Phase 1/2 trial of cirmtuzumab and ibrutinib: Planned analysis of phase 1 CLL cohorts.

Abstract

7527 Background: Cirmtuzumab (C) is a humanized mAb that binds ROR1 and blocks Wnt5a from binding and activating ROR1 on CLL and mantle cell lymphoma (MCL); C does not bind normal adult tissues. A phase 1 trial of C showed excellent safety and inhibition of Wnt5a-ROR1 signaling. Ibrutinib (Ibr) does not inhibit the ROR1 pathway, and C+Ibr exert synergistic effects in CLL and MCL. The current clinical trial combines C+Ibr for patients (pts) with CLL and MCL. A planned analysis of the phase 1 CLL portion is presented. Methods: Eligible pts had CLL needing treatment according to iwCLL guidelines. C was given at 2, 4, 8, or 16 mg/kg q 2 wk for 8 wk, then q 28 d to 52 wk. Ibr 420 mg PO daily was started on d 28. Results: 3 pts were treated at each C dose level with age 57-86; 75% were previously treated (median 2); 3 pts had del(11q), 3 had trisomy 12, and 6 pts had unmutated IGVH genes. There were no discontinuations for toxicity and no dose limiting toxicities. Treatment with C alone and combined with Ibr was well-tolerated. One SAE occurred with C monotherapy (hospitalization for tonsillitis). Adverse events on C+Ibr were consistent with the known Ibr safety profile, with one grade 3 hyperkalemia and 1 atrial fibrillation event. All other AEs were grade 1 or 2. The overall response rate after 16-48 weeks of treatment was 67% with 1 confirmed complete response (CR) with no morphologic evidence of CLL in the marrow, 1 clinical CR, 6 partial responses (PR) and 4 stable disease. No patient had progressive disease. The typical redistributive lymphocytosis seen with Ibr was blunted, with only a 50% mean rise in ALC, rapidly returning to baseline. PRs were observed in all C dose levels. Conclusions: The combination of C+Ibr is well-tolerated and effective. CRs were observed in 2 cases, a result that would be highly unusual with Ibr monotherapy in CLL. Based on these findings, Cirm 600 mg was selected as the RP2D for the randomized phase 2 portion of this protocol, which will prospectively compare the complete response rates between C+Ibr and Ibr alone. Clinical trial information: NCT03420183.