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NCT03462719 · CITED IN SOURCE DOCUMENTS

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)

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
ACTIVE NOT RECRUITING
Registry last update
2026-08-31

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).

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Progression Free Survival (PFS)

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outcome · POSTED

Minimal Residual Disease (MRD) Negative Rate

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outcome · POSTED

Complete Response Rate (CRR)

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outcome · POSTED

Overall Response Rate (ORR)

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outcome · POSTED

Overall Survival (OS)

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outcome · POSTED

Duration of Response (DOR)

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outcome · POSTED

Time-to-Next Treatment

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outcome · POSTED

Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level Questionnaire (EQ-5D-5L)

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outcome · POSTED

Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30)

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outcome · POSTED

Time to Worsening and Time to Improvement as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score

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outcome · POSTED

Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability

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outcome · POSTED

Number of Participants With Abnormal Clinical Laboratory Findings

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outcome · POSTED

Percentage of Participants With Sustained Hemoglobin Improvement

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outcome · POSTED

Percentage of Participants With Sustained Platelet Improvement

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outcome · POSTED

Plasma Concentration of Ibrutinib and Venetoclax

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
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
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    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.
    intervention Names
    1. Drug: Ibrutinib
    2. Drug: Venetoclax
    3. Drug: Ibrutinib (as Subsequent Therapy)
    label
    Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)
    type
    EXPERIMENTAL
  2. description
    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.
    intervention Names
    1. Drug: Chlorambucil
    2. Drug: Obinutuzumab
    3. Drug: Ibrutinib (as Subsequent Therapy)
    label
    Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)
    type
    ACTIVE_COMPARATOR
interventions
  1. arm Group Labels
    1. Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)
    description
    Participants will receive ibrutinib 420 mg orally once daily up to 15 cycles.
    name
    Ibrutinib
    type
    DRUG
  2. arm Group Labels
    1. Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)
    description
    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.
    name
    Venetoclax
    type
    DRUG
  3. arm Group Labels
    1. Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)
    description
    Participants will receive chlorambucil at a dose of 0.5 mg/kg body weight on Days 1 and 15 of Cycles 1 to 6.
    name
    Chlorambucil
    type
    DRUG
  4. arm Group Labels
    1. Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)
    description
    Participant will receive obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of Cycle 1, and Day 1 of Cycles 2 to 6.
    name
    Obinutuzumab
    type
    DRUG
  5. arm Group Labels
    1. Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)
    2. Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)
    description
    Participants will receive ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity during the subsequent therapy phase.
    name
    Ibrutinib (as Subsequent Therapy)
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
211
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    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.
    measure
    Progression Free Survival (PFS)
    time Frame
    Up to 2 years 10 months
secondary Outcomes
  1. description
    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.
    measure
    Minimal Residual Disease (MRD) Negative Rate
    time Frame
    Up to 2 years 10 months
  2. description
    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.
    measure
    Complete Response Rate (CRR)
    time Frame
    Up to 2 years 10 months
  3. description
    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.
    measure
    Overall Response Rate (ORR)
    time Frame
    Up to 2 years 10 months
  4. description
    OS is defined as the time from date of randomization to date of death from any cause.
    measure
    Overall Survival (OS)
    time Frame
    Up to 4 years 10 months
  5. description
    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.
    measure
    Duration of Response (DOR)
    time Frame
    Up to 2 years 10 months
  6. description
    Time-to-next treatment was measured from the date of randomization to the start date of any subsequent anti-leukemic therapy.
    measure
    Time-to-Next Treatment
    time Frame
    Up to 2 years 10 months
  7. description
    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).
    measure
    Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level Questionnaire (EQ-5D-5L)
    time Frame
    Up to 2 years 10 months
  8. description
    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).
    measure
    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
  9. description
    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).
    measure
    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
  10. description
    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.
    measure
    Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability
    time Frame
    Up to 4 years 10 months
  11. description
    Number of participants with abnormal clinical laboratory findings (hematology and serum chemistry) were reported.
    measure
    Number of Participants With Abnormal Clinical Laboratory Findings
    time Frame
    Up to 4 years 10 months
  12. description
    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.
    measure
    Percentage of Participants With Sustained Hemoglobin Improvement
    time Frame
    Up to 2 years 10 months
Full study description
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).
Source references
references
  1. citation
    Kater AP, Owen C, Moreno C, Follows G, Munir T, Levin MD, Benjamini O, Janssens A, Osterborg A, Robak T, Simkovic M, Stevens D, Voloshin S, Vorobyev V, Ysebaert L, Qin R, Steele AJ, Schuier N, Baeten K, Caces DB, Niemann CU. Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities. NEJM Evid. 2022 Jul;1(7):EVIDoa2200006. doi: 10.1056/EVIDoa2200006. Epub 2022 May 13.
    pmid
    38319255
    type
    DERIVED
  2. citation
    Niemann CU, Munir T, Moreno C, Owen C, Follows GA, Benjamini O, Janssens A, Levin MD, Robak T, Simkovic M, Voloshin S, Vorobyev V, Yagci M, Ysebaert L, Qi K, Qi Q, Sinet P, Parisi L, Srinivasan S, Schuier N, Baeten K, Howes A, Caces DB, Kater AP. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1423-1433. doi: 10.1016/S1470-2045(23)00452-7. Epub 2023 Nov 6.
    pmid
    37944541
    type
    DERIVED
  3. citation
    Moreno C, Solman IG, Tam CS, Grigg A, Scarfo L, Kipps TJ, Srinivasan S, Mali RS, Zhou C, Dean JP, Szafer-Glusman E, Choi M. Immune restoration with ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia: the phase 2 CAPTIVATE study. Blood Adv. 2023 Sep 26;7(18):5294-5303. doi: 10.1182/bloodadvances.2023010236.
    pmid
    37315225
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
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      occurrences
      1. context exact
        ty and value of MRD could not be determined from this trial due to its design.</li></ul></div></li><li>A prospective randomized trial (<a href="/clinicaltrials/NCT03462719">GLOW</a> [NCT03462719]) included 211 patients with previously untreated CLL. Patients were aged 65 and older or aged 18 to 64 with comorbidities and an Easter
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      2. context exact
        ld not be determined from this trial due to its design.</li></ul></div></li><li>A prospective randomized trial (<a href="/clinicaltrials/NCT03462719">GLOW</a> [NCT03462719]) included 211 patients with previously untreated CLL. Patients were aged 65 and older or aged 18 to 64 with comorbidities and an Eastern Cooperative Oncology
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      source title
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      source update dates
      1. context
        Updated: April 25, 2025
        datetime
        2025-04-25T12:00:00Z
        display
        April 25, 2025

    Preserved source evidence · Not medical advice