Cirmtuzumab is a novel humanized monoclonal antibody that binds the oncoembryonic ROR1 antigen and blocks the Wnt5a receptor from binding and activating ROR1 in chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma (MCL). Because ROR1 is expressed by tumor cells in many cancers, including CLL and MCL, it is a logical target for anticancer therapy. Cirmtuzumab does not bind normal adult tissues, and a phase 1 trial showed promising safety and inhibition of Wnt5a-ROR1 signaling. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, does not inhibit the ROR1 pathway; therefore, it was postulated that cirmtuzumab plus ibrutinib exerts synergistic effects in CLL and MCL.
At the ASCO 2019 Annual Meeting, a planned analysis of the phase 1 CLL portion of the clinical trial combining cirmtuzumab and ibrutinib was presented. Eligible patients were those with CLL in need of treatment according to International Workshop on Chronic Lymphocytic Leukemia guidelines. Patients received a 2-, 4-, 8-, or 16-mg/kg dose of cirmtuzumab every 2 weeks for the first 8 weeks, then every 28 days up to 52 weeks. Ibrutinib 420 mg was given daily in accordance with FDA-approved dosing for 48 weeks.
Participating patients (N = 12) ranged from age 57 to 86 years; 75% were treated previously. Several patients had high-risk disease features, including 3 with del(11q), 3 with trisomy 12, and 6 with unmutated IGHV. Two patients discontinued treatment, one patient due to worsening heart failure and the other secondary to atrial fibrillation, pericardial effusion, and tamponade. Neither discontinuation was attributable to cirmtuzumab. Adverse events with cirmtuzumab plus ibrutinib were consistent with the known ibrutinib safety profile.
In terms of efficacy, the on-treatment objective response rate was 91.7% as of the data cutoff. There was 1 confirmed complete response (CR) with no morphologic evidence of CLL in the marrow and 2 patients had clinical CR. Cirmtuzumab 600 mg and ibrutinib 420 mg were selected as the recommended dose regimen for Part 2 of the trial, which will prospectively compare cirmtuzumab plus ibrutinib with ibrutinib alone.
Abstract 7527; Choi MY, et al.