Working…
Help guide our efforts to modernize ClinicalTrials.gov.
Send us your comments by March 14, 2020.
ClinicalTrials.gov
ClinicalTrials.gov Menu

A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03462719
Recruitment Status : Active, not recruiting
First Posted : March 12, 2018
Last Update Posted : January 21, 2020
Sponsor:
Collaborator:
Pharmacyclics LLC.
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Tracking Information
First Submitted Date  ICMJE March 6, 2018
First Posted Date  ICMJE March 12, 2018
Last Update Posted Date January 21, 2020
Actual Study Start Date  ICMJE April 17, 2018
Estimated Primary Completion Date February 2, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 6, 2018)
Progression-Free Survival (PFS) [ Time Frame: From date of randomization to date of disease progression (PD) or death, whichever occurs first (Up to approximately 6 years) ]
PFS is defined as the duration from date of randomization to date of disease progression (PD) or death, whichever occurs first. PD is defined according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL 2008 Guidelines).
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03462719 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 20, 2019)
  • Percentage of Participants who are Minimal Residual Disease (MRD) Negative [ Time Frame: Up to approximately 6 years ]
    MRD negative disease status is defined as less than (<) 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or < 0.01 % in the bone marrow. MRD will be assessed by flow cytometry.
  • Overall Response Rate (ORR) [ Time Frame: Up to approximately 6 years ]
    ORR: percentage of participants with CR, complete response with an incomplete marrow recovery (CRi), nodular PR (nPR) and partial response (PR), for at least 2 months. CR: lymph nodes none greater than (>) 1.5 centimeter (cm), no hepatomegaly and splenomegaly, bone marrow normocellular with less than (<) 30% lymphocytes and no lymphoid nodules, blood lymphocytes<4,000 per microliter (mcL), platelet count>100,000/mcL, hemoglobin >11 gram per deciliter (g/dL), neutrophils >1500/mcL. CRi: complete response with a peripheral cytopenia and incomplete recovery of the bone marrow, manifested by persistent cytopenias. nPR: response that meets criteria for CR, but bone marrow biopsy shows lymphoid nodules. PR: at least 50% reduction in at least 2 Group A (lymphadenopathy, hepatomegaly, splenomegaly, blood lymphocytes and marrow infiltrates) and improvement in at least 1 Group B (platelet count, hemoglobin and neutrophils).
  • Complete Response (CR) Rate [ Time Frame: Up to approximately 6 years ]
    CR is lymph nodes none > 1.5 cm, no hepatomegaly and splenomegaly, < 30% lymphocytes, bone marrow normocellular and no lymphoid nodules.
  • Duration of Response (DOR) [ Time Frame: From the date of initial documentation of a response to the date of first documented evidence of progressive disease or death (up to approximately 6 years) ]
    DOR is defined as duration in days from the date of initial documentation of a response to the date of first documented evidence of progressive disease or death. Response and PD are defined according to iwCLL 2008 Guidelines.
  • Overall Survival (OS) [ Time Frame: From the date of randomization to the date of death from any cause (up to approximately 6 years) ]
    OS is defined as the time from the date of randomization to the date of the participant's death from any cause.
  • Time-to-Next Treatment [ Time Frame: From date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment (up to approximately 6 years) ]
    The time from date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment.
  • Time to Worsening as Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]
    Worsening in functional and global QoL scales is defined by clinically important negative change. Differences >= 10 points on EORTC scales are considered clinically important.
  • Time to Worsening as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score [ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]
    Worsening is defined by clinically important negative change. A difference of >= 3 points in FACIT-Fatigue score is considered clinically important.
  • Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level questionnaire (EQ-5D 5L) [ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]
    Worsening is defined by clinically important negative change. A minimum difference of >= 0.07 points change in utility score is considered clinically important; for the VAS health rating, a minimum important difference is >= 7 points change.
  • Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability [ Time Frame: Up to approximately 18 months ]
    An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product.
  • Number of Participants with Abnormal Clinical Laboratory Findings [ Time Frame: Up to approximately 18 months ]
    The number of participants with abnormal clinical laboratory findings will be reported.
  • Percentage of Participants with Sustained Hemoglobin Improvement [ Time Frame: Up to approximately 6 years ]
    The percentage of study participants with sustained hemoglobin improvement from baseline will be reported
  • Percentage of Participants with Sustained Platelet Improvement [ Time Frame: Up to approximately 6 years ]
    Sustained platelet improvement rate is defined as the percentage of participants who achieve a sustained increase of platelet levels from baseline.
  • Concentration at End of Dosing Interval (24h) at Steady-state (Ctrough, ss) [ Time Frame: Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days) (up to approximately 6 years) ]
    Ctrough,ss is defined as concentration at the end of dosing interval (24h) at steady-state. Ibrutinib and venetoclax Ctrough, ss data will be evaluated.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 6, 2018)
  • Percentage of Participants who are Minimal Residual Disease (MRD) Negative [ Time Frame: Up to approximately 6 years ]
    MRD negative disease status is defined as less than (<) 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or < 0.01 % in the bone marrow. MRD will be assessed by flow cytometry.
  • Overall Response Rate (ORR) [ Time Frame: Up to approximately 6 years ]
    ORR is defined as percentage of participants with complete response [CR], complete response with an incomplete marrow recovery (CRi), partial response (PR), and nodular PR (nPR), for at least 2 months. CR: lymph nodes none greater than (>) 1.5 centimeter (cm), no hepatomegaly and splenomegaly, bone marrow normocellular with less than (<) 30% lymphocytes and no lymphoid nodules, blood lymphocytes < 4,000 per microliter (mcL), platelet count >100,000/mcL, hemoglobin >11 gram per deciliter (g/dL), neutrophils >1500/mcL. PR is at least 50% reduction in at least 2 Group A (lymphadenopathy, hepatomegaly, splenomegaly, blood lymphocytes and marrow infiltrates) and improvement in at least 1 Group B (platelet count, hemoglobin and neutrophils). CRi: complete response with an incomplete recovery of the participant's bone marrow. nPR: response that meets criteria for CR, but bone marrow biopsy shows lymphoid nodules.
  • Complete Response (CR) Rate [ Time Frame: Up to approximately 6 years ]
    CR is lymph nodes none > 1.5 cm, no hepatomegaly and splenomegaly, < 30% lymphocytes, bone marrow normocellular and no lymphoid nodules.
  • Duration of Response (DOR) [ Time Frame: From the date of initial documentation of a response to the date of first documented evidence of progressive disease or death (up to approximately 6 years) ]
    DOR is defined as duration in days from the date of initial documentation of a response to the date of first documented evidence of progressive disease or death. Response and PD are defined according to iwCLL 2008 Guidelines.
  • Overall Survival (OS) [ Time Frame: From the date of randomization to the date of death from any cause (up to approximately 6 years) ]
    OS is defined as the time from the date of randomization to the date of the participant's death from any cause.
  • Time-to-Next Treatment [ Time Frame: From date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment (up to approximately 6 years) ]
    The time from date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment.
  • Time to Worsening as Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]
    Worsening in functional and global QoL scales is defined by clinically important negative change. Differences >= 10 points on EORTC scales are considered clinically important.
  • Time to Worsening as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score [ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]
    Worsening is defined by clinically important negative change. A difference of >= 3 points in FACIT-Fatigue score is considered clinically important.
  • Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level questionnaire (EQ-5D 5L) [ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]
    Worsening is defined by clinically important negative change. A minimum difference of >= 0.07 points change in utility score is considered clinically important; for the VAS health rating, a minimum important difference is >= 7 points change.
  • Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability [ Time Frame: Up to approximately 18 months ]
    An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product.
  • Number of Participants with Abnormal Clinical Laboratory Findings [ Time Frame: Up to approximately 18 months ]
    The number of participants with abnormal clinical laboratory findings will be reported.
  • Percentage of Participants with Sustained Hemoglobin Improvement [ Time Frame: Up to approximately 6 years ]
    The percentage of study participants with sustained hemoglobin improvement from baseline will be reported
  • Percentage of Participants with Sustained Platelet Improvement [ Time Frame: Up to approximately 6 years ]
    Sustained platelet improvement rate is defined as the percentage of participants who achieve a sustained increase of platelet levels from baseline.
  • Concentration at End of Dosing Interval (24h) at Steady-state (Ctrough, ss) [ Time Frame: Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days) (up to approximately 6 years) ]
    Ctrough,ss is defined as concentration at the end of dosing interval (24h) at steady-state. The ibrutinib Ctrough, ss data in the absence and presence of venetoclax will be evaluated.
Current Other Pre-specified Outcome Measures
 (submitted: September 10, 2019)
Overall Response Rate (ORR) (Subsequent Therapy Phase) [ Time Frame: Up to 6 years ]
ORR in the participants who received single-agent ibrutinib will be examined. ORR is defined as the percentage of participants who achieve a response (CR, CRi, nPR, and PR) for at least two months.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Official Title  ICMJE A Randomized, Open-label, Phase 3 Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Subjects With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).
Brief Summary The purpose of this study is to assess progression‑free survival (PFS) from treatment with ibrutinib plus venetoclax (I+VEN) compared with obinutuzumab plus chlorambucil (G-Clb) as assessed by an Independent Review Committee (IRC).
Detailed Description The hypothesis is treatment with combination of I+VEN will result in longer PFS compared with G-Clb in participants with previously untreated chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) who meet International Workshop on CLL (iwCLL) treatment criteria. The study includes screening (30 days), treatment (from randomization until treatment discontinuation) and follow-up phase (from treatment discontinuation until Subsequent Therapy Phase [if applicable], death, lost to follow up, consent withdrawal, or study end, whichever occurs first). Participants without progression will continue disease evaluations until disease progression or death. Participants from either treatment arm that develop progressive disease may be eligible to receive single-agent ibrutinib until disease progression or unacceptable toxicity (Subsequent Therapy Phase). Participation in this phase of the study is not mandatory and is based on investigator's discretion. Study duration is approximately 6 years. Safety includes review of adverse events and laboratory tests performed over time.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Leukemia, Lymphocytic, Chronic, B-Cell
Intervention  ICMJE
  • Drug: Ibrutinib
    Participants will receive ibrutinib 420 mg orally once daily up to 15 cycles.
  • Drug: Venetoclax
    Participants will receive venetoclax in combination with ibrutinib for a total of 12 cycles, beginning at Cycle 4. For the first 5 weeks of venetoclax treatment, the treatment dose will be ramped up from 20 to 400 mg.
  • Drug: Chlorambucil
    Participants will receive chlorambucil at a dose of 0.5 mg/kg body weight on Days 1 and 15 of Cycles 1 to 6.
  • Drug: Obinutuzumab
    Participant will receive obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of Cycle 1, and Day 1 of Cycles 2 to 6.
  • Drug: Ibrutinib (as Subsequent Therapy)
    Participants will receive ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity during the subsequent therapy phase.
Study Arms  ICMJE
  • Experimental: Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)
    Participants will initially receive ibrutinib (420 mg [milligrams]/day) for 3 cycles. Venetoclax dose ramp up (from 20 to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles (each cycle is equivalent to 28 days). Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Ibrutinib
    • Drug: Venetoclax
    • Drug: Ibrutinib (as Subsequent Therapy)
  • Active Comparator: Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)
    Participants will receive chlorambucil and obinutuzumab (G-Clb) for 6 cycles. Participants will receive obinutuzumab, 1000 mg intravenously (IV) on Days 1, 8 and 15 of Cycle 1, and on Day 1 of Cycles 2 to 6 and chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight, on Days 1 and 15 of Cycles 1 to 6. Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Chlorambucil
    • Drug: Obinutuzumab
    • Drug: Ibrutinib (as Subsequent Therapy)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 27, 2019)
211
Original Estimated Enrollment  ICMJE
 (submitted: March 6, 2018)
200
Estimated Study Completion Date  ICMJE April 30, 2024
Estimated Primary Completion Date February 2, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adult participants who are: (a) greater than or equal to (>=) 65 years old or, (b) 18 to 64 years old and have at least 1 of the following:

    1. Cumulative Illness Rating Scale (CIRS) score > 6
    2. Creatinine clearance (CrCl) estimated less than (<) 70 milliliter per minute (mL/min) using Cockcroft-Gault equation
  • Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that meets International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
  • Measurable nodal disease (by computed tomography [CT]), defined as at least one lymph node > 1.5 centimeter (cm) in longest diameter
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Grade less than or equal to (<=) 2
  • Active CLL/SLL requiring treatment per the iwCLL criteria

Exclusion Criteria:

  • Prior anti-leukemic therapy for CLL or SLL
  • Presence of deletion of the short arm of chromosome 17 (del17p) or known TP53 mutation detected at a threshold of >10 percent (%) variable allele frequency (VAF)
  • Major surgery within 4 weeks of first dose of study treatment
  • Known bleeding disorders (example, von Willebrand's disease or hemophilia)
  • Central nervous system (CNS) involvement or suspected Richter's syndrome
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Canada,   Czechia,   Denmark,   France,   Israel,   Netherlands,   Poland,   Russian Federation,   Spain,   Sweden,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03462719
Other Study ID Numbers  ICMJE CR108428
2017-004699-77 ( EudraCT Number )
54179060CLL3011 ( Other Identifier: Janssen Research & Development, LLC )
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.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Janssen Research & Development, LLC
Study Sponsor  ICMJE Janssen Research & Development, LLC
Collaborators  ICMJE Pharmacyclics LLC.
Investigators  ICMJE
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
PRS Account Janssen Research & Development, LLC
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP