On December 9, 2019 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported the presentation of 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 chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) (Press release, Oncternal Therapeutics, DEC 9, 2019, View Source [SID1234552138]). The results were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando. A copy of the poster presentation is available online at www.oncternal.com.

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Thirty-four patients with CLL who had never been treated with a BTK inhibitor were enrolled in the dose-finding and dose-confirming cohorts of this clinical trial, including 12 treatment-naïve and 22 relapsed/refractory patients, and all 34 were evaluable for efficacy. As of the data cut-off in early November 2019,

Twenty-nine of the 34 patients achieved a response, for an overall best objective response rate of 85%.
One patient achieved a complete response (CR) and remained in remission six months after completion of the trial and discontinuation of all anti-CLL therapy. In addition, three patients met radiographic and hematologic response criteria for Clinical CR, bone marrow biopsy not performed but pending.
Five patients had stable disease.
The total clinical benefit rate was 100%.
None of the patients progressed or died, for a progression-free survival (PFS) of 100% with a median follow-up of 7.4 months.
Patients achieved responses rapidly, with 68% of patients achieving a clinical response by three months on combination therapy.
The rise in leukemic cell counts that is typically seen in the first six months with ibrutinib monotherapy was blunted with the cirmtuzumab plus ibrutinib combination, and leukemic cell counts returned toward baseline and normal levels rapidly.
Twelve patients with relapsed/refractory MCL, eight of whom were evaluable for efficacy, were enrolled in the dose-finding cohort of this trial. As of the data cut-off, five of the eight evaluable patients had achieved a clinical response, for an overall best objective response rate of 63% at a median follow-up of six months. Two patients with aggressive or bulky and heavily pre-treated MCL achieved CR, the longest of which is continuing with the patient on study for over 17 months. In addition, three patients had stable disease, for a total clinical benefit rate of 100%.

Cirmtuzumab as a single agent has been very well tolerated in this study. The combination of cirmtuzumab plus ibrutinib has also 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.

Genetic analysis of CLL cells from three patients showed pre-treatment transcriptome profiles associated with a stemness signature and NF-kB-driven inflammation. Both genetic signatures were reversed in these patients following cirmtuzumab treatment.

"It is exciting to see that cirmtuzumab in combination with ibrutinib continues to be well tolerated and has demonstrated 100% progression-free survival in patients with CLL, as well as encouraging early signals of efficacy in patients with MCL," said Michael Choi, M.D., Associate Clinical Professor of Medicine in the Division of Hematology-Oncology at University of California San Diego School of Medicine, who is the lead investigator for the CIRLL clinical trial.

The CIRLL clinical trial is supported by a grant from the California Institute for Regenerative Medicine (CIRM) and is being conducted in collaboration with the UC San Diego School of Medicine.

"We are encouraged by the evidence of clinical activity and the safety data demonstrated by cirmtuzumab in the ongoing CIRLL clinical trial. We continue to be excited about its potential for the treatment of patients with ROR1-expressing cancers, including CLL, MCL, Her2-negative breast cancer and other solid tumors," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO.

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 chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL). Part 1 of the clinical trial was a Phase 1 dose-finding cohort designed to determine the Phase 2 dose, or recommended dosing regimen (RDR). Part 2 is a Phase 1b expansion cohort to confirm the RDR. Part 3 of the study, which is now open for enrollment, is a Phase 2 study in which approximately 90 patients with CLL will be randomized to receive either ibrutinib alone or ibrutinib plus cirmtuzumab, with a primary endpoint of complete response rate. 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 and 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. CIRM has also provided funding to support development programs for cirmtuzumab and a CAR-T therapy that targets ROR1, which is currently in preclinical development as a potential treatment for hematologic cancers and solid tumors.

ROR1 is a potentially attractive target for cancer therapy because it is an oncofetal antigen – a protein that confers a survival and fitness advantage when reactivated and expressed by tumor cells. When expressed by hematologic malignancies such as CLL and MCL, ROR1 acts as a receptor for the tumor growth factor Wnt5a. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to inhibiting Wnt5a activation, 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 U.S. Food and Drug Administration for any indication.