Phase 1b/2 Study of Cirmtuzumab and Ibrutinib in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL)
Authors: Lee Hun Ju , Choi Michael , Siddiqi Tanya , Barrientos Jacqueline , Wierda William G. , Isufi Iris , Tuscano Joseph , Lamanna Nicole , Subbiah Suki , Koff Jean L. , Leslie Lori A. , Goldenberg Alec , Chung Gina G , Breitmeyer James B. , Yazji Salim , Wang Yao , Wang Michael , Jamieson Catriona , Kipps Thomas J. 
Published: November 2021

Abstract
Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and has demonstrated additive/synergistic activity with many anticancer agents, including ibrutinib (Ibr).
Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment-naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr). MCL Part 1 is closed, and Part 2 is open for enrollment. CLL Parts 1, 2 & 3 are closed for enrollment.

Results: As of 18Jun2021 data cutoff, 28, 34 and 28 pts were treated in MCL Parts 1 & 2, CLL Parts 1 & 2, and CLL Part 3 (Cirm/Ibr (n=18) or Ibr (n=10)). In Parts 1 & 2 MCL, the median number (#) of prior systemic regimens was 1.5 (1-4) including pts relapsing after Ibr (n=4), auto-SCT (n=6), auto-SCT/allo-SCT (n=1), or auto-SCT/CAR-T (n=1). Ki-67 ≥30% and extra-nodal disease was present in 54% and 68% of pts, respectively. The median # of prior systemic regimens for CLL Parts 1 & 2 and CLL Part 3 (RR), was 2 (1-15) including auto-SCT (n=1), and 2 (1-6). Pts entered with Rai staging ≥ Grade 2 in 71% and 64%.
Safety (MCL and CLL): Most frequent treatment emergent (TEAEs) (≥30%) for both MCL and CLL pts treated with Cirm/Ibr (N=80), (all grades; regardless of causality) included contusion & fatigue (both 40.0%), and diarrhea (37.5%). Most frequent (≥5%) Grade ≥3 TEAEs, regardless of causality included hypertension (10.0%), fatigue, neutropenia, pneumonia, and atrial fibrillation (all 6.3%), leukocytosis and anemia (both 5.0%). Grade ≥3 TEAEs of myelosuppression, regardless of causality, include anemia (5.0%), thrombocytopenia (1.3%), and neutropenia (6.3%). Most TEAEs in MCL or CLL pts were considered related by Investigator to Ibr alone 64% or 84% vs. Cirm alone 14.3% or 16%.
Efficacy (MCL): The best response of 20 evaluable pts in Parts 1 & 2 included CR 35%, PR 45%, SD 10%, and 10% PD. At a median follow-up of 14.9 mos., the objective response rate (ORR), clinical benefit rate (CBR) and median duration of response (DOR) for overall, ≥30% Ki-67, and &gt;1 prior systemic regimen subgroups, were 80%, 90% and (not reached) NR (95% CI: 11.9, NR), 81.8%, 81.8% and 13.8 (95% CI: 8.7, NR), and 90%, 100% and NR (95% CI: 8.7, NR). Responses occurred in all evaluable pts who received prior SCT+/- CAR-T (4CR, 2PR) or prior Ibr (2CR, 2PR). The median PFS (mPFS) for overall, pts achieving CR, and &gt;1 prior systemic regimen subgroups were all NR with varying 95% CI: (16.5, NR), (0.03, NR), and (0.03, NR).
Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 & 2 included 94.1% ORR, 11.8% CR, 82.3% PR/PR-L, and 5.9% SD for a CBR of 100%. In Part 3, evaluable Cirm/Ibr TN (n=8) or RR (n=7) and Ibr TN (n=4) or RR (n=3) arms achieved 100% or 85.7% and 100% or 100% ORR, 12.5% or 0% and 0% or 0% CR, 87.5% or 85.7% and 100% or 100% PR/PR-L, 0% or 14.3% and 0% or 0% SD. No pts had PD as best response. All pts had a CBR of 100%. For Parts 1 & 2, at a median follow-up of 24.8 mos., the DOR for overall and &gt;1 prior systemic regimen subgroups, was NR (8.3, 35.9) and NR (12.0, 29.6). In Part 3, at a median follow-up of 14.7 mos., the DOR for TN or RR Cirm/Ibr and Ibr arms is NR (7.7, 18.6) or NR (9.2, 14.8) and NR (11.2, 18.5) or NR (8.3, 14.2). The mPFS (Parts 1 & 2) for overall, pts achieving CR, and &gt;1 prior systemic regimen subgroups were NR (9.1, 35.8), NR (95% CI: 22.5, NR), and NR (9.1, 35.2). In Part 3, mPFS for TN or RR Cirm/Ibr and Ibr arms is all NR.
Conclusions: Cirm/Ibr is well-tolerated. ORR, CR, DOR, and mPFS were similar across all subgroups of MCL and CLL pts regardless of number of prior systemic regimens or poor risk factors. Striking responses were observed in patients with MCL as evidenced by a mPFS that was NR (95% CI: 16.5, NR), CR of 35%, and a DOR of NR (95% CI: 11.9, NR) within the study period. These data compare very favorably to the mPFS of 12.8 mos, CR of 20%, and a DOR of 18.6 mos., reported for Ibr alone (Rule 2017). For CLL pts treated with Cirm/Ibr, results continue to be encouraging as they mature. The study is ongoing, with MCL enrollment expanded to include Cirm + Ibr in pts who have had an inadequate response to an Ibr regimen, or who are refractory to approved BTKi agents.
Figure 1 Figure 1.

Disclosures
Lee: Oncternal: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Seagen: Research Funding; BMS: Honoraria, Research Funding; Aptitude Health: Honoraria; Guidepoint: Honoraria; Century Therapeutics: Consultancy; Pharmacyclics: Research Funding; Janssen: Honoraria. Choi: Abbvie: Other: Institution: Research Grant/Funding; Pharmacyclics: Other: Institution: Research Grant/Funding; Oncternal: Other: Institution: Research Grant/Funding; Velosbio: Other: Institution: Research Grant/Funding; Merck: Other: Institution: Research Grant/Funding; Geron: Other: Institution: Research Grant/Funding. Siddiqi: Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Speakers Bureau; Oncternal: Research Funding; TG Therapeutics: Research Funding. Wierda: Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Karyopharm: Research Funding; Xencor: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; KITE Pharma: Research Funding; Miragen: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; Loxo Oncology, Inc.: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Tuscano: BMS: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding. Leslie: Abbvie: Consultancy, Honoraria; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy. Breitmeyer: Oncternal Therapeutics: Current Employment, Membership on an entity's Board of Directors or advisory committees. Yazji: Oncternal Therapeutics: Current Employment. Wang: Oncternal Therapeutics: Current Employment. Wang: OMI: Honoraria; Moffit Cancer Center: Honoraria; Chinese Medical Association: Honoraria; Newbridge Pharmaceuticals: Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; InnoCare: Consultancy, Research Funding; Scripps: Honoraria; Mumbai Hematology Group: Honoraria; VelosBio: Consultancy, Research Funding; BioInvent: Research Funding; Hebei Cancer Prevention Federation: Honoraria; Epizyme: Consultancy, Honoraria; Anticancer Association: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Lilly: Research Funding; Physicians Education Resources (PER): Honoraria; Dava Oncology: Honoraria; Clinical Care Options: Honoraria; Molecular Templates: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Imedex: Honoraria; Juno: Consultancy, Research Funding; Celgene: Research Funding; Genentech: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Bayer Healthcare: Consultancy; BGICS: Honoraria; CAHON: Honoraria; Oncternal: Consultancy, Research Funding; CStone: Consultancy. Jamieson: Forty Seven Inc.: Patents & Royalties. Kipps: Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; Genentech/Roche: Honoraria; European Research Initiative on CLL (ERIC): Honoraria; Genetech: Honoraria, Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Bionest Partner: Other; DAVA Pharmaceuticals: Speakers Bureau; DAVAOncology: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; Moores Cancer Center: Current Employment; MedImmune Inc: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbott Laboratories: Consultancy, Research Funding.