Phase I/II dose-escalation trial of patupilone every 3 weeks in patients with relapsed/refractory ovarian cancer

Abstract

5056 Background: Pts with newly diagnosed advanced ovarian cancer generally receive platinum plus taxane therapy. For pts who do not respond or relapse within 6 months, outlook remains poor. Patupilone, a natural epothilone, is a microtubule-targeting cytotoxic that has demonstrated clinical activity in taxane-sensitive and -resistant tumors. In a phase I/II study, we are investigating the safety and efficacy of patupilone in pts with advanced ovarian cancer who had failed to respond to or had relapsed within 6 months of first-line platinum therapy. Methods: Pts receive patupilone at a starting dose of 6.5 mg/m2 via 10- to 20-min IV infusion once every 3 wk (q3w) with proactive diarrhea management. Results: To date, 31 pts have been enrolled in 9 cohorts receiving 6.5 (n = 3), 7.0 (n = 3), 7.5 (n = 3), 8.0 (n = 6), 8.5 (n = 3), 9.0 (n = 6), 9.5 (n = 3), 10.0 (n = 3), and 10.5 (n = 1) mg/m2 patupilone. Currently, 29 pts are eligible for assessment; 90% had received prior taxane therapy. DLTs were not reported until the 8.0- and 8.5-mg/m2 cohorts; 1 pt in each had grade (gr) 3 fatigue. Gr 4 serum uric acid, gr 3 hypomagnesemia, and gr 2 serum creatinine precipitated by surgical ileus were reported on day 21 of the first cycle by a pt enrolled in the 9.0-mg/m2 cohort. However, these toxicities were deemed unrelated to study drug, the cohort was expanded and no DLTs were reported. Dose escalation has continued to the ongoing 10.5-mg/m2 cohort. Gr 3 diarrhea, gr 3/4 fatigue/malaise, and gr 3 vomiting were reported in 17%, 14%, and 7% of pts, respectively. Eight (28%) pts had gr 1/2 neuropathy/paresthesia; 1 case became gr 3 in a heavily (19 platinum cycles) pretreated pt. Hematologic toxicity was uncommon and 3 pts had gr 1 alopecia. Of the 19 pts evaluable for tumor response by RECIST, 1 had CR, 1 had PR, and 7 had SD; 1 additional pt had CR based on ascites disappearance. Of the 24 pts who had increased CA-125 at baseline, 7 (29%) had a 50% reduction in CA-125 levels (2 confirmed, 5 unconfirmed). Conclusions: Preliminary data indicate that patupilone administered once q3w is safe and well tolerated. The MTD has not been reached; dose escalation continues. Preliminary antitumor response is promising in this previously treated platinum-resistant pt population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Novartis Pharmaceuticals AG Novartis Novartis Novartis