Cirmtuzumab, an Anti-ROR1 Antibody, in Combination with Ibrutinib: Clinical Activity in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL) from a Phase 1/2 Study

Introduction: Cirmtuzumab (Cirm) is a high-affinity humanized monoclonal antibody designed to inhibit the tumor promoting activity of ROR1. In this study, we examined the safety and efficacy of Cirm in combination with ibrutinib (Ibr) in patients (pts) with MCL or CLL. ROR1 is an onco-embryonic tyrosine kinase-like receptor that is found at high levels on the cell surface of many hematologic and solid cancers. Activation of ROR1 by binding its ligands such as Wnt5a results in increased intracellular signaling, tumor growth and survival, enhanced cancer cell stemness and epithelial mesenchymal transition.

Methods: Pts with relapsed or refractory (RR) MCL or treatment naïve (TN) or RR CLL were enrolled and treated in separate groups. In Part 1 Dose Escalation (DE), groups of MCL and CLL pts received Cirm IV q2wks x5 doses then q4wks at assigned doses of 2-16 mg/kg, and in CLL, additional fixed dose levels of 300 or 600 mg were evaluated. The safety and PK of single-agent Cirm was assessed during the first 28 days, and then Ibr was started at 560 mg/day PO for MCL or 420 mg/day PO for CLL. After reviewing the safety and PK data from Part 1, a recommended regimen of fixed dose Cirm 600 mg IV q2wks x3 then q4wks plus Ibr starting D0 was chosen for use in Parts 2 and 3. In Part 3, CLL pts (only) were randomized to either Cirm/Ibr vs. Ibr alone

Results: As of April 30, 2020, 12 evaluable MCL pts were enrolled into Part 1 DE. Of these pts, 83% (10) had received ≥ 2 separate prior treatment regimens. In CLL, 34 pts (12 TN and 22 RR pts) enrolled into Part 1 DE (n= 18) or Part 2 Expansion (n= 16). At least 79% of CLL pts in Parts 1 and 2 were high risk as determined by unmutated IGHV, del17p, and/or del11q. Safety: For both MCL and CLL, the most common adverse events (AEs) considered at least possibly related to Cirm alone were grade 1/2 (e.g. fatigue, 6%) with no dose limiting toxicities or discontinuations. The combination of Cirm plus Ibr was well tolerated, with no new or accentuated AEs compared to the known safety profile of Ibr alone. Cirm may be lowering the rates of certain AEs normally seen with Ibr; for example, neutropenic events were <10%, while neutropenia is commonly reported in about 40% of patients receiving single-agent Ibr. Efficacy for MCL: 12 pts in Part 1 were evaluable: 83% ORR (10), 58% CR/CMR (7), 25% PR (3), 17% SD (2). CR/CMR was achieved at a median of 3.8 mos and was achieved in heavily pretreated pts who had relapsed after Ibr (2), auto-SCT (2), auto-SCT and allo-SCT (1), auto-SCT and CAR-T. In high-risk pts based on Ki-67 levels ≥50% (n= 4), 2 CRs (50%) and 1 PR (25%) were observed, compared to a CR rate reported for Ki67 high MCL pts of 17% when treated with Ibr + rituximab (Wang, et al. Lancet Onc 2016). Median follow-up was 8.3 mos, and the median PFS was 17.5 mos. Efficacy for CLL pts in Parts 1 and 2: 88% ORR [92% TN (11/12), 86% RR (19/22)], 3% CR (1), 85% PR (25)/PR-L (4), 12% SD (4). In addition, 3 PR pts met radiologic and other criteria for CR except for marrow involvement. The CLL pt achieving a CR had RR disease with unmutated IGHV and del11q; this pt remains in remission >8 mos after stopping all therapy. At a median follow-up of 12.8 mos, 100% of CLL pts were free of disease progression and 82% remained on study. CLL cells collected after the first 28 days of treatment showed a decrease in stemness signature (Choi et al, Cell Stem Cell 2019), with similar reductions seen with single agent Cirm or Cirm + Ibr. Additional pts have been enrolled into Part 2 Expansion MCL and into Part 3 CLL. Early data from these arms are not yet available and will be reported later.

Conclusions: Cirmtuzumab in combination with ibrutinib is a well-tolerated and active regimen for RR MCL and TN or RR CLL. The 58% CR/CMR rate for MCL compares favorably to published data with single agent Ibr of 27% (Rule, et al. Haematologica 2019) and it is encouraging that responses occurred in heavily pretreated pts, including those with high Ki-67 expression. In CLL, the high ORR and interim PFS are encouraging; the significance of these observations will be determined with longer follow-up. These data support the continued investigation of this regimen in ROR1-expressing hematologic and solid malignancies. This study is ongoing, and due to the high CR rate in MCL pts, the number of pts to be enrolled in the Part 2 Expansion will be increased to further characterize the safety and efficacy of this combination.