On June 30, 2020 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported an updated clinical strategy for its investigational ROR1 monoclonal antibody, cirmtuzumab, that prioritizes development in mantle cell lymphoma (MCL), based on encouraging interim clinical results from the ongoing Cirmtuzumab and Ibrutinib targeting ROR1 for Leukemia and Lymphoma (CIRLL) Phase 1/2 clinical trial that were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Annual Meeting (ASCO 2020) in May 2020 (Press release, Oncternal Therapeutics, JUN 30, 2020, View Source [SID1234561582]).
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The Company reported a 58% complete response (CR) rate, a 83% overall best objective response rate (ORR), and a progression free survival rate of 17.5 months with a median follow-up of 8.3 months, for patients with relapsed/refractory MCL in the ongoing Phase 1/2 CIRLL clinical trial of cirmtuzumab in combination with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, at ASCO (Free ASCO Whitepaper) 2020. These response rates in heavily pre-treated patients were higher than the historical published CR of 23% and ORR of 67% for single-agent ibrutinib for patients with MCL who had received more than one prior therapy (Rule 2019, Haematologica). Four of these patients with MCL had been previously treated with and responded to ibrutinib, prior to participating in the CIRLL study. All four of these patients responded to the combination of cirmtuzumab and ibrutinib, two achieving CRs and two achieving partial responses. The Company believes that the interim results presented at ASCO (Free ASCO Whitepaper) 2020 are clinically relevant given the unmet medical need for patients with MCL.
As a result, the Company is amending the CIRLL study to increase the number of patients with relapsed/refractory MCL to be enrolled in the Phase 2 Expansion Cohort to at least 20 patients and to allow enrollment of patients with a broader range of prior BTK inhibitor treatments.
The Company has also requested a meeting with the U.S. Food and Drug Administration (FDA) to discuss the results of the recent interim analysis of the CIRLL study and to seek guidance on a potential accelerated approval pathway for cirmtuzumab plus ibrutinib in patients with relapsed/refractory MCL.
At ASCO (Free ASCO Whitepaper) 2020, the Company also reported a 100% progression-free survival rate, 88% ORR and 3% CR rate, with a median follow-up of 12.8 months, for patients with chronic lymphocytic leukemia (CLL) treated with cirmtuzumab in combination with ibrutinib in the CIRLL study. These interim data did not satisfy the hypothesis that ibrutinib plus cirmtuzumab would produce a CR rate 25% greater than the historical response rate for ibrutinib alone. Based on these interim results, Oncternal will continue treatment and follow-up of the patients with CLL who are already enrolled in the CIRLL study for up to two years or until disease progression, but will limit total enrollment of patients in the randomized Phase 2 CLL cohort to approximately 35 patients, in order to focus resources on the MCL portion of the study. The Company believes that, while significant unmet medical need exists in both CLL and MCL, the MCL indication may offer a more rapid path to potential regulatory approval.
Additionally, Oncternal plans to further explore clinical combination strategies for cirmtuzumab for patients with hematologic malignancies. Accordingly, the Company is supporting a new, investigator-sponsored Phase 2 clinical trial of cirmtuzumab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL in collaboration with the University of California San Diego School of Medicine (UC San Diego). Preclinical studies performed in the laboratory of Dr. Thomas Kipps at UC San Diego reported synergy between cirmtuzumab and venetoclax, providing a rationale for this combination clinical trial (Rassenti 2017, PNAS).
"We are excited about the promising clinical data reported for cirmtuzumab in combination with ibrutinib for patients with relapsed/refractory MCL, for whom a significant unmet medical need exists for well-tolerated therapies that provide more complete and durable responses. We plan to prioritize the development of cirmtuzumab for patients with MCL and expect that the planned changes will accelerate the Company’s timetable for initiating a potential registrational study for cirmtuzumab, while having an overall favorable budget impact," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "Additionally, we are pleased to support a new, investigator-sponsored Phase 2 clinical trial of cirmtuzumab in combination with venetoclax for the treatment of patients with CLL, based on promising published preclinical data. Our collaborators at UC San Diego and the California Institute for Regenerative Medicine (CIRM) have indicated that they support our revised development strategy for cirmtuzumab."
About the CIRLL Clinical Trial
The CIRLL clinical trial (Cirmtuzumab and Ibrutinib for Relapsed Lymphoma and Leukemia, Study CIRM-0001) is a Phase 1/2 trial evaluating cirmtuzumab in combination with ibrutinib in separate groups of patients with MCL or CLL. Enrollment has been completed in the dose-finding cohorts in CLL and MCL, and the dose-expansion cohort in CLL. Based on the data from the dose-finding cohorts, the recommended dosing regimen was determined to be 600 mg of cirmtuzumab administered intravenously every two weeks for three doses, followed by dosing every four weeks, in combination with 560 mg of ibrutinib once daily for patients with MCL, or 420 mg of ibrutinib administered once daily for patients with CLL, which are the FDA-approved doses of ibrutinib in these indications.
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 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. Cirmtuzumab is in clinical development and has not been approved by the FDA for any indication.