Zilovertamab Plus Ibrutinib Under Further Evaluation in Relapsed/Refractory MCL

The FDA has agreed upon key elements, including design features and operational details, for the phase 3 ZILO-301 trial, which will evaluate zilovertamab in combination with ibrutinib in patients with relapsed or refractory mantle cell lymphoma.

The FDA has agreed upon key elements, including design features and operational details, for the phase 3 ZILO-301 trial, which will evaluate zilovertamab (formerly cirmtuzumab, UC-961) in combination with ibrutinib (Imbruvica) in patients with relapsed or refractory mantle cell lymphoma (MCL).1

The regulatory input follows a successful end-of-phase 2 meeting. The trial protocol and statistical analysis plan is in the process of being finalized based on these insights, according to Oncternal Therapeutics, Inc.

“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 CEO of Oncternal Therapeutics, stated in the 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.”

ROR1 is a potentially attractive target for cancer therapy due to its classification as an onco-embryonic antigen. This antigen is typically not expressed in adult cells, and its expression elicits a survival and fitness advantage when reactivated in tumor cells. Researchers from UC San Diego School of Medicine previously discovered that targeting the ROR1 epitope was key to targeting ROR1-expressing tumors.2 Zilovertamab binds to ROR1, block Wnt5a signaling, inhibits tumor cell proliferation, migration, and survival, and induces differentiation of the tumor cells.

The phase 3 ZILO-301 trial will be conducted on an international level in a least 50 centers with demonstrated expertise in treating MCL. Investigators plan to randomize patients with relapsed or refractory MCL who have experienced stable disease or a partial response (PR) after receiving 4 months of oral ibrutinib therapy. Patients will be administered either zilovertamab or placebo, and all patients will continue receiving oral ibrutinib.

The primary end point of the trial will be progression-free survival (PFS), which is intended to support the submission of a biologics license application (BLA). Additionally, an interim analysis will be conducted on the primary end points of overall response rate (ORR) and duration of response (DOR); these data will also be used to support the BLA seeking accelerated approval of the combination.

The trial is expected to begin in the second quarter of 2022.

Moreover, the combination is also slated for further evaluation as part of the open-label companion ZILO-302 study, which will be done in patients who experienced disease progression during the first 4 months of ibrutinib monotherapy from ZILO-301.

Prior results from the phase 1/2 CIRLL trial (NCT03088878), which were presented during the 2021 ASH Annual Meeting, showed that the combination elicited high response rates and durable responses with favorable tolerability in both patients with chronic lymphocytic leukemia (CLL) and MCL.3

The trial enrolled patients with treatment-naïve or relapsed/refractory CLL/small lymphocytic lymphoma or relapsed/refractory MCL. Notably, prior treatment with a BTK inhibitor was permitted for those with MCL.

Part 1 of the trial enrolled 18 patients with CLL and 12 patients with MCL to the dose-finding cohort. Zilovertamab was examined at 2 mg/kg, 4 mg/kg, 8 mg/kg, 16 mg/kg, 300 mg/kg, and 600 mg/kg. Ibrutinib was added following 1 month of treatment; it was given at a daily dose of 420 mg in those with CLL and 560 mg in those with MCL. In part 2, investigators sought to confirm the recommended phase 2 dose of the regimen, which is 600 mg of zilovertamab and the approved dose of ibrutinib in a dose-expansion cohort; 16 patients with CLL are enrolled and the phase 2 MCL cohort is enrolling.

Part 3 of the trial enrolled 31 patients with CLL who were randomized 2:1 to receive the combination or ibrutinib alone. The primary end point of this portion of the research is CR rate. Part 4, which is exploratory, seeks to evaluate the combination in patients with MCL who refractory to previous BTK inhibition or who have experienced an inadequate response to previous ibrutinib treatment; this cohort is open for enrollment.

The population examined in the trial were considered to have high-risk disease and to be heavily pretreated. The ECOG performance status was 0 or 1 in 90.3% of patients with MCL (n = 31) and in all patients with CLL who comprised the part 1 and 2 cohorts (n = 34).

Moreover, 100% and 64.7% of patients, respectively, received prior systemic regimens and the median number of regimens received was 1 (range, 1-4) and 2 (range, 1-15), respectively. More patients with MCL underwent prior transplant or cell therapy vs those with CLL, at 25.8% and 2.9%, respectively. Notably, 16.1% of patients with MCL previously received a BTK inhibitor.

The median duration of follow-up for those with MCL (n = 26) was 14.4 months (95% CI, 11.38-19.31) vs 29.0 months (95% CI, 27.64-31.61) for those with CLL.

The doublet induced an overall response rate (ORR) of 80.8% in patients with MCL (n = 26), which included a complete response (CR) rate of 34.6% (n = 9) and a partial response (PR) rate of 46.2% (n = 12). In this subset, the median duration of response (DOR) with the combination was 34.13 months (95% CI, 13.67-34.13). In patients with CLL (n = 34), the doublet resulted in an ORR of 91.2% (n = 31), with a CR rate of 5.9% (n = 2) and a PR rate of 85.3% (n = 29). In this subset, the median DOR was 33.5 months (95% CI, 0.0-33.5).

When broken down by MCL subgroup, the combination produced an ORR of 84.6% in those with a Ki-67 of 30% or higher (n = 13), 83.3% in those with p53 alterations (n = 6), 80.0% in those who previously received a BTK inhibitor (n = 5), 100.0% in those who previously underwent transplant or received CAR T-cell therapy (n = 7), and 81.8% in those who received more than 1 prior systemic regimen (n = 11).

The median DORs in these groups were 13.84 months (95% CI, 13.67–not evaluable [NE]), 13.84 months (95% CI, 11.93-13.84), 13.67 months (95% CI, 11.93–NE), 34.13 months (95% CI, 13.84-34.13), not reached (NR) in those who received 2 prior lines (95% CI, 1.51–NE), and 34.13 months (95% CI, 13.84-34.13) in those who received 3 or more prior lines.

Among those with CLL, the doublet elicited an ORR of 90.9% in those who received 1 or more prior systemic regimen (n =22) with a median DOR that was NR (95% CI, 7.4-28.0) in those who received 1 prior line, NR (95% CI, 2.8-28.1) in those who received 2 prior lines, and 33.54 months (95% CI, 19.57-33.54) in those who received 3 or more prior lines.

In the subset of patients with RAI stage 3 or higher disease (n = 9), the ORR was 100.0% and the median DOR was NR (95% CI, 2.8-27.6). Lastly, in the subset of patients with a lactate dehydrogenase level of greater than 250 U/L (n = 15), the ORR was 86.7% and the median DOR was NR (95% CI, 19.57–NE).

After a median follow-up of 29.0 months, the median progression-free survival (PFS) in the patients with CLL was NR (95% CI, 36.26–NE). In those with CLL who received 2 or fewer prior lines of systemic treatment (n = 92), the median PFS was NR; in those who received more than 2 prior lines (n = 103), the median PFS was approximately 36.1 months (HR, 0.509; 95% CI, 0.325-0.799). In those with MCL, the median PFS was 35.93 months (95% CI, 16.52-35.93). These data with the combination compared favorably with historical data with ibrutinib monotherapy.

“The positive data from our ongoing phase 1/2 CIRLL study recently presented at 2021 ASH Annual Meeting underscore [the] advantages [of zilovertamab] and are supportive of our registration strategy,” Breitmeyer added.

Zilovertamab has been granted orphan drug designations for treatment of MCL and CLL.


  1. Oncternal therapeutics announces agreement with US FDA on phase 3 registrational study design for zilovertamab in the treatment of mantle cell lymphoma. News release. January 4, 2022. Accessed January 5, 2022. https://bit.ly/3G30XR4
  2. Phase I trial finds experimental drug safe in treating chronic lymphocytic leukemia. News release. UC San Diego Health; June 1, 2018. Accessed January 5, 2022. https://bit.ly/3JMrGU1
  3. 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. doi:10.1182/blood-2021-148779
  4. Oncternal Therapeutics announces orphan drug designations of cirmtuzumab ROR1 antibody for treatment of mantle cell lymphoma and for treatment of chronic lymphocytic leukemia. News release. Oncternal Therapeutics, Inc.; June 30, 2020. Accessed January 11, 2022. https://bwnews.pr/3FcLJYs
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