Ibrutinib and Obinutuzumab With or Without Venetoclax in Treating Older Patients With Untreated Chronic Lymphocytic Leukemia

Brief Summary:
This phase III trial studies how well ibrutinib and obinutuzumab with or without venetoclax work in treating older patients with untreated chronic lymphocytic leukemia. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab, may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as venetoclax work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ibrutinib and obinutuzumab with venetoclax may work better at treating chronic lymphocytic leukemia compared to ibrutinib and obinutuzumab.

Detailed Description:

PRIMARY OBJECTIVES:
I. To compare the progression-free survival (PFS) between control treatment and experimental treatment strategies: ibrutinib/obinutuzumab (IO) with ibrutinib maintenance (IM) versus ibrutinib/venetoclax/obinutuzumab (IVO) regardless of IM or observation.

SECONDARY OBJECTIVES:
I. To compare bone marrow (BM) minimal residual disease (MRD)- complete response (CR) rates and depth of response at cycle 15 day 1 between patients treated with IO versus IVO.

II. To compare overall survival (OS) between the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.

III. To compare the 5-year PFS and overall survival (OS) for the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.

IV. To describe the toxicity profile for each of the treatment strategies and by each treatment course.

CORRELATIVES OBJECTIVES:
I. To compare MRD status between blood and bone marrow at the end of induction treatment/cycle 15 day 1 to determine whether blood MRD can be used as a surrogate to bone marrow MRD with these treatment regimens.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Patients also receive obinutuzumab intravenously (IV) on days 1, 2, 8, and 15 of cycle 1, and on day 1 of cycles 2-6. Treatment repeats every 28 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 15, patients receive ibrutinib PO QD every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive ibrutinib PO QD on days 1-28. Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of cycle 1, and on day 1 of cycles 2-6. Beginning cycle 3, patients also receive venetoclax PO QD on days 1-28. Treatment repeats every 28 days for 14 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 15, patients who do not achieve a BM MRD negative CR, receive ibrutinib PO QD every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve a BM MRD negative CR undergo observation every 3 cycles for 6 years, then every 6 cycles thereafter.

After completion of study treatment, followed every 6 months until 10 years from registration.


Study Type: Interventional  (Clinical Trial)
Estimated Enrollment: 454 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase III Study of Ibrutinib Plus Obinutuzumab Versus Ibrutinib Plus Venetoclax and Obinutuzumab in Untreated Older Patients (>/= 70 Years of Age) With Chronic Lymphocytic Leukemia (CLL)
Actual Study Start Date: January 4, 2019
Estimated Primary Completion Date: June 1, 2027
Estimated Study Completion Date: June 1, 2027

Arm:
- Active Comparator: Arm I (ibrutinib, obinutuzumab)
- Experimental: Arm II (ibrutinib, obinutuzumab, venetoclax)