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

Phase 2

Completed

Conditions: Chronic Lymphocytic Leukemia

Interventions: Drug: Venetoclax

Registration Number: NCT02141282

Lead Sponsor: AbbVie

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 127

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ABT-199 after idelalisib therapy	Venetoclax	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.
ABT-199 after ibrutinib therapy: Expansion Cohort	Venetoclax	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.
ABT-199 after ibrutinib therapy	Venetoclax	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.
ABT-199 after idelalisib therapy: Expansion Cohort	Venetoclax	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.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	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 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.

Secondary Outcome Measures

Name	Time	Method
Time to Progression (TTP)	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	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.
Overall Survival (OS)	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	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.
Duration of Response (DOR)	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	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.
Progression-free Survival (PFS)	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	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.

Trial Locations

Locations (15): Beth Israel Deaconess Medical Center /ID# 134509
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Boston, Massachusetts, United States
University of Utah /ID# 130813
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Salt Lake City, Utah, United States
Moores Cancer Center at UC San Diego /ID# 128535
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La Jolla, California, United States
University of California, Los Angeles /ID# 127262
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Los Angeles, California, United States
Stanford University School of Med /ID# 126495
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Stanford, California, United States
Georgetown University Hospital /ID# 127261
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Washington, District of Columbia, United States
Emory Midtown Infectious Disease Clinic /ID# 131249
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Atlanta, Georgia, United States
Northwestern University Feinberg School of Medicine /ID# 126497
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Chicago, Illinois, United States
Dana-Farber Cancer Institute /ID# 126496
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Boston, Massachusetts, United States
New York Presbyterian Hospital Weill Cornell Medical Center /ID# 129648
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New York, New York, United States
Columbia Univ Medical Center /ID# 128536
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New York, New York, United States
Univ Rochester Med Ctr /ID# 130011
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Rochester, New York, United States
The Ohio State University /ID# 127263
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Columbus, Ohio, United States
University of Texas MD Anderson Cancer Center /ID# 126498
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Houston, Texas, United States
University of Pennsylvania /ID# 126860
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Philadelphia, Pennsylvania, United States