Abstract CT340: Phase 1b/2a study of the nanopharmaceutical CRLX101 with bevacizumab (bev) in the treatment of patients (pts) with refractory metastatic renal cell carcinoma (mRCC): results from the planned interim analysis
Authors: Keefe Stephen M. , Hennessy Meliessa , Gunnarsson Orvar , Mamtani Ronac , Vaughn David , Hoffman-Censits Jean , Nathanson Katherine , Lal Priti , Lal Priti , Pryma Daniel , Eliasof Scott , Garmey Edward , Cohen Roger B. , Haas Naomi B. 
Published: May 2015

Abstract
Introduction: The inactivation of VHL occurs in most clear cell RCC (ccRCC) tumors and gives rise to the HIF hypoxia response program and to tumor angiogenesis. While antiangiogenic therapies are active in ccRCC, resistance develops in all pts. We hypothesize that dual inhibition strategies will be useful in overcoming resistance. CRLX101 (Cerulean Pharma, Inc., Cambridge, MA, USA), a novel tumor-targeted nanopharmaceutical platform containing camptothecin as its payload, has been shown in pre-clinical models to target HIF and is synergistic with bevacizumab (bev). We combined CRLX101 with bev in refractory mRCC in order to determine the safety and the recommended phase 2 dose (RP2D) of the combination, and to determine its preliminary therapeutic activity in this setting. Experimental Procedures: Pts with mRCC of all histologic subtypes refractory to conventional antiangiogenic therapies were treated every 2 weeks with bev 10 mg/kg and escalating doses of CRLX101 (12 mg/m2, 15 mg/m2) in a standard 3+3 design with an expansion at the RP2D. Pts were treated until progression, death, or prohibitive toxicity. Adverse events were classified (CTCAE v 4.0), and radiographic results were assessed (RECIST v 1.1). Results Summary: 10 pts were enrolled on study with histologies of the following distribution - 6 clear cell, 2 papillary, 2 chromophobe. Pts had a median of 2 prior therapies. No dose limiting toxicities (DLTs) were observed. CRLX101 at its single-agent RP2D (15 mg/m2) was safely combined with standard bev. Two (2) episodes of grade 3 non-infectious cystitis and 1 episode of grade 3 hypertension were observed. All other toxicities were grade 1 or 2. The median progression free survival (PFS) was 7.6 months. One third of evaluable pts (33%) achieved a confirmed partial response (PR) including 1 patient with papillary mRCC; 4 pts (44%) had stable disease, and 2 had progressive disease as their best overall response. Prior therapies in the 3 PRs included sunitinib (all) and everolimus (all). PFS results from the stage 1 cohort exceeded the pre-specified threshold and have triggered 2nd stage accrual. Conclusions: CRLX101 can be safely combined with standard doses of bev in pts with refractory mRCC at a RP2D of 15 mg/m2 q2w of CRLX101. Preliminary outcomes to date are superior to historical controls in refractory ccRCC and suggest potential for clinical benefit across histologic subtypes of mRCC.
Citation Format: Stephen M. Keefe, Meliessa Hennessy, Orvar Gunnarsson, Ronac Mamtani, David Vaughn, Jean Hoffman-Censits, Katherine Nathanson, Priti Lal, Priti Lal, Daniel Pryma, Scott Eliasof, Edward Garmey, Roger B. Cohen, Naomi B. Haas. Phase 1b/2a study of the nanopharmaceutical CRLX101 with bevacizumab (bev) in the treatment of patients (pts) with refractory metastatic renal cell carcinoma (mRCC): results from the planned interim analysis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT340. doi:10.1158/1538-7445.AM2014-CT340