On December 7, 2020 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported updated interim clinical data from the ongoing Phase 1/2 CIRLL (Cirmtuzumab and Ibrutinib targeting ROR1 for Leukemia and Lymphoma) clinical trial, in which cirmtuzumab, an investigational anti-ROR1 monoclonal antibody, is being evaluated in combination with ibrutinib in patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) (Press release, Oncternal Therapeutics, DEC 7, 2020, View Source [SID1234572351]). The clinical trial is being partially funded by the California Institute for Regenerative Medicine. The data were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2020 Virtual Annual Meeting, and a copy of the poster presentation is available online at www.oncternal.com:
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
Abstract Title: 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 (abstract # 2942)
Session Title: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma – Clinical Studies: Poster III
Session Date and Time: December 7, 2020, 7:00 a.m. – 3:30 p.m. (Pacific Time)
"The interim data from the combination of cirmtuzumab and ibrutinib are quite promising in relapsed/refractory (r/r) MCL, with an impressive 87% best ORR that has improved over time. The time to response, depth and durability of responses make cirmtuzumab a compelling candidate for further development," said Hun Ju Lee, M.D., Associate Professor of Medicine in the Department of Lymphoma & Myeloma at the University of Texas MD Anderson Cancer Center, who is an investigator on the CIRLL clinical trial and was also the first author on the 2020 ASCO (Free ASCO Whitepaper) poster presentation.
"We are pleased that median PFS has not yet been reached after a median follow-up of over 12 months in the MCL patients, and are encouraged that both PFS and ORR have improved with longer follow-up," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "We are in active dialogue with FDA on pivotal study design in order to define the path to approval in MCL."
As of the data cut-off date of October 30, 2020, 15 patients with relapsed/refractory MCL enrolled in the dose-finding and dose-expansion cohorts of this clinical trial were evaluable for efficacy:
The overall best objective response rate (ORR) was 87% (13 of 15 evaluable patients), improved over the 83% ORR reported at ASCO (Free ASCO Whitepaper) 2020.
The complete response (CR) rate, determined by Cheson criteria, remains 57% (7 of 12 evaluable patients) for Part 1 of the study, and is 47% (7 of 15 evaluable patients) for Part 1 + Part 2, including the three patients from Part 2 who have shorter followup. One of the seven patients had a complete metabolic response (CMR) as assessed by PET scan, with an indeterminate bone marrow biopsy on blinded review. All complete responses remained durable, ranging from 5-25 months as of the cutoff date, with no progressions reported after achieving a CR. Six patients (40%) achieved a partial response (PR). In addition, two patients had stable disease (SD), for a total best clinical benefit rate (CR, PR and SD) of 100%.
Median progression-free survival (PFS) was not reached, with the 95% confidence interval above 17.5 months, after a median follow-up of 12.1 months.
Patients had received a median of two prior therapies (range 1-5) before participating in this clinical trial, with 73% of patients with two or more prior lines of therapy. Four patients had received prior treatment with ibrutinib and all four achieved clinical responses in this clinical trial, with two CRs and two PRs. Fourteen of the 15 evaluable patients (93%) had high or intermediate MCL International Prognostic Index (MIPI-b) risk score at study entry.
Historical data published for single-agent ibrutinib for 370 patients with r/r MCL, who had received a median of two prior therapies, reported an ORR of 66%, CR rate of 20%, PR rate of 46%, and median PFS of 12.8 months (Rule et al., 2017, British Journal of Haematology).
As of the data cut-off date on October 30, 2020, 56 evaluable patients with CLL were enrolled in the dose-finding, dose-confirming and randomized cohorts of this clinical trial, 49 of whom were treated with the combination of cirmtuzumab and ibrutinib:
Forty-five of the 49 patients achieved a clinical response, for an overall best objective response rate of 92%, including one patient who achieved a CR. In addition, four patients had stable disease, for a total clinical benefit rate (CR, PR, and SD) of 100%.
The median PFS was not reached for patients with treatment-naïve CLL (n=19) after a median follow-up of 16.6 months, and median PFS was 29.5 months for patients with r/r CLL (n=30) after a median follow-up of 17.1 months.
The combination of cirmtuzumab plus ibrutinib has been well tolerated, with adverse events consistent with those reported for ibrutinib alone. There have been no dose-limiting toxicities and no serious adverse events attributed to cirmtuzumab alone.
About the CIRLL Clinical Trial
The CIRLL clinical trial (CIRM-0001) is a Phase 1/2 trial evaluating cirmtuzumab in combination with ibrutinib in separate groups of patients with CLL or MCL. Enrollment of the dose-finding cohorts in CLL and MCL, dose-expansion cohort in CLL and randomized Phase 2 cohort in CLL has been completed. Enrollment of the dose-expansion cohort in MCL is ongoing. Additional information about the CIRM-0001 clinical trial and other clinical trials of cirmtuzumab may be accessed at ClinicalTrials.gov.
About Cirmtuzumab
Cirmtuzumab is an investigational, potentially first-in-class monoclonal antibody targeting ROR1, or Receptor tyrosine kinase-like Orphan Receptor 1. Cirmtuzumab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of CLL or MCL, in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, an investigator-initiated Phase 1 clinical trial of cirmtuzumab in combination with paclitaxel for women with metastatic breast cancer is being conducted at the UC San Diego School of Medicine.
ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen – not usually expressed on adult cells, and its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically targeting ROR1 expressing tumors. This led to the development of cirmtuzumab, that binds this critical epitope of ROR1, which is highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when cirmtuzumab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to cirmtuzumab for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. Cirmtuzumab is in clinical development and has not been approved by the FDA for any indication.