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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)

NCT03462719

Description:

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).

Related Conditions:
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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: 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).

Clinical Trial IDs

  • ORG STUDY ID: CR108428
  • SECONDARY ID: 2017-004699-77
  • SECONDARY ID: 54179060CLL3011
  • NCT ID: NCT03462719

Conditions

  • Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

DrugSynonymsArms
IbrutinibTreatment Arm A: Ibrutinib and Venetoclax (I+VEN)
VenetoclaxTreatment Arm A: Ibrutinib and Venetoclax (I+VEN)
ChlorambucilTreatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)
ObinutuzumabTreatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)

Purpose

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 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. Study
      duration is approximately 6 years. Safety includes review of adverse events and laboratory
      tests performed over time.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)ExperimentalParticipants will initially receive ibrutinib (420 mg [milligrams]/day) for 3 cycles. Venetoclax dose ramp up (from 20 mg to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles. Following the completion of I+VEN treatment, ibrutinib will be given for another 3 cycles for a total of up to 18 cycles of treatment (each cycle is equivalent to 28 days).
  • Ibrutinib
  • Venetoclax
Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)Active ComparatorParticipants 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.
  • Chlorambucil
  • Obinutuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  Adult subjects 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 greater than (>) 6

               2. Creatinine clearance (CrCl) estimated less than (<) 70 milliliter per minute
                  (mL/min) using the 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]) is defined as at least one
             lymph node > 1.5 centimeter (cm) in longest diameter

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Percentage of Participants who are Minimal Residual Disease (MRD) Negative
Time Frame:Up to approximately 6 years
Safety Issue:
Description: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.
Measure:Overall Response Rate (ORR)
Time Frame:Up to approximately 6 years
Safety Issue:
Description: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.
Measure:Complete Response (CR) Rate
Time Frame:Up to approximately 6 years
Safety Issue:
Description:CR is lymph nodes none > 1.5 cm, no hepatomegaly and splenomegaly, < 30% lymphocytes, bone marrow normocellular and no lymphoid nodules.
Measure: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)
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:From the date of randomization to the date of death from any cause (up to approximately 6 years)
Safety Issue:
Description:OS is defined as the time from the date of randomization to the date of the participant's death from any cause.
Measure: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)
Safety Issue:
Description:The time from date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment.
Measure: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)
Safety Issue:
Description:Worsening in functional and global QoL scales is defined by clinically important negative change. Differences >= 10 points on EORTC scales are considered clinically important.
Measure: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)
Safety Issue:
Description:Worsening is defined by clinically important negative change. A difference of >= 3 points in FACIT-Fatigue score is considered clinically important.
Measure: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)
Safety Issue:
Description: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.
Measure:Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability
Time Frame:Up to approximately 18 months
Safety Issue:
Description:An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product.
Measure:Number of Participants with Abnormal Clinical Laboratory Findings
Time Frame:Up to approximately 18 months
Safety Issue:
Description:The number of participants with abnormal clinical laboratory findings will be reported.
Measure:Percentage of Participants with Sustained Hemoglobin Improvement
Time Frame:Up to approximately 6 years
Safety Issue:
Description:The percentage of study participants with sustained hemoglobin improvement from baseline will be reported
Measure:Percentage of Participants with Sustained Platelet Improvement
Time Frame:Up to approximately 6 years
Safety Issue:
Description:Sustained platelet improvement rate is defined as the percentage of participants who achieve a sustained increase of platelet levels from baseline.
Measure: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)
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Janssen Research & Development, LLC

Last Updated

April 18, 2018