A phase 1b study of the nanoparticle-drug conjugate (NDC) CRLX101 in combination with weekly paclitaxel in patients (pts) with platinum-resistant ovarian cancer (OC)

Abstract

Background: Cerulean Pharma, Inc. is developing CRLX101, an investigational NDC with a camptothecin payload. CRLX101 has been investigated in more than 350 pts as monotherapy or in combination with bevacizumab in pts with renal cell carcinoma (Keefe, ASCO 2015, abstract #4543) and platinum-refractory OC (Krasner, ASCO 2014, abstract #5581). Preclinical and early clinical data suggest synergy between taxanes and topoisomerase 1 inhibitors. We started a Phase 1b trial for this combination in pts with platinum-resistant OC. Methods: Cohorts of 3 pts were accrued in this trial. Two dose levels of CRLX101 (every other week) in combination with weekly [wkly] paclitaxel 80 mg/m2 (3 wks on/1 wk off ) were planned: dose level 1, CRLX101 12 mg/m2; dose level 2, CRLX101 15 mg/ m2 . The primary objective was to determine the maximum tolerated dose of CRLX101 in combination with wkly paclitaxel. Secondary objectives included pharmacokinetics, safety, tolerability, and clinical activity. Results: As of March 11, 2016, 9 pts have been enrolled and treated at dose levels 1 (n = 3) and 2 (n = 6); all pts were evaluable for safety and response. Median age was 61 years (range, 49-73); median number of previous regimens was 3 (range, 1-4). GOG score performance status was 0 (6 pts) or 1 (3 pts). No dose-limiting toxicities have been reported at either dose level, thus the RP2D is CRLX101 15 mg/m2 (every other week) and paclitaxel 80 mg/m2 (3 weeks on/1 week off ). Treatment-related adverse events (AEs) included fatigue (6/9, 67%), neutrophil count decreased (4/9, 44%), nausea (4/9, 44%), vomiting, alopecia, headache, infusion-related reaction, and urinary tract infection (2/9, 22% for all). The only grade ≥3 treatment-related AE was neutropenia, which occurred in 2 pts (1 grade 3; 1 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% (3/9) of pts. Two pts (at 15 mg/m2) are still receiving therapy. Conclusions: CRLX101 given every other wk in combination with wkly paclitaxel has demonstrated early signs of antitumor activity and has been generally well tolerated to date in pts with platinum-resistant OC.