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

Primary Purpose

Lymphoma, Mantle-Cell, Lymphoma, Lymphoproliferative Disorders

Status
Withdrawn
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Zilovertamab
Ibrutinib
Placebo
Sponsored by
Oncternal Therapeutics, Inc
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoma, Mantle-Cell focused on measuring Mantle cell lymphoma, Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1), Bruton Tyrosine Kinase (BTK) inhibitor, Ibrutinib, Zilovertamab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Other protocol-defined inclusion/exclusion criteria will apply.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm Type

    Experimental

    Experimental

    Placebo Comparator

    Arm Label

    Oral Ibrutinib

    Arm A: IV Infusion of Ziloveramab and Oral Ibrutinib

    Arm B: IV Infusion of Placebo and Oral Ibrutinib

    Arm Description

    Open Label Ibrutinib Monotherapy Phase (16 weeks)

    Randomized, Double-Blind Treatment Phase

    Randomized, Double-Blind Treatment Phase

    Outcomes

    Primary Outcome Measures

    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.

    Secondary Outcome Measures

    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.
    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.
    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.
    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.
    Overall Survival (OS)
    OS among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo.
    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.

    Full Information

    First Posted
    June 9, 2022
    Last Updated
    April 19, 2023
    Sponsor
    Oncternal Therapeutics, Inc
    Collaborators
    Pharmacyclics LLC.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05431179
    Brief Title
    A Study of Zilovertamab and Ibrutinib in Patients With Relapsed or Refractory Mantle Cell Lymphoma
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    April 2023
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Due to a strategic reprioritization based on the rapidly changing clinical and commercial landscape for Bruton's tyrosine kinase inhibitors (BTK inhibitors)
    Study Start Date
    March 2023 (Anticipated)
    Primary Completion Date
    November 2026 (Anticipated)
    Study Completion Date
    December 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Oncternal Therapeutics, Inc
    Collaborators
    Pharmacyclics LLC.

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. 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).
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Lymphoma, Mantle-Cell, Lymphoma, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Diseases, Lymphoma, Non-Hodgkin, Lymphoma, B-Cell
    Keywords
    Mantle cell lymphoma, Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1), Bruton Tyrosine Kinase (BTK) inhibitor, Ibrutinib, Zilovertamab

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Oral Ibrutinib
    Arm Type
    Experimental
    Arm Description
    Open Label Ibrutinib Monotherapy Phase (16 weeks)
    Arm Title
    Arm A: IV Infusion of Ziloveramab and Oral Ibrutinib
    Arm Type
    Experimental
    Arm Description
    Randomized, Double-Blind Treatment Phase
    Arm Title
    Arm B: IV Infusion of Placebo and Oral Ibrutinib
    Arm Type
    Placebo Comparator
    Arm Description
    Randomized, Double-Blind Treatment Phase
    Intervention Type
    Drug
    Intervention Name(s)
    Zilovertamab
    Other Intervention Name(s)
    Cirmtuzumab, UC961
    Intervention Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    Ibrutinib
    Other Intervention Name(s)
    Imbruvica
    Intervention Description
    All participants will receive oral Ibrutinib (560mg) daily.
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    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.
    Primary Outcome Measure Information:
    Title
    Progression-free survival (PFS)
    Description
    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.
    Time Frame
    Approximately 2 years
    Secondary Outcome Measure Information:
    Title
    Objective Response Rate (ORR)
    Description
    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.
    Time Frame
    Approximately 4 years
    Title
    Duration of Response (DOR)
    Description
    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.
    Time Frame
    Approximately 4 years
    Title
    Complete Response Rate
    Description
    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.
    Time Frame
    Approximately 4 years
    Title
    Proportion of subjects experiencing Grade 3 to 4 neutrophil count decrease
    Description
    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.
    Time Frame
    Approximately 4 years
    Title
    Overall Survival (OS)
    Description
    OS among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo.
    Time Frame
    Approximately 4 years
    Title
    Overall Safety Profile
    Description
    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.
    Time Frame
    Approximately 4 years

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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.

    12. IPD Sharing Statement

    Plan to Share IPD
    Undecided
    Citations:
    PubMed Identifier
    25113753
    Citation
    Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.
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    A Study of Zilovertamab and Ibrutinib in Patients With Relapsed or Refractory Mantle Cell Lymphoma

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