Optimal Dose Finding Study ABT-199 and Ibrutinib in MCL

Study Overview
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Brief Summary
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The purpose of this study is to determine the optimal dosing scheme for the combination of ibrutinib with ABT-199 for the treatment of relapsed or refractory mantle cell lymphoma (MCL).

Detailed Description
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This is a multi-center, study which will be open at up to 4 clinical sites. The purpose of this study is to determine the optimal dosing scheme for the combination of ibrutinib with ABT-199 for the treatment of relapsed or refractory mantle cell lymphoma (MCL). The main criterion for eligibility is MCL with measurable disease which is relapsed or refractory to at least 1 chemotherapy-containing regimen and has not been previously treated with ibrutinib. This dose finding study will use a continual reassessment method, which accounts for both toxicity and efficacy in combinations of agents, to determine the optimal combination of the approved treatment ibrutinib with the investigational agent ABT-199. This study will accrue patients in two stages. In the initial stage, subjects will be accrued to dosing cohorts of increasing dosages of ABT-199 in combination with ibrutinib. The modeling is initiated once 1 subject experiences a dose limiting toxicity (DLT). During the modeling stage, treatment assignments will be made based on model prediction. Subjects will remain on treatment until progression or unacceptable toxicity, and will be monitored for safety during the treatment interval. Safety will be evaluated by incidence of adverse events and number of discontinuations due to AEs. Efficacy endpoints include Overall Response Rate (ORR), Complete Response Rate (CRR), minimal residual disease response rate, and survival (PFS and OS). The study will also include exploratory analysis of the gene expression pattern in subjects who progress on treatment.

Official Title
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Multi-institution Phase I/Ib Study of Ibrutinib With ABT-199 in Relapsed/Refractory Mantle Cell Lymphoma

Conditions
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Lymphoma, Mantle-Cell, Recurrent Lymphoma, Mantle-Cell

Intervention / Treatment
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* Drug: ABT-199 and Ibrutinib Combination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with Mantle Cell Lymphoma and has had at least one chemotherapy. Subjects must have measurable or evaluable disease. ECOG Performance Status of 0-2. Must be referred for treatment with ibrutinib. Must have adequate organ function. Exclusion Criteria: Subject is pregnant. Prior malignancy (except nonmelanomatous skin cancer) unless disease free for a minimum of 2 years; non-invasive conditions such as carcinoma in situ of the breast, oral cavity, or cervix are all permissible. Known CNS lymphoma. Prior or current treatment with certain medications. Talk to Study Contact for specifics. Subject is at high risk for TLS. Subject has malabsorption syndrome or other condition which may affect an enteral route of administration. Subject has known contraindication or allergy to both xanthine oxidase inhibitors and rasburicase. Significant history of heart disease. Subject has an active infection. Known active Hepatitis B or Hepatitis C. A serious uncontrolled medical disorder that in the opinion of the investigator would impair the ability of the subject to receive protocol therapy.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABT-199 and Ibrutinib Combination<br>Participants will take ABT-199 (dose 100-400 mg) and Ibrutinib (dose 280-560 mg). | Drug: ABT-199 and Ibrutinib Combination<br>* Both are administered orally once daily.<br>* Other names: PCI-32765;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities |  | 30 Days Following Start of Treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Adverse Events |  | Through 30 Days Following the Last Treatment | 
| Overall Response Rate |  | Every Year Until Death; an Average of 2 Years | 
| Complete Response Rate |  | Every Year Until Death; an Average of 2 Years | 
| Progression-Free Survival |  | Every Year Until Death; an Average of 2 Years | 
| Overall Survival |  | Every Year Until Death; an Average of 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed, Laboratory biomarker research, Pharmacologic study, Bruton's tyrosine kinase inhibitor, BCL-2 inhibitor