A randomized phase 2 trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma

Nanoparticle-drug conjugates (NDC) enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel NDC containing camptothecin a potent inhibitor of topoisomerase I and the hypoxia-inducible factors (HIF) 1α and 2α. In a phase 1b/2 trial, CRLX101+bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase 2 trial comparing CRLX101+bevacizumab versus standard of care (SOC) in refractory mRCC.

Patients with mRCC and 2-3 prior lines of therapy were randomized 1:1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary endpoint was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety.

One hundred eleven patients were randomized and received ≥1 dose of drug (CRLX101+bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101+bevacizumab and SOC arms was 3.7 months (95% confidence interval [CI]: 2.0-4.3) and 3.9 months (95% CI: 2.2-5.4), respectively (stratified Log-rank p = 0.831). The ORR by IRR was 5% with CRLX101+bevacizumab versus 14% with SOC (Mantel-Haenszel test, p = 0.836). Consistent with previous studies, the CRLX101+bevacizumab combination was generally well tolerated, and no new safety signal was identified.

Despite promising efficacy data on the earlier phase 1b/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101+bevacizumab combination when compared to approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned.

NCT02187302 (NIH).

Annals of oncology : official journal of the European Society for Medical Oncology. 2017 Sep 11 [Epub ahead of print]

M H Voss, A Hussain, N Vogelzang, J L Lee, B Keam, S Y Rha, U Vaishampayan, W B Harris, S Richey, J M Randall, D Shaffer, A Cohn, T Crowell, J Li, A Senderowicz, E Stone, R Figlin, R J Motzer, N B Haas, T Hutson

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA., Department of Medicine, Greenebaum Cancer Center, University of Maryland, Baltimore, USA., Department of Hematology/Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, USA; US Oncology Research., Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea., Department of Internal Medicine,Seoul National University Hospital, Seoul, Korea., Department of Medicine, Severance Hospital, Seoul, Korea., Department of Oncology, Karmanos Cancer Institute, Detroit, USA., Department of Hematology/Oncology, Emory University Winship Cancer Institute, Atlanta, USA., Department of Medicine, Texas Oncology- Fort Worth, USA; US Oncology Research., Department of Medicine, University of California, San Diego, La Jolla, USA., Department of Medicine, Albany Medical Center, NYOH, Albany, USA; US Oncology Research., Department of Clinical Research, Rocky Mountain Cancer Centers, Denver, USA; US Oncology Research., Department of Medicine, Cerulean Pharma Inc., Waltham, USA., Department of Medicine, Cedars-Sinai Medical Center; Los Angeles, USA., Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA., Department of Medicine, Texas Oncology, Dallas, USA; US Oncology Research.