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

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• Leukemia 5,446
• Leukemia, Lymphoid 1,783
• Leukemia, Lymphocytic, Chronic, B-Cell 1,602

Keywords

• Cancer
• Chronic Lymphocytic Leukemia
• 17p Deletion
• Debulking
• Obinutuzumab
• Bendamustine
• Tumor lysis syndrome
• Venetoclax
• Small Lymphocytic Lymphoma

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.

  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.

  Drug: Obinutuzumab · Drug: Bendamustine · Drug: Venetoclax

Interventions

• DrugObinutuzumab

  Administered via intravenous infusion

  Also known as: Gazyva

• DrugBendamustine

  Administered via intravenous infusion

  Also known as: Bendeka

• DrugVenetoclax

  The venetoclax dose was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. Venetoclax was continued for a total duration of up to 53 weeks, including the 5-week ramp-up schedule. 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.

  Also known as: Venclexta, ABT-199, GDC-0199

Primary outcomes

1. Percentage of Participants Achieving Low Tumor Burden Status With Induction of Obinutuzumab or Obinutuzumab Plus Bendamustine (Debulking Period)

   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.

   Time frame: From Baseline to the end of Cycles 2, 4, and 6, up to approximately 24 weeks after initial dose of study drug

2. Complete Remission Rate

   Complete remission 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 * 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.

   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

Secondary outcomes

1. Overall Response Rate (ORR)

   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.

   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

2. Duration of Response (DoR)

   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.

   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

3. Progression-Free Survival (PFS)

   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 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

4. Time to Progression (TTP)

   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.

   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

5. Overall Survival (OS)

   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.

   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

6. Undetectable Minimal Residual Disease (UMRD) Rate

   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 ).

   Time frame: From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021)

Baseline characteristics

Publications

• Flinn IW, Andorsky D, Melear J, Manda S, Anz B III, Kolibaba K, Yimer H, Burke JM, Fanning S, Courtright J, Islas-Ohlmayer M, Kambhampati S, Vizkelety T, Pesko J, Chyla B, Jiang D, Sharman JP. Debulking Before Initiation of Venetoclax Therapy in Untreated Patients with Chronic Lymphocytic Leukemia: Results from a Phase 3b Study. American Society of Hematology - 63rd Annual Meeting. 2021
• Sharman J, Andorsky D, Melear J, Manda S, Anz B III, Kolibaba K, Yimer H, Burke J, Fanning S, Courtright J, Islas-Ohlmayer M, Kambhampati S, Jiang D, Pesko D, Vizkelety T, Sharmokh S, Nielsen J, Flinn I. Phase 3b study to evaluate debulking regimens prior to initiating venetoclax therapy in untreated patients with chronic lymphocytic leukemia. Florida Society of Clinical Oncology-2020 Fall Session
• Flinn I, Andorsky D, Melear J, Manda S, Anz B III, Kolibaba K, Yimer H, Burke J, Fanning S, Courtright J, Islas-Ohlmayer M, Kambhampati S, Jiang D, Pesko D, Vizkelety T, Sharmokh S, Sharman J. Debulking Regimens Prior To Initiating Venetoclax Therapy in Untreated Patients with Chronic Lymphocytic Leukemia: Interim Results from a Phase 3b Study. American Society of Hematology - 62nd Annual Meeting. 2020
• Sharman J, Andorsky D, Melear J, Manda S, Anz B III, Kolibaba K, Yimer H, Burke J, Fanning S, Courtright J, Islas-Ohlmayer M, Kambhampati S, Jiang D, Pesko J, Vizkelety T, Sharmokh S, Nielsen J, Flinn I. Phase 3b Study to Evaluate Debulking Regimens Prior to Initiating Venetoclax Therapy in Untreated Patients with Chronic Lymphocytic Leukemia. Society of Hematologic Oncology-8th Annual Meeting. 2020
• Sharman J, Andorsky D. Melear J, Manda S, Anz B II, Kolibaba K, Yimer H, Burke J, Fanning S, Courtright J, Islas-Ohlmayer M, Kambhampati S, Jiang D, Pesko J, Vizkelety T, Sharmkokh S, Nielsen J, Flinn I. Phase 3b study to evaluate debulking regimens prior to initiating venetoclax therapy in untreated patients with chronic lymphocytic leukemia. European Hematology Association-25th Congress. 2020
• Sharman J, Andorsky D, Melear J, Manda S, Anz B III, Kolibaba K, Yimer H, Burke J, Fanning S, Courtright J, Islas-Ohlmayer M, Kambhampati S, Al Masud A, Zimmerman T, Nielsen J, Vizkelety T, Jiang D, Flinn I. Debulking eliminates need for hospitalization prior to initiating frontline venetoclax therapy in previously untreated CLL patients: a phase 3b study. American Society of Hematology - 61st Annual Meeting. 2019

Related links

• Related Info ↗

Study documents

• Study protocol · Dec 19, 2019
• Statistical analysis plan · Jun 26, 2023

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — 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 information: Study protocol, Sap, Csr