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)
Condition: Chronic Lymphocytic Leukemia
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Bendamustine; Venetoclax; Rituximab
Intervention description: Bendamustine will be administered at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles.; Venetoclax will be administered at an initial dose of 20 mg via tablet orally QD, incremented weekly up to a maximum dose of 400 mg during a 5-week ramp-up period. Venetoclax will be continued at 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression (PD) or 2 years, whichever occurs first.
R/C Substudy: venetoclax will be administered for 5-week dose ramp-up period to reach the target dose of 400 mg QD. Venetoclax will continue to be administered during the rituximab cycles until disease progression or for a maximum of 2 years from Cycle 1R/C Day 1 of the R/C Substudy.; Rituximab will be administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.
R/C Substudy: Following the venetoclax ramp-up period, rituximab will be administered for 6 cycles consisting of a single infusion on the first day of each 28-day cycle.
Intervention MeSH terms: Rituximab; Venetoclax; Bendamustine Hydrochloride
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 389.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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