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; 1–11. 2012 AACR.

Introduction inhibitor class, is widely used to treat patients with colo- Etirinotecan pegol is a unique, long acting topoisomerase rectal cancer and other solid tumors (1–10). SN-38 binds to I inhibitor that provides prolonged systemic exposure to and stabilizes the topoisomerase I-DNA complex, leading to SN-38 the active metabolite of irinotecan, which is primar- single- and double-stranded DNA breaks and inhibiting ily responsible for its efficacy (1), at the site of the tumor. DNA repair. Irinotecan and SN-38 have terminal elimina- Irinotecan, an antineoplastic agent of the topoisomerase I tion half-lives (t1/2) of 9 to 12 hours and 12 to 47 hours, respectively (1, 11). Irinotecan treatment can be associated with severe diarrhea and severe neutropenia, limiting the Authors' Affiliations: 1Virginia G. Piper Cancer Center at Scottsdale frequency with which it can be administered to patients. 2 Healthcare (VGPCC)/TGen, Scottsdale; Mayo Clinic, Phoenix, Arizona; Therefore, irinotecan is typically administered every 14 to 3Norton Healthcare, Louisville, Kentucky; 4US Oncology Research - Florida Institute of Research, Cancer Center, Ocoee, Florida; 5US Oncology 21 days, which results in a better safety profile than the Research - Rocky Mountain Cancer Centers, Denver, Colorado; 6Premiere weekly administration of irinotecan. Oncology, Santa Monica; and 7Nektar Therapeutics, San Francisco, California Etirinotecan pegol is designed to reduce maximal SN-38 systemic concentrations while providing continuous expo- Prior presentations: This study was presented at 2008 EORTC-NCI-AACR Symposium, Poster 595. The study abstract was presented at the 2008 sure to tumors, even when administered in 14- or 21-day ASCO Annual Meeting (abstract 13518). cycles. The pharmacokinetic (PK) profile of etirinotecan Corresponding Author: Gayle S. Jameson, MSN, ACNP-BC, AOCN, pegol leads to both improved efficacy and safety compared 10510 North 92nd Street, Suite 200, Scottsdale, AZ 85258. Phone: 480- with irinotecan in preclinical models of cancer. 323-1350; Fax: 480-323-1359; E-mail: [email protected]. In mouse models of human tumors, etirinotecan pegol doi: 10.1158/1078-0432.CCR-12-1201 resulted in marked dose-related and sustained tumor 2012 American Association for Cancer Research. growth inhibition in colorectal, lung, breast, and ovarian

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nase 3 times or less upper limit of normal (ULN; 5 ULN Translational Relevance if liver metastasis is confirmed), creatinine 1.5 ULN or Etirinotecan pegol is a unique, long acting topoisom- creatinine clearance 60 mL/min or more. erase I inhibitor that provides prolonged systemic expo- Patients were excluded from the trial if they had received sure to SN-38. In this study, 76 patients with refractory chemotherapy, including any investigational agents or tumors were treated on various dose levels and sche- radiotherapy within 4 weeks (6 weeks for nitrosoureas or dules. Dose limiting toxicities included late, noncho- mitomycin C) before the commencement of dosing. In linergic diarrhea and neutropenia, both manageable addition, they must have recovered to at least a grade 1 with dose modifications. In this phase I trial, 25 toxicity, as defined by the National Cancer Institute Com- (32.9%) patients showed some type of antitumor mon Terminology Criteria for Adverse Events, version 3.0, effect; 8 (11%) had a confirmed partial response to (CTCv3.0); alopecia of any grade was allowed. Additional treatment including 1 patient with colon cancer who exclusion criteria included major surgery within 4 weeks; had experienced disease progression on a prior irino- pregnant or nursing; unstable symptoms from brain metas- tecan based regimen. Two (2.6%) additional patients tases; serologically positive for hepatitis B or C, or history of had an unconfirmed partial response. The benefit of human immunodeficiency virus; cerebrovascular accident the prolonged SN-38 t1/2 of 50 days following etir- or transient ischemia; and history of hypersensitivity to inotecan pegol administration appears to be transla- irinotecan, other camptothecin derivatives, or pegylated tional to the clinic. The agent is being actively studied drugs. The presence of the UGT1A128 allele was assessed in ongoing phase II and III trials. for heterozygosity or homozygosity, but it was not exclu- sionary. The study received approval by the Western Insti- tutional Review Board and each institutional ethics board. The study was conducted in accordance with the provisions cancers (2, 12). Tumor growth inhibition in all of these of the Declaration of Helsinki (13). cancers was significantly greater than that observed at equivalent doses of irinotecan (2). Pharmacokinetic studies Study drug in mice, rats, and dogs showed lower maximum concen- Etirinotecan pegol was manufactured by Nektar Thera- tration (Cmax) and clearance values for SN-38 and corre- peutics, and supplied in amber glass vials containing lyoph- spondingly greater systemic exposure to SN-38, following ilized etirinotecan pegol powder equivalent to 100 mg etirinotecan pegol dosing, compared with irinotecan. These irinotecan. Each patient’s dose was reconstituted with 5% animal studies suggest that etirinotecan pegol may be more Dextrose Injection, USP (D5W), total volume 500 mL, to efficacious than irinotecan because of greater topoisomer- final concentrations of 0.12 to 2.8 mg irinotecan equiva- ase I inhibition resulting from prolonged tumor cell expo- lents/mL, and administered via intravenous (i.v.) infusion sure to SN-38 (12). over 90 minutes. The reconstituted drug required protection The primary objectives of this first-in-human phase 1 from direct ambient lighting at room temperature (15 C– clinical trial were to characterize the safety profile and 30 C) for up to 2 hours before the start of infusion and drug establish a maximum tolerated dose (MTD) of etirinotecan could also be stored protected from direct lighting at 2 Cto pegol following 3 separate dosing regimens in patients with 8 C for up to 8 hours before the start of infusion. A central refractory solid tumors. Secondary objectives included the venous catheter was not required for drug administration. determination of the plasma PKs and metabolites, as well as The protocol recommended that patients receive preme- an evaluation of clinical antitumor activity of etirinotecan dication with antiemetic agents including dexamethasone pegol. given in conjunction with a 5-HT3 at least 30 minutes 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 2 mg/ istered on day 1 of a 21-day (q21d) period (dose escalations dL or less, aspartate transaminase, and alanine transami- in increments of 25 mg/m2 were allowed if there were no

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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 up to 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 acid, 7-ethyl-10-(4-N-(5-aminopentanoic acid)-1-piperi- protocol, dose reduction evaluations with an expanded

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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.

number of patients being treated continued until a dose free deﬁned DLT window limited to the ﬁrst cycle, the investi- from DLTs was observed. Overall, the dose of 115 mg/m2 gators and sponsor agreed to reduce the MTD to the next was found to be well tolerated with less than 33% of patients lower dose level of 145 mg/m2 in both the 14- and 21-day experiencing a DLT and was subsequently declared the MTD schedules. Additional patients were not added as 0 of the 3 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, patients experienced grade 3 diarrhea after the protocol at doses 115 mg/m2 or more, 7 of 9 (78%) patients’ reported

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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)

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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.

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- gous, did not correlate with the occurrence of neutropenia can pegol at a dosing schedule of w 3q4w, q21d, or q14d

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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). 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, imately 35-fold lower compared with irinotecan admin- therefore, assessable for response by RECIST 1.0. Twenty-five

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AB Cumulative AUC (ng/mL ‘h) 100,000 Plasma irinotecan 2.5 ×107 10,000 2.0 ×107 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 15,000 Predicted plasma concentration (ng/mL) Predicted plasma concentration 1 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.

(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 RECIST 1.0, including 2 patients in treatment group 1 (2.6%) additional patients had an unconﬁrmed partial

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.

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Etirinotecan Pegol Phase I in Patients with Solid Tumors

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. response. The median duration of response was 86 days be tolerated for multiple cycles. Patients in treatment groups (range, 60–273 days; Table 4). The longest observed con- 2 (q21d) and 3 (q14d), had similar experiences with doses firmed partial response of 9 months was seen in a 47-year-old of 145!170!195!220!245!220!195!170 mg/m2, male with a neuroendocrine tumor of the sinus. The ana- and 145!170!195!220!195!170 mg/m2, respective- tomical locations of primary tumors for patients with con- ly. Overall, the MTD for treatment group 1 (w 3q4w), firmed partial responses were lung (n ¼ 2), colorectal (n ¼ 1), was declared to be 115 mg/m2. The MTD for both for pancreas (n ¼ 1), breast (n ¼ 1), cervix (n ¼ 1), bladder (n ¼ treatment group 2 (q21d) and treatment group 3 (q14d) 1), and head and neck (n ¼ 1). The assessments, which did was 145 mg/m2. not meet formal RECIST guidelines, revealed that in the 17 All 3 therapeutic regimens were found to be well tolerated patients with signs of antitumor response, 2 (colorectal and at the defined MTD dose levels and most importantly, ovarian tumors) had unconfirmed partial responses, 3 (eso- resulted in sustained and controlled systemic exposure to phagus, ovarian, and breast tumors) had declines in tumor SN-38 with preliminary evidence of antitumor activity. markers suggestive of antitumor activity, and 12 had stable These findings are consistent with in vitro and in vivo studies disease with durations ranging from 99 days to 343 days. in tumor-bearing mice which showed the unique properties Excluding stable disease as a measure of antitumor activ- of etirinotecan pegol and found that topoisomerase I inhi- ity, more antitumor activity was seen in patients treatment bitors displayed exposure time–dependent rather than con- group 1 (15.6%; 5/32) and treatment group 3 (36.8%; centration-dependent cytotoxicity (23–27). In preclinical 7/19) than in treatment group 2 (4.0%; 1/25). However, studies, the antitumor activity of etirinotecan pegol was in general, there were too few patients in each group to much greater than irinotecan when studied at equivalent, as conduct comparative analyses. well as lower doses, in various xenograft models in mice. Animals treated with etirinotecan pegol displayed durable Discussion tumor growth suppression at and below the maximum Etirinotecan pegol, is a unique long acting topoisomerase feasible dose administered, whereas animals treated with I inhibitor that provides prolonged systemic exposure to irinotecan at MTD had temporary tumor growth inhibition SN-38. This first-in-human study shows that etirinotecan as their best response. The prolonged tumor cell exposure pegol has significant antitumor activity in patients with to SN-38 following etirinotecan pegol administration is various solid tumors and some differences in safety profile greater than the intermittent exposure produced by all compared with the irinotecan historical profile. Data from existing topoisomerase I inhibitor therapies. These results this study presents the versatility of etirinotecan pegol to confirm the hypothesis that etirinotecan pegol, as designed, provide several successful therapeutic regimens. would provide prolonged cellular exposure to SN-38 and as Because of the long t1/2 of etirinotecan pegol, defining the a result would result in greater DNA damage. MTD based on the first cycle of treatment was challenging. Both etirinotecan pegol and irinotecan can cause signif- The protocol stipulated that only adverse events in the first icant diarrhea that is successfully treated with prompt cycle were considered DLT’s. The cycle lengths varied aggressive clinical intervention. However, unlike irinote- between schedules from 2 to 4 weeks. It was not until patients can, etirinotecan pegol did not exhibit cholinergic symp- received additional cycles that we started seeing rather severe toms that indicated premedication with atropine was diarrhea. As a result, we evaluated successive downward dose needed and neutropenia was significantly less common. reductions in additional patients. For treatment group 1 (w Diarrhea was more frequent and severe at doses above the 3q4w), dosing went from 58!115!173!230!173! RP2D with onset greater than 24 hours after study drug 145!115 mg/m2, which was the determined dose that could administration. The plasma concentrations of both

www.aacrjournals.org Clin Cancer Res; 2012 OF9

Jameson et al.

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

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www.aacrjournals.org Clin Cancer Res; 2012 OF11

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 Published OnlineFirst November 7, 2012.

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

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