A Study of Zilovertamab and Ibrutinib in Patients With Relapsed or Refractory Mantle Cell Lymphoma

Phase 3

Withdrawn

• Conditions: Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Mantle-Cell; Immune System Diseases; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoproliferative Disorders; Lymphoma, B-Cell
• Interventions: Drug: Ibrutinib; Drug: Zilovertamab; Drug: Placebo

• Registration Number: NCT05431179
• Lead Sponsor: Oncternal Therapeutics, Inc

Brief Summary

This is a Phase 3 study to investigate the safety and efficacy of the investigational drug, zilovertamab, when given in combination with ibrutinib in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL).

Detailed Description

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study that will be conducted in multiple phases in patients with R/R MCL. The study phases will include a Screening Phase, an Open-Label Ibrutinib Monotherapy Treatment Phase, a Randomized Double-Blind Treatment Phase, and a Long-Term Follow-Up Phase. When patients meet all study eligibility requirements in the Screening Phase, they will enter the Open-Label Ibrutinib Monotherapy Treatment Phase and will receive ibrutinib alone daily. After approximately 16 weeks patients who have a partial response (PR) or stable disease (SD) will enter the Randomized Double-Blind Treatment Phase and will be receive an intravenous infusion of zilovertamab or placebo and will continue to receive ibrutinib daily. Patients who discontinue study drug will enter the Long-Term Follow-Up Phase.

Study Timeline

• Study First Submitted: 2022-06-09
• Study First Submitted QC: 2022-06-21
• Study First Posted: 2022-06-24
• Study Start: 2023-03
• Status Verified: 2023-04
• Last Update Submitted: 2023-04-19
• Last Update Posted: 2023-04-21
• Primary Completion: 2026-11
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Histologically confirmed MCL
• Has received one prior regimen for MCL
• Disease is relapsed or refractory
• At least 1 measurable site of disease that is ≥ 2.0 cm
• PET-CT performed less than 28 days before study entry
• If a subject has toxicities due to prior therapy for the treatment of MCL, must be stable and recovered
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• Study-specific laboratory parameters must be met
• Females of childbearing potential and males must use highly effective contraception

Exclusion Criteria

• Received more than one month of prior therapy with ibrutinib or any other Bruton's tyrosine kinase inhibitor
• Concurrent enrollment in another investigational study
• Transfusion-dependent thrombocytopenia
• Anticancer therapy within 25 days before the start of the study
• History of other malignancy, cancer, or carcinoma for at least three years before the start of the study
• Central nervous system (CNS) involvement with lymphoma
• CNS disorder ≤ 6 months of study entry
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, active arrhythmias, class 3 or 4 congestive heart failure, or other clinically significant cardiac disease ≤ 6 months of study entry
• Active or prior cardiac (atrial or ventricular) lymphoma involvement
• History of atrial fibrillation or left or right bundle branch block
• History of symptomatic deep vein thrombosis or pulmonary embolism ≤ 6 months of study entry
• Chronic liver disease with hepatic impairment, Child-Pugh class B or C
• Bleeding disorder
• Prior stem cell transplant that requires ongoing immunosuppressive therapy or active clinical graft versus host disease
• Primary severe immunodeficiency
• Human immunodeficiency virus infection (HIV) or active hepatitis B or C infection
• Active infection requiring IV antimicrobial (antiviral, antibiotic, anti-fungal) therapy at the time of study entry
• Vaccination with a live, attenuated vaccine ≤ 4 weeks of the start of the study
• Hypersensitivity reaction to any of the agents used in this study
• Requires treatment with a strong cytochrome P450 enzyme (CYP) 3A (CYP3A) inhibitor/inducer.
• Unable or swallow capsules or tablets or has malabsorption syndrome or disease affecting gastrointestinal function
• Major surgery ≤ 4 weeks of study start
• Medical condition likely to interfere with assessment of safety or efficacy of the study drug
• Not eligible in the opinion of the Investigator
• Pregnant or breastfeeding

Other protocol-defined inclusion/exclusion criteria will apply.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B: IV Infusion of Placebo and Oral Ibrutinib	Ibrutinib	Randomized, Double-Blind Treatment Phase
Arm B: IV Infusion of Placebo and Oral Ibrutinib	Placebo	Randomized, Double-Blind Treatment Phase
Oral Ibrutinib	Ibrutinib	Open Label Ibrutinib Monotherapy Phase (16 weeks)
Arm A: IV Infusion of Ziloveramab and Oral Ibrutinib	Zilovertamab	Randomized, Double-Blind Treatment Phase
Arm A: IV Infusion of Ziloveramab and Oral Ibrutinib	Ibrutinib	Randomized, Double-Blind Treatment Phase

Primary Outcome Measures

Name	Time	Method
Progression-free survival (PFS)	Approximately 2 years	PFS as assessed by Blinded Independent Central Review (BICR) per Lugano Classification is superior for ibrutinib plus zilovertamab compared to ibrutinib plus placebo among subjects with relapsed or refractory (R/R) mantle cell lymphoma (MCL) that had a PR or SD after 16 weeks of ibrutinib monotherapy.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Approximately 4 years	Assessed by BICR per Lugano Classification, among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo.
Duration of Response (DOR)	Approximately 4 years	Assessed by BICR per Lugano Classification, among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo.
Overall Survival (OS)	Approximately 4 years	OS among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo.
Overall Safety Profile	Approximately 4 years	Overall safety profile among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo. This would include incidence of treatment-emergent adverse events and laboratory abnormalities.
Complete Response Rate	Approximately 4 years	Assessed by BICR per Lugano Classification Classification among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo.
Proportion of subjects experiencing Grade 3 to 4 neutrophil count decrease	Approximately 4 years	Proportion of subjects experiencing Grade 3 to 4 neutrophil count decrease among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo based on laboratory abnormalities.