On December 12, 2019 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported the presentation of interim data from the ongoing, investigator-sponsored Phase 1b clinical study of cirmtuzumab, its investigational anti-ROR1 monoclonal antibody, in combination with paclitaxel in patients with HER2-negative, metastatic or locally-advanced unresectable breast cancer (Press release, Oncternal Therapeutics, DEC 12, 2019, View Source [SID1234552329]). The results were presented at the San Antonio Breast Cancer Symposium (SABCS) in San Antonio, TX. A copy of the poster presentation is available online at www.oncternal.com.

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As of the data cut-off date of November 27, 2019, a total of eight patients with HER2-negative, metastatic or locally-advanced unresectable breast cancer were enrolled in the study. Seven of the eight patients were evaluable for safety and efficacy. Four of the patients had triple negative breast cancer (TNBC) at study enrollment.

Four of the seven evaluable patients achieved a partial response, for an objective response rate of 57%, including one partial response that continued on cirmtuzumab alone for 30 weeks after discontinuing paclitaxel.

The combination of cirmtuzumab and paclitaxel has been well tolerated in this trial, with no study discontinuations for toxicity and no dose-limiting toxicities observed to date. Adverse events have been consistent with the known safety profile of paclitaxel alone.

Pharmacokinetic analysis of serial plasma samples for free unbound antibody from two patients provided results similar to those observed in previous studies of chronic lymphocytic leukemia patients, consistent with a projected half-life of 30 days. No decline in antibody concentration over time was observed, consistent with the absence of neutralizing antibodies.

"It is encouraging to see that cirmtuzumab in combination with paclitaxel has been well tolerated and is active. Future studies will determine whether cirmtuzumab is contributing to the known activity of paclitaxel. Advanced breast cancer patients are in need of improved treatment options with acceptable side effects. We look forward to completing enrollment and treating additional patients in this study," said Rebecca Shatsky, M.D., Assistant Clinical Professor, Medicine at University of California San Diego School of Medicine, lead investigator who presented the poster.

Funding for this trial was provided by Oncternal Therapeutics, California Institute for Regenerative Medicine, UC San Diego Alpha Stem Cell Clinic and Sanford Stem Cell Clinical Center, UC San Diego Moores Cancer Center, Padres Pedal the Cause Grant, and Gonick Breast Cancer Research Funds.

"The early activity signals for cirmtuzumab in combination with paclitaxel for patients with breast cancer seen in this study are encouraging. We believe these data, taken together with the previously updated clinical data in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) from the CIRLL study presented at the annual ASH (Free ASH Whitepaper) meeting, reinforce the encouraging safety data and provide evidence of clinical activity of cirmtuzumab and its potential for the treatment of patients with breast cancer and other ROR1-expressing solid tumors and hematological malignancies," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO.

About the Clinical Trial

This clinical trial is an investigator-sponsored Phase 1b Pilot Clinical Trial of Cirmtuzumab, an Anti-ROR1 Monoclonal Antibody, in Combination with Paclitaxel for the Treatment of Patients with Metastatic, or Locally Advanced, Unresectable Breast Cancer. The objectives of the trial include the evaluation of safety, tolerability, pharmacokinetics, and clinical activity. Eligible patients are those with locally-advanced, unresectable or metastatic HER2-negative breast cancer who had not received paclitaxel in the metastatic setting. Study treatment included a fixed dose of 600 mg cirmtuzumab given on days 1 and 15 of cycle 1, and then on day 1 of each subsequent 28-day cycle. Paclitaxel was given weekly at a dose of 80 mg/m2. Additional information about the clinical trial may be accessed at ClinicalTrials.gov (NCT02776917).

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 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. 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.