Study Design Confirmed for Phase 3 Trial of Zilovertamab/Ibrutinib in Mantle Cell Lymphoma


A design for the phase 3 ZILO-301 clinical trial, assessing the efficacy of zilovertamab plus ibrutinib for patients with mantle cell lymphoma, has been selected

Drug developer Oncternal Therapeutics has come to an agreement with the FDA on a design for the phase 3 ZILO-301 clinical trial assessing the efficacy of zilovertamab (previously, cirmtuzumab) in combination with ibrutinib (Imbruvica) in mantle cell lymphoma (MCL), according to a press release.1

In addition to agreeing on the design, the FDA reviewed and confirmed key trial features and operational details with regard to the study protocol and statistical analysis plan, which will be finalized based on the regulatory organization’s input. The ZILO-301 trial will take place in at least 50 centers specializing in the treatment of MCL and is set to begin in the second quarter of 2022.

“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,” James Breitmeyer, MD, PhD, president and chief executive officer at Oncternal Therapeutics, said 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. 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.”

A first-in-class, humanized monoclonal antibody, zilovertamab achieves high-affinity binding with to an epitope on ROR1 that is expressed on the plasma membrane of different cancer cells.2 ROR1 expression has been associated with a dedifferentiated oncogenic state and when expressed by hematologic malignancies, can act as a receptor for tumor growth factor Wnt5a. Notably, the therapeutic binds to a variety of different cancer cells, although it is not able to recognize healthy adult tissues. Zilovertamab blocks this receptor upon binding with ROR1 and both induces differentiation and inhibits tumor cell proliferation, migration, and survival.

Data on the agent recently read out at the 2021 American Society of Hematology Annual Meeting and Exposition from the phase 1/2 CIRLL trial (NCT03088878), which assessed the combination of zilovertamab and ibrutinib in patients with B-cell malignancies.3 The trial included 31 patients who had been diagnosed with relapsed/refractory MCL. Investigators reported that patients with heavily pre-treated MCL experienced an objective response rate (ORR) of 81% after being treated with the combination; this compared favorably with the historical ORR yielded with ibrutinib monotherapy (66%). Additionally, the regimen resulted in a complete response rate of 35% compared with the historical rate of 20% for ibrutinib alone. After a median follow-up of 14.4 months, patients with MCL also experienced a median progression-free survival of 35.9 months compared with 12.8 months with historical results for ibrutinib monotherapy in this patient population. Moreover, the combination appears to have a well-tolerated safety profile that is either consistent or improved compared with ibrutinib alone.

The trial also included 34 patients with chronic lymphocytic leukemia (CLL) for whom the median PFS had not yet been reached among those who received 2 or fewer prior lines of therapy. Notably, those who were previously treated with more than 2 prior lines of therapy had a median PFS of 36.1 months after a median follow-up of 29.0 months. Among those previously treated with more than 2 prior lines of therapy, the landmark PFS rates were approximately 85% and 65% at 24 months and 36 months, respectively. Those who received 2 or fewer previous lines of therapy had a landmark PFS rate of 100% at 36 months.

Zilovertamab was also assessed as part of the phase 1 MK-2140-001 study (NCT03833180) in a population of patients with lymphoid malignancies, including 15 patients with MCL, 7 with CLL, 5 with diffuse large B-cell lymphoma, 3 with follicular lymphoma, 1 with Richter transformation lymphoma, and 1 with marginal zone lymphoma.4 Investigators reported that 47% of patients with MCL had an objective response, as well as 60% of patient with DLBCL.

Investigators concluded the agent did not yield any unexpected toxicities and the data provided evidence of antitumor activity demonstrated by clinical proof of concept for selective targeting of ROR1 as a possible new treatment approach.


  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. January 4, 2022. Accessed January 5, 2022.
  2. Oncternal Therapeutics. Zilovertamab. Accessed January 5, 2022.
  3. Oncternal Therapeutics presents updated interim data for zilovertamab in combination with ibrutinib at ASH 2021. News release. Oncternal Therapeutics. December 13, 2021. Accessed January 5, 2022.
  4. Wang ML, Barrientos JC, Furman RR, et al. Zilovertamab vedotin targeting of ROR1 as therapy for lymphoid cancers. N Engl J Med. Published online October 12, 2021. doi:10.1056/EVIDoa2100001
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