Abstract 2419: A phase Ib-IIa study evaluating the nanopharmaceutical CRLX101 in combination with bevacizumab in the treatment of patients (pts.) with advanced renal cell carcinoma.
Authors: Keefe Stephen M. , Cohen Roger B. , Eliasof Scott , Garmey Edward G. , Hennessy Meliessa , Mykulowicz Kristine M. , Pryma Daniel A. , Haas Naomi 
Published: August 2014

Abstract
Background:
Topoisomerase-1 (topo-1)-inhibiting agents demonstrate activity across multiple cancer types but use of these agents remains limited by insufficient tumor exposure and toxicity. CRLX101, a novel cyclodextrin-containing polymer conjugate of camptothecin (CPT) that self-assembles into nanoparticles, delivers sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. In vitro and in vivo data suggest superior activity of CRLX101 compared to approved agents in multiple animal tumor models. A monotherapy maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of 15 mg/m2 IV every 2 weeks (wks.) was reported previously and over 100 cancer pts. have now been treated with CRLX101 across three ongoing phase 2 clinical trials. To be presented separately at this conference, CRLX101 further appears to inhibit HIF1α, a hypoxia-induced transcription factor implicated in tumor angiogenesis, invasion, and metastasis. We hypothesize that observed synergistic activity between CRLX101 and the VEGF-inhibiting monoclonal antibody bevacizumab occurs as a result of overcoming HIF-mediated resistance to VEGF-inhibition. Clear cell renal cell carcinoma (ccRCC), accounting for approximately 85% of RCC, provides an ideal clinical setting in which to evaluate the potential of this drug-drug combination. The most commonly observed genetic abnormality in ccRCC results in higher intracellular levels of HIF1α. Bevacizumab was chosen as a combination partner here because of its proven activity in the treatment of RCC as well as a history of successful combination with chemotherapy partners including topo-1 inhibitors.
Methods:
This clinical trial examines the combination of bevacizumab and CRLX101 in the treatment of pts. with advanced metastatic RCC. The primary objective is to determine the RP2D of CRLX101 administered in ombination with bevacizumab. In a preliminary stage 1b, a standard 3+3 dose-escalation design is being employed and no fewer than 6 pts. will be evaluated at the MTD. A secondary objective is to evaluate progression-free survival (PFS). Based on a preliminary test for futility, the study will be terminated if ≤ 3 of the initial 12 pts. survive without progression to 16 wks. Otherwise, an additional 10 pts. will be enrolled for a total of 22 pts. and the combination will be viewed as active and worthy of further examination if the PFS rate at 16 wks. is ≥ 50%. Additional exploratory endpoints include a comparison of bone marrow histology and molecular features among pts. treated with 12 mg/m2 vs. 15 mg/m2 of CRLX101. Finally, tumor expression of CAIX, a well-studied surrogate for HIF1α activity, will be measured using 124I-cG250, a CAIX antibody, with real-time PET imaging employed to determine the degree of CRLX101-mediated HIF1α modulation.
Citation Format: Stephen M. Keefe, Roger B. Cohen, Scott Eliasof, Edward G. Garmey, Meliessa Hennessy, Kristine M. Mykulowicz, Daniel A. Pryma, Naomi Haas. A phase Ib-IIa study evaluating the nanopharmaceutical CRLX101 in combination with bevacizumab in the treatment of patients (pts.) with advanced renal cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2419. doi:10.1158/1538-7445.AM2013-2419