Back to resultsA 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
Primary Purpose
Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Obinutuzumab
Bendamustine
Venetoclax
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Lymphocytic Leukemia (CLL) focused on measuring Cancer, Chronic Lymphocytic Leukemia, 17p Deletion, Debulking, Obinutuzumab, Bendamustine, Tumor lysis syndrome, Venetoclax, Small Lymphocytic Lymphoma
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
Sites / Locations
- Arizona Oncology Associates, PC-HOPE /ID# 202335
- Rocky Mountain Cancer Centers - Denver Midtown /ID# 202328
- MidAmerica Division, Inc. /ID# 201099
- Oncology Hematology Care, Inc. /ID# 202397
- Willamette Valley Cancer Institute and Research Center /ID# 201201
- Prisma Health Cancer Inst - Eastside /ID# 202329
- Tennessee Oncology - Chattanooga /ID# 202840
- Tennessee Oncology-Nashville Centennial /ID# 201098
- Texas Oncology - Austin Midtown /ID# 201199
- Texas Oncology - Beaumont /ID# 202359
- Texas Oncology - Medical City Dallas /ID# 201196
- Texas Oncology - McAllen /ID# 202331
- Texas Oncology - San Antonio Medical Center /ID# 202332
- Texas Oncology - Northeast Texas /ID# 201211
- Northwest Cancer Specialists, P.C. /ID# 201198
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Obinutuzumab
Obinutuzumab/bendamustine
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
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/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
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.
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.
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 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.
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.
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 ).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03406156
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
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
August 10, 2018 (Actual)
Primary Completion Date
October 12, 2021 (Actual)
Study Completion Date
July 10, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AbbVie
4. Oversight
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
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)
Keywords
Cancer, Chronic Lymphocytic Leukemia, 17p Deletion, Debulking, Obinutuzumab, Bendamustine, Tumor lysis syndrome, Venetoclax, Small Lymphocytic Lymphoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
120 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Obinutuzumab
Arm Type
Experimental
Arm Description
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.
Arm Title
Obinutuzumab/bendamustine
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Obinutuzumab
Other Intervention Name(s)
Gazyva
Intervention Description
Administered via intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Bendamustine
Other Intervention Name(s)
Bendeka
Intervention Description
Administered via intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
Venclexta, ABT-199, GDC-0199
Intervention Description
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.
Primary Outcome Measure Information:
Title
Percentage of Participants Achieving Low Tumor Burden Status With Induction of Obinutuzumab or Obinutuzumab Plus Bendamustine (Debulking Period)
Description
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
Title
Complete Response Rate
Description
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.
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 Outcome Measure Information:
Title
Overall Response Rate (ORR)
Description
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
Title
Duration of Response (DoR)
Description
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
Title
Progression-Free Survival (PFS)
Description
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
Title
Time to Progression (TTP)
Description
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
Title
Overall Survival (OS)
Description
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
Title
Undetectable Minimal Residual Disease (UMRD) Rate
Description
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
ABBVIE INC.
Organizational Affiliation
AbbVie
Official's Role
Study Director
Facility Information:
Facility Name
Arizona Oncology Associates, PC-HOPE /ID# 202335
City
Tempe
State/Province
Arizona
ZIP/Postal Code
85284-1812
Country
United States
Facility Name
Rocky Mountain Cancer Centers - Denver Midtown /ID# 202328
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
MidAmerica Division, Inc. /ID# 201099
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64132
Country
United States
Facility Name
Oncology Hematology Care, Inc. /ID# 202397
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45236-2725
Country
United States
Facility Name
Willamette Valley Cancer Institute and Research Center /ID# 201201
City
Eugene
State/Province
Oregon
ZIP/Postal Code
97401-6043
Country
United States
Facility Name
Prisma Health Cancer Inst - Eastside /ID# 202329
City
Greenville
State/Province
South Carolina
ZIP/Postal Code
29615
Country
United States
Facility Name
Tennessee Oncology - Chattanooga /ID# 202840
City
Chattanooga
State/Province
Tennessee
ZIP/Postal Code
37404-1108
Country
United States
Facility Name
Tennessee Oncology-Nashville Centennial /ID# 201098
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203-1632
Country
United States
Facility Name
Texas Oncology - Austin Midtown /ID# 201199
City
Austin
State/Province
Texas
ZIP/Postal Code
78705
Country
United States
Facility Name
Texas Oncology - Beaumont /ID# 202359
City
Beaumont
State/Province
Texas
ZIP/Postal Code
77701-4691
Country
United States
Facility Name
Texas Oncology - Medical City Dallas /ID# 201196
City
Dallas
State/Province
Texas
ZIP/Postal Code
75230
Country
United States
Facility Name
Texas Oncology - McAllen /ID# 202331
City
McAllen
State/Province
Texas
ZIP/Postal Code
78503
Country
United States
Facility Name
Texas Oncology - San Antonio Medical Center /ID# 202332
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78240-5251
Country
United States
Facility Name
Texas Oncology - Northeast Texas /ID# 201211
City
Tyler
State/Province
Texas
ZIP/Postal Code
75702
Country
United States
Facility Name
Northwest Cancer Specialists, P.C. /ID# 201198
City
Vancouver
State/Province
Washington
ZIP/Postal Code
98684
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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 URL
https://vivli.org/ourmember/abbvie/
Links:
URL
http://www.rxabbvie.com/
Description
Related Info
Learn more about this trial
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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