Global ZILO-301 Study of Zilovertamab for MCL to Initiate in Q3 2022

Oncternal Therapeutics is focusing its resources on a global trial of zilovertamab plus ibrutinib (Imbruvica) for patients with relapsed/refractory mantle cell lymphoma (R/R MCL) in late 2022, according to a press release.¹

The company announced it was terminating its phase 1/2 study of ONCT-216 (NCT02657005) in patients with relapsed/refractory Ewing sarcoma to focus on the randomized phase 3 ZILO-301 trial comparing zilovertamab plus ibrutinib versus ibrutinib alone in R/R MCL, which will be initiated in the third quarter of 2022.

“This asset prioritization allows us to further sharpen our focus on hematological malignancies and prostate cancer, while deploying our capital towards meaningful catalysts as we navigate this historically challenging pandemic, geopolitical and capital markets macroenvironment,” said James Breitmeyer, MD, PhD, Oncternal’s president and CEO, in a statement.

Zilovertamab, formerly called cirmtuzumab, is a monoclonal antibody that inhibits the type I tyrosine kinase-like orphan receptor ROR1, which has low expression in non-malignant tissues in adults due to ROR1 being an onco-embryonic antigen.

Investigators at the UC San Diego School of Medicine discovered in preclinical studies that zilovertamab binds to a critical epitope on ROR1, which blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. Zilovertamab has been granted an orphan drug designation by the FDA for MCL and chronic lymphocytic leukemia (CLL)/small leukocytic lymphoma.

In an interim analysis of Oncternal’s ongoing phase 1b/2 CIRLL trial (NCT03088878), zilovertamab has shown encouraging efficacy when combined with ibrutinib in patients with MCL or CLL. In the cohort of 20 patients with MCL, there was an 81% objective response rate including 35% of which were complete responses, and median progression-free survival (PFS) was not reached at a median follow-up of 14.4 months.² 

The global multicenter registrational phase 3 ZILO-301 trial will enroll patients with R/R MCL who were assessed as having stable disease or partial response after receiving ibrutinib for 4 months.¹ Patients will then receive either zilovertamab or placebo while continuing to receive ibrutinib. The primary end point will be PFS, and an interim analysis will assess the ORR and duration of response. The start date in the third quarter of 2022 is accounting for geopolitical factors and COVID-19–related supply chain issues.

Oncternal reached an agreement with the FDA on a ZILO-301 study design that will aim for regular FDA approval of zilovertamab in an end-of-phase 2 meeting in January 2022.³ The company also planned to conduct a study called ZILO-302, an open-label companion study of zilovertamab plus ibrutinib in patients who have progressive disease during the initial 4 months of receiving ibrutinib before beginning the zilovertamab component of the ZILO-301 trial.

Zilovertamab is also being investigated at the UC San Diego School of Medicine in an upcoming single-arm phase 1b trial (NCT05156905) combined with docetaxel for patients with metastatic castration-resistant prostate cancer.¹ Patients must have received prior abiraterone (Zytiga) and/or a next-generation androgen receptor antagonist.

It is also being investigated in a phase 2 trial (NCT04501939) as consolidation therapy for patients receiving venetoclax (Venclexta) for R/R CLL to determine if it can result in improved rates of undetectable minimal residual disease.

In addition to its research on targeting ROR1 with zilovertamab, Oncternal announced that it plans to submit an investigational new drug (IND) application for a ROR1-targeted chimeric antigen receptor T-cell therapy, ONCT-808, in mid-2022 based on receiving supportive preclinical data and a pre-IND meeting with the FDA.

_References:

_{1. Oncternal Therapeutics deprioritizes development of ONCT-216 to focus resources on phase 3 trial for zilovertamab in the treatment of mantle cell lymphoma. Oncternal Therapeutics. Published April 13, 2022. Accessed April 26, 2022. https://bit.ly/3Kq9eQi}

_{2. Lee HJ, Choi M, Siddiqi T, et al. Phase 1b/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL). Blood. 2021;138(suppl 1):3534-3534. doi:10.1182/blood-2021-148779}

_{3. Oncternal Therapeutics announces agreement with U.S. FDA on phase 3 registrational study design for zilovertamab in the treatment of mantle cell lymphoma. Oncternal Therapeutics. Published January 4, 2022. Accessed April 26, 2022. https://bit.ly/3Kg5tg9}