Published OnlineFirst November 7, 2012; DOI: 10.1158/1078-0432.CCR-12-1201 Clinical Cancer Cancer Therapy: Clinical 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. 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. Ó2012 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 Ó2012 American Association for Cancer Research. with irinotecan in preclinical models of cancer. 268 Clin Cancer Res; 19(1) January 1, 2013 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst November 7, 2012; DOI: 10.1158/1078-0432.CCR-12-1201 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 UGT1A1Ã28 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