Study Evaluating Venetoclax in Subjects With Hematological Malignancies

Study Overview
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Brief Summary
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This study is evaluating the safety, pharmacokinetic profile and efficacy of venetoclax under a once daily dosing schedule in Japanese participants with hematological malignancies.

Official Title
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A Phase 1/2 Study Evaluating the Safety, Pharmacokinetics and Efficacy of Venetoclax in Japanese Subjects With Hematological Malignancies

Conditions
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Non-Hodgkin Lymphoma (NHL), Multiple Myeloma (MM), Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: azacitadine
* Drug: venetoclax
* Drug: rituximab / IDEC-C2B8
* Drug: rituximab / IDEC-C2B8


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have histologically documented diagnosis of NHL (and exhausted options considered standard of care) as defined in the World Health Organization classification scheme and relapsed following or be refractory to standard treatments such as R-CHOP, R-CVP, or fludarabine based regimens. Participants with other lymphoproliferative diseases can be considered in consultation with the AbbVie medical monitor Relapsed or refractory multiple myeloma participants must have been previously treated with at least one prior line of therapy and have measurable disease Chronic lymphocytic leukemia/small lymphocytic lymphoma participants must have relapsed or be refractory to standard treatments such as fludarabine based regimens or alkylator based regimens Untreated AML subjects or Relapsed or refractory AML subjects must have been previously treated with at least one prior line of therapy Eastern Cooperative Oncology Group (ECOG) performance score less than or equal to 1; adequate bone marrow independent of growth factor support per local laboratory reference range; and adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening Participants with a history of autologous or allogenic stem cell transplantation must have adequate blood counts independent of growth factor support and have recovered from any transplant-related toxicity(s) and be at least 100 days post-autologous transplant (multiple myeloma) or 6 month post-autologous transplant (NHL) prior to first dose of study drug or at least 6 months post-allogenic transplant (multiple myeloma) prior to first dose of study drug and not have active graft-versus-host disease (GVHD), i.e., requiring treatment Exclusion Criteria: NHL participants who have undergone an allogeneic stem cell transplant or were diagnosed with Post-Transplant Lymphoproliferative Disease, Burkitt's lymphoma, Burkitt-like lymphoma, or lymphoblastic lymphoma/leukemia Participant tested positive for HIV Participant has a cardiovascular disability status of New York Heart Association Class greater or equal to 2 Participant has a significant history of renal, neurologic, psychiatric, pulmonary, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in the opinion of the Investigator would adversely affect his/her participating in this study. Participant received a monoclonal antibody for anti-neoplastic intent within 8 weeks prior to the first dose of study drug.

Ages Eligible for Study
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Minimum Age: 20 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Phase 1)<br>Step-up doses of venetoclax to the designated cohort dose administered in participants with relapsed or refractory (R/R) Non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) | Drug: venetoclax<br>* Step-up doses of venetoclax to the designated cohort dose<br>|
| Experimental: Arm B (Phase 1)<br>Step-up doses of venetoclax to the designated dose administered in participants with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) | Drug: venetoclax<br>* Step-up doses of venetoclax to the designated cohort dose<br>|
| Experimental: Arm C (Phase 1)<br>Step-up doses of venetoclax to the designated dose with the addition of azacitidine administered in participants with acute myeloid leukemia (AML) | Drug: azacitadine<br>* 75 mg/m2 by IV infusion or subcutaneous dosing<br>Drug: venetoclax<br>* Step-up doses of venetoclax to the designated cohort dose<br>|
| Experimental: Arm D (Phase 2)<br>Step-up doses of venetoclax to the designated dose with the addition of rituximab in participants with R/R CLL | Drug: venetoclax<br>* Step-up doses of venetoclax to the designated cohort dose<br>Drug: rituximab / IDEC-C2B8<br>* 375 mg/m2 on Week 6<br>Drug: rituximab / IDEC-C2B8<br>* 500 mg/m2 Week 10 Day 1 and thereafter<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants having treatment-emergent adverse events | Collect all adverse events at each visit | Approximately 2 years | 
| Time to maximum plasma concentration (Tmax) of venetoclax |  | Approximately 8 days | 
| Maximum plasma concentration (Cmax) of venetoclax |  | Approximately 8 days | 
| Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of venetoclax |  | Approximately 8 days | 
| Objective Response Rate (Phase 2) | The proportion of participants with response (e.g., partial, complete response) using IWCLL (International Workshop on Chronic Lymphocytic Leukemia) criteria for CLL participants will be computed for all participants with active disease at baseline (in the opinion of the investigator). | Approximately 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (Phase 1) | The proportion of participants with response (e.g., partial, complete response) using IWG (International Working Group) response criteria for NHL participants, IMWG (International Myeloma Working Group) response criteria for multiple myeloma participants, IWCLL (International Workshop on Chronic Lymphocytic Leukemia) criteria for CLL participants or IWG (International Working Group) criteria for AML participants will be computed for all participants with active disease at baseline (in the opinion of the investigator). | Approximately 48 months | 
| Minimal Residual Disease (MRD) |  | Approximately 2 years | 
| Duration of Response | Duration of response is defined as the number of days from the participant's initial response (e.g., partial, complete response per disease-appropriate response criteria) to the day that disease progression is objectively documented. | Approximately 48 months | 
| Time to disease progression | Time to disease progression is defined as the number of days from the date the subject started the study drug to the date of the subject's progression (all events of progression will be included). | Approximately 48 months | 
| complete response or remission (CR) rate | CR rate will be defined as the proportion of participants who achieved a complete response or remission (CR) or complete response with incomplete bone marrow recovery or complete remission with incomplete count recovery (CRi) per the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. | Approximately 48 months | 
| Partial response or remission (PR) rate | PR rate will be defined as the proportion of subjects who achieved a nodular PR (nPR) or PR per the 2008 IWCLL criteria. | Approximately 48 months | 
| Progression Free Survival (PFS) | Duration of progression-free survival (PFS) will be defined as the number of days from the date of first dose to the date of earliest disease progression or death. | Approximately 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsed multiple myeloma, refractory multiple myeloma, Lymphoma, Non-Hodgkin, Lymphoproliferative Disorders, Lymphatic Diseases, relapsed chronic lymphocytic leukemia, small lymphocytic lymphoma, relapsed small lymphocytic lymphoma, refractory small lymphocytic lymphoma, refractory chronic lymphocytic leukemia, acute myeloid leukemia