Immune System Diseases, Immunoproliferative Disorders, Lymphatic Diseases, Lymphoma, Lymphoma, B-Cell, Lymphoma, Mantle-Cell, Lymphoma, Non-Hodgkin, Lymphoproliferative Disorders
Conditions
Keywords
Mantle cell lymphoma, Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1), Bruton Tyrosine Kinase (BTK) inhibitor, Ibrutinib, Zilovertamab
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.
Interventions
DRUGZilovertamab
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.
DRUGIbrutinib
All participants will receive oral Ibrutinib (560mg) daily.
DRUGPlacebo
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.
Sponsors
Pharmacyclics LLC.
Oncternal Therapeutics, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Outcome results
None listed