A Phase 1b Study Evaluating the Safety and Tolerability of ABT-199 in Combination With Rituximab in Subjects With Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Study Overview
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Brief Summary
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This is a Phase 1b, open-label, multicenter study evaluating the safety and tolerability of ABT-199 in combination with rituximab in up to 50 subjects with Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. The primary objectives of this study are to assess the safety profile, to determine the maximum tolerated dose and establish the Recommended Phase Two Dose of ABT-199 when administered in combination with rituximab. The dose escalation portion of the study will include approximately 30 subjects. Once the recommended phase two dose and schedule have been determined, up to 20 additional subjects will be enrolled in an expanded safety portion of the study. Subjects who meet criteria for CR, CRi, or MRD-negative PR during the study may discontinue ABT 199. If disease progression occurs, as defined by iwCLL NCI/WG criteria for tumor response, or MRD progression, subjects may re-initiate ABT-199.

Official Title
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A Phase 1b Study Evaluating the Safety and Tolerability of ABT-199 in Combination With Rituximab in Subjects With Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Conditions
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Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: ABT-199
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be greater then or equal to 18 years of age. Subject must have relapsed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma. Subject has an Eastern Cooperative Oncology Group performance score of less than or equal to 1. Subject must have adequate bone marrow independent of growth factor support per local laboratory reference range at Screening. Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening. Exclusion Criteria: Chronic lymphocytic leukemia or Small Lymphocytic Lymphoma subject has undergone an allogeneic or autologous stem cell transplant. Subject has uncontrolled autoimmune hemolytic anemia or thrombocytopenia. Subject has tested positive for human immunodeficiency virus. Seropositivity for hepatitis B surface antigen or hepatitis C virus antibody or ribonucleic acid. History of severe allergic or anaphylactic reactions to rituximab. Subject has received a live viral vaccine within 6 months prior to the first dose of study drug. Subject has received a monoclonal antibody for anti-neoplastic intent within 8 weeks prior to the first dose of study drug. Subject has received any of the following within 14 days prior to the first dose of study drug, or has not recovered to less than grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy: Any anti-cancer therapy including chemotherapy, immunotherapy, or radiotherapy; Investigational therapy, including targeted small molecule agents. Subject has a cardiovascular disability status of New York Heart Association Class greater then or equal to 2. Class 2 is defined as cardiac disease in which subjects are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea or anginal pain. Subject 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. Subject has a history of other active malignancies other than CLL/SLL within the past 2 years prior to study entry, with the exception of: Adequately treated in situ carcinoma of the cervix uteri; Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent. Subject has malabsorption syndrome or other condition that precludes enteral route of administration. Subject exhibits evidence of other clinically significant ongoing or recent condition(s) including, but not limited to: Ongoing systemic infection (viral, bacterial, or fungal); Diagnosis of fever and neutropenia within 1 week prior to study drug administration

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Arm 1<br>Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL) | Drug: ABT-199<br>* ABT-199 is taken continuously once daily. This is a dose escalation study, therefore the dose of ABT-199 will change throughout the study.<br>* Other names: venetoclax;Drug: Rituximab<br>* Rituximab will be given by intravenous infusion on day 1 of Months 1, 2, 3, 4, 5, and 6. May be reinitiated for an additional 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the safety profile, to determine the maximum tolerated dose and Recommended Phase Two Dose of ABT-199 when administered in combination with rituximab (R) in subjects with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma. | Protocol-defined events, which are attributed as having a reasonable possibility of being related to the administration of ABT-199 and/or rituximab, or can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, underlying disease or concomitant medication, will be considered a dose limiting toxicity. | Continuous dosing at designated dose level up to Month 6. At end of combination treatment, ABT-199 monotherapy may continue up to 8 years following the date of the last subject enrolled. If disease progression occurs, subjects may re-initiate ABT-199. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of peak concentration (Cmax) of ABT-199 and/or Rituximab. | Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points. | PK samples collected up to Month 6 for ABT-199 and Rituximab | 
| Assess the exploratory efficacy of the combination ABT-199 and rituximab. | Tumor response or clinical disease progression (Objective Response Rate) | Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose. | 
| Determination of trough concentration (Ctrough) of ABT-199 and/or Rituximab | Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points. | PK samples collected up to Month 6 for ABT-199 and Rituximab | 
| Determination of area under the concentration versus time curve (AUC) of ABT-199 and/or Rituximab | Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points. | PK samples collected up to Month 6 for ABT-199 and Rituximab | 
| Assess the exploratory efficacy of the combination ABT-199 and rituximab | Tumor response or clinical disease progression for (Overall Survival) | Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose. | 
| Assess the exploratory efficacy of the combination ABT-199 and rituximab | Tumor response or clinical disease progression for (Progression Free Survival) | Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose. | 
| Assess the exploratory efficacy of the combination ABT-199 and rituximab | Tumor response or clinical disease progression for (Time to Tumor Progression) | Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose. | 
| Assess the exploratory efficacy of the combination ABT-199 and rituximab | Tumor response or clinical disease progression for (Duration Of Response) | Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia, Rituximab, Tolerability, Pharmacokinetics, ABT-199, Cancer, Preliminary, Efficacy, Maximum Tolerated Dose, Venetoclax