Following a successful End-of-Phase 2 meeting Oncternal Therapeutics, a clinical-stage biopharmaceutical company, and U.S. Food and Drug Administration (FDA) reached a consensus on the design and major details of the Phase 3 superiority Study ZILO-301, to treat patients with relapsed or refractory mantel cell lymphoma (MCL) with zilovertamab (previously known as cirmtuzumab and UC-961) plus ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech)
Zilovertamab is an investigational, potentially first-in-class monoclonal antibody targeting ROR1, or Receptor tyrosine kinase-like Orphan Receptor 1.
The drug 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 Therapeutics is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine, including 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 a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL.
Unmet medical need
Mantel cell lymphoma and chronic lymphocytic leukemia are cancers of B-cells that can cause disabling constitutional symptoms including lymph node and/or spleen/liver enlargement, and bone marrow infiltration. In turn, this causes marrow failure, immune deficiency, morbidity, and early mortality.
In the United States approximately 4,200 and 21,000persons respectively are diagnosed with MCL and CLL annually. There are currently no curative therapies. Patients with MCL or CLL generally require successive rounds of therapy and often develop refractory disease.
Ibrutinib (IMBRUVICA®) is an orally administered inhibitor of Bruton’s tyrosine kinase, that has become a standard of care in the modern treatment of CLL and MCL. However, most patients with CLL achieve only a partial response with ibrutinib, which then must be administered continuously, resulting in a greater potential for side effects, which is an enhanced health care burden for patients, and substantial therapeutic costs. The proportion of patients with CLL who achieve a complete response to ibrutinib after 12 months of therapy is below 10%.
In previously treated patients with MCL, rates of complete response range from 12.5% to 23%, even with long-term, continuous therapy. Resistance to ibrutinib eventually develops in many patients with CLL and the great majority of patients with MCL. Hence, a new therapeutic agent that increases the complete response rate of CLL and MCL to ibrutinib is urgently needed.
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 target ROR1 expressing tumors. This led to the development of zilovertamab, which 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.
Oncternal Therapeutics 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). 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.
“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, Ph.D., Oncternal’s President and Chief Executive Officer.
“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 2021 underscore those advantages and are supportive of our registration strategy,” Breitmeyer added.
Phase 3 Study: ZILO-301
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 the new phase 3 superiority study ZILO-301. The study randomizes patients with relapsed or refractory MCL who have experienced stable disease or 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.
The ZILO-301 study 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.
Oncternal Therapeutics 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.
Extension Study of UC-961 (Cirmtuzumab) for Patients With Chronic Lymphocytic Leukemia Treated Previously With UC-961 – NCT02860676
UC-961 (Cirmtuzumab) in Relapsed or Refractory Chronic Lymphocytic Leukemia – NCT02222688
Study of Cirmtuzumab and Paclitaxel for Metastatic or Locally Advanced, Unresectable Breast Cancer – NCT02776917
A Study of Cirmtuzumab and Ibrutinib in Patients With B-Cell Lymphoid Malignancies – NCT03088878
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 (ZILO-301)
Highlights of prescribing information
Ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech)(Perscription Information)
 Zhang S, Zhang H, Ghia EM, Huang J, Wu L, Zhang J, Lam S, Lei Y, He J, Cui B, Widhopf GF 2nd, Yu J, Schwab R, Messer K, Jiang W, Parker BA, Carson DA, Kipps TJ. Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody. Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1370-1377. doi: 10.1073/pnas.1816262116. Epub 2019 Jan 8. PMID: 30622177; PMCID: PMC6347692.
 Balakrishnan A, Goodpaster T, Randolph-Habecker J, Hoffstrom BG, Jalikis FG, Koch LK, Berger C, Kosasih PL, Rajan A, Sommermeyer D, Porter PL, Riddell SR. Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues. Clin Cancer Res. 2017 Jun 15;23(12):3061-3071. doi: 10.1158/1078-0432.CCR-16-2083. Epub 2016 Nov 16. PMID: 27852699; PMCID: PMC5440207.
Featured image: Low magnification micrograph of mantle cell lymphoma of the terminal ileum. Endoscopic biopsy. H&E stain. Photo Courtesy: 2020. Nephron. This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.