A Study in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Subjects, Excluding Those With the 17p Deletion, to Evaluate Debulking Regimens Prior to Initiating Venetoclax Combination Therapy

• ClinicalTrials.gov Identifier: NCT03406156
• Recruitment Status: Active, not recruiting
• First Posted: January 23, 2018
• Results First Posted: November 3, 2022
• Last Update Posted: November 3, 2022
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: January 16, 2018
• First Posted Date: January 23, 2018
• Results First Submitted Date: October 7, 2022
• Results First Posted Date: November 3, 2022
• Last Update Posted Date: November 3, 2022
• Actual Study Start Date: August 10, 2018
• Actual Primary Completion Date: October 12, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 7, 2022)

• Percentage of Participants Achieving Low Tumor Burden Status With Induction of Obinutuzumab or Obinutuzumab Plus Bendamustine (Debulking Period) [ Time Frame: From Baseline to the end of Cycles 2, 4, and 6, up to approximately 24 weeks after initial dose of study drug ]
  Low tumor burden is defined as absolute lymphocyte count (ALC) < 25 × 10^9 /L and all lymph nodes < 5 cm per computed tomography (CT) scans.
• Complete Response Rate [ Time Frame: From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days ]
  Complete response rate is defined as the percentage of participants achieving complete remission (CR) or complete remission with incomplete marrow recovery (CRi) as their best response based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following:

  • Peripheral blood lymphocytes <4000/μL
  • Absence of lymphadenopathy by physical examination and computed tomography scan
  • No hepatomegaly or splenomegaly by physical examination
  • Absence of disease or constitutional symptoms (unexplained fevers >38°C, drenching night sweats, ≥10% weight loss in last 6 months)
  • Blood counts above the following:
    • Neutrophils >1500/μL
    • Platelets >100,000/μL
    • Hemoglobin >11.0 g/dL
  • Bone marrow at least normocellular for age, <30% lymphocytes

  CRi was defined as participants with CR who had persistent cytopenia unrelated to CLL but related to drug toxicity.

Original Primary Outcome Measures (submitted: January 16, 2018)

• Percent of Participants Achieving Low Tumor Burden Status with induction of Obinutuzumab or Obinutuzumab plus Bendamustine (Debulking Period) [ Time Frame: Up to approximately 24 weeks after initial dose of study drug ]
  Low tumor burden is defined by peripheral lymphocyte counts of < 25,000 and all lymph nodes < 5 cm per CT scans.
• Complete Remission Rate (CR) and Complete Remission with Incomplete Marrow Recovery (CRi) [ Time Frame: Up to approximately 65 weeks after initial dose of venetoclax ]
  Defined as the proportion of subjects who achieved CR or CRi (per the 2008 Modified International Workshop on Chronic Lymphocytic Leukemia National Cancer Institute-sponsored Working Group [IWCLL NCI-WG] criteria).

Current Secondary Outcome Measures (submitted: October 7, 2022)

• Overall Response Rate (ORR) [ Time Frame: From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days ]
  ORR is defined as the percentage of participants who achieved a best response of complete remission (CR), complete remission with incomplete marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR) based on the 2008 Modified IWCLL NCI-WG criteria at any time during the study as assessed by investigator up through the completion of the 65-week disease response assessment after the start of venetoclax. Participants who did not respond were considered non-responders.
• Duration of Response (DoR) [ Time Frame: From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days ]
  DoR is defined as the number of days from the date of first response (CR, CRi, nPR, or PR per the 2008 Modified IWCLL NCI-WG criteria) to the date of disease progression or death, whichever occurs first. All disease progression was to be included regardless whether the event occurred during or after the participant was taking any study drug (either venetoclax, obinutuzumab, or bendamustine). Duration of response was analyzed by Kaplan-Meier (K-M) methodology.
• Progression-Free Survival (PFS) [ Time Frame: From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days ]
  PFS is defined as the number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to the date of disease progression or death, whichever occurs first. All disease progression was to be included regardless whether the event occurred during or after the participant was taking any study drug. Progression-free survival was analyzed by Kaplan-Meier methodology.
• Time to Progression (TTP) [ Time Frame: From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days ]
  TTP is defined as the number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to date of disease progression. All disease progression was to be included regardless of whether the event occurred during or after the participant was taking any study drug.The distribution of the time to progression was estimated using Kaplan-Meier methodology.
• Overall Survival (OS) [ Time Frame: From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days ]
  OS is defined as number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to the date of death. If a participant had not died, their data was censored at the date when they were last known to be alive prior to the cutoff date.The distribution of OS was estimated using Kaplan-Meier methodology.
• Undetectable Minimal Residual Disease (UMRD) Rate [ Time Frame: From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021) ]
  The level of MRD was assessed in the peripheral blood of all participants at 5 months after last dose of obinutuzumab, and at 3 months after last dose of venetoclax/end of treatment (including early study termination) to determine the rate of UMRD. Undetectable Minimal Residual Disease is defined as less than one CLL cell per 10,000 leukocytes (< 10^-4 ).

Original Secondary Outcome Measures (submitted: January 16, 2018)

• Overall Response Rate (ORR) [ Time Frame: Up to approximately 3.5 years after initial dose of study drug ]
  ORR is defined as the proportion of participants with an overall response (CR, CRi, nodular partial remission [nPR] plus partial remission [PR]) per the 2008 Modified IWCLL NCI-WG criteria.
• Duration of Response (DoR) [ Time Frame: Up to approximately 3.5 years after initial dose of study drug ]
  DOR defined as the number of days from the date of first response (CR, CRi, nPR, or PR) (per the 2008 Modified IWCLL NCI-WG criteria) to the date of disease progression. All disease progression will be included regardless whether the event occurred during or after the participant was taking any study drug (either venetoclax, obinutuzumab, or bendamustine).
• Progression-Free Survival (PFS) [ Time Frame: Up to approximately 3.5 years after initial dose of study drug ]
  PFS is defined as the number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to the date of disease progression or death, whichever occurs first. All disease progression will be included regardless whether the event occurred during or after the participant was taking any study drug.
• Time to Progression (TTP) [ Time Frame: Up to approximately 3.5 years after initial dose of study drug ]
  TPP is defined as the number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to date of disease progression. All disease progression will be included regardless whether the event occurred during or after the participant was taking any study drug.
• Overall Survival (OS) [ Time Frame: Up to approximately 3.5 years after initial dose of study drug ]
  OS is defined as number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to the date of death.
• Minimal Residual Disease (MRD) Negativity Rate [ Time Frame: Up to approximately 3.5 years after initial dose of study drug ]
  MRD negativity defined as less than one CLL cell per 10,000 leukocytes (or below 10^-4). Rate of MRD status will be defined as the proportion of participants who have MRD negativity status.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Subjects, Excluding Those With the 17p Deletion, to Evaluate Debulking Regimens Prior to Initiating Venetoclax Combination Therapy
• Official Title: A Phase 3b Study in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Subjects, Excluding Those With the 17p Deletion, to Evaluate Debulking Regimens Prior to Initiating Venetoclax Combination Therapy
• Brief Summary: This is a multi-cohort, open-label study in previously untreated participants with chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), excluding those with the 17p deletion, to evaluate a debulking strategy that would enable all participants to receive subsequent venetoclax as outpatients, with lower risk of tumor lysis syndrome.
• Detailed Description: Safety and efficacy data through 13 October 2021 are included in the interim analysis, which was conducted after all participants completed the post-treatment Week 65 visit or discontinued from the study.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Chronic Lymphocytic Leukemia (CLL)
• Small Lymphocytic Lymphoma (SLL)

Intervention

• Drug: Obinutuzumab
  Administered via intravenous infusion
  Other Name: Gazyva
• Drug: Bendamustine
  Administered via intravenous infusion
  Other Name: Bendeka
• Drug: Venetoclax
  The venetoclax dose was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. Participants were instructed to take venetoclax tablets with a meal and water at approximately the same time each day. Venetoclax tablets were to be swallowed whole and not chewed, crushed, or broken prior to swallowing.
  Other Names:

  • Venclexta
  • ABT-199
  • GDC-0199

Study Arms

• Experimental: Obinutuzumab

  Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen.

  After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.

  Interventions:

  • Drug: Obinutuzumab
  • Drug: Venetoclax
• Experimental: Obinutuzumab/bendamustine

  Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen.

  Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.

  Interventions:

  • Drug: Obinutuzumab
  • Drug: Bendamustine
  • Drug: Venetoclax

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 1, 2021): 120
• Original Estimated Enrollment (submitted: January 16, 2018): 100
• Estimated Study Completion Date: July 20, 2023
• Actual Primary Completion Date: October 12, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Adequate hematology, kidney and liver function as described in the protocol
• Diagnosis of previously untreated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) according to 2008 Modified International Workshop on Chronic Lymphocytic Leukemia National Cancer Institute-sponsored Working Group (IWCLL NCI-WG) criteria
• Eastern Cooperative Oncology Group (ECOG) performance score of 0 - 1
• CLL requires treatment according to the IWCLL criteria
• Medium tumor burden (any lymph node [LN] 5 to < 10 cm OR absolute lymphocyte count [ALC] ≥ 25 × 10^9/L) OR High tumor burden (any LN ≥ 10 cm OR ALC ≥ 25 × 10^9/L and LN ≥ 5 cm)

Exclusion Criteria:

• Presence of 17p deletion at Screening
• Richter's syndrome (transformation of CLL/SLL to aggressive non-Hodgkin's lymphoma or Hodgkin's lymphoma)
• Prolymphocytic leukemia

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: NCT03406156
• Other Study ID Numbers: M16-788
• Has Data Monitoring Committee: Yes

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 and 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: Not Provided

Investigators

• Study Director: ABBVIE INC.; AbbVie

• PRS Account: AbbVie
• Verification Date: October 2022