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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)

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ClinicalTrials.gov Identifier: NCT03462719
Recruitment Status : Active, not recruiting
First Posted : March 12, 2018
Results First Posted : March 28, 2022
Last Update Posted : August 15, 2022
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
Results First Submitted Date  ICMJE February 25, 2022
Results First Posted Date  ICMJE March 28, 2022
Last Update Posted Date August 15, 2022
Actual Study Start Date  ICMJE April 17, 2018
Actual Primary Completion Date February 26, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 25, 2022)
Progression Free Survival (PFS) [ Time Frame: Up to 2 years 10 months ]
PFS: time between date of randomization and date of disease progression, as assessed by IRC, or date of death due to any cause, whichever occurs first, regardless of use of subsequent anti-cancer therapy prior to PD or death using iWCLL2008 criteria : New enlarged lymph nodes >15 mm, new hepatomegaly or splenomegaly, or other organ infiltrates, bone lesion, ascites or pleural effusion due to CLL; >=50% increase in longest diameter (LDi) from nadir in existing lymph node (LDi >15 mm) or >=50% increase from nadir in sum of diameters of multiple nodes (and at least 1 node with LDi >15 mm); >=50% increase from nadir in enlargement of liver/spleen; >=50% increase from baseline in lymphocyte count (ALC; to >=5*10^9/L); or >=50% increase from nadir in ALC in >=2 serial assessments if ALC is >=30000*10^9/L and lymphocyte doubling time is rapid unless considered treatment-related lymphocytosis; new cytopenia attributable to CLL; transformation to more aggressive histology.
Original 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).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2022)
  • Minimal Residual Disease (MRD) Negative Rate [ Time Frame: Up to 2 years 10 months ]
    MRD-negative rate is defined as the percentage of participants who achieved MRD-negative status (that is, less than [<] 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or <0.01 percentage [%]) in the bone marrow as assessed by next-generation sequencing (NGS). Participants with missing MRD data were considered MRD positive.
  • Complete Response Rate (CRR) [ Time Frame: Up to 2 years 10 months ]
    Complete response rate is defined as the percentage of participants who achieved complete response or complete response with an incomplete marrow recovery (CRi) on or prior to initiation of subsequent anti-leukemic therapy per the IRC assessment. International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.5*10^9/liter (L), platelets >100*10^9/L, Hgb >11 gram per deciliter (g/dL), absolute lymphocyte count <4000/microliter (mcL) and normocellular bone marrow with <30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow.
  • Overall Response Rate (ORR) [ Time Frame: Up to 2 years 10 months ]
    ORR: percentage of participants who achieved best overall response of either CR, CRi, nodular PR (nPR) and partial response (PR). iWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.5*10^9/liter (L), platelets >100*10^9/L, Hgb >11 g/dL and ALC <4000/mcL, normocellular bone marrow with <30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but bone marrow biopsy shows B-lymphoid nodules (reflecting residual disease); PR-2 of following when abnormal at baseline: >=50% decrease in ALC, >=50% decrease in sum of products of multiple nodes, >=50% decrease in enlargement of spleen or liver; and 1 of following: neutrophils >1.5*10^9/L, Platelets >100*10^9/L and Hgb>11 g/dL or >=50% improvement over baseline in any of these; 50% reduction in bone marrow infiltrates or B lymphoid nodules; no new enlarged nodes or new hepatosplenomegaly.
  • Overall Survival (OS) [ Time Frame: Up to 3 years 4 months ]
    OS is defined as the time from date of randomization to date of death from any cause.
  • Duration of Response (DOR) [ Time Frame: Up to 2 years 10 months ]
    DOR is defined as the interval between the date of initial documentation of a response including partial response with lymphocytosis (PRL) and the date of first documented evidence of PD or death or date of censoring per the IRC assessment. iWCLL 2008 criteria for PD: New enlarged nodes >1.5 cm, new hepatomegaly or splenomegaly, or other organ infiltrates; >= 50% increase from nadir in existing lymph node or >=50% increase from nadir in sum of product of diameters of multiple nodes; >=50% increase from nadir in enlargement of liver or spleen; >=50% increase from baseline in lymphocyte count (and to >=5*10^9/L) unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b or platelets) attributable to CLL; transformation to a more aggressive histology.
  • Time-to-Next Treatment [ Time Frame: Up to 2 years 10 months ]
    Time-to-next treatment was measured from the date of randomization to the start date of any subsequent anti-leukemic therapy.
  • Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level Questionnaire (EQ-5D-5L) [ Time Frame: Up to 2 years 10 months ]
    Time to worsening= time interval (months) from randomization to first observation of deterioration. EQ-5D-5L consists of a 5-item descriptive system and the EuroQol visual analog scale (EQ-5D VAS). EQ-5D-VAS self-rating records respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Worsening is defined as a decrease of >= 7 points (on a 0-100 scale). EQ-5D-5L descriptive system comprises 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe participant's current health state. Responses for 5 dimensions are combined into a 5-digit number describing respondents health state that can be converted into a single index value or utility score (using the United Kingdom weights), ranging from -1 to 1, where lower scores indicate a worse health status. Worsening is defined as a decrease of >=0.08 points (on a 0-1 scale).
  • Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) [ Time Frame: Up to 2 years 10 months ]
    Time to worsening= time interval from randomization to first observation of deterioration. EORTC QLQ-C30 includes 30 separate items: 5 functional scales (physical, role, emotional, cognitive, and social Functioning), 1 global health status (GHS) and QoL scale, 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each item, except GHS, is answered on 4-point scale (1=not at all to 4=very much) and GHS is measured on 1-7 scale: 1=very poor and 7=excellent. Scores derived using validated scoring algorithms as per EORTC QLQ-C30 Manual and linearly transformed in a range from 0-100. For functional and global QoL scales, higher scores=better level of functioning/QoL. For symptom-oriented scales, higher score=more severe symptoms. Worsening in functional and global health scores=decrease of >=10 points (on 0-100 scale) and in symptom scores=increase of >=10 points (on 0-100 scale).
  • Time to Worsening and Time to Improvement as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score [ Time Frame: Up to 2 years 10 months ]
    Responses to the 13-item FACIT Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). Time to Worsening is defined as time interval (months) from randomization to first observation of deterioration. Worsening is defined as a decrease >= 3 points (on a 0-52 scale). Time to improvement is defined as the time interval (months) from randomization to the first observation of improvement. Improvement is defined as an increase >=3 points (on a 0-52 scale).
  • Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability [ Time Frame: Up to 3 years 4 months ]
    An adverse event (AE) is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.
  • Number of Participants With Abnormal Clinical Laboratory Findings [ Time Frame: Up to 2 years 10 months ]
    Number of participants with abnormal clinical laboratory findings (hematology and serum chemistry) were reported.
  • Percentage of Participants With Sustained Hemoglobin Improvement [ Time Frame: Up to 2 years 10 months ]
    Sustained hemoglobin improvement is defined as the percentage of participants who achieved an increase in hemoglobin levels from baseline by >= 2 grams per deciliter (g/dL) and lasts for at least 56 days without blood transfusion or growth factors.
  • Percentage of Participants With Sustained Platelet Improvement [ Time Frame: Up to 2 years 10 months ]
    Sustained platelet improvement is defined as the percentage of participants who achieved an increase in platelet levels from baseline by >= 50% and lasts for at least 56 days without blood transfusion or growth factors.
  • Plasma Concentration of Ibrutinib and Venetoclax [ Time Frame: Ibrutinib: Pre-dose-Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days), Venetoclax: Pre-dose-Day 1 of Cycles 5 and 6 ]
    Plasma concentrations of ibrutinib and venetoclax were determined by validated liquid chromatography-tandem mass spectrometry.
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 Not Provided
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 5, 2024
Actual Primary Completion Date February 26, 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
Current Responsible Party Janssen Research & Development, LLC
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Janssen Research & Development, LLC
Original Study Sponsor  ICMJE Same as current
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 August 2022

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