Randomized Multicenter Phase II Trial Comparing Two Schedules of Etirinotecan Pegol (NKTR-102) in Women With Recurrent Platinum-Resistant/Refractory Epithelial Ovarian Cancer

Abstract

Purpose Etirinotecan pegol (NKTR-102) is a unique, long-acting topoisomerase-I inhibitor with prolonged systemic exposure to SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan. This randomized phase II trial investigated two dosing schedules of etirinotecan pegol in patients with platinum-resistant/refractory ovarian carcinoma. Patients and Methods A total of 71 eligible patients were randomly assigned to receive etirinotecan pegol 145 mg/m2 every 14 or 21 days until progression or unacceptable adverse events (AEs). The primary end point was objective response rate (ORR) by RECIST (version 1.0). Secondary end points included response by Gynecologic Cancer Intergroup criteria, duration of ORR, progression-free survival (PFS), and overall survival (OS). Results The overall confirmed ORR was 20% (95% CI, 10% to 30%): 20% for once every 14 days, and 19% for once every 21 days. Median response duration was 4.1 months for once every 14 days and 4.0 months for once every 21 days. Median PFS for every 14 and every 21 days was 4.1 and 5.3 months, respectively, and median OS was 10.0 and 11.7 months, respectively. Etirinotecan pegol was well tolerated, with the most common grade 3 to 4 AEs being dehydration (24%) and diarrhea (23%). Diarrhea, dehydration, nausea, and neutropenia were less frequent with the schedule of once every 21 days than with that of once every 14 days. Conclusion Both schedules of etirinotecan pegol showed activity in patients with heavily pretreated ovarian cancer, with encouraging ORR and PFS rates. The schedule of once every 21 days was better tolerated and had slightly longer PFS and OS rates. The treatment schedule of etirinotecan pegol 145 mg/m2 once every 21 days was selected for the expanded phase II study and is preferred for future phase III studies. These findings provide support to directly compare etirinotecan pegol versus one of the approved drugs (eg, pegylated liposomal doxorubicin or topotecan) in platinum-resistant ovarian cancer.

Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2–SN-38 Antibody Conjugate (Sacituzumab Govitecan)

“…SN-38G concentrations were not reported in this preclinical study, but clinical results have indicated substantially higher levels of SN-38G than SN-38. Promising antitumor responses have been reported for etirinotecan pegol clinically, with dose-limiting toxicity being severe diarrhea that is not manifested until a median of 63 days from the start of therapy (32,33). Clinical studies with IMMU-132 found dose-limiting neutropenia occurring within 1 week of the start of treatment, but the incidence of severe diarrhea is greatly reduced.…”

“…While providing improved responses in animal models, the agent failed to provide an indication of clinical benefit (29). Etirinotecan pegol is a PEG conjugate composed of a 4-arm, branched PEG, with each arm harboring irinotecan, which has been reported to extend the halflife of SN-38 to about 50 hours (30)(31)(32)(33). Preclinical studies in rats showed etirinotecan pegol serum concentrations decreasing from about 700 to 30 mg/mL over 12 hours, with low levels ($30 ng/ mL) of both irinotecan and SN-38 detected within the first few minutes; SN-38 concentrations then remained between 10 and 20 ng/mL over 14 days (31).…”

Factors favouring long-term survival following recurrence in ovarian cancer

“…The response to chemotherapy after recurrence also affected OS after recurrence. The response rates to second-line chemotherapy are generally different according to the platinum-sensitivity status: 20-25% for platinum-sensitive cases, and 10-20% for platinum-resistant cases (16,17). Our results suggested that the patients who exhibited complete or partial response to second-line regimens may become LS.…”

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

“…Grade 3/4 toxicities included dehydration (24%) and diarrhoea (23%), whereas neutropaenia was less frequent (11.3%). 56 On a side note, the study suggested the use of the TOP1 gene as a biomarker prior to treatment in order to predict sensitively and reduce potential toxicities. 53 Other NKTR-102 clinical studies include an open-label multicenter extension study of NKTR-102 in subjects previously enrolled in NKTR-102 studies (ClinicalTrials.gov identifier NCT01457118); a phase IIa/IIb multicenter open-label study to evaluate NKTR-102 in combination with cetuximab vs. irinotecan in combination with cetuximab in second-line colorectal cancer patients (ClinicalTrials.gov identifier NCT00598975); a phase II study in cancer patients with hepatic impairment to evaluate the pharmacokinetics and safety of NKTR-102 (ClinicalTrials.gov identifier NCT01991678); a phase I study of NKTR-102 in bevacizumab-resistant high grade glioma (ClinicalTrials.gov identifier NCT01663012); a phase II study in patients with relapsed SCLC (ClinicalTrials.gov identifier NCT01876446); a new phase II study in patients with second-line, irinotecan-naïve, KRASmutant colorectal cancer (ClinicalTrials.gov identifier NCT00856375); and a phase II study in NSCLC (ClinicalTrials.gov identifier NCT01773109).…”