FDA Okays Phase 3 Study of Zilovertamab in R/R Mantle Cell Lymphoma

Following phase 2 success, zilovertamab vedotin will be evaluated in a pivotal phase 3 study for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL), announced Oncternal Therapeutics, Inc, in a press release.¹

Based on an agreement between the developer and the FDA, the phase 3 study will follow an FDA-cleared design, protocol, and statistical analysis plan.

“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, president, and chief executive officer of Oncternal, in a press release. “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.

Zilovertamab is an antibody-drug conjugate comprising a monoclonal antibody that recognizes extracellular ROR1. According to early research, the agent demonstrated preliminary anti-tumor activity in lymphoid malignancies without unexpected toxicity.² In the CIRLL study of zilovertamab plus ibrutinib (Imbruvica) for the treatment of patients with MCL or chronic lymphocytic leukemia, an objective response rate (ORR) of 81was observed in the heavily pretreated population. In comparison with the historic ORR of 66%, the addition of zilovertamab to ibrutinib was favorable. The complete response (CR) rate observed in the MCL cohort was 35% compared with the historic ibrutinib monotherapy CR rate of 20%.³

In terms of survival, the combination of zilovertamab and ibrutinib achieved a median progression-free survival of 35.9 months in patients with MCL who were followed for a median of 14.4 months compared with 12.8 months with ibrutinib alone.

The combination was also well-tolerated in patients. No dose-limiting toxicities or serious adverse events attributed to zilovertamab alone were observed during the study. The safety profile was either consistent or an improvement when compared with the historic control.

“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,” added Breitmeyer, in the press release.¹

The upcoming Study ZILO-301 will be conducted internationally at a minimum of 50 centers. The prospective initiation of the study is in the second quarter of 2022. With a primary end point of PFS, patients with relapsed or refractory MCL will be randomized to an arm of zilovertamab in combination with ibrutinib or placebo. This primary end point is meant to support the future filing of a biologics license application and lead to regular FDA approval. To potentially be granted accelerated FDA approval, the interim analysis of the study will evaluate the coprimary end point ORR and duration of response.

Planning in also in the works for a companion trial Study ZILO-302, which will investigate zilovertamab plus ibrutinib in patients who have progressive disease during the initial four months of ibrutinib monotherapy from Study ZILO-301.

_References

_{1. Oncternal Therapeutics announces agreement with U.S. FDA on phase 3 registrational study design for zilovertamab in the treatment of mantle cell lymphoma. News release.Oncternal Therapeutics, Inc. January 4, 2022. Accessed January 6, 2022. https://bit.ly/337GN9K}

_{2. Wang ML, Barrientos JC, Furman RR, et al. Zilovertamab vedotin targeting of ROR1 as therapy for lymphoid cancers. NEJM Evidence. Published online October 12, 2021. Doi: 10.1056/EVIDoa2100001}

_{3. Oncternal Therapeutics presents updated interim data for zilovertamab in combination with ibrutinib at ASH 2021. News release. Oncternal Therapeutics, Inc. December 13, 2021. Accessed January 6, 2021. https://bit.ly/3eVd1HU}