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.

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

“…In January 2018, a phase Ib/II Study (NCT03088878) was implemented, investigating the safety and effectiveness of a combined treatment with cirmtuzumab and ibrutinib in patients with B cell lymphoid malignancies. Interim results again showed a good tolerability, no dose-limiting toxicity, and an acceptable effectiveness [ 174 ].…”

Immunotherapeutic Strategies in Chronic Lymphocytic Leukemia: Advances and Challenges

“…The ability of re-converting the immune system from CLL patients to a more effective status has led to the addition of ibrutinib to other regimens, with significant improvement of tumor control. Preclinical and clinical results have already demonstrated the ability of ibrutinib in i) improving the efficacy of the novel mAbs cirmtuzumab ( 52 , 53 ), ianalumab ( 59 ) and BI 836826 ( 48 ), ii) enhancing the susceptibility of CLL cells to BiTE-mediated killing ( 66 , 67 ), and iii) potentiating the generation, functionality and curative effects of CAR T cells ( 88 , 89 ). Similarly, other agents capable of modulating the immune system, such as avadomide, have shown promising results when administered in combination with checkpoint inhibitors ( 23 ), thus leading to reconsider active immunotherapy as a potential therapeutic option for patients with CLL.…”

“…A recent target being explored in patients with CLL is the receptor tyrosine kinase-like orphan receptor 1 (ROR1), that is selectively expressed only on cancer cells. The combination of ibrutinib with cirmtuzumab, a ROR1-directed mAb, was investigated in a phase 1/2 trial, showing a good tolerability together with a significant efficacy ( 52 , 53 ). Interestingly, the anti-ROR1 antibody-drug conjugate zilovertamab vedotin (VLS-101) has shown a strong activity in xenograft models of CLL transformed into Richter syndrome (RS) ( 54 ), thus providing the basis for the currently ongoing phase 1 clinical trial investigating VLS-101 safety and efficacy in patients with hematologic malignancies, including CLL (NCT03833180).…”