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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Withdrawn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

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

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

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

NCT ID

NCT05431179

First Posted

June 9, 2022

Last Updated

April 19, 2023

Sponsor

Oncternal Therapeutics, Inc

Collaborators

Pharmacyclics LLC.

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

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

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

Time Frame

Approximately 4 years

Title

Proportion of subjects experiencing Grade 3 to 4 neutrophil count decrease

Description

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

Time Frame

Approximately 4 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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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