A Phase 2 Open-Label Study of the Efficacy and Safety of ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia (CLL) Subjects With Relapse or Refractory to B-Cell Receptor Signaling Pathway Inhibitor Therapy

Study Overview
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Brief Summary
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This was an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of ABT-199 in 127 participants with relapsed or refractory chronic lymphocytic leukemia (CLL) after B-cell receptor signaling pathway inhibitors (BCR PI) treatment.

Official Title
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A Phase 2 Open-Label Study of the Efficacy and Safety of ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Subjects With Relapse or Refractory to B-Cell Receptor Signaling Pathway Inhibitor Therapy

Conditions
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Chronic Lymphocytic Leukemia

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 chronic lymphocytic leukemia (CLL) that meets 2008 Modified International Workshop on Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria Participant has relapsed/refractory disease with an indication for treatment Participant has refractory disease or developed recurrence after therapy with a B-cell receptor pathway inhibitor (BCR PI) Participant must have an Eastern Cooperative Oncology Group performance score of ≤ 2 Participant must have adequate bone marrow function at Screening Participant must have adequate coagulation profile, renal, and hepatic function, per laboratory reference range at Screening Exclusion Criteria: Participant has undergone an allogeneic stem cell transplant within the past year Participant has developed Richter's transformation confirmed by biopsy Participant has active and uncontrolled autoimmune cytopenia Participant has malabsorption syndrome or other condition that precludes enteral route of administration Participant is human immunodeficiency virus (HIV) positive or has chronic hepatitis B or hepatitis C virus requiring treatment Participant has known contraindication or allergy to both xanthine oxidase inhibitors and rasburicase

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABT-199 after ibrutinib therapy<br>Participants with ibrutinib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 593 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. | Drug: Venetoclax<br>* Each dose of venetoclax was to be taken with approximately 240 mL of water within 30 minutes after the completion of breakfast or the participant's first meal of the day.<br>* Other names: VENCLEXTA®;|
| Experimental: ABT-199 after idelalisib therapy<br>Participants with idelalisib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 1023 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. | Drug: Venetoclax<br>* Each dose of venetoclax was to be taken with approximately 240 mL of water within 30 minutes after the completion of breakfast or the participant's first meal of the day.<br>* Other names: VENCLEXTA®;|
| Experimental: ABT-199 after ibrutinib therapy: Expansion Cohort<br>Participants with ibrutinib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 622 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants enrolled into the Expansion Cohort with bulky disease at study entry who were non-responders or those who showed signs of clinical progression after completing the ramp up to 400 mg either by clinical disease assessment or by CT/MRI scan between Week 6 to Week 12 may have been permitted to escalate venetoclax to a daily dose of 600 mg. | Drug: Venetoclax<br>* Each dose of venetoclax was to be taken with approximately 240 mL of water within 30 minutes after the completion of breakfast or the participant's first meal of the day.<br>* Other names: VENCLEXTA®;|
| Experimental: ABT-199 after idelalisib therapy: Expansion Cohort<br>Participants with idelalisib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 1189 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants enrolled into the Expansion Cohort with bulky disease at study entry who were non-responders or those who showed signs of clinical progression after completing the ramp up to 400 mg either by clinical disease assessment or by CT/MRI scan between Week 6 to Week 12 may have been permitted to escalate venetoclax to a daily dose of 600 mg. | Drug: Venetoclax<br>* Each dose of venetoclax was to be taken with approximately 240 mL of water within 30 minutes after the completion of breakfast or the participant's first meal of the day.<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) | Overall response rate is defined as the percentage of participants with an overall response (per the investigator assessment) 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (IWCLL) National Cancer Institute-Working Group (NCI-WG) criteria. | At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR is defined as the number of days from the date of first response (complete response [CR], complete response with incomplete marrow recovery [CRi], nodular partial remission [nPR], or partial remission [PR]) to the earliest recurrence or progressive disease. DOR was analyzed by Kaplan-Meier (K-M) methodology. | At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort | 
| 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 (PD). TTP was analyzed by Kaplan-Meier (K-M) methodology. | At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort | 
| 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 (PD) or death. PFS was analyzed by Kaplan-Meier methodology. | At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort | 
| Overall Survival (OS) | OS is defined as the number of days from the date of first dose to the date of death for all dosed participants. For participants who did not die, their data was censored at the date of last study visit or the last known date to be alive, whichever was later. OS was estimated using Kaplan-Meier methodology. | At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncology, Chronic Lymphocytic Leukemia, Cancer of the blood and bone marrow