A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

The purpose of this open-label, multicenter, randomized, Phase III study is to evaluate the benefit of venetoclax in combination with rituximab compared with bendamustine in combination with rituximab in participants with relapsed or refractory CLL. Participants will be randomly assigned in 1:1 ratio to receive either venetoclax + rituximab (Arm A) or bendamustine + rituximab (Arm B).


Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of CLL per diagnostic criteria for relapsed or refractory CLL per the international workshop on chronic lymphocytic leukemia (iwCLL) guidelines
* Previously treated with 1-3 lines of therapy (example: completed greater than or equal to \[\>/=\] 2 treatment cycles per therapy), including at least one standard chemotherapy-containing regimen
* Participants previously treated with bendamustine only if their duration of response was \>/= 24 months
* Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (\</=) 1
* Adequate bone marrow function
* Adequate renal and hepatic function
* Participants must use effective birth control throughout study until at least 30 days after study treatment or 1 year after rituximab treatment, whichever is later; female participants must not be pregnant or breast-feeding
* For participants with the 17p deletion, previously treated with 1-3 lines of therapy, including at least one prior standard chemotherapy-containing regimen or at least one prior alemtuzumab-containing therapy

Inclusion Criteria R/C Substudy:

* Participants randomized to Arm A or Arm B with a confirmed disease progression of CLL per iwCLL criteria
* Participants who have not received new anti-CLL therapy following disease progression in Arm A or Arm B
* Adequate renal and hepatic function per laboratory reference range

Exclusion Criteria:

* Transformation of CLL to aggressive non-Hodgkin lymphoma or central nervous system (CNS) involvement by CLL
* Undergone an allogenic stem cell transplant
* A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular or hepatic disease
* Hepatitis B or C or known human immunodeficiency virus (HIV) positive
* Receiving warfarin treatment
* Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug
* Received any anti-cancer or investigational therapy within 28 days prior to the first dose of study drug or has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy
* Received cytochrome P450 3A4 (CYP3A4) inhibitors (such as fluconazole, ketoconazole and clarithromycin) or inducers (such as rifampin, carbamazapine, phenytoin, St. John's Wort) within 7 days prior to the first dose of venetoclax
* History of prior venetoclax treatment
* Participants with another cancer, history of another cancer considered uncured on in complete remission for \<5 years, or currently under treatment for another suspected cancer except non-melanoma skin cancer or carcinoma in situ of the cervix that has been treated or excised and is considered resolved
* Malabsorption syndrome or other condition that precludes enteral route of administration
* Other clinically significant uncontrolled condition(s) including, but not limited to, systemic infection (viral, bacterial or fungal)
* Vaccination with a live vaccine within 28 days prior to randomization
* Consumed grapefruit or grapefruit products, seville oranges (including marmalade containing seville oranges), or star fruit within 3 days prior to the first dose of study treatment
* A cardiovascular disability status of New York Heart Association Class \>/=3. Class 3 is defined as cardiac disease in which participants are comfortable at rest but have marked limitation of physical activity due to fatigue, palpitations, dyspnea, or anginal pain
* Major surgery within 30 days prior to the first dose of study treatment
* A participant who is pregnant or breastfeeding
* Known allergy to both xanthine oxidase inhibitors and rasburicase

Exclusion Criteria R/C Substudy:

* Transformation of CLL to aggressive NHL (e.g., Richter's transformation, prolymphocytic leukemia, or DLBCL) or CNS involvement by CLL
* Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal)
* Development of other malignancy since enrollment into the study, with the exception of curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
* Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
* History of severe (i.e., requiring permanent discontinuation of prior rituximab therapy) prior allergic or anaphylactic reactions to rituximab
* Known HIV positivity
* Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen \[HbsAg\] serology)
* Positive test results for hepatitis C virus (HCV; HCV antibody serology testing)
* Requires the use of warfarin (due to potential drug interactions that may potentially increase the exposure of warfarin)
* Has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy
* Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 7 days prior to the first dose of study treatment
* Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort) within 7 days prior to the first dose of study treatment
* Consumed grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study treatment
* A cardiovascular disability status of New York Heart Association Class \>/= 3
* A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the participants's participation in this study or interpretation of study outcomes
* Major surgery within 30 days prior to the first dose of study treatment
* A participant who is pregnant or breastfeeding
* Malabsorption syndrome or other condition that precludes enteral route of administration
* Known allergy to both xanthine oxidase inhibitors and rasburicase
* Vaccination with a live vaccine within 28 days prior to randomization