Therapy Areas: Oncology
Oncternal Therapeutics Opens Phase 1b Expansion Cohort of Clinical Trial of Cirmtuzumab in Combination with Ibrutinib in Patients with Mantle Cell Lymphoma
4 October 2019 - - US-based clinical-stage biopharmaceutical company Oncternal Therapeutics, Inc. (NASDAQ: ONCT) has opened for enrollment a Phase 1b expansion cohort of its Phase 1/2 clinical trial of cirmtuzumab, a ROR1-targeted monoclonal antibody, combined with ibrutinib, in patients with mantle cell lymphoma, the company said.

The decision to open an expansion cohort in MCL of the ongoing Phase 1/2 CIRLL (Cirmtuzumab and Ibrutinib targeting ROR1 for Leukemia and Lymphoma) clinical trial was based on favorable interim results from the dose-finding cohort of the trial, including that the combination was well-tolerated and that complete responses were observed in two heavily pre-treated patients who had received and failed multiple chemotherapy regimens and an autologous transplant, as well as either an allotransplant or CAR-T therapy, prior to participating in this clinical trial.

In June, the company presented interim data at the American Society of Clinical Oncology annual meeting, including the preliminary results from the first six patients with MCL treated in the CIRLL clinical trial.

One patient with MCL, who had relapsed following an allogeneic stem cell transplant, experienced a confirmed complete response after three months of cirmtuzumab plus ibrutinib treatment, including complete resolution of a large mediastinal mass.

This CR appears to be sustained and has been confirmed to be ongoing after completing 12 months of cirmtuzumab plus ibrutinib treatment. Following ASCO, a second confirmed CR occurred in a patient who had progressive disease after failing several different chemotherapy regimens, autologous transplant and CAR-T therapy.

Additional data from this clinical trial will be presented at a future medical conference.

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

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 or mantle cell lymphoma.

Part 1 of the clinical trial was a Phase 1 dose-finding portion designed to determine the Phase 2 dose, or recommended dosing regimen.

Part 2 is a Phase 1b expansion cohort to confirm the RDR.

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.

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 US Food and Drug Administration for any indication.

Oncternal Therapeutics is a clinical-stage biopharmaceutical company focused on developing product candidates for the treatment of cancers with critical unmet medical need.

Oncternal focuses drug development on promising yet untapped biological pathways implicated in cancer generation or progression.

The pipeline includes cirmtuzumab, an investigational monoclonal antibody designed to inhibit the ROR1 receptor, a type I tyrosine kinase-like orphan receptor, that is being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma, and TK216, an investigational small-molecule compound that is designed to inhibit E26 transformation specific family oncoproteins, that is being evaluated in a Phase 1 clinical trial for patients with Ewing sarcoma alone and in combination with vincristine chemotherapy.

In addition, Oncternal has a program to develop a CAR-T therapy that targets ROR1, which is currently in preclinical development as a potential treatment for hematologic cancers and solid tumors.
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