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

• ClinicalTrials.gov Identifier: NCT02141282
• Recruitment Status: Completed
• First Posted: May 19, 2014
• Results First Posted: December 19, 2022
• Last Update Posted: December 19, 2022
• Sponsor: AbbVie
• Collaborator: Roche-Genentech
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: May 12, 2014
• First Posted Date: May 19, 2014
• Results First Submitted Date: November 18, 2022
• Results First Posted Date: December 19, 2022
• Last Update Posted Date: December 19, 2022
• Actual Study Start Date: September 10, 2014
• Actual Primary Completion Date: December 22, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 18, 2022)

Overall Response Rate (ORR) [ Time Frame: 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.

Original Primary Outcome Measures (submitted: May 15, 2014)

Overall response rate (ORR) [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]

To evaluate the efficacy of ABT-199 monotherapy in subjects with chronic lymphocytic leukemia (CLL) relapsed or refractory to B-cell Receptor Signaling Pathway Inhibitors. Assessed by the investigator, based on laboratory results, physical examinations, CT scans, and bone marrow examinations

Current Secondary Outcome Measures (submitted: November 18, 2022)

• Duration of Response (DOR) [ Time Frame: 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.
• Time to Progression (TTP) [ Time Frame: 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.
• Progression-free Survival (PFS) [ Time Frame: 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.
• Overall Survival (OS) [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: May 15, 2014)

• Duration of response [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  The number of days from the date of first response (complete response (CR) or partial response (PR)) to the earliest recurrence or disease progression (PD)
• Time to progression (TTP) [ Time Frame: Measured up to 5 years after the last subject has enrolled in the study. ]
  The number of days from the date of first dose or enrollment if not dosed to the date of earliest PD
• Progression-free survival (PFS) [ Time Frame: Measured up to 5 years after the last subject has enrolled in the study. ]
  The number of days from the date of first dose to the date of earliest PD or death
• Overall survival (OS) [ Time Frame: Measured up to 5 years after the last subject has enrolled in the study. ]
  The number of days from the date of first dose to the date of death for all dosed subjects

Current Other Pre-specified Outcome Measures (submitted: November 18, 2022)

• Time to Next Anti-Chronic Lymphocytic Leukemia Treatment (TNNT) [ Time Frame: Collected every 3 months for a period of 5 years after the last participant had enrolled into the study ]
  TNNT is defined as the number of days from the date of the first dose of venetoclax to the date of first dose of any non-protocol anti-leukemia therapy (NPT) or death from any cause. For participants who did not take NPT, their data was censored at the last known date to be free of NPT. TTNT was analyzed by Kaplan-Meier methodology.
• Percentage of Participants With Minimal Residual Disease (MRD) Negativity Status [ Time Frame: Assessed at Week 24, Day 1; after the first Complete Response, Complete Remission with Incomplete Marrow Recovery, or Partial Response; at 12-week interval visits until two consecutive negative MRD levels were reported ]
  The rate of MRD response is defined as the percentage of participants who had MRD negative status.

Original Other Pre-specified Outcome Measures (submitted: May 15, 2014)

• Time to Next Anti-CLL Treatment (TNT) [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  The number of days from the date of first dose of ABT-199 to the date of first dose of new non-protocol anti-leukemia therapy (NPT) or death from any cause
• Rate of minimal residual disease (MRD) negativity status [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  The presence of less that once CLL cell per 10,000 leukocytes in either peripheral blood and/or bone marrow

Descriptive Information

• Brief Title: 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
• Official Title: 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Lymphocytic Leukemia

Intervention

Drug: Venetoclax

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.

Other Names:

• ABT-199
• VENCLEXTA®

Study Arms

• Experimental: ABT-199 after ibrutinib therapy
  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.
  Intervention: Drug: Venetoclax
• Experimental: ABT-199 after idelalisib therapy
  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.
  Intervention: Drug: Venetoclax
• Experimental: ABT-199 after ibrutinib therapy: Expansion Cohort
  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.
  Intervention: Drug: Venetoclax
• Experimental: ABT-199 after idelalisib therapy: Expansion Cohort
  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.
  Intervention: Drug: Venetoclax

Publications *

• Roberts AW, Ma S, Kipps TJ, Coutre SE, Davids MS, Eichhorst B, Hallek M, Byrd JC, Humphrey K, Zhou L, Chyla B, Nielsen J, Potluri J, Kim SY, Verdugo M, Stilgenbauer S, Wierda WG, Seymour JF. Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood. 2019 Jul 11;134(2):111-122. doi: 10.1182/blood.2018882555. Epub 2019 Apr 25.
• Coutre S, Choi M, Furman RR, Eradat H, Heffner L, Jones JA, Chyla B, Zhou L, Agarwal S, Waskiewicz T, Verdugo M, Humerickhouse RA, Potluri J, Wierda WG, Davids MS. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018 Apr 12;131(15):1704-1711. doi: 10.1182/blood-2017-06-788133. Epub 2018 Jan 5.
• Jones JA, Mato AR, Wierda WG, Davids MS, Choi M, Cheson BD, Furman RR, Lamanna N, Barr PM, Zhou L, Chyla B, Salem AH, Verdugo M, Humerickhouse RA, Potluri J, Coutre S, Woyach J, Byrd JC. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018 Jan;19(1):65-75. doi: 10.1016/S1470-2045(17)30909-9. Epub 2017 Dec 12.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 19, 2018): 127
• Original Estimated Enrollment (submitted: May 15, 2014): 40
• Actual Study Completion Date: December 22, 2021
• Actual Primary Completion Date: December 22, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02141282
• Other Study ID Numbers: M14-032
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols, analyses plans, clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: For details on when studies are available for sharing visit https://vivli.org/ourmember/abbvie/
• Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous independent scientific research, and will be provided following review and approval of a research proposal and statistical analysis plan and execution of a data sharing statement. Data requests can be submitted at any time after approval in the US and/or EU and a primary manuscript is accepted for publication. For more information on the process, or to submit a request, visit the following link https://www.abbvieclinicaltrials.com/hcp/data-sharing/
• URL: https://vivli.org/ourmember/abbvie/

• Current Responsible Party: AbbVie
• Original Responsible Party: Same as current
• Current Study Sponsor: AbbVie
• Original Study Sponsor: Same as current
• Collaborators: Roche-Genentech

Investigators

• Study Director: ABBVIE INC.; AbbVie

• PRS Account: AbbVie
• Verification Date: November 2022