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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL)	Drug: Obinutuzumab; Drug: Bendamustine; Drug: Venetoclax	Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 120 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: August 10, 2018
• Actual Primary Completion Date: October 12, 2021
• Estimated Study Completion Date: July 20, 2023

Arms and Interventions

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 Name: 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 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

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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 ).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Arizona

Arizona Oncology Associates, PC-HOPE /ID# 202335

Tempe, Arizona, United States, 85284-1812

United States, Colorado

Rocky Mountain Cancer Centers - Denver Midtown /ID# 202328

Denver, Colorado, United States, 80218

United States, Missouri

MidAmerica Division, Inc. /ID# 201099

Kansas City, Missouri, United States, 64132

United States, Ohio

Oncology Hematology Care, Inc. /ID# 202397

Cincinnati, Ohio, United States, 45236-2725

United States, Oregon

Willamette Valley Cancer Institute and Research Center /ID# 201201

Eugene, Oregon, United States, 97401-6043

United States, South Carolina

Prisma Health Cancer Inst - Eastside /ID# 202329

Greenville, South Carolina, United States, 29615

United States, Tennessee

Tennessee Oncology - Chattanooga /ID# 202840

Chattanooga, Tennessee, United States, 37404-1108

Tennessee Oncology-Nashville Centennial /ID# 201098

Nashville, Tennessee, United States, 37203-1632

United States, Texas

Texas Oncology - Austin Midtown /ID# 201199

Austin, Texas, United States, 78705

Texas Oncology - Beaumont /ID# 202359

Beaumont, Texas, United States, 77701-4691

Texas Oncology - Medical City Dallas /ID# 201196

Dallas, Texas, United States, 75230

Texas Oncology - McAllen /ID# 202331

McAllen, Texas, United States, 78503

Texas Oncology - San Antonio Medical Center /ID# 202332

San Antonio, Texas, United States, 78240-5251

Texas Oncology - Northeast Texas /ID# 201211

Tyler, Texas, United States, 75702

United States, Washington

Northwest Cancer Specialists, P.C. /ID# 201198

Vancouver, Washington, United States, 98684

Sponsors and Collaborators

AbbVie

Investigators

• Study Director: ABBVIE INC.; AbbVie

  Study Documents (Full-Text)

Documents provided by AbbVie:

Study Protocol  [PDF] December 19, 2019

Statistical Analysis Plan  [PDF] October 8, 2019

More Information

Additional Information:

Related Info 

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT03406156
• Other Study ID Numbers: M16-788
• First Posted: January 23, 2018
• Results First Posted: November 3, 2022
• Last Update Posted: November 3, 2022
• Last Verified: October 2022

Individual Participant Data (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; Statistical Analysis Plan (SAP); 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/

• 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

Keywords provided by AbbVie:

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

Additional relevant MeSH terms:

Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Venetoclax; Bendamustine Hydrochloride; Obinutuzumab; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological