A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy vs Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients With Chronic Lymphocytic Leukemia (CLL)
Overview
- Phase
- Phase 3
- Status
- Active, not recruiting
- Enrollment
- 529
- Locations
- 1,564
- Primary Endpoint
- Progression-free Survival (PFS) Rate at 3 Years
Overview
Brief Summary
This phase III trial studies ibrutinib and rituximab to see how well they work compared to fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as fludarabine phosphate and cyclophosphamide, 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. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. It is not yet known whether fludarabine phosphate, cyclophosphamide, and rituximab may work better than ibrutinib and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.
Detailed Description
PRIMARY OBJECTIVE:
I. To evaluate the ability of ibrutinib-based induction therapy to prolong progression free survival (PFS) compared to standard fludarabine phosphate, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy for younger patients with chronic lymphocytic leukemia (CLL).
SECONDARY OBJECTIVES:
I. Evaluate overall survival (OS) of patients based on treatment arm. II. Monitor and assess toxicity of treatment with ibrutinib-based induction relative to standard FCR chemotherapy.
III. To compare quality of life (QOL) in CLL patients during the first 6 months of treatment among patients receiving ibrutinib-based induction therapy relative to standard FCR chemoimmunotherapy.
IV. To compare QOL over the long-term in CLL patients receiving continuous therapy using ibrutinib to that of CLL patients who completed FCR therapy.
V. Determine the effect of pretreatment clinical and biological characteristics (e.g. disease stage, immunoglobulin heavy chain variable region gene [IGHV] mutation status, fluorescent in situ hybridization [FISH]) on clinical outcomes (e.g. complete response, PFS) of the different arms.
VI. Determine if the minimal residual disease (MRD) status as assessed by flow cytometry at different time points during and after treatment is an effective surrogate marker for prolonged PFS and overall survival.
VII. Compare the genetic abnormalities and dynamics of intra-clonal architecture of CLL patients before and after treatment with chemoimmunotherapy (CIT) and non-CIT approaches and explore relationships with treatment resistance.
VIII. Explore the effects of FCR and ibrutinib-based therapy on T-cell immune function.
IX. Conduct confirmatory validation genotyping of single nucleotide polymorphisms (SNPs) associated with the efficacy and toxicity of fludarabine-based therapy as in a prior Eastern Cooperative Oncology Group (ECOG) genome-wide association study (GWAS) analysis in the E2997 trial.
X. Evaluate the ability of prognostic model that incorporates clinical and biologic characters to predict a response to therapy and clinical outcome (PFS, OS).
XI. Evaluate signaling networks downstream of the B-cell receptor in patients receiving ibrutinib-based therapy.
XII. Collect relapse samples to study mechanisms of resistance to both FCR and ibrutinib-based therapy.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM A: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Beginning cycle 2, patients also receive rituximab intravenously (IV) over 4 hours on days 1 and 2 of cycle 2, and day 1 of cycles 3-7. Treatment repeats every 28 days for 7 cycles in the absence of unacceptable toxicity. In the absence of disease progression, patients may continue ibrutinib PO QD for a maximum of 10 years.
ARM B: Patients receive rituximab IV over 4 hours on days 1 and 2 of cycle 1, and day 1 of cycles 2-6. Patients also receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 cycles in the absence of unacceptable toxicity.
After completion of study treatment, patients are followed up for 10 years.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Diagnosis of CLL according to the National Cancer Institute (NCI)/Internal Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria; this includes previous documentation of:
- •Biopsy-proven small lymphocytic lymphoma or
- •Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following:
- •Peripheral blood lymphocyte count of greater than 5 x 10\^9/L
- •Immunophenotype consistent with CLL defined as:
- •The predominant population of lymphocytes share both B-cell antigens (cluster of differentiation \[CD\]19, CD20 \[typically dim expression\], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc)
- •Clonality as evidenced by kappa or lambda light chain restriction (typically dim immunoglobulin expression)
- •Negative FISH analysis for t(11;14)(immunoglobulin heavy locus \[IgH\]/cyclin D1 \[CCND1\]) on peripheral blood or tissue biopsy (e.g. marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g. marrow aspirate or lymph node biopsy)
- •No prior chemotherapy, Bruton's tyrosine kinase (BTK) inhibitor therapy, or monoclonal anti-body therapy for treatment of CLL or SLL
- •Has met at least one of the following indications for treatment:
Exclusion Criteria
- Not provided
Arms & Interventions
Arm A (ibrutinib, rituximab)
Patients receive ibrutinib PO QD on days 1-28. Beginning cycle 2, patients also receive rituximab IV over 4 hours on days 1 and 2 of cycle 2, and day 1 of cycles 3-7. Treatment repeats every 28 days for 7 cycles in the absence of unacceptable toxicity. In the absence of disease progression, patients may continue ibrutinib PO QD for a maximum of 10 years.
Intervention: Laboratory Biomarker Analysis (Other)
Arm A (ibrutinib, rituximab)
Patients receive ibrutinib PO QD on days 1-28. Beginning cycle 2, patients also receive rituximab IV over 4 hours on days 1 and 2 of cycle 2, and day 1 of cycles 3-7. Treatment repeats every 28 days for 7 cycles in the absence of unacceptable toxicity. In the absence of disease progression, patients may continue ibrutinib PO QD for a maximum of 10 years.
Intervention: Pharmacogenomic Study (Other)
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
Patients receive rituximab IV over 4 hours on days 1 and 2 of cycle 1, and day 1 of cycles 2-6. Patients also receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 cycles in the absence of unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis (Other)
Arm A (ibrutinib, rituximab)
Patients receive ibrutinib PO QD on days 1-28. Beginning cycle 2, patients also receive rituximab IV over 4 hours on days 1 and 2 of cycle 2, and day 1 of cycles 3-7. Treatment repeats every 28 days for 7 cycles in the absence of unacceptable toxicity. In the absence of disease progression, patients may continue ibrutinib PO QD for a maximum of 10 years.
Intervention: Ibrutinib (Drug)
Arm A (ibrutinib, rituximab)
Patients receive ibrutinib PO QD on days 1-28. Beginning cycle 2, patients also receive rituximab IV over 4 hours on days 1 and 2 of cycle 2, and day 1 of cycles 3-7. Treatment repeats every 28 days for 7 cycles in the absence of unacceptable toxicity. In the absence of disease progression, patients may continue ibrutinib PO QD for a maximum of 10 years.
Intervention: Quality-of-Life Assessment (Other)
Arm A (ibrutinib, rituximab)
Patients receive ibrutinib PO QD on days 1-28. Beginning cycle 2, patients also receive rituximab IV over 4 hours on days 1 and 2 of cycle 2, and day 1 of cycles 3-7. Treatment repeats every 28 days for 7 cycles in the absence of unacceptable toxicity. In the absence of disease progression, patients may continue ibrutinib PO QD for a maximum of 10 years.
Intervention: Rituximab (Biological)
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
Patients receive rituximab IV over 4 hours on days 1 and 2 of cycle 1, and day 1 of cycles 2-6. Patients also receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 cycles in the absence of unacceptable toxicity.
Intervention: Cyclophosphamide (Drug)
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
Patients receive rituximab IV over 4 hours on days 1 and 2 of cycle 1, and day 1 of cycles 2-6. Patients also receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 cycles in the absence of unacceptable toxicity.
Intervention: Fludarabine Phosphate (Drug)
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
Patients receive rituximab IV over 4 hours on days 1 and 2 of cycle 1, and day 1 of cycles 2-6. Patients also receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 cycles in the absence of unacceptable toxicity.
Intervention: Pharmacogenomic Study (Other)
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
Patients receive rituximab IV over 4 hours on days 1 and 2 of cycle 1, and day 1 of cycles 2-6. Patients also receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 cycles in the absence of unacceptable toxicity.
Intervention: Quality-of-Life Assessment (Other)
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
Patients receive rituximab IV over 4 hours on days 1 and 2 of cycle 1, and day 1 of cycles 2-6. Patients also receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 cycles in the absence of unacceptable toxicity.
Intervention: Rituximab (Biological)
Outcomes
Primary Outcomes
Progression-free Survival (PFS) Rate at 3 Years
Time Frame: Assessed every 3 months until progression up to 4 years and 8 months
PFS was defined as the time from randomization to CLL progression or death, whichever occurred first. Progression is characterized by any of the following: * ≥ 50% increase from nadir since start of treatment (tx) in the sum of the products of at least 2 lymph nodes on 2 consecutive examinations 2 weeks apart * ≥ 50% increase from nadir since start of tx in the size of liver and/or spleen * ≥ 50% increase in the absolute number of circulating lymphocytes not due to tumor flare reaction. The absolute lymphocyte count must be ≥ 5x10\^9/L to qualify as disease progression. * Transformation to a more aggressive histology (e.g. Richter's syndrome or prolymphocytic leukemia with \> 55% prolymphocytes). For patients who achieve a complete response or nodular partial response, progression is defined as recurrence of circulating leukemia cell clone in the peripheral blood and an absolute lymphocyte count \> 5x10\^9/L and/or recurrence of palpable lymphadenopathy \> 1.5 cm by physical exam.
Secondary Outcomes
- The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) Score at 6 Months(Assessed at 6 months)
- Progression-free Survival (PFS) by Measurable Residual Disease (MDR) Status at 2 Years(Assessed every 3 months until progression up to 5 years)
- Overall Survival (OS) Rate at 3 Years(Assessed every 3 months until progression; after progression, assessed every 3 months for first 2 years, every 6 months for years 3-5, up to 4 years and 8 months)
- The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) Score at 12 Months(Assessed at 12 months)
- The Association Between Baseline Rai Stage and Complete Response (CR) Rate(Assessed at baseline, every 3 months for the first 2 years, and every 6 months for years 3-5)