On January 4, 2022 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported that following a successful End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) for zilovertamab, the company’s investigational anti-ROR1 monoclonal antibody, the company and the FDA agreed on key elements of the company’s potentially pivotal Phase 3 clinical trial of zilovertamab for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL) (Press release, Oncternal Therapeutics, JAN 4, 2022, View Source [SID1234598085]). The FDA has also reviewed and agreed upon the key design features and operational details of the company’s Phase 3 clinical trial protocol and Statistical Analysis Plan, which is being finalized based on the FDA’s input.
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"The completion of End-of-Phase 2 meetings and consensus on clinical trial design and other program elements mark a meaningful and encouraging milestone for Oncternal Therapeutics," said James Breitmeyer, MD, PhD, Oncternal’s President and CEO. "The agreement underscores our productive dialogue with the FDA on key elements of our program and the Phase 3 clinical trial design as we align on the potential path to commercialization for zilovertamab, which offers potential advantages to patients suffering from aggressive lymphomas such as MCL. The positive data from our ongoing Phase 1/2 CIRLL study recently presented at ASH (Free ASH Whitepaper) 2021 underscore those advantages and are supportive of our registration strategy."
The Phase 3 superiority clinical trial ZILO-301 is entitled, "Randomized, Double-blind, Placebo-controlled, Multi-center Phase 3 Study of Zilovertamab (A ROR1 Antibody) Plus Ibrutinib Versus Ibrutinib Plus Placebo in Patients with Relapsed or Refractory Mantle Cell Lymphoma." Michael Wang MD, Endowed Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, will serve as the U.S. Principal Investigator and Chairman of the steering committee for this study. The study will randomize patients with relapsed or refractory MCL who have experienced stable disease or a partial response after receiving four months of oral ibrutinib therapy to receive either blinded zilovertamab or placebo, and all patients will continue receiving oral ibrutinib. The primary endpoint, intended to support submission of a Biologics License Application (BLA) seeking regular FDA approval, will be progression-free survival (PFS). An interim analysis potentially supporting submission of a BLA seeking accelerated FDA approval will be conducted with a primary endpoint of Overall Response Rate (ORR) plus Duration of Response (DOR). The FDA previously provided positive feedback on the sufficiency of the preclinical and pharmacology studies of zilovertamab needed to support a BLA submission.
Study ZILO-301 will be conducted internationally in at least 50 centers with demonstrated expertise treating MCL, with initiation expected in the second quarter of 2022. Sample size calculations are being finalized for this novel enrichment study, based on input from the FDA.
The company is also planning to conduct Study ZILO-302, an open-label companion study of zilovertamab plus ibrutinib for patients who have progressive disease during the initial four months of ibrutinib monotherapy from Study ZILO-301.
Oncternal Therapeutics will host a conference call today at 4:30 p.m. ET to provide further details on this important milestone. The live webcast of the call will be available online at investor.oncternal.com and the call will be archived there for at least 30 days.
The company will also provide details on its overall pipeline advancement during an R&D Day on January 25, 2022.
About Zilovertamab (formerly Cirmtuzumab)
Zilovertamab is an investigational, potentially first-in-class monoclonal antibody targeting ROR1, or Receptor tyrosine kinase-like Orphan Receptor 1. Zilovertamab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of MCL or chronic lymphocytic leukemia (CLL), 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, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine: (i) a Phase 1b clinical trial of zilovertamab in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer, and (ii) a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL.
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 zilovertamab, 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 zilovertamab 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 zilovertamab for the treatment of patients with MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication.