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

Abstract

Background: 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 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 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.Results: 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.Conclusions: 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.Clinical trial identification: NCT02187302 (NIH)

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