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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Zilovertamab (an ROR1 Antibody) Plus Ibrutinib Versus Ibrutinib Plus Placebo in Subjects With Relapsed or Refractory Mantle Cell Lymphoma

Conditions
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Lymphoma, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Diseases, Lymphoma, Non-Hodgkin, Lymphoma, B-Cell, Lymphoma, Mantle-Cell

Intervention / Treatment
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* Drug: Zilovertamab
* Drug: Ibrutinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Ibrutinib<br>Open Label Ibrutinib Monotherapy Phase (16 weeks) | Drug: Ibrutinib<br>* All participants will receive oral Ibrutinib (560mg) daily.<br>* Other names: Imbruvica;|
| Experimental: Arm A: IV Infusion of Ziloveramab and Oral Ibrutinib<br>Randomized, Double-Blind Treatment Phase | Drug: Zilovertamab<br>* After 16 weeks in the open-label Ibrutinib phase, participants will receive zilovertamab (600mg) administered by IV every 2 weeks for 3 administrations and then every 4 weeks thereafter.<br>* Other names: UC961;Drug: Ibrutinib<br>* All participants will receive oral Ibrutinib (560mg) daily.<br>* Other names: Imbruvica;|
| Placebo Comparator: Arm B: IV Infusion of Placebo and Oral Ibrutinib<br>Randomized, Double-Blind Treatment Phase | Drug: Ibrutinib<br>* All participants will receive oral Ibrutinib (560mg) daily.<br>* Other names: Imbruvica;Drug: Placebo<br>* After 16 weeks in the open-label Ibrutinib phase, participants will receive placebo administered by IV every 2 weeks for 3 administrations and then every 4 weeks thereafter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | 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. | Approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | 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. | Approximately 4 years | 
| Duration of Response (DOR) | 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. | Approximately 4 years | 
| Complete Response Rate | 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. | Approximately 4 years | 
| Proportion of subjects experiencing Grade 3 to 4 neutrophil count decrease | 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. | Approximately 4 years | 
| Overall Survival (OS) | OS among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo. | Approximately 4 years | 
| Overall Safety Profile | 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. | Approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ibrutinib, Mantle cell lymphoma, Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1), Bruton Tyrosine Kinase (BTK) inhibitor, Zilovertamab