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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL)
• Intervention / Treatment: Drug: Obinutuzumab; Drug: Venetoclax; Drug: Bendamustine

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
• Enrollment (Actual): 120
• Phase: Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tempe, Arizona, United States, 85284-1812
      • Arizona Oncology Associates, PC-HOPE /ID# 202335
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Centers - Denver Midtown /ID# 202328
  • Missouri
    • Kansas City, Missouri, United States, 64132
      • MidAmerica Division, Inc. /ID# 201099
  • Ohio
    • Cincinnati, Ohio, United States, 45236-2725
      • Oncology Hematology Care, Inc. /ID# 202397
  • Oregon
    • Eugene, Oregon, United States, 97401-6043
      • Willamette Valley Cancer Institute and Research Center /ID# 201201
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Prisma Health Cancer Inst - Eastside /ID# 202329
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404-1108
      • Tennessee Oncology - Chattanooga /ID# 202840
    • Nashville, Tennessee, United States, 37203-1632
      • Tennessee Oncology-Nashville Centennial /ID# 201098
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology - Austin Midtown /ID# 201199
    • Beaumont, Texas, United States, 77701-4691
      • Texas Oncology - Beaumont /ID# 202359
    • Dallas, Texas, United States, 75230
      • Texas Oncology - Medical City Dallas /ID# 201196
    • McAllen, Texas, United States, 78503
      • Texas Oncology - McAllen /ID# 202331
    • San Antonio, Texas, United States, 78240-5251
      • Texas Oncology - San Antonio Medical Center /ID# 202332
    • Tyler, Texas, United States, 75702
      • Texas Oncology - Northeast Texas /ID# 201211
  • Washington
    • Vancouver, Washington, United States, 98684
      • Northwest Cancer Specialists, P.C. /ID# 201198

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 97 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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; Administered via intravenous infusion; Other Names: Gazyva; 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
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; Administered via intravenous infusion; Other Names: Gazyva; 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; Drug: Bendamustine; Administered via intravenous infusion; Other Names: Bendeka

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From Baseline to the end of Cycles 2, 4, and 6, up to approximately 24 weeks after initial dose of study drug
Complete Response Rate	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/μLPlatelets >100,000/μLHemoglobin >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.	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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
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.	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
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.	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
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.	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
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.	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
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 ).	From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021)

Collaborators and Investigators

• Sponsor: AbbVie
• Investigators: Study Director: ABBVIE INC., AbbVie

Publications and helpful links

General Publications

• Chyla B, Jiang D, Pesko J, Courtright J, Sharman J, Andorsky D, et al. 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

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2018
• Primary Completion (Actual): October 12, 2021
• Study Completion (Actual): July 10, 2023

Study Registration Dates

• First Submitted: January 16, 2018
• First Submitted That Met QC Criteria: January 16, 2018
• First Posted (Actual): January 23, 2018

Study Record Updates

• Last Update Posted (Actual): January 29, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Cancer; Venetoclax; Obinutuzumab; Chronic Lymphocytic Leukemia; Bendamustine; Small Lymphocytic Lymphoma; Tumor lysis syndrome; 17p Deletion; Debulking
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Venetoclax; Bendamustine Hydrochloride; Obinutuzumab
• Other Study ID Numbers: M16-788

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Time Frame: For details on when studies are available for sharing visit https://vivli.org/ourmember/abbvie/
• IPD Sharing 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/
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• 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