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The addition of zilovertamab to ibrutinib will be compared with ibrutinib plus placebo in patients with relapsed/refractory mantle cell lymphoma as part of the phase 3 ZILO-301 trial.
The addition of zilovertamab (formerly cirmtuzumab; UC-961) to ibrutinib (Imbruvica) will be compared with ibrutinib plus placebo in patients with relapsed/refractory mantle cell lymphoma (MCL) as part of the phase 3 ZILO-301 trial (NCT05431179).1
Although ibrutinib monotherapy has been shown to produce favorable activity in patients with relapsed/refractory MCL who achieve a complete response (CR), additional treatment options are needed for those who experience an inadequate response to this approach. ZILO-301 and its companion trial, the phase 3 ZILO-302 study, will evaluate the combination of ibrutinib and zilovertamab in this patient population.
“Ibrutinib was the first BTK inhibitor in the market, and its approval changed the treatment paradigm for patients suffering from certain hematological malignancies,” James Breitmeyer, MD, PhD, president and chief executive officer of Oncternal, stated in a press release.2 “We are pleased that this collaboration will support the development of an innovative combination of zilovertamab and ibrutinib that we believe may address important unmet needs of patients with MCL.”
In January 2022, the FDA agreed upon key elements, including design features and operational details, for ZILO-301. The study is now expected to initiate in the third quarter of 2022. The phase 3 trial stemmed from results of the phase 1/2 CIRLL trial (NCT03088878), which showed that the combination of zilovertamab and ibrutinib elicited an overall response rate (ORR) of 80.8% in patients with MCL (n = 26), including a CR rate of 34.6% (n = 9) and a partial response (PR) rate of 46.2% (n = 12).3
The ZILO-301 trial will enroll patients who are at least 18 years of age, and who have histologically confirmed relapsed/refractory MCL and received at least 1 prior line of therapy. Patients will be required to have measurable disease of at least 2 cm, an ECOG performance status of 0 or 1, stable laboratory parameters, and highly effective contraceptive use.
Key exclusion criteria will include having received more than 1 month of prior treatment with a BTK inhibitor, transfusion-dependent thrombocytopenia, known central nervous system (CNS) or cardiac involvement, history or presence of CNS disorder, bleeding disorder, chronic liver disease, or being pregnant or breastfeeding.
The trial is slated to enroll approximately 365 patients who will receive 4 months of oral ibrutinib. Those who achieve a complete response (CR) to treatment will continue to receive ibrutinib off study protocol. Those who experience disease progression will be moved to the phase 3 ZILO-302 trial to receive ibrutinib plus zilovertamab. Patients who experience a PR or stable disease will be randomized as a part of ZILO-301 to receive ibrutinib plus zilovertamab or ibrutinib plus placebo.
Three data analyses will be conducted on patients who undergo randomization on the trial. The first will consist of a futility analysis based on ORR. The second, which is expected to occur as early as 2 years after the first patient is enrolled, will analyze ORR, duration of response (DOR), and safety for the potential application for early marketing authorization.
Regardless of the results at the second analysis, the study will continue without modification to the third analysis, which will take place at the end of the study for the primary end point of progression-free survival and any remaining secondary end points. The third analysis could take place as early as 3 years after the enrollment of the first patient.
Along with the primary end point of PFS, secondary end points will include ORR, DOR, CR rate, overall survival, rates of grade 3 or 4 decreased neutrophil counts, and safety.