A Study to Customize Ibrutinib Treatment Regimens for Participants With Previously Untreated Chronic Lymphocytic Leukemia

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of ibrutinib + venetoclax (I+V) and ibrutinib monotherapy regimens in which dosing of ibrutinib is either proactively reduced or reactively modified in response to adverse events (AEs).

Official Title
-----------------
Multicohort Study to Customize Ibrutinib Treatment Regimens for Patients With Previously Untreated Chronic Lymphocytic Leukemia

Conditions
-----------------
Small Lymphocytic Lymphoma, Leukemia, Lymphocytic, Chronic, B-Cell

Intervention / Treatment
-----------------
* Drug: Ibrutinib
* Drug: Venetoclax


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) as per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 diagnostic criteria For ibruinib + venetocIax (I+V) cohorts: eastern cooperative oncology group (ECOG) performance status of 0-1. For ibrutinib monotherapy cohorts: ECOG performance status of 0-2 Measurable nodal disease by computed tomography (CT), defined as at least 1 lymph node greater than and equal to (>=) 1.5 centimeters (cm) in longest diameter A participant using oral contraceptives must use an additional contraceptive method A participant must agree not to be pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or until 1 month after last dose or per local label if more conservative (for example, 3 months in European Union or Canada and 1 month in United States) Exclusion Criteria: Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, such as those participants with a declining hemoglobin level or platelet count secondary to autoimmune destruction within the 4 weeks prior to first dose of study treatment, or the need for prednisone greater than (>) 20 milligrams (mg) daily (or corticosteroid equivalent) to treat or control the autoimmune disease Known bleeding disorders (example, von Willebrand's disease or hemophilia) Stroke or intracranial hemorrhage within 6 months prior to enrollment Known or suspected Richter's transformation or central nervous system (CNS) involvement Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class II, III, or IV congestive heart failure as defined by the New York Heart Association Functional Classification

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1a: Ibrutinib Lead-in+Fixed Duration Ibrutinib+Venetoclax<br>Participants will receive ibrutinib 420 milligrams (mg) capsule every day (QD) for a lead-in of 3 cycles (1 cycle = 28 days). From Cycle 4, venetoclax 400 mg tablet dose ramp-up (from 20 to 400 mg over 5 weeks) will begin, and venetoclax 400 mg QD will be administered with ibrutinib 420 mg QD, orally for 12 cycles through Cycle 15. | Drug: Ibrutinib<br>* Ibrutinib capsules will be administered orally.<br>* Other names: JNJ-54179060, IMBRUVICA;Drug: Venetoclax<br>* Venetoclax tablets will be administered orally.<br>* Other names: VENCLEXTA, VENCLYXTO;|
| Experimental: Cohort 1b: Ibrutinib Lead-in+Fixed Duration Ibrutinib+Venetoclax<br>Participants will receive ibrutinib 420 mg capsule QD for a lead-in of 3 cycles (1 cycle = 28 days). From Cycle 4, venetoclax 400 mg tablet dose ramp-up (from 20 to 400 mg over 5 weeks) will begin and ibrutinib dose will be reduced to 280 mg and will be administered QD, venetoclax 400 mg tablets QD will be administered with ibrutinib 280 mg for 12 cycles through Cycle 15. | Drug: Ibrutinib<br>* Ibrutinib capsules will be administered orally.<br>* Other names: JNJ-54179060, IMBRUVICA;Drug: Venetoclax<br>* Venetoclax tablets will be administered orally.<br>* Other names: VENCLEXTA, VENCLYXTO;|
| Experimental: Cohort 2a: Continuous Ibrutinib Monotherapy<br>Participants will receive ibrutinib 420 mg QD (or last tolerated dose) until disease progression (PD) or unacceptable toxicity. | Drug: Ibrutinib<br>* Ibrutinib capsules will be administered orally.<br>* Other names: JNJ-54179060, IMBRUVICA;|
| Experimental: Cohort 2b: Continuous Ibrutinib Monotherapy<br>Participants will receive ibrutinib 420 mg QD for 1 cycle (1 cycle = 28 days) followed by Ibrutinib 280 mg QD (or last tolerated dose) and continue until disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* Ibrutinib capsules will be administered orally.<br>* Other names: JNJ-54179060, IMBRUVICA;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate (ORR) | Best ORR is defined as the percentage of participants who achieve complete remission (CR), complete remission with an incomplete marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria as assessed by investigator. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate | CR rate is defined as the percentage of participants achieving a best overall response of CR or CRi per iwCLL 2018 criteria as assessed by investigator. | Up to 5 years | 
| Duration of Response (DOR) | DOR is defined as the duration in days from the date of initial documentation of PR or better to the date of first documented evidence of PD or death. | Up to 5 years | 
| Progression Free Survival (PFS) | PFS by investigator assessment is defined as the duration from date of randomization to date of PD or death due to any cause, whichever occurs first. | Up to 5 years | 
| Overall Survival (OS) | OS is defined as the time from date of randomization to date of death from any cause. | Up to 5 years | 
| Cohorts 1a and 1b: Minimal Residual Disease (MRD) Negative Rate | MRD-negative rate is defined as the percentage of participants who reach MRD-negative status (that is, less than [<] 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or <0.01 percentage [%]) in the peripheral blood. | Up to 5 years | 
| Number of Participants with Adverse Events (AEs) | 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. | Up to 5 years | 
| Number of Participants with AEs by Severity | An AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event. | Up to 5 years | 
| Percentage of Participants with Rate of Discontinuation due to AEs | Percentage of participants with rate of discontinuation due to AEs will be reported. | Up to 5 years | 
| Percentage of Participants with Dose Reduction due AEs | Percentage of participants with dose reduction due AEs will be reported. | Up to 5 years | 
| Adherence Rates | The adherence rate is defined as the percentage of total dose taken over the total dose prescribed. | Up to 5 years | 
| Duration of Treatment | Duration of treatment is defined as the time period in days between the date of first study treatment administration and date of last administration. | Up to 5 years | 
| Time to Worsening as Measured by EuroQol 5 Dimension 5 Level Questionnaire (EQ-5D-5L) | Time to worsening is defined as time interval (months) from randomization to first observation of deterioration. Time to worsening as measured by EQ-5D-5L will be reported. | Up to 5 years | 
| Time to Worsening as Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) | Time to worsening is defined as time interval from randomization to first observation of deterioration. Time to worsening as measured by EORTC QLQ-C30 will be reported. | Up to 5 years | 
| Time to Worsening as Measured by EORTC QLQ-CLL17 | Time to worsening is defined as time interval from randomization to first observation of deterioration. Time to worsening as measured by EORTC QLQ-CLL17 will be reported. | Up to 5 years | 
| Time to Worsening as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score | Time to Worsening is defined as time interval (months) from randomization to first observation of deterioration. Time to worsening as measured by FACIT-fatigue total score will be reported. | Up to 5 years |