Sequential Phase II clinical trials evaluating CRLX101 as monotherapy and in combination with bevacizumab in recurrent ovarian cancer

Abstract

BackgroundTopoisomerase-1 inhibitors are an important class of cytotoxics associated with toxicity that limits their use. CRLX101 is a novel cyclodextrin-containing polymer conjugate of camptothecin (CPT) that self-assembles into nanoparticles to deliver sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. MethodsWe conducted sequential phase II, open label, single arm clinical trials to evaluate CRLX101 as a single agent (n = 29) and with bevacizumab (Bev) (n = 34). Patients (pts) had measurable recurrent epithelial ovarian, tubal or primary peritoneal cancer, that could be platinum refractory, resistant or sensitive. Cohort A (Single agent CRLX101) allowed up to 3 prior chemotherapy regimens, but no prior topo-1 inhibitors. Pts received CRLX101 15 mg/m2 IV every 14 days Q28 with response evaluation every 2 cycles. Cohort B also received Bev 10 mg/kg D1,15 Q28, and included only platinum resistant disease with up to 2 prior lines, and more rigorous eligibility criteria. ResultsCRLX101 was well tolerated other than nausea, fatigue and anemia. 29 pts. received a median of 3 (1–16) cycles with a clinical benefit rate (CBR) of 68% and overall response rate (ORR) of 11%. With the addition of Bev in Cohort B (n = 34), the CBR was increased to 95% and the ORR to 18%. PFS was 4.5 months (0.9 to 15.9 months) in Cohort A and 6.5 months (2.8 to 14.4 months) in Cohort B. Bev increased the incidence of hypertension and qualitatively increased bladder toxicities, but without SAEs. ConclusionsCRLX101 meets the clinical need for an effective and tolerable topoisomerase I inhibitor and can be safely combined with bevacizumab.