Study to Assess Change in Disease Activity and Adverse Events of Oral Venetoclax in Combination With Intravenous (IV) Obinutuzumab or Oral Ibrutinib in Adult Participants With Untreated Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Study Overview
=================
Brief Summary
-----------------
Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, representing approximately 30% of all adult leukemias. There is a large difference in proportion of malignant lymphoma between the United States (US) and Japan was seen in CLL/small lymphocytic lymphoma (SLL) (Japan, 3.2%; US, 24.1%). The purpose of this study is to assess how well venetoclax works in combination with obinutuzumab (V+G, Cohort 1) or with ibrutinib (V+I, Cohort 2) in Japanese participants with previously untreated CLL/Small Lymphocytic Lymphoma (SLL). Adverse events and change in disease activity will be assessed. Venetoclax is an approved drug for the treatment of CLL and SLL. Study doctors put the participants in 1 of 2 groups, called treatment arms, based on variable alternating assignment. Approximately 20 adult participants with previously untreated CLL/SLL will be enrolled in the study in approximately 20 sites in Japan. Participants in group 1 will receive oral venetoclax + intravenous (IV) obinutuzumab (V+G) in 28-day cycles for a total of 12 cycles, and participants in group 2 will receive oral venetoclax + oral ibrutinib (V+I) in 28-day cycles for a total of 15 cycles. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, and checking for side effects.

Official Title
-----------------
A Phase 2 Study of the Safety and Efficacy of Venetoclax in Combination With Obinutuzumab or Ibrutinib in Japanese Subjects With Previously Untreated Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Conditions
-----------------
Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult male or female, at least ≥ 65 years old; or 20 to 64 years old and have at least 1 of the following: Cumulative Illness Rating Scale (CIRS) score > 6. Creatinine clearance (CrCl) estimated < 70 mL/min using Cockcroft-Gault equation. Must have measurable nodal disease (by computed tomography [CT]), defined as at least one lymph node > 1.5 cm in longest diameter. Diagnosed Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) that requires treatment according to the Modified 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Exclusion Criteria: Transformation of Chronic Lymphocytic Leukemia (CLL) to aggressive non-Hodgkin lymphoma (NHL; Richter's transformation or pro-lymphocytic leukemia). Previous treatment history for CLL/SLL.

Ages Eligible for Study
-----------------
Minimum Age: 20 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: Venetoclax + Obinutuzumab (V+G)<br>Participants will receive venetoclax + obinutuzumab for twelve 28-day cycles. | Drug: Venetoclax<br>* Oral Tablet<br>* Other names: GDC-0199;Drug: Obinutuzumab<br>* Intravenous (IV) Infusion<br>* Other names: RO5072759;|
| Experimental: Venetoclax + Ibrutinib (V+I)<br>Participants will receive venetoclax + ibrutinib for fifteen 28-day cycles. | Drug: Venetoclax<br>* Oral Tablet<br>* Other names: GDC-0199;Drug: Ibrutinib<br>* Oral Capsule<br>* Other names: Imbruvica;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission (CR) with an Incomplete Marrow Recovery (CRi) Rate, as Assessed by an Independent Review Committee (IRC) per Modified 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) for Venetoclax + Obinutuzumab (V+G) | CR rate is defined as the percentage of participants achieving a best response of CR or CRi. | Up to Week 32 | 
| CR/CRi Rate, as Assessed by an IRC per iwCLL for Venetoclax + Ibrutinib (V+I) | CR rate is defined as the percentage of participants achieving a best response of CR or CRi. | Up to Week 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR/CRi Rate, as Assessed by an Investigator per iwCLL for (V+G) | CR rate is defined as the percentage of participants achieving a best response of CR or CRi. | Up to Week 32 | 
| CR/CRi Rate, as Assessed by an Investigator per iwCLL for (V+I) | CR rate is defined as the percentage of participants achieving a best response of CR or CRi. | Up to Week 56 | 
| Overall response rate (ORR) as Assessed by IRC for (V+G) | ORR is defined as the proportion of participants with a best overall response of CR, CRi, partial remission (PR) or nodular partial remission (nPR) per 2008 iwCLL criteria as assessed by an IRC. | Up to Week 32 | 
| ORR as Assessed by IRC (V+I) | ORR is defined as the proportion of participants with a best overall response of CR, CRi, partial remission (PR) or nodular partial remission (nPR) per 2008 iwCLL criteria as assessed by an IRC. | Up to Week 56 | 
| ORR as Assessed by Investigator for (V+G) | ORR is defined as the proportion of participants with a best overall response of CR, CRi, partial remission (PR) or nodular partial remission (nPR) per 2008 iwCLL criteria as assessed by an investigator. | Up to Week 32 | 
| ORR Assessed by Investigator + Ibrutinib (V+I) | ORR is defined as the proportion of participants with a best overall response of CR, CRi, partial remission (PR) or nodular partial remission (nPR) per 2008 iwCLL criteria as assessed by an investigator. | Up to Week 56 | 
| Progression-Free Survival (PFS) as Assessed by IRC for (V+G) | PFS is defined as the time from the date of first dose of any study drug until the date of disease progression or death due to any cause, whichever occurs first, as determined by an IRC according to iwCLL criteria. | Up to Week 32 | 
| PFS as Assessed by IRC for (V+I) | PFS is defined as the time from the date of first dose of any study drug until the date of disease progression or death due to any cause, whichever occurs first, as determined by an IRC according to iwCLL criteria. | Up to Week 56 | 
| PFS as Assessed by Investigator for (V+G) | PFS is defined as the time from the date of first dose of any study drug until the date of disease progression or death due to any cause, whichever occurs first, as determined by an investigator according to iwCLL criteria. | Up to Week 32 | 
| PFS as Assessed by Investigator for (V+I) | PFS is defined as the time from the date of first dose of any study drug until the date of disease progression or death due to any cause, whichever occurs first, as determined by an investigator according to iwCLL criteria. | Up to Week 56 | 
| Duration of response (DOR) as Assessed by IRC for (V+G) | DOR is defined as the time from the first occurrence of overall response (CR, CRi, PR or nPR) until disease progression or death due to any cause, whichever occurs first, as determined by an IRC according to iwCLL criteria. | Up to Week 32 | 
| DOR as Assessed by IRC for (V+I) | DOR is defined as the time from the first occurrence of overall response (CR, CRi, PR or nPR) until disease progression or death due to any cause, whichever occurs first, as determined by an IRC according to iwCLL criteria. | Up to Week 56 | 
| DOR as Assessed by Investigator for (V+G) | DOR is defined as the time from the first occurrence of overall response (CR, CRi, PR or nPR) until disease progression or death due to any cause, whichever occurs first, as determined by an investigator according to iwCLL criteria. | Up to Week 32 | 
| DOR as Assessed by Investigator for (V+I) | DOR is defined as the time from the first occurrence of overall response (CR, CRi, PR or nPR) until disease progression or death due to any cause, whichever occurs first, as determined by an investigator according to iwCLL criteria. | Up to Week 56 | 
| Overall Survival (OS) for (V+G) | OS is defined as the time from the date of the first dose of any study drug until death due to any cause. | Up to Week 32 | 
| OS for (V+I) | OS is defined as the time from the date of the first dose of any study drug until death due to any cause. | Up to Week 56 | 
| Time to progression (TTP) as Assessed by IRC for (V+G) | TTP is defined as the time from the date of first dose of any study drug until the date of disease progression, as determined by an IRC according to iwCLL criteria. | Up to Week 32 | 
| TTP as Assessed by IRC for (V+I) | TTP is defined as the time from the date of first dose of any study drug until the date of disease progression, as determined by an IRC according to iwCLL criteria. | Up to Week 56 | 
| TTP as Assessed by Investigator for (V+G) | TTP is defined as the time from the date of first dose of any study drug until the date of disease progression, as determined by an investigator according to iwCLL criteria. | Up to Week 32 | 
| TTP as Assessed by Investigator for (V+I) | TTP is defined as the time from the date of first dose of any study drug until the date of disease progression, as determined by an investigator according to iwCLL criteria. | Up to Week 56 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Ibrutinib, Imbruvica, Venetoclax, Venclexta, Venclyxto, Obinutuzumab, GA101, Gazyva, RO5072759