Ibrutinib Plus Venetoclax in Subjects With Treatment-naive Chronic Lymphocytic Leukemia /Small Lymphocytic Lymphoma (CLL/SLL)

Study Overview
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Brief Summary
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This is a multicenter, 2-cohort Phase 2 study assessing both minimal residual disease (MRD)-guided discontinuation and fixed duration therapy with the combination of ibrutinib + venetoclax in subjects with treatment-naïve CLL or SLL.

Official Title
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Phase 2 Study of the Combination of Ibrutinib Plus Venetoclax in Subjects With Treatment-naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Conditions
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Small Lymphocytic Lymphoma, Leukemia, Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: ibrutinib
* Drug: venetoclax
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of CLL/SLL that meets 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) diagnostic criteria (Hallek et al), with active disease meeting at least 1 IWCLL criteria for requiring treatment. Measurable nodal disease by computed tomography (CT) Adequate hepatic, and renal function Adequate hematologic function absolute neutrophil count >750/µL platelet count >30,000 /μL hemoglobin >8.0 g/dL Exclusion Criteria: Any prior therapy used for treatment of CLL/SLL Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk for tumor lysis syndrome (TLS)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fixed Duration (FD) Cohort: Open Label Ibrutinib + Venetoclax<br>Participants receive 420 mg of single-agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until disease progression or unacceptable toxicity. | Drug: ibrutinib<br>* ibrutinib administered orally once daily (three 140 mg capsules)<br>Drug: venetoclax<br>* venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg.<br>|
| Experimental: MRD Cohort/Confirmed Undetectable MRD (uMRD): Randomized to Ibrutinib (Blinded)<br>Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD are randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, disease progression (PD), or unacceptable toxicity. After MRD-positive relapse or disease progression (PD) by iwCLL criteria, participants can reintroduce 400 mg venetoclax with a 5-week ramp up. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. | Drug: ibrutinib<br>* ibrutinib administered orally once daily (three 140 mg capsules)<br>Drug: venetoclax<br>* venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg.<br>|
| Placebo Comparator: MRD Cohort/Confirmed uMRD: Randomized Placebo (Blinded)<br>Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD are randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity. If MRD-positive relapse or PD is confirmed after restaging per iwCLL criteria, participants can first reintroduce oral daily ibrutinib with the option of subsequently reintroducing 400 mg venetoclax with a 5-week ramp up, if subsequent disease relapse per iwCLL criteria occurs after ibrutinib reintroduction. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. | Drug: ibrutinib<br>* ibrutinib administered orally once daily (three 140 mg capsules)<br>Drug: venetoclax<br>* venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg.<br>Drug: Placebo<br>* placebo capsules to match ibrutinib administered orally once daily<br>|
| Experimental: MRD Cohort/uMRD Not Confirmed: Randomized to Ibrutinib (Open-Label)<br>Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre randomization phase). Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. In case of confirmed PD after restaging per iwCLL criteria, participants can continue ibrutinib and reintroduce venetoclax treatment. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. | Drug: ibrutinib<br>* ibrutinib administered orally once daily (three 140 mg capsules)<br>Drug: venetoclax<br>* venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg.<br>|
| Experimental: MRD Cohort/uMRD Not Confirmed: Randomized Ibrutinib + Venetoclax (Open-Label)<br>Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre randomization phase). Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase. | Drug: ibrutinib<br>* ibrutinib administered orally once daily (three 140 mg capsules)<br>Drug: venetoclax<br>* venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRD Cohort: 1-Year Disease-Free Survival (DFS) Rate in Confirmed uMRD Randomized Participants | DFS is defined as time from randomization date to MRD-positive relapse, or disease progression per investigator assessment (per 2008 International Workshop for Chronic Lymphocytic Leukemia [IWCLL] criteria [Halleck et al]) or death from any cause, whichever occurred first. 1-year DFS estimated using Kaplan-Meier method at 12 months landmark time. | 1 year after randomization | 
| FD Cohort: Complete Response Rate (CRR; Complete Response/Complete Response With Incomplete Blood Count Recovery [CR/CRi]) Rate | CR/CRi rate is defined as the percentage of participants achieving a best overall response of complete response (CR), CR with incomplete blood count recovery (CRi) per 2008 IWCLL criteria (halleck et al.) on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurred earlier. | From the first dose of ibrutinib to the first confirmed PD up to primary analysis data cutoff date of 15 December 2020. Median follow-up time was 27.9 months at the time of the primary analysis. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRD Cohort: CRR (CR/CRi Rate) | CR/CRi rate is defined as the percentage of participants achieving a best overall response of CR or CRi per 2008 IWCLL criteria (Halleck et al.) on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurred earlier. | From the first dose of ibrutinib to the first confirmed PD (up to primary analysis data cutoff date of 15 December 2020). Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020). | 
| MRD Cohort: Overall Response Rate (ORR) | ORR, defined as the percentage of participants achieving a best overall response of protocol-specified complete response (CR), CR with incomplete blood count recovery (CRi), nodular partial response (nPR), partial response (PR), or PR with lymphocytosis (PRL) evaluated in accordance with the 2008 IWCLL criteria (Halleck et al). Participants who did not have any postbaseline response assessment were considered as non-responders. This table is based on response assessments performed on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurs earlier. Kaplan-Meier estimate. | From the first dose of ibrutinib to the first confirmed PD (up to primary analysis data cutoff date of 15 December 2020). Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020). | 
| MRD Cohort: Duration of Response (DOR) | Duration of response was calculated for participants achieving a response (CR, CRi, nPR, PR) based on 2008 IWCLL response criteria (Halleck et al.) and defined as the interval between the date of initial documentation of a response including PR with lymphocytosis, until disease progression (PD) or death from any cause, whichever occurred first. As the median DOR was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of DOR at 36 months landmark time was presented. | From initial documentation of a response, until PD or death from any cause, whichever occurs first. Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020). | 
| MRD Cohort: MRD-Negativity Rate (MRR) | MRR is defined as the percentage of participants who achieve MRD-negativity in either peripheral blood (PB) or bone marrow (BM) and achieve confirmed clinical response PR or better per 2008 IWCLL criteria (Halleck et al.). MRD-negativity is defined as <1 CLL cell per 10,000 leukocytes (<1 x 10^4), as assessed by flow cytometry of a PB or BM aspirate sample. Confirmed MRD-negative response for randomization purposes requires MRD-negativity serially over at least 3 cycles, with negativity in both BM and PB. This rate is calculated in the uMRD Not Confirmed randomized population during the period from randomization date and before any reintroduced treatment. | From randomization date until before any reintroduced treatment. Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020). | 
| MRD Cohort: Tumor Lysis Syndrome (TLS) Risk Reduction Rate With 3-Cycle Ibrutinib Lead-In (Percentage of Participants No Longer High Risk After 3-cycle Lead-in) | TLS risk reduction was summarized by the percentage of participants with TLS risk reduced from high at baseline to medium or low after ibrutinib lead-in. A reduction in TLS risk from high risk to medium or low risk is clinically meaningful because there is a reduction in the extent of TLS monitoring and risk of hospitalization. TLS risk category is defined as the tumor burden category, where: Low=All lymph nodes (LN) < 5 cm AND absolute lymphocyte count (ALC) < 25 x 10^9/L; Medium=Any LN 5 cm to < 10 cm OR ALC ≥ 25 x 10^9/L; High=Any LN ≥ 10 cm OR ALC ≥ 25 x10^9/L AND any LN ≥ 5 cm. | Baseline, and last post-baseline value on or prior to venetoclax first dose date (cycle 4 day 1) or, for participants who never received venetoclax, the post-baseline value closest to cycle 4 day 1 (i.e. 84 days after the first dose date of ibrutinib). | 
| MRD Cohort: Kaplan-Meier Estimate of Progression Free Survival (PFS) Rate at 36 Months Landmark Time | PFS was defined as time from the first dose date of study treatment until disease progression (PD) or death from any cause, whichever occurs first. Assessment of PD was conducted in accordance with the 2008 IWCLL criteria (Halleck et al). As the median PFS was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of PFS rate at 36 months landmark time was presented. | From the first dose of ibrutinib to the first confirmed PD or death. Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020). | 
| MRD Cohort: Kaplan-Meier Estimate of Overall Survival (OS) Rate at 36 Months Landmark Time | OS is defined as the time from the first dose date of study treatment until date of death due to any cause. As the median OS was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of OS rate at 36 months landmark time was presented. | From the first dose of ibrutinib to the first confirmed PD or death (up to primary analysis data cutoff date of 15 December 2020). Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020). | 
| MRD Cohort: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Discontinuations Due to TEAEs | An adverse event (AE) is any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires unplanned in-patient hospitalization >24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity of events were graded according to the Common Terminology Criteria for Adverse Events version 4.03: mild=grade1, moderate=grade 2, severe=grade 3, life-threatening=grade 4, death=grade 5. Causal relation of study drug and event was assessed as not related, unlikely, possibly or probably related to the study drug. | From first dose until 30 days following last dose of study drug (up to data cutoff date of 15 Dec 2020). Treatment duration for the MRD cohort was 28.7 months for ibrutinib and 15.4 for venetoclax. | 
| FD Cohort: ORR | ORR is defined as the percentage of participants who achieve a best overall response CR, CRi, nPR, PR, or PRL as evaluated by investigator using 2008 IWCLL criteria (Halleck et al.). Participants who did not have any postbaseline response assessment were considered as non-responders. This table is based on response assessments performed on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurs earlier. Kaplan-Meier estimate. | From the first dose of ibrutinib to the first confirmed PD up to primary analysis data cutoff date of 15 December 2020. Median follow-up time was 27.9 months at the time of the primary analysis. | 
| FD Cohort: DOR | Duration of response was calculated for participants achieving a response (CR, CRi, nPR, PR) based on 2008 IWCLL response criteria (Halleck et al.) and defined as the interval between the date of initial documentation of a response including PR with lymphocytosis, until disease progression (PD) or death from any cause, whichever occurred first. As the median DOR was not reached as of the median 27.9 months study follow-up, the Kaplan-Meier estimate of DOR at 24 months landmark time was presented. | From initial documentation of a response, until PD or death from any cause, whichever occurs first. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020). | 
| FD Cohort: MRR | MRR is defined as the percentage of participants who achieve MRD-negativity in either peripheral blood (PB) or bone marrow (BM) and achieve confirmed clinical response PR or better per 2008 IWCLL criteria (Halleck et al.). MRD-negativity is defined as <1 CLL cell per 10,000 leukocytes (<1 x 10^4), as assessed by flow cytometry of a PB or BM aspirate sample. Confirmed MRD-negative response for randomization purposes requires MRD-negativity serially over at least 3 cycles, with negativity in both BM and PB. | From randomization date until before any reintroduced treatment. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020). | 
| FD Cohort: Kaplan-Meier Estimate of PFS Rate at 24 Months Landmark Time | PFS was defined as time from the first dose date of study treatment until disease progression (PD) or death from any cause, whichever occurs first. Assessment of PD was conducted in accordance with the 2008 IWCLL criteria (Halleck et al). As the median PFS was not reached as of the median 27.9 months study follow-up, the Kaplan-Meier estimate of PFS rate at 24 months landmark time was presented. | From the first dose of ibrutinib to the first confirmed PD or death. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020). | 
| FD Cohort: Kaplan-Meier Estimate of OS Rate at 24 Months Landmark Time | OS is defined as the time from the first dose date of study treatment until date of death due to any cause. As the median OS was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of OS rate at 24 months landmark time was presented. | From the first dose of ibrutinib to time of death. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020). | 
| FD Cohort: TLS Risk Reduction Rate With 3-Cycle Ibrutinib Lead-In (Percentage of Participants No Longer High Risk After 3-cycle Lead-in) | TLS risk reduction was summarized by the percentage of participants with TLS risk reduced from high at baseline to medium or low after ibrutinib lead-in. A reduction in TLS risk from high risk to medium or low risk is clinically meaningful because there is a reduction in the extent of TLS monitoring and risk of hospitalization. TLS risk category is defined as the tumor burden category, where: Low=All lymph nodes (LN) < 5 cm AND absolute lymphocyte count (ALC) < 25 x 10^9/L; Medium=Any LN 5 cm to < 10 cm OR ALC ≥ 25 x 10^9/L; High=Any LN ≥ 10 cm OR ALC ≥ 25 x10^9/L AND any LN ≥ 5 cm. | Baseline, and last post-baseline value on or prior to venetoclax first dose date (cycle 4 day 1) or, for participants who never received venetoclax, the post-baseline value closest to cycle 4 day 1 (i.e. 84 days after the first dose date of ibrutinib). | 
| FD Cohort: Percentage of Participants With TEAEs, Treatment-Emergent SAEs, and Discontinuations Due to TEAEs | An AE is any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires unplanned in-patient hospitalization >24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity of events were graded according to the Common Terminology Criteria for Adverse Events version 4.03: mild=grade1, moderate=grade 2, severe=grade 3, life-threatening=grade 4, death=grade 5. Causal relation of study drug and event was assessed as not related, unlikely, possibly or probably related to the study drug. | From first dose until 30 days following last dose of study drug (up to data cutoff date of 15 Dec 2020). Treatment duration for the FD cohort was 13.3 months for ibrutinib and 11.1 for venetoclax. | 
| MRD Cohort: Pharmacokinetics (PK) of Ibrutinib When Dosed in Combination With Venetoclax: Observed Maximum Concentration (Cmax) |  | Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min) | 
| MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Time to Cmax (Tmax); Time of Last Measurable Concentration (Tlast); Terminal Elimination Half-Life (t1/2,Term) |  | Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min) | 
| MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Area Under the Plasma Concentration-Time Curve (AUC) Over the Last 24-hour Dosing Interval (AUC0-24h); AUC From Time Zero to the Time of Last Quantifiable Concentration (AUClast) |  | Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min) | 
| MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Terminal Elimination Rate Constant (λz) |  | Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min) | 
| MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Apparent Total Clearance at Steady-State (CLss/F) |  | Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min) | 
| MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Cmax |  | Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min) | 
| MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Tmax |  | Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min) | 
| MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: AUC0-24h |  | Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min) | 
| MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: CLss/F |  | Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min) |