A Multicenter, Phase I, Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Etirinotecan Pegol in Patients with Refractory Solid Tumors

Published OnlineFirst November 7, 2012; DOI: 10.1158/1078-0432.CCR-12-1201

Clinical Cancer Cancer Therapy: Clinical Research

Gayle S. Jameson1, John T. Hamm3, Glen J. Weiss1, Carlos Alemany4, Stephen Anthony1, Michele Basche5, Ramesh K. Ramanathan1, Mitesh J. Borad2, Raoul Tibes2, Allen Cohn5, Ioana Hinshaw5, Robert Jotte5, Lee S. Rosen6, Ute Hoch7, Michael A. Eldon7, Robert Medve7, Katrina Schroeder1, Erica White1, and Daniel D. Von Hoff1

Abstract Purpose: This study was designed to establish the maximum tolerated dose (MTD) and to evaluate tolerability, pharmacokinetics, and antitumor activity of etirinotecan pegol. Experimental Design: Patients with refractory solid malignancies were enrolled and assigned to escalating-dose cohorts. Patients received 1 infusion of etirinotecan pegol weekly 3 times every 4 weeks (w 3q4w), or every 14 days (q14d), or every 21 days (q21d), with MTD as the primary end point using a standard 3 þ 3 design. Results: Seventy-six patients were entered onto 3 dosing schedules (58–245 mg/m2). The MTD was 115 mg/m2 for the w 3q4w schedule and 145 mg/m2 for both the q14d and q21d schedules. Most adverse events related to study drug were gastrointestinal disorders and were more frequent at higher doses of etirinotecan pegol. Late onset diarrhea was observed in some patients, the frequency of which generally correlated with dose density. Cholinergic diarrhea commonly seen with irinotecan treatment did not occur in patients treated with etirinotecan pegol. Etirinotecan pegol administration resulted in sustained and controlled systemic exposure to SN-38, which had a mean half-life of approximately 50 days. Overall, the pharmacokinetics of etirinotecan pegol are predictable and do not require complex dosing adjustments. Confirmed partial responses were observed in 8 patients with breast, colon, lung (small and squamous cell), bladder, cervical, and neuroendocrine cancer. Conclusion: Etirinotecan pegol showed substantial antitumor activity in patients with various solid tumors and a somewhat different safety profile compared with the irinotecan historical profile. The MTD recommended for phase II clinical trials is 145 mg/m2 q14d or q21d. Clin Cancer Res; 19(1); 268–78. 2012 AACR.

Introduction tumor. Irinotecan, an antineoplastic agent of the topo- Etirinotecan pegol is a unique, long acting topoisom- isomerase I inhibitor class, is widely used to treat patients erase I inhibitor that provides prolonged systemic expo- with colorectal cancer and other solid tumors (1–10). SN- sure to SN-38 the active metabolite of irinotecan, which is 38 binds to and stabilizes the topoisomerase I-DNA primarily responsible for its efficacy (1), at the site of the complex, leading to single- and double-stranded DNA breaks and inhibiting DNA repair. Irinotecan and SN-38 have terminal elimination half-lives (t1/2)of9to12hours Authors' Affiliations: 1Virginia G. Piper Cancer Center at Scottsdale and 12 to 47 hours, respectively (1, 11). Irinotecan 2 Healthcare (VGPCC)/TGen, Scottsdale; Mayo Clinic, Phoenix, Arizona; treatment can be associated with severe diarrhea and 3Norton Healthcare, Louisville, Kentucky; 4US Oncology Research - Florida Institute of Research, Cancer Center, Ocoee, Florida; 5US Oncology severe neutropenia, limiting the frequency with which it Research - Rocky Mountain Cancer Centers, Denver, Colorado; 6Premiere can be administered to patients. Therefore, irinotecan is Oncology, Santa Monica; and 7Nektar Therapeutics, San Francisco, California typically administered every 14 to 21 days, which results in a better safety profile than the weekly administration of Prior presentations: This study was presented at 2008 EORTC-NCI-AACR Symposium, Poster 595. The study abstract was presented at the 2008 irinotecan. ASCO Annual Meeting (abstract 13518). Etirinotecan pegol is designed to reduce maximal SN-38 Corresponding Author: Gayle S. Jameson, MSN, ACNP-BC, AOCN, systemic concentrations while providing continuous expo- 10510 North 92nd Street, Suite 200, Scottsdale, AZ 85258. Phone: 480- sure to tumors, even when administered in 14- or 21-day 323-1350; Fax: 480-323-1359; E-mail: [email protected]. cycles. The pharmacokinetic (PK) profile of etirinotecan doi: 10.1158/1078-0432.CCR-12-1201 pegol leads to both improved efficacy and safety compared 2012 American Association for Cancer Research. with irinotecan in preclinical models of cancer.

268 Clin Cancer Res; 19(1) January 1, 2013

Etirinotecan Pegol Phase I in Patients with Solid Tumors

2 mg/dL or less, aspartate transaminase, and alanine trans- Translational Relevance aminase 3 times or less upper limit of normal (ULN; 5 Etirinotecan pegol is a unique, long acting topoisom- ULN if liver metastasis is confirmed), creatinine 1.5 erase I inhibitor that provides prolonged systemic expo- ULN or creatinine clearance 60 mL/min or more. sure to SN-38. In this study, 76 patients with refractory Patients were excluded from the trial if they had received tumors were treated on various dose levels and sche- chemotherapy, including any investigational agents or dules. Dose limiting toxicities included late, noncholi- radiotherapy within 4 weeks (6 weeks for nitrosoureas or nergic diarrhea and neutropenia, both manageable with mitomycin C) before the commencement of dosing. In dose modifications. In this phase I trial, 25 (32.9%) addition, they must have recovered to at least a grade 1 patients showed some type of antitumor effect; 8 (11%) toxicity, as defined by the National Cancer Institute Com- had a confirmed partial response to treatment including mon Terminology Criteria for Adverse Events, version 3.0, 1 patient with colon cancer who had experienced disease (CTCv3.0); alopecia of any grade was allowed. Additional progression on a prior irinotecan based regimen. Two exclusion criteria included major surgery within 4 weeks; (2.6%) additional patients had an unconfirmed partial pregnant or nursing; unstable symptoms from brain metas- response. The benefit of the prolonged SN-38 t1/2 of 50 tases; serologically positive for hepatitis B or C, or history of days following etirinotecan pegol administration human immunodeficiency virus; cerebrovascular accident appears to be translational to the clinic. The agent is or transient ischemia; and history of hypersensitivity to being actively studied in ongoing phase II and III trials. irinotecan, other camptothecin derivatives, or pegylated drugs. The presence of the UGT1A128 allele was assessed for heterozygosity or homozygosity, but it was not exclu- sionary. The study received approval by the Western Insti- In mouse models of human tumors, etirinotecan pegol tutional Review Board and each institutional ethics board. resulted in marked dose-related and sustained tumor The study was conducted in accordance with the provisions growth inhibition in colorectal, lung, breast, and ovarian of the Declaration of Helsinki (13). cancers (2, 12). Tumor growth inhibition in all of these cancers was significantly greater than that observed at Study drug equivalent doses of irinotecan (2). Pharmacokinetic studies Etirinotecan pegol was manufactured by Nektar Thera- in mice, rats, and dogs showed lower maximum concen- peutics, and supplied in amber glass vials containing lyoph- tration (Cmax) and clearance values for SN-38 and corre- ilized etirinotecan pegol powder equivalent to 100 mg spondingly greater systemic exposure to SN-38, following irinotecan. Each patient’s dose was reconstituted with 5% etirinotecan pegol dosing, compared with irinotecan. These Dextrose Injection, USP (D5W), total volume 500 mL, to animal studies suggest that etirinotecan pegol may be more final concentrations of 0.12 to 2.8 mg irinotecan equiva- efficacious than irinotecan because of greater topoisomer- lents/mL, and administered via intravenous (i.v.) infusion ase I inhibition resulting from prolonged tumor cell expo- over 90 minutes. The reconstituted drug required protection sure to SN-38 (12). from direct ambient lighting at room temperature (15C– The primary objectives of this first-in-human phase 1 30C) for up to 2 hours before the start of infusion and drug clinical trial were to characterize the safety profile and could also be stored protected from direct lighting at 2Cto establish a maximum tolerated dose (MTD) of etirinotecan 8C for up to 8 hours before the start of infusion. A central pegol following 3 separate dosing regimens in patients with venous catheter was not required for drug administration. refractory solid tumors. Secondary objectives included the The protocol recommended that patients receive preme- determination of the plasma PKs and metabolites, as well as dication with antiemetic agents including dexamethasone an evaluation of clinical antitumor activity of etirinotecan given in conjunction with a 5-HT3 at least 30 minutes pegol. before administration of etirinotecan pegol, and written instructions for aggressive antidiarrheal treatment. Materials and Methods Patient selection Study design Eligible patients had histologically confirmed, evaluable, This was a multicenter, first-in-human, open-label, phase or measurable malignant solid tumors, metastatic or unre- 1, dose-escalation study of etirinotecan pegol in patients sectable, for which standard curative or palliative treatments with advanced refractory tumors. All patients received the do not exist. All were required to be 18 years or more of age, study drug by i.v. infusion over 90 minutes. Three etirino- have an Eastern Cooperative Oncology Group performance tecan pegol treatment schedules were evaluated: (i) in status of 0 or 1, with an estimated life expectancy of 12 treatment group 1, 3 doses of etirinotecan pegol 58 mg/ weeks or more. Other eligibility criteria included adequate m2 were administered on days 1, 8, and 15 of a 28-day organ/bone marrow function, absolute neutrophil count [weekly 3 times every 4 weeks (w 3q4w)] period [dose 1,500/mm3 or more without colony-stimulating support escalations in increments of 58 mg/m2 were allowed if there for 3 weeks, white blood cell count 3,000/mm3 or more, were no dose-limiting toxicities (DLT)]; (ii) in treatment platelet count 100,000/mm3 or more, hemoglobin 9 g/dL group 2, 1 dose of etirinotecan pegol 145 mg/m2 admin- or more without transfusion support, total bilirubin istered on day 1 of a 21-day (q21d) period (dose escalations

www.aacrjournals.org Clin Cancer Res; 19(1) January 1, 2013 269

Jameson et al.

in increments of 25 mg/m2 were allowed if there were no acid, 7-ethyl-10-(4-N-(5-aminopentanoic acid)-1-piperi- DLTs); and (iii) in treatment group 3, 1 dose of etirinotecan dine)carbonyloxycamptothecin (APC), and primary amine pegol 145 mg/m2 administered on day 1 of a 14-day (q14d) metabolite of irinotecan, 7-ethyl-10-(4-amino-1-piperidino) period (dose escalations in increments of 25 mg/m2 were carbonyloxycamptothecin (NPC), were assayed using vali- allowed if there were no DLTs). dated liquid chromatography–mass spectrometry methods. Etirinotecan pegol doses were escalated according to the Beginning preinfusion, plasma samples were collected at standard 3 þ 3 rule. Intrapatient dose escalations were not scheduled times during cycles 1 and 3, and were continued allowed. Adverse events were defined and graded according daily for the first week and then weekly before each subse- to CTCv3.0. A DLT was defined as the following adverse quent dose and upto 4 weeks after final dosing. Each patient’s events related to etirinotecan pegol during cycle 1: grade 4 observed concentration-time data for etirinotecan pegol and neutropenia lasting more than 3 days in the absence of its metabolites were fit with PK equations using nonlinear growth factor support; grade 4 neutropenia associated with mixed effects modeling (Monolix 2.3, INRIA Saclay) to fever more than 38.5C; any other grade 4 hematologic predict a concentration-time profile for the duration of toxicity; grade 3 thrombocytopenia with hemorrhage; grade dosing. The resulting model-predicted concentration-time 3 or grade 4 nausea, vomiting, or diarrhea despite prophy- profiles were subsequently analyzed with noncompartmen- laxis or treatment with an optimal antiemetic or antidiar- tal methods to estimate customary PK parameters, such as rheal regimen; any other grade 3 or higher nonhematologic Cmax, time to maximum plasma concentration (Tmax), area toxicity that occurred during the study, unless it was clearly under the plasma concentration curve (AUC), total plasma unrelated to etirinotecan pegol (e.g., because of disease clearance (CL), volume of distribution (V), and t1/2. To progression); or a toxicity within the first 21 days of cycle allow comparisons between etirinotecan pegol and irinote- 1 in the treatment group 1 (w 3q4w) and treatment group can, plasma irinotecan and SN-38 concentration-time pro- 2 (q21d) dosing schedules or within the first 14 days of cycle files after irinotecan administration were simulated using a 1 in the treatment group 3 (q14d) dosing schedule that population PK model for irinotecan (16). made the administration of the study drug impossible. The highest dose of etirinotecan pegol in which less than 33% of Statistical methods patients experienced a DLT was considered the MTD (14). The safety population included all enrolled patients who Once the MTD was determined, additional patients were received at least 1 dose (or partial dose) of etirinotecan accrued at that dose to further characterize its safety and pegol. Safety, PK, and tumor evaluation data were summa- tolerability in the dosing schedule. rized using descriptive statistics. The initial w 3q4w schedule was chosen based on prior clinical experience with irinotecan. Subsequent expansions Results of the schedule to q14d and q21d were driven by clinical observations at each dose/schedule combination, and by Patients initial PK data suggesting that disposition and elimination The demographics of patients in this study were similar in humans were notably slower than observed in animals. across the 3 treatment schedules (Table 1). A total of 76 patients with a wide variety of solid tumors were enrolled in Assessments this trial. The most commonly represented anatomical n ¼ Patient eligibility screening was conducted within 14 days locations for the primary tumor were lung ( 18), colo- n ¼ n ¼ n ¼ n ¼ of enrollment. Safety assessments included physical exam- rectal ( 17), pancreas ( 5), ovary ( 5), cervix ( n ¼ n ¼ ination, DLTs, and the clinical laboratory parameters 5), esophagus ( 5), and breast ( 4). (hematology, serum chemistry, and urinalysis) for adverse Treatment group 1 (w 3q4w) enrolled 32 patients, events, vital sign measurements, and a 12-lead electrocar- treatment group 2 (q21d) enrolled 25 patients, and treat- diogram. Patients also underwent radiologic examinations ment group 3 (q14d) enrolled 19 patients. A total of 73 [computed tomography (CT) or magnetic resonance ima- patients (96.1%) had tumors measurable to assess for ging] at screening, at the completion of each alternate response by RECIST 1.0. All patients who received at least treatment cycle, and at the end of study treatment. After 1 dose (or partial dose) of etirinotecan pegol were included completion of every other treatment cycle, tumor assess- in the response and safety analysis. ment was conducted by CT scan and interpreted according Aside from the time since prior systemic chemotherapy, to Response Evaluation Criteria in Solid Tumors (RECIST) other trends in the patients’ medical histories were similar 1.0 (15). All partial or complete tumor responses to treat- across the 3 treatment arms. ment required confirmation by repeat assessment of tumor measurements no less than 4 weeks apart. Patients with a Dose escalation partial or complete tumor response or with stable disease In treatment group 1 (w 3q4w), dose escalation con- were continued on regimen if adverse events were tolerable. tinued until the maximum administered dose of 230 mg/m2 was reached. Patients in the first 3 ascending dosing cohorts Pharmacokinetic methods (58, 115, and 173 mg/m2, respectively) did not experience Etirinotecan pegol and its metabolites irinotecan, SN-38, DLTs. The DLTs were first observed in this schedule at a dose SN-38-glucuronide (SN-38-G), aminopentane carboxylic of 230 mg/m2, when 3 patients had grade 3 diarrhea. Per the

270 Clin Cancer Res; 19(1) January 1, 2013 Clinical Cancer Research

Etirinotecan Pegol Phase I in Patients with Solid Tumors

Table 1. Patient demographics and clinical characteristics by etirinotecan pegol dosing schedule (N ¼ 76).

Treatment group 1 Treatment group 2 Treatment group 3 Total no. (w 3q4w) (q21d) (q14d) of patients Characteristics n ¼ 32 n ¼ 25 n ¼ 19 N ¼ 76 Sex, n,% Male 15 (46.9) 13 (52.0) 12 (63.2) 40 (52.6) Female 17 (53.1) 12 (48.0) 7 (36.8) 36 (47.4) Age, y Mean (SD) 58.1 (14.50) 59.3 (11.71) 58.8 (13.59) 58.7 (13.25) Median 60 59 56 58.5 Range 26–81 31–78 32–78 26–81 ECOG performance status, n,% 0 15 (46.9) 6 (24.0) 7 (36.8) 28 (36.8) 1 17 (53.1) 19 (76.0) 12 (63.2) 48 (63.2) Race or ethnic background, n,% White 29 (90.6) 24 (96.0) 18 (94.7) 71 (93.4) Black 1 (3.1) 1 (4.0) 0 2 (2.6) Hispanic or Latino 2 (6.3) 0 0 2 (2.6) Asian 0 0 1 (5.3) 1 (1.3) Tumor sites, n Lung 9 6 3 18 Small cell 2 1 0 3 Non–small cell 7 5 3 15 Colorectal 6 5 6 17 Cervix 3 1 1 5 Esophagus 4 1 0 5 Ovary 2 2 1 5 Pancreas 2 1 2 5 Breast 0 2 2 4 Head and Neck 1 0 2 3 Prostate 0 2 0 2 Bladder 0 0 1 1 Other 5 5 1 11 UGT1A128 status, n,% Homozygousa 2 (6.3) 5 (20.0) 3 (15.8) 10 (13.2) Not homozygousb 30 (93.8) 17 (68.0) 16 (84.2) 63 (82.9) Unknown 0 3 (12.0) 0 3 (3.9)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; G, grade. aPatients with 2 copies of the UGT1A128 allele. bPatients with 0 or 1 copies of the UGT1A128 allele. protocol, dose reduction evaluations with an expanded patients experienced grade 3 diarrhea after the protocol number of patients being treated continued until a dose deﬁned DLT window limited to the ﬁrst cycle, the investi- free from DLTs was observed. Overall, the dose of 115 mg/ gators and sponsor agreed to reduce the MTD to the next m2 was found to be well tolerated with less than 33% of lower dose level of 145 mg/m2 in both the 14- and 21-day patients experiencing a DLT and was subsequently declared schedules. Additional patients were not added as 0 of the 3 the MTD for treatment group 1. treated at the 145 mg/m2 dose level in treatment groups 2 In treatment group 2 (q21d), the dose was escalated to and 3 experienced a DLT. 245 mg/m2, and in treatment group 3 (q14d), the dose was escalated to 220 mg/m2. In both of these groups, a similar Safety dose deescalation with expanded dose cohorts occurred All patients experienced 1 or more treatment-emergent until the dose level of 170 mg/m2 was reached. Only 2 of adverse events during the study. The most clinically signif- 12 patients experienced a DLT at the 170 mg/m2 dose in icant adverse events related to study drug across all cycles both schedules combined. However, because of the long of treatment were gastrointestinal disorders, including diar- terminal half-life of SN-38 and the observation that 4 of 12 rhea, nausea, and vomiting (Table 2). In treatment group 1,

www.aacrjournals.org Clin Cancer Res; 19(1) January 1, 2013 271

Jameson et al.

Table 2. Most common adverse events related to etirinotecan pegol across all cycles of study treatment (occurring in >10% of patients in each treatment schedule)

58 mg/m2 115 mg/m2 145 mg/m2 173 mg/m2 230 mg/m2 Total n ¼ 3 n ¼ 6 n ¼ 6 n ¼ 14 n ¼ 3 N ¼ 32 Treatment group 1 (w 3q4w) Adverse event, n All G3a All G3a All G3a All G3a All Gr3a All G3a Diarrhea 2 0 5 1 6 4 14 7 3 3 30 15 Nausea 3 0 4 0 3 1 13 1 3 0 26 2 Fatigue 3 0 2 2 3 0 6 0 1 0 15 2 Vomiting 1 0 2 0 2 1 8 1 2 0 15 2 Anorexia 0 0 1 0 4 2 7 2 1 0 13 4 Decreased hemoglobin 20 00 31 30 10 91 Alopecia 10 20 10 30 10 80 Decreased neutrophil count 0 0 1 1 3 0 3 2 1 0 8 3 Blurred vision 00 30 10 20 10 70 Dehydration 00 20 21 21 10 72 Abdominal pain 00 00 10 40 00 50 Hypokalemia 00 00 20 31 00 51 Hypomagnesemia 00 00 10 40 00 50 Decreased weight 00 10 10 20 00 40 Flatulence 00 00 20 20 00 40 Treatment group 2 (q21d)

145 mg/m2 170 mg/m2 195 mg/m2 220 mg/m2 245 mg/m2 Total n ¼ 3 n ¼ 6 n ¼ 5 n ¼ 5 n ¼ 6 N ¼ 25

Adverse event, n All G3a All G3a All G3a All G3a All G3a All G3a

Diarrhea 1 0 6 2 3 2 5 2 6 5 21 11 Nausea 1 0 5 0 4 0 4 0 4 2 18 2 Vomiting 0 0 4 1 2 0 4 0 2 1 12 2 Fatigue 00 11 20 31 32 94 Dehydration 00 21 11 30 33 95 Hypokalemia 00 20 21 21 31 93 Anemia 00 10 11 10 21 52 Anorexia 00 10 00 10 32 52 Hypomagnesemia 00 10 10 10 20 50 Abdominal pain 00 00 10 00 30 40 Alopecia 00 00 00 10 30 40 Hyponatremia 00 20 00 00 22 42 Neutropenia 00 00 11 11 21 43 Decreased weight 00 10 20 00 00 30 Hypophosphatemia 00 10 11 00 10 31 Increased blood creatinine 0 0 2 0 1 0 0 0 0 0 3 0 Leukopenia 00 10 10 10 00 30 Peripheral edema 00 10 10 10 00 30 Treatment group 3 (q14d)

145 mg/m2 170 mg/m2 195 mg/m2 220 mg/m2 Total n ¼ 3 n ¼ 6 n ¼ 5 n ¼ 5 N ¼ 19

Adverse event All G3a All G3a All G3a All G3a All G3a

Fatigue 2 0 4 1 4 0 5 2 15 3 Nausea 3 0 3 0 4 0 5 1 15 1 Diarrhea 2 2b 42 41 43 148 Vomiting 3 0 2 0 2 0 3 1 10 1 (Continued on the following page)

272 Clin Cancer Res; 19(1) January 1, 2013 Clinical Cancer Research

Etirinotecan Pegol Phase I in Patients with Solid Tumors

Table 2. Most common adverse events related to etirinotecan pegol across all cycles of study treatment (occurring in >10% of patients in each treatment schedule) (Cont'd ) Treatment group 3 (q14d)

145 mg/m2 170 mg/m2 195 mg/m2 220 mg/m2 Total n ¼ 3 n ¼ 6 n ¼ 5 n ¼ 5 N ¼ 19

Adverse event All G3a All G3a All G3a All G3a All G3a

Anorexia 1 0 1 0 2 0 3 0 7 0 Alopecia 1 0 2 0 1 0 2 0 6 0 Abdominal pain 0 0 3 0 1 1 1 0 5 1 Anemia 0 0 1 0 1 1 3 0 5 1 Hypomagnesemia 0 0 1 0 1 0 3 0 5 0 Dehydration 0 0 1 1 1 0 2 1 4 2 Hypokalemia 0 0 1 0 0 0 3 1 4 1 Dizziness 0 0 1 0 0 0 2 0 3 0 Blurred vision 0 0 1 0 0 0 2 0 3 0 Abdominal distension 0 0 0 0 0 0 2 0 2 0 Abnormal urine odor 1 0 1 0 0 0 0 0 2 0 Decreased appetite 0 0 0 0 0 0 2 0 2 0 Increased blood alkaline phosphatase 0 0 1 0 1 0 0 0 2 0 Increased gamma-glutamyl transferase 0 0 1 0 1 0 0 0 2 0 Hypophosphatemia 0 0 1 0 0 0 1 1 2 1 Lymphopenia 0 0 1 1 1 1 0 0 2 2 Stomatitis 0 0 1 0 1 0 0 0 2 0

aAdverse events were evaluated using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. bOne patient's diarrhea began on cycle 2 day 12 and the other on cycle 3 day 11.

at doses 115 mg/m2 or more, 7 of 9 (78%) patients’ reported gous, did not correlate with the occurrence of neutropenia diarrhea (1 with grade 3) and nausea with only 3 of 9 (33%) or diarrhea. No other adverse event was correlated with the reporting vomiting. However, as the dose escalated to 145 presence of this allele. No patients in the cohorts establish- mg/m2 or more, all patients treated reported diarrhea from ing MTD were homozygous for UGT1A128. Other grade 1 to 3 along with a higher incidence of nausea and observed treatment-emergent adverse events were not unex- vomiting. In treatment group 2, 7 patients (78%) experi- pected and were of a random nature throughout the patient enced diarrhea and 6 patients (67%) experienced nausea at population. No changes in the electrocardiogram, includ- doses of 170 mg/m2 or less, with 2 patients (22%) having ing prolongation of the corrected QT intervals, were grade 3 diarrhea. In treatment group 3, 6 patients (67%) observed. Over the course of the study, 11 deaths were experienced fatigue, diarrhea, and nausea at doses of 170 reported. Two of the deaths were considered to be related mg/m2 or less, with 1 patient (11%) having grade 3 fatigue to the study drug; the remaining 9 were not, with 8 attributed and 4 patients (44%) having grade 3 diarrhea. Prevention to disease progression, and 1 attributed to cardiopulmonary and management of diarrhea included prompt initiation of arrest (probable result of malignancy related pulmonary loperamide 4 mg orally, at the first change in bowel habits, embolus or aspiration). The 2 deaths related to the study then 2 mg every 2 hours during the day and 4 mg every 4 drug were attributed to neutropenic sepsis (n ¼ 1; 245 mg/m2 hours at night until the patient was free of diarrhea for at q21d) and diarrhea (n ¼ 1; 220 mg/m2 q14d). Nine patients least 12 hours (17). Other interventions included Lomotil, experienced unexpected adverse events, including involun- activated charcoal (18), octreotide (19), tincture of opium, tary muscle contractions and twitching, but all of these were and neomycin (20, 21). Management of persistent diarrhea painless and resolved within 24 hours. The underlying in some patients treated at doses above the MTD included mechanism for these adverse events is unclear, and these hospitalization, bowel rest, aggressive IV hydration, total patients had no significant electrolyte abnormalities. Drug- parenteral nutrition support, and continuous infusion of related blurred vision, grade 1, that was transient and that high doses of octreotide (22). The occurrence of neutrope- resolved spontaneously occurred in 10 patients (13%). nia was reported in treatment group 1 (22% of the patients treated with a dose 145 mg/m2) and in group 2 (16% of Pharmacokinetic data the patients treated with a dose 195 mg/m2), but it was not Plasma PK data were obtained for every (n ¼ 76) patient reported in group 3. Unlike with irinotecan, the presence of in the trial. Observed and model-predicted concentration- a UGT1A1 variant allele, either homozygous or heterozy- time profiles for representative patients receiving etirinote-

www.aacrjournals.org Clin Cancer Res; 19(1) January 1, 2013 273

Jameson et al.

Pt 2004, 115 mg/m2 w×3q4w Pt 1020, 145 mg/m2 q21d Pt 1022, 145 mg/m2 q14d 1,000,000 1,000,000 1,000,000

100,000 100,000 100,000

10,000 10,000 10,000

1,000 1,000 1,000

100 100 100

10 10 10

Plasma analyte concentration (ng/mL) Plasma analyte concentration 1 1 1

0.1 0.1 0.1 0.0 0.5 1.0 5 10 15 20 25 0.0 0.5 1.0 5 10 15 20 25 0.0 0.5 1.0 5 10 15 20 25 Time (wk) Time (wk) Time (wk)

Figure 1. Observed and model-predicted concentration-time proﬁles for a representative patient receiving etirinotecan pegol w 3q4w, q21d, or q14d at the MTD for each schedule. Symbols represent observed concentrations, solid lines represent the model-predicted concentrations for etirinotecan pegol (red squares), irinotecan (green up triangles), SN-38-G (black open down triangles), APC (pink circles), and SN-38 (blue ﬁlled down triangles).

can pegol at a dosing schedule of w 3q4w, q21d, or q14d imately 35-fold lower compared with irinotecan admin- are shown in Fig. 1. In all patients, etirinotecan pegol was istration, whereas total irinotecan AUC is reduced 4-fold slowly metabolized to irinotecan and its known metabolites (Fig. 2B). SN-38, SN-38-G, APC, and NPC, with the magnitude of Mean PK parameter values are presented in Table 3. concentration in the following order: etirinotecan pegol >>> Because patients received different doses using different irinotecan SN-38-G > APC > SN-38. Plasma NPC con- schedules and for different durations, and because all ana- centrations were near the limit of quantitation and patient lytes exhibited dose-linear PK, mean Cmax and AUC values variable, precluding meaningful PK analysis of this metab- are presented after normalization for dose. olite. Steep declines in concentrations during the initial Etirinotecan pegol and metabolites followed biphasic disposition phase were observed for etirinotecan pegol and disposition kinetics with terminal disposition half-lives of irinotecan, whereas SN-38, SN-38-G, and APC showed more 21, 27, 50, 61, and 53 days for etirinotecan pegol, irinote- shallow declines from maximal concentrations (see Fig. 1). can, SN-38, SN-38-G, and APC, respectively. Importantly, trough concentrations of irinotecan, SN-38, As expected, etirinotecan pegol Cmax values were SN-38-G, and APC were detectable after etirinotecan pegol observed shortly after the end of infusion. Etirinotecan dosing with all 3 schedules, providing evidence of sustained pegol CL, V, and t1/2 values were independent of dose and exposure between dosing intervals even when administered schedule, which is consistent with the observed dose lin- q21d. The exposure pattern for etirinotecan pegol is differ- earity of Cmax and AUC. ent from those for irinotecan and SN-38 after irinotecan Among etirinotecan pegol metabolites, Cmax values administration where concentrations fall below quantita- decreased in the following order: irinotecan SN-38-G > tion limits before the next dose is administered. APC > SN-38. Tmax increased in relation to the proposed In general, the plasma concentrations of all analytes metabolic progression (irinotecan < SN-38 < SN-38-G < increased in proportion to the etirinotecan pegol dose, inde- APC), providing further evidence that etirinotecan pegol pendent of the dosing schedule, with Cmax after the first dose results in prolonged exposure. As observed with etirinote- increasing linearly with the size of the first dose and cumu- can pegol, irinotecan, SN-38, SN-38-G, and APC, CL/F, V/F lative AUC increasing linearly with the total dose adminis- and t1/2 values were independent of dose and schedule. tered for etirinotecan pegol, irinotecan, and SN-38 (Fig. 2A). The reported interpatient variability for SN-38 after irino- Similar plots were obtained for the remaining metabolites. tecan administration ranges between 40% and 58% (16, 23), Comparisons of model-predicted concentration-time which is similar to the interpatient variability observed for profiles for irinotecan and SN-38 after the administration SN-38 after administration of etirinotecan pegol. of 350 mg/m2 irinotecan q21d (approved dose and schedule) or 145 mg/m2 etirinotecan pegol q21d at the Evidence of response recommended phase 2 dose (RP2D), show that irinotecan Seventy-three of the 76 patients (96.1%) with a variety of Cmax after administration of etirinotecan pegol is approx- solid tumors had measurable disease at baseline and were,

274 Clin Cancer Res; 19(1) January 1, 2013 Clinical Cancer Research

Etirinotecan Pegol Phase I in Patients with Solid Tumors

AB Cumulative AUC (ng/mL ‘h) 100,000 Plasma irinotecan 2.5 ×107 × 7 10,000 2.0 10 1.5 ×107 1,000 1.0 ×107 × 6 NKTR-102 5.0 10 100 0.0 10 150,000 1 125,000 100,000 75,000 Plasma SN38 50,000

Irinotecan 25,000 10 0

20,000

Predicted plasma concentration (ng/mL) Predicted plasma concentration 1 15,000 10,000

SN-38 5,000 0.1 0 036912 Time (wk) 0 500 1,000 1,500 2,000 2,500 3,000 Total dose administered (mg/m2)

w×3q4w q21d q14d

2 Figure 2. A, etirinotecan pegol, irinotecan, and SN-38 Cmax and cumulative AUC values as a function of cumulative dose for patients receiving 58 to 245 mg/m of etirinotecan pegol across all schedules. B, predicted plasma irinotecan and SN-38 concentration-time profiles after administration of 145 mg/m2 of etirinotecan pegol (solid line) or 350 mg/m2 irinotecan (dashed line) q21. Simulation of concentration-time data after irinotecan administration is based on Xie and colleagues (16). Model-predicted concentration-time data after etirinotecan pegol administration were derived using the population pharmacokinetic model developed for this study. AUC, area under the concentration vs. time curve from t ¼ 0 through end of dosing; Cmax, maximum observed plasma concentration after administration of the first dose; w 3q4w, weekly 3 every 4 weeks; q21d, every 21 days; q14d, every 14 days. therefore, assessable for response by RECIST 1.0. Twenty-five RECIST 1.0, including 2 patients in treatment group 1 (32.9%) patients showed some type of antitumor response; 8 (6.5%; 2/31), 1 patient in treatment group 2 (4.3%; 1/23), (11%) had a partial response to treatment confirmed by and 5 patients in treatment group 3 (26.3%; 5/19). Two

Table 3. Mean (%CV) plasma pharmacokinetic parameters for etirinotecan pegol, irinotecan, SN-38, and SN-38- glucuronide in 76 patients with advanced tumors, after a 90-minute i.v. infusion of etirinotecan pegol doses between 58 to 245 mg/m2, using schedules of w 3q4w, q21d, and q14d

Cmax/dose, AUC/dose, CL or CL/F, 2 2 2 2 1 Analyte ng/mL/mg/m Tmax,h h ng/mL/mg/m L/h/m V or V/F, L/m T /2,d Etirinotecan Pegol 440 (23) 1.8 (31) 8230 (28) 0.000113 (23) 0.1 (45) 21 (20) Irinotecan 1 (46) 4 (91) 44 (32) 24 (29) 22 27 (13) SN-38 0.02 (55) 13 (170) 8 (52) 170 (59) 27 50 (28) SN-38-G 0.33 (76) 16 (69) 114 (75) 14 (76) 25 61 (37) APC 0.08 (118) 20 (41) 13 (73) 96 (49) 170 58 (8)

Abbreviations: %CV, coefﬁcient of variance; Cmax/dose, maximum observed plasma concentration after administration of the ﬁrst dose

divided by the ﬁrst etirinotecan pegol dose; Tmax, time that Cmax was observed; AUC/dose, area under the concentration versus time curve from t ¼ 0 through end of dosing divided by the total etirinotecan pegol dose; CL, total plasma clearance for etirinotecan pegol; CL/F, total plasma metabolite clearance divided by the fraction of metabolite formed; V, volume of distribution for etirinotecan pegol;

V/F, metabolite volume of distribution divided by the fraction of metabolite formed; t1/2, terminal elimination half-life.

www.aacrjournals.org Clin Cancer Res; 19(1) January 1, 2013 275

Jameson et al.

Table 4. Conﬁrmed partial responses to etirinotecan pegol based on RECIST 1.0, by schedule and dose

Etirinotecan Pegol schedule Dose, mg/m2 Primary tumor type Response duration, d W 3q4w 58 Small cell lung cancer 109 W 3q4w 173 Cervix 60a q21d 170 Triple-negative breast cancer 87 q14d 145 Bladder—neuroendocrine features 68 q14d 170 Maxillary sinus—neuroendocrine 273 q14d 195 Pancreas—neuroendocrine 84b q14d 220 Colorectal 97c q14d 220 Lung—squamous cell 84d

aPatient came off study for surgical resection before disease progression. bPatient came off study before disease progression and frequent hospitalizations. cExperienced disease progression on irinotecan approximately 9 months before initiation of etirinotecan pegol. dPatient came off study before disease progression because of an unacceptable toxicity; namely, diarrhea.

(2.6%) additional patients had an unconfirmed partial diarrhea. As a result, we evaluated successive downward dose response. The median duration of response was 86 days reductions in additional patients. For treatment group 1 (w (range, 60–273 days; Table 4). The longest observed con- 3q4w), dosing went from 58!115!173!230!173! firmed partial response of 9 months was seen in a 47-year-old 145!115 mg/m2, which was the determined dose that could male with a neuroendocrine tumor of the sinus. The ana- be tolerated for multiple cycles. Patients in treatment groups tomical locations of primary tumors for patients with con- 2 (q21d) and 3 (q14d), had similar experiences with doses firmed partial responses were lung (n ¼ 2), colorectal (n ¼ 1), of 145!170!195!220!245!220!195!170 mg/m2, pancreas (n ¼ 1), breast (n ¼ 1), cervix (n ¼ 1), bladder and 145!170!195!220!195!170 mg/m2, respective- (n ¼ 1), and head and neck (n ¼ 1). The assessments, ly. Overall, the MTD for treatment group 1 (w 3q4w), which did not meet formal RECIST guidelines, revealed was declared to be 115 mg/m2. The MTD for both for that in the 17 patients with signs of antitumor response, 2 treatment group 2 (q21d) and treatment group 3 (q14d) (colorectal and ovarian tumors) had unconfirmed partial was 145 mg/m2. responses, 3 (esophagus, ovarian, and breast tumors) had All 3 therapeutic regimens were found to be well declines in tumor markers suggestive of antitumor activ- tolerated at the defined MTD dose levels and most ity, and 12 had stable disease with durations ranging from importantly, resulted in sustained and controlled sys- 99 days to 343 days. temic exposure to SN-38 with preliminary evidence of Excluding stable disease as a measure of antitumor activ- antitumor activity. These findings are consistent with in ity, more antitumor activity was seen in patients treatment vitro and in vivo studies in tumor-bearing mice which group 1 (15.6%; 5/32) and treatment group 3 (36.8%; showed the unique properties of etirinotecan pegol and 7/19) than in treatment group 2 (4.0%; 1/25). However, found that topoisomerase I inhibitors displayed expo- in general, there were too few patients in each group to sure time–dependent rather than concentration-depen- conduct comparative analyses. dent cytotoxicity (23–27). In preclinical studies, the antitumor activity of etirinotecan pegol was much greater Discussion than irinotecan when studied at equivalent, as well as Etirinotecan pegol, is a unique long acting topoisom- lower doses, in various xenograft models in mice. Ani- erase I inhibitor that provides prolonged systemic expo- mals treated with etirinotecan pegol displayed durable sure to SN-38. This first-in-human study shows that tumor growth suppression at and below the maximum etirinotecan pegol has significant antitumor activity in feasible dose administered, whereas animals treated with patients with various solid tumors and some differences irinotecan at MTD had temporary tumor growth inhibi- in safety profile compared with the irinotecan historical tion as their best response. The prolonged tumor cell profile. Data from this study presents the versatility of exposure to SN-38 following etirinotecan pegol admin- etirinotecan pegol to provide several successful therapeu- istration is greater than the intermittent exposure pro- tic regimens. duced by all existing topoisomerase I inhibitor therapies. Because of the long t1/2 of etirinotecan pegol, defining the These results confirm the hypothesis that etirinotecan MTD based on the first cycle of treatment was challenging. pegol, as designed, would provide prolonged cellular The protocol stipulated that only adverse events in the first exposure to SN-38 and as a result would result in greater cycle were considered DLT’s. The cycle lengths varied DNA damage. between schedules from 2 to 4 weeks. It was not until patients Both etirinotecan pegol and irinotecan can cause received additional cycles that we started seeing rather severe significant diarrhea that is successfully treated with prompt

276 Clin Cancer Res; 19(1) January 1, 2013 Clinical Cancer Research

Etirinotecan Pegol Phase I in Patients with Solid Tumors

aggressive clinical intervention. However, unlike irinote- required for intestinal health (28). These developments, if can, etirinotecan pegol did not exhibit cholinergic symp- successful, may enhance the efficacy and tolerability of this toms that indicated premedication with atropine was class of antineoplastic. needed and neutropenia was significantly less common. In conclusion, in this first-in-human study, the MTD Diarrhea was more frequent and severe at doses above the was established for the administration of etirinotecan RP2D with onset greater than 24 hours after study drug pegol following 3 different dosing schedules. Etirinotecan administration. The plasma concentrations of both irino- pegol showed antitumor activity in a broad spectrum of tecan and SN-38 following etirinotecan pegol administra- cancers. An optimal response profile was seen with sus- tion resulted in sustained and controlled systemic exposure, tained exposure to SN-38 throughout a 21-day dosing which likely contributed to the observed reductions in interval in patients with lower peak concentration. An cholinergic diarrhea and neutropenia while maintaining improved safety profile regarding hematologic toxicity evidence of antitumor response. was noted when compared historically to irinotecan, The sustained and controlled systemic exposure to most likely because of reduced irinotecan exposure sec- irinotecan and SN-38 is the result of the molecular design ondary to slow release from etirinotecan pegol. Overall, of etirinotecan pegol. The MTD of 145 mg/m2 for etir- etirinotecan pegol administration to patients with cancer inotecan pegol resulted in approximately the same plas- results in sustained and controlled systemic exposure to ma SN-38 AUC as the 350 mg/m2 dose of irinotecan with SN-38. The pharmacokinetics of etirinotecan pegol and 1 cycle of therapy, but exposure was continuous rather metabolites are predictable and do not require complex than intermittent and maximal concentrations were dosing adjustments. Etirinotecan pegol is being studied in approximately 10-fold less (16). Following the adminis- phase II and III trials of patients with cancers that have tration of etirinotecan pegol, an elimination t1/2 for SN- failed prior chemotherapy treatment, including patients 38 (50 days) was measured that is significantly different with platinum-resistant ovarian cancer, phase II, (29) and than that for SN-38 after irinotecan administration (12 metastatic breast cancer, phase II (30) and III. The benefit to 47 hours; refs. 1, 11). of the prolonged SN-38 t1/2 of 50 days following etir- PK modeling and simulation using results from this inotecan pegol administration may offer future research study, as well as published irinotecan data, showed plasma opportunities exploring alternative dosing schedules, SN-38 concentrations were sustained throughout a 21-day including a model of induction and subsequent mainte- dosing interval after etirinotecan pegol was administered at nance therapy. 145 mg/m2 which translates into continuous and sustained antitumor activity. This is not the case following irinotecan Disclosure of Potential Conflicts of Interest (350 mg/m2) administration where 70% of the 21-day M.A. Eldon reported major support from Nektar, Inc. (employment). Lee S. Rosen received a commercial research grant from Nektar. No other dosing interval was drug free. The simulation also shows potential conflicts of interest were disclosed by the other authors. some accumulation of SN-38 as would be expected after q21d administration of a drug having a terminal disposition Authors' Contributions half-life of approximately 50 days. SN-38 AUC after 4 cycles Conception and design: J.T. Hamm, L.S. Rosen, M.A. Eldon Development of methodology: L.S. Rosen, M.A. Eldon (Fig 2B) is approximately 80% of the predicted steady-state Acquisition of data (provided animals, acquired and managed patients, AUC; therefore neither rapid nor extensive additional accu- provided facilities, etc.): G.S. Jameson, J.T. Hamm, G.J. Weiss, C. Alemany, mulation is expected when the recommended q21d sched- S. Anthony, M. Basche, R.K. Ramanathan, M.J. Borad, R. Tibes, A. Cohn, I. Hinshaw, R. Jotte, L.S. Rosen, K. Schroeder, E. White ule is used. Analysis and interpretation of data (e.g., statistical analysis, biosta- Once etirinotecan pegol is metabolized to irinotecan, the tistics, computational analysis): G.S. Jameson, G.J. Weiss, M.J. Borad, R. irinotecan metabolic profile is the same as that for irinote- Tibes, A. Cohn, L.S. Rosen, U. Hoch, M.A. Eldon, E. White Writing, review, and/or revision of the manuscript: G.S. Jameson, J.T. can administration. However, the rates of formation for Hamm, G.J. Weiss, C. Alemany, S. Anthony, R.K. Ramanathan, M.J. Borad, R. each metabolite are much slower and the proportions Tibes, A. Cohn, R. Jotte, L.S. Rosen, U. Hoch, M.A. Eldon, R. Medve, D.D. Von Hoff formed are very different than those after administration Administrative, technical, or material support (i.e., reporting or orga- of irinotecan. These differences can be characterized as a nizing data, constructing databases): R. Tibes shift away from hepatic oxidation of irinotecan to APC and Study supervision: S. Anthony, R.K. Ramanathan, A. Cohn, R. Jotte, L.S. Rosen, K. Schroeder, D.D. Von Hoff NPC via CYP3A4. This may be secondary to protection of irinotecan from metabolism while bound to the polymer Acknowledgments core, as well as a corresponding greater proportion of The authors thank the patients and their families for their participation in irinotecan metabolized to SN-38 once released from the this trial. polymer core. Diarrhea is an ongoing concern in the development of Grant Support Commercial research funding was provided to each participating insti- new topoisomerase I inhibitors as SN-38 levels in the tution by Nektar Therapeutics. intestinal lumen play a key role in the delayed diarrhea The costs of publication of this article were defrayed in part by the payment that limits dose intensification and efficacy. Encouraging of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. work is being done to identify potent and selective inhibitors of bacterial b-glucuronidases to eliminate the GI tox- Received April 27, 2012; revised October 17, 2012; accepted October 22, icity of irinotecan without killing the bacterial symbiotes 2012; published OnlineFirst November 7, 2012.

www.aacrjournals.org Clin Cancer Res; 19(1) January 1, 2013 277

Jameson et al.

References 1. Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. 17. Abigerges D, Armand JP, Chabot GG, Da Costa L, Fadel E, Cote C, Nat Rev 2006;6:789–802. et al. Irinotecan (CPT-11) high-dose escalation using intensive high- 2. Persson H, Antonian L, Staschen C-M, Viegas T, Bentley M. Polyeth- dose loperamide to control diarrhea. J Natl Cancer Inst 1994;86: ylene glycol conjugation of irinotecan improves its antitumor activity in 446–9. three mouse xenograft models. Proc Am Assoc Cancer Res 2007:259. 18. Michael M, Brittain MA, Nagai J, Feld R, Hedley D, Oza A, et al. Phase II Abstract C10. study of activated charcoal to prevent irinotecan-induced diarrhea. J 3. Shimada Y, Rougier P, Pitot H. Efficacy of CPT-11 (irinotecan) as a Clin Oncol 2004;22:4410–7. single agent in metastatic colorectal cancer. Eur J Cancer 1996;32A 19. Saltz LB. Understanding and managing chemotherapy-induced diar- (suppl 3):S13–7. rhea. J Support Oncol 2003;1:35–46. 4. Rothenberg ML. CPT-11: an original spectrum of clinical activity. 20. Schmittel A, Jahnke K, Thiel E, Keilholz U. Neomycin as secondary Semin Oncol 1996;23(1 suppl 3):21–6. prophylaxis for irinotecan-induced diarrhea. Ann Oncol 2004;15:1296. 5. Bleiberg H. CPT-11 in gastrointestinal cancer. Eur J Cancer 1999;35: 21. Kehrer DF, Sparreboom A, Verweij J, de Bruijn P, Nierop CA, van de 371–9. Schraaf J, et al. Modulation of Irinotecan-induced diarrhea by co- 6. Pizzolato JF, Saltz LB. Irinotecan (Campto) in the treatment of pan- treatment with neomycin in cancer patients. Clin Can Res 2001;7: creatic cancer. Expert Rev Anticancer Ther 2003;3:587–93. 1136–41. 7. Von Hoff D. Future directions for the clinical research with CPT-11 22. Petrelli NJ, Rodriguez-Bigas M, Rustum Y, Herrera L, Creaven P. (irinotecan). Eur J Cancer 1996;32A(suppl 3):S9–12. Bowel rest, intravenous hydration, and continuous high-dose infusion 8. Abigerges D, Chabot GG, Armand JP, Herait P, Gouyette A, Gandia D. of octreotide acetate for the treatment of chemotherapy-induced Phase I and pharmacologic studies of the camptothecin analog irino- diarrhea in patients with colorectal carcinoma. Cancer 1993;72: tecan administered every 3 weeks in cancer patients. J Clin Oncol 1543–6. 1995;13:210–21. 23. Xie R, Mathijssen RH, Sparreboom A, Verweij J, Karlsson MO. Clinical 9. Rothenberg ML. Topoisomerase I inhibitors: review and update. Ann pharmacokinetics of irinotecan and its metabolites in relation with Oncol 1997;8:837–55. diarrhea. Clin Pharmacol Ther 2002;72:265–75. 10. Rothenberg ML, Cox JV, DeVore RF, Hainsworth JD, Pazdur R, Rivkin 24. Burris HA III, Hanauske AR, Johnson RK, Marshall MH, Kuhn JG, SE, et al. A multicenter, phase II trial of weekly irinotecan (CPT-11) in Hilsenbeck SG, et al. Activity of topotecan, a new topoisomerase I patients with previously treated colorectal carcinoma. Cancer 1999; inhibitor, against human tumor colony-forming units in vitro. J Natl 85:786–95. Cancer Inst 1992;84:1816–20. 11. Kehrer DF, Yamamoto W, Verweij J, de Jonge MJ, de Bruijn P, 25. Supko JG, Plowman J, Dykes DJ, Zaharko DS. Relationship between Sparreboom A. Factors involved in prolongation of the terminal dis- the schedule dependence of 9-amino-20(S)-camptothecin (AC; NSC position phase of SN-38: clinical and experimental studies. Clin Cancer 603071) antitumor activity in mice and its plasma pharmacokinetics. Res 2000;6:3451–8. Proc Am Assoc Cancer Res 1992;33:432. 12. Eldon MA, Staschen CM, Viegas T, et al.: NKTR-102, a novel PEGy- 26. Houghton PJ, Cheshire PJ, Hallman JD II, Lutz L, Friedman HS, Danks lated-irinotecan conjugate, results in sustained tumor growth inhibition MK, et al. Efficacy of topoisomerase I inhibitors, topotecan and in mouse models of human colorectal and lung tumors that is asso- irinotecan, administered at low dose levels in protracted schedules ciated with increased and sustained tumor SN-38 exposure. Proc Am to mice bearing xenografts of human tumors. Cancer Chemother Assoc Cancer Res 2007:306. Abstract C157. Pharmacol 1995;36:393–403. 13. World Medical Association. WMA Declaration of Helsinki—Ethical 27. Furuta T, Yokokura T. Effect of administration schedules on the Principles for Medical Research Involving Human Subjects, October antitumor activity of CPT-11, a camptothecin derivative. Gan To 2008. Available at: www.wma.net/en/30publications/10policies/b3/ Kagaku Ryoho 1990;17:121–30. index.html. Accessed March 8, 2012. 28. Wallace BD, Wang H, Lane KT, Scott JE, Orans J, Koo JS. Alleviating 14. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. cancer drug toxicity by inhibiting a bacterial enzyme. Science 2010; Accelerated titration designs for phase I clinical trials in oncology. 330:831. J Natl Cancer Inst 1997;89:1138–47. 29. Vergote IB, Micha JP, Pippitt CH Jr, Rao GG, Spitz DL, Reed N, et al. 15. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Phase II study of NKTR-102 in womenwithplatinum-resistant/ Rubinstein L, et al. New guidelines to evaluate the response to refractory ovarian cancer. J Clin Oncol 2010;28(15s):393s. Abstract treatment in solid tumors. European Organization for Research and 5013. Treatment of Cancer, National Cancer Institute of the United States, 30. Awada A, Chan S, Jerusalem G, Huizing M, Coleman RE, Mehdi A, et al. National Cancer Institute of Canada. J Natl Cancer Inst 2000;92: Significant efficacy in a phase 2 study of NKTR-102, a novel polymer 205–16. conjugate of irinotecan, in patients with pre-treated metastatic breast 16. Xie R, Mathijssen RH, Sparreboom A, Verweij J, Karlsson MO. Clinical cancer (MBC). Presented at: 33rd Annual CTRC-AACR San Antonio pharmacokinetics of irinotecan and its metabolites: a population Breast Cancer Symposium; December 12, 2010; San Antonio, TX. analysis. J Clin Oncol 2002;20:3293–301. Abstract P6–11–01.

278 Clin Cancer Res; 19(1) January 1, 2013 Clinical Cancer Research

A Multicenter, Phase I, Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Etirinotecan Pegol in Patients with Refractory Solid Tumors

Gayle S. Jameson, John T. Hamm, Glen J. Weiss, et al.

Clin Cancer Res 2013;19:268-278. Published OnlineFirst November 7, 2012.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-12-1201

Cited articles This article cites 26 articles, 6 of which you can access for free at: http://clincancerres.aacrjournals.org/content/19/1/268.full#ref-list-1

Citing articles This article has been cited by 2 HighWire-hosted articles. Access the articles at: http://clincancerres.aacrjournals.org/content/19/1/268.full#related-urls

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at Subscriptions [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/19/1/268. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.