Background: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101+bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101+bevacizumab versus standard of care (SOC) in refractory mRCC. Patients and methods: 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 end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. Results: In total, 111 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, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0 .831). The objective response rate 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. Conclusions: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101+bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned.
Bibliographical noteFunding Information:
This trial was supported by Cerulean Pharmaceuticals (no grant number applies).
Patients treated at Memorial Sloan Kettering Cancer Center were supported in part by Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748).
MHV reports consulting/advisory role for Eisai, Exelixis, Novartis, Pfizer and has received research support from Roche/ Genentech and BMS. AH reports consulting/advisory role for Novartis and BMS. NV reports speaking engagements for BMS, Exelixis, and Roche/Genentech; consulting/advisory role for Norvartis, Pfizer, and Cerulean. JLL reports consulting/advisory role for AstraZeneca and Astellas and honoraria for AstraZeneca, Astellas, and Pfizer. UNV reports consulting/advisory role for Genentech, BMS, Exelixis, Novartis, Pfizer and has received research support from Novartis and BMS. SR reports consulting/ advisory role for Exelixis, Pfizer, Prometheus, and Sanofi and has received research funding from Novartis, BMS, Eisai, Genentech/ Roche, GSK, and Abbvie. AC reports consulting for BMS, Roche/ Genentech and speaker bureau for Merrimack. RJM reports consulting/advisory role for Pfizer, Novartis, Eisai, Exelixis and has received research support from BMS, Pfizer, Genentech/Roche, Eisai, Exelixis, and Novartis. NBH reports consulting/advisory role for Cerulean Pharmaceuticals, Novartis, and Exelixis. TH reports consulting/advisory role and has received research support for Pfizer, Novartis, Roche/Genentech, BMS, AVEO, Eisai, and Exelixis. The following authors are employees of Cerulean Pharmaceuticals: TC, JL, AS, and ES. All remaining authors have declared no conflicts of interest.
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