Gynecologic Oncology

Biography

Biography: Adrian Senderowicz

Abstract

Background: Cerulean Pharma, Inc. is developing CRLX101, an investigational NDC with a camptothecin payload. CRLX101 has been investigated in more than 350 patients to date. Regimens administered have included monotherapy and combination therapy with bevacizumab in patients with renal cell carcinoma (Keefe, ASCO 2015, abstract #4543) and platinum-refractory ovarian cancer (Krasner, ASCO 2014, abstract #5581). Based on preclinical and early clinical data suggesting synergy between taxanes and topoisomerase 1 inhibitors, we started a Phase 1b trial for this combination in patients with platinum-resistant ovarian cancer. Methods: Cohorts of 3 patients were accrued in this trial. Two dose levels were planned as dose level 1: CRLX101 12 mg/m2 (every other week) in combination with paclitaxel 80 mg/m2 (weekly, 3 weeks on/1 week off); and dose level 2: CRLX101 15 mg/m2 (every other week) in combination with the same regimen of paclitaxel 80 mg/m2. The primary objective was to determine the maximum tolerated dose (MTD) administered in combination with weekly paclitaxel. Secondary objectives included pharmacokinetics, overall safety, tolerability, and initial signs of clinical activity of CRLX101 with weekly paclitaxel. Results: As of March 11, 2016, a total of 9 patients have been enrolled and treated at dose levels one (n=3) and two (n=6) and all 9 patients are evaluable for safety and response. Median age is 61 years (range, 49–73); median number of previous regimens was 3 (range, 1–4); GOG score performance status was 0 (6 patients) or 1 (3 patients). No dose-limiting toxicities have been reported at either dose level, thus the RP2D for this schedule is CRLX101 15 mg/m2 (every other week) and paclitaxel 80 mg/m2 (3 weeks on/1 week off). Adverse events (AEs) suspected to be related to study treatment were fatigue (6 patients, 67%), neutrophil count decreased (4 patients, 44%), nausea (4 patients, 44%), vomiting, alopecia, headache, infusion-related reaction, and urinary tract infection (all seen in 2 patients, 22%), as well as dizziness, sinusitis, ALT increased, AST increased, constipation, cystitis noninfective, dyspnea, anemia, and peripheral sensory neuropathy (all seen in 1patient, 11%). The only grade ≥3 treatment-related AE was neutropenia, which occurred in 2 patients (one grade 3 and one grade 4). Partial response and stable disease rates were 56% (5/9), and 11% (1/9), respectively. Moreover, CA125 responses (≥50% decline from baseline) were demonstrated in 33% of patients (3/9). As of March 11, 2016, 2 patients (at 15 mg/m2) are still receiving therapy. Conclusions: CRLX101 given every other week in combination with weekly paclitaxel (3 weeks on/1 week off) has demonstrated early signs of antitumor activity and has been generally welltolerated to date in patients with platinum-resistant ovarian cancer.