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

Sponsor

Oncternal Therapeutics, Inc (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05431179

Collaborator

Pharmacyclics LLC. (Industry)

365

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Mantle-Cell Lymphoma Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Lymphoma, Non-Hodgkin Lymphoma, B-Cell	Drug: Zilovertamab Drug: Ibrutinib Drug: Placebo	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

365 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Nov 1, 2026

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oral Ibrutinib Open Label Ibrutinib Monotherapy Phase (16 weeks)	Drug: Ibrutinib All participants will receive oral Ibrutinib (560mg) daily. Other Names: Imbruvica
Experimental: Arm A: IV Infusion of Ziloveramab and Oral Ibrutinib Randomized, Double-Blind Treatment Phase	Drug: Zilovertamab 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. Other Names: Cirmtuzumab UC961 Drug: Ibrutinib All participants will receive oral Ibrutinib (560mg) daily. Other Names: Imbruvica
Placebo Comparator: Arm B: IV Infusion of Placebo and Oral Ibrutinib Randomized, Double-Blind Treatment Phase	Drug: Ibrutinib All participants will receive oral Ibrutinib (560mg) daily. Other Names: Imbruvica Drug: Placebo 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.

Arm

Intervention/Treatment

Experimental: Oral Ibrutinib

Open Label Ibrutinib Monotherapy Phase (16 weeks)

Drug: Ibrutinib

All participants will receive oral Ibrutinib (560mg) daily.

Other Names:

Imbruvica

Experimental: Arm A: IV Infusion of Ziloveramab and Oral Ibrutinib

Randomized, Double-Blind Treatment Phase

Drug: Zilovertamab

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.

Other Names:

Cirmtuzumab

UC961

Drug: Ibrutinib

All participants will receive oral Ibrutinib (560mg) daily.

Other Names:

Imbruvica

Placebo Comparator: Arm B: IV Infusion of Placebo and Oral Ibrutinib

Randomized, Double-Blind Treatment Phase

Drug: Ibrutinib

All participants will receive oral Ibrutinib (560mg) daily.

Other Names:

Imbruvica

Drug: Placebo

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.

Outcome Measures

Primary Outcome Measures

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

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.
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.
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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