ Anti-hypertensive (high blood pressure) Moxifloxacin Antibiotic (bacterial infection) Nicardipine Anti-hypertensive (high blood pressure) Nilotinib Anti-cancer (leukemia) Nortriptyline Tricyclic antidepressant (depression) Octreotide Endocrine (acromegaly/carcinoid diarrhoea) Ofloxacin Antibiotic (bacterial infection) Ondansetron Anti-emetic (nausea and vomiting) Oxytocin Oxytocic (labor stimulation) Paliperidone Anti-psychotic (schizophrenia) Paroxetine Anti-depressant (depression) Protriptyline Tricyclic antidepressant (depression) Quetiapine Anti-psychotic (schizophrenia)
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3096 Risperidone Anti-psychotic (schizophrenia) Roxithromycin Antibiotic (bacterial infection) Salmeterol Sympathomimetic (asthma, COPD) Sertraline Antidepressant Association not clear (depression) Solifenacin Muscarinic receptor antagonist (treatment of overactive bladder) Sulfamethoxazole/trimethoprim Antibiotic (bacterial infection) Sunitinib Anti-cancer (renal cell carcinoma, gastrointestinal stromal tumors) Tacrolimus Immune suppressant TdP Cases in Literature Tamoxifen Anti-cancer (breast cancer) Telithromycin Antibiotic (bacterial infection) Tizanidine Muscle relaxant Trimipramine Tricyclic antidepressant (depression) Vardenafil Phosphodiesterase inhibitor (vasodilator) Venlafaxine Antidepressant (depression) Voriconazole Anti-fungal (fungal infection) Ziprasidone Anti-psychotic (schizophrenia) 3097 3098
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3099 18.4 CYP3A4/5 and CYP1A2 Prohibited Medications 3100 3101 Up to date, more comprehensive list of abstracts/inducers/inhibitors cna be found at 3102 http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the Physicians' 3103 Desk Reference may also provide this information. 3104 CYP3A4/5 and CYP1A2 Prohibited Medications Inhibitors Inducers Atazanavir Carbamazepine Boceprevir Dexamethasone Chloramphenical Enzalutamide Clarithromycin Fosphenytoin Cobicistat containing Mitotane coformulations Nafcillin Conivaptan Nevirapine Darunavir Oxcarbazepine Delavirdine Pentobarbital Fosamprenavir Phenobarbital Indinavir Phenytoin Itrconazole Primidone Ketoconazole Rifabutin Lopinavir Rifampin (rifampicin) Nefazodone Rifapentine Nelfinavir St John’s Wort Nicardipine Posaconazole Ritonavir and ritonavir containing coformulations Saquinavir Telaprevir Telithromycin Voriconazole 3105
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3106 18.5 New York Heart Association Classifications 3107 3108 3109 Need for Physical Ability 3110 Class Cardiac Symptoms Limitations Additional Rest* To Work** 3111 3112 I None None None Full Time 3113 3114 II Only moderate Slight Usually only slight Usually full time 3115 or occasional 3116 3117 III Defined, with less Marked Usually moderate Usually part time 3118 than ordinary 3119 activity 3120 3121 IV May be present Extreme Marked Unable to work 3122 even at rest, & any 3123 activity increases 3124 discomfort 3125 3126 * To control or relieve symptoms, as determined by the patient, rather than as advised by the 3127 physician. 3128 3129 ** At accustomed occupation or usual tasks. 3130
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