A Study of Venetoclax in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Study Overview
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Brief Summary
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This is a Phase 2, open-label, multicenter study, evaluating the efficacy of venetoclax in participants with relapsed or refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) either in presence of 17p deletion (Cohort 1) or those who have failed a B-receptor signaling pathway inhibitor (BCRI) therapy and who have also failed, or were unable to receive chemoimmunotherapy (CIT) irrespective of 17p status (Cohort 2).

Official Title
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A Phase 2 Open-Label Study of the Efficacy of Venetoclax in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Conditions
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Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)

Intervention / Treatment
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* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have a diagnosis of relapsed or refractory chronic lymphocytic leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) that meets 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (iwCLL) National Cancer Institute-Working Group (NCI-WG) Guidelines and the following: Participant must have an indication for treatment according to the 2008 Modified iwCLL NCI-WG Guidelines. SLL participant must have measurable disease (B-lymphocytosis greater than 5 × 10^9/L or an enlarged lymph node(s) (Longest Diameter (LDi) > 1.5 cm at baseline) or hepatomegaly or splenomegaly due to CLL). SLL participant must have presence of lymphadenopathy and absence of cytopenias caused by a clonal marrow infiltrate. Participant must have relapsed or refractory CLL/SLL after receiving at least one prior line of therapy. Participants (in Cohort 1) must have 17p deletion, assessed by a central laboratory. Participants (in Cohort 2) must meet both of the following: Relapsed/refractory disease to B-Cell Receptor Signaling Pathway Inhibitor (BCRI) treatment; And either of the following: (a) relapsed/refractory disease to chemoimmunotherapy (CIT), or (b) ineligible to receive CIT, defined as having known 17p deletion or TP53 mutation, or Cumulative Illness Rating Scale (CIRS) >6 or calculated creatinine clearance <70 mL/min, or participants in whom the investigator evaluated that the use of CIT was inappropriate. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2. Participant must have adequate bone marrow function, coagulation profile, renal, and hepatic function, per laboratory reference range at Screening. No known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Exclusion Criteria: Participant has undergone an allogeneic stem cell transplant. Participant has developed Richter's transformation confirmed by biopsy. Participant has prolymphocytic leukemia. Participant has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to screening), including autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura (ITP). Participant has previously received venetoclax. Participant is known to be positive for Human Immunodeficiency Virus (HIV). Participant has received a biologic agent for anti-neoplastic intent within 30 days prior to the first dose of study drug. Participant has received any of the following within 14 days or 5 half-lives (whichever is shorter) prior to the first dose of venetoclax, or has not recovered to less than Common Toxicity Criteria for Adverse Events (CTCAE) grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy: Any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy or targeted small molecule agents. Investigational therapy, including targeted small molecule agents. Participant has known allergy to both xanthine oxidase inhibitors and rasburicase.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Venetoclax<br>Participants with 17p deletion status will receive various doses of venetoclax once daily (QD). | Drug: Venetoclax<br>* Tablet; Oral<br>* Other names: Venclexta;|
| Experimental: Cohort 2: Venetoclax<br>Participants who have failed a B-Cell Receptor Signaling Pathway Inhibitor (BCRI) therapy and who have also failed, or were unable to receive chemoimmunotherapy (CIT) irrespective of 17p status will receive various doses of venetoclax once daily (QD). | Drug: Venetoclax<br>* Tablet; Oral<br>* Other names: Venclexta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is the proportion of participants with an overall response (complete remission [CR], plus complete remission with incomplete bone marrow recovery [CRi], plus nodular partial remission [nPR], plus partial remission [PR]) per the National Cancer Institute-Working Group (NCI-WG) guidelines as assessed by the Independent Review Committee (IRC). | Measured up to 2 years after the last participant has enrolled in the study. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate (CRR) | CRR is defined as the proportion of subjects who achieved (CR + CRi) per the 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (iwCLL) NCI-WG criteria. | Measured up to 2 years after the last participant has enrolled into the study. | 
| Duration of Overall Response (DOR) | DOR is defined as the number of days from the date of first (CR + CRi + nPR + PR) to the earliest disease progression or death | Measured up to 2 years after the last participant has enrolled into the study. | 
| Progression Free Survival (PFS) | PFS is defined as the number of days from the date of first dose to the date of earliest disease progression (determined by the IRC) or death. | Measured up to 5 years after the last participant has enrolled into the study. | 
| Event Free Survival (EFS) | EFS is defined as the number of days from the date of first dose to the date of earliest disease progression, death, or start of a new anti-leukemic therapy. | Measured up to 5 years after the last participant has enrolled into the study. | 
| Time to Progression (TTP) | TTP is defined as the number of days from the date of first dose to the date of earliest disease progression (determined by the IRC). | Measured up to 5 years after the last participant has enrolled into the study. | 
| Time to 50% reduction in absolute lymphocyte count (ALC) | Time to 50% reduction in ALC is defined as the number of days from the date of first dose to the date when the ALC has reduced to 50% of the baseline value. | Measured up to 2 years after the last participant has enrolled into the study. | 
| Overall Survival (OS) | OS is defined as number of days from the date of first dose to the date of death. | Measured up to 5 years after the last participant has enrolled into the study. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed chronic lymphocytic leukemia (CLL), Refractory chronic lymphocytic leukemia (CLL), 17p deletion, Venetoclax, Leukemia, Lymphoproliferative Disorders, Small Lymphocytic Lymphoma (SLL), Venclexta