NCT02048813 · CITED IN SOURCE DOCUMENTS

Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: ACTIVE NOT RECRUITING
Registry last update: 2026-08-28

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Progression-free Survival (PFS) Rate at 3 Years

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outcome · POSTED

Overall Survival (OS) Rate at 3 Years

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outcome · NOT POSTED

The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) Score at 6 Months

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outcome · NOT POSTED

The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) Score at 12 Months

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outcome · NOT POSTED

The Association Between Baseline Rai Stage and Complete Response (CR) Rate

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outcome · NOT POSTED

Progression-free Survival (PFS) by Measurable Residual Disease (MDR) Status at 2 Years

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outcome · NOT POSTED

Distribution of Genetic Abnormalities Before and After Treatment

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outcome · NOT POSTED

T-cell Counts at 12 Months

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outcome · NOT POSTED

Association Between Single Nucleotide Polymorphisms (SNPs) and PFS

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outcome · NOT POSTED

Prognostic Model to Predict PFS

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outcome · NOT POSTED

Signaling Networks Downstream of the B-cell Receptor

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outcome · NOT POSTED

Collection of Relapse Samples

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: 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: * Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin \[Hg\] \< 11 g/dl) and/or thrombocytopenia (platelets \< 100 x 10\^9/L) * Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly * One or more of the following disease-related symptoms: * Weight loss \>= 10% within the previous 6 months * Grade 2 or 3 fatigue attributed to CLL * Fevers \> 100.5 Fahrenheit (F) for 2 weeks without evidence of infection * Clinically significant night sweats without evidence of infection * Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of \> 50% over a two-month period or an anticipated doubling time of less than six months * Age ≥ 18 years and ≤ 70 * ECOG performance status between 0-2 * Life expectancy of \>= 12 months * Ability to tolerate FCR based therapy * No deletion of 17p13 on cytogenetic analysis by FISH * Glomerular filtration rate (GFR) \> 40 mL/minute as calculated by the Cockcroft-Gault formula (obtained =\< 14 days prior to registration) * Total bilirubin =\< 2.5 x upper limit of normal (ULN) (obtained =\< 14 days prior to registration) unless due to Gilbert's disease; for those with a total bilirubin \> 2.5 x ULN, a direct bilirubin should be performed and must be \< 1.5 mg/dL for Gilbert's to be diagnosed * If value is higher due to hepatic involvement by CLL, patient is eligible * Serum glutamic oxaloacetic transaminase (SGOT) (aspartate transaminase \[AST\])/serum glutamate-pyruvate transaminase (SGPT) (alanine transaminase \[ALT\]) =\< 3.0 x the institutional ULN (obtained =\< 14 days prior to registration) * If value is higher due to hepatic involvement by CLL, patient is eligible * Prothrombin time (PT)/international normalized ratio (INR) \< 1.5 ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time \[aPTT\]) \< 1.5 X ULN (obtained =\< 14 days prior to registration) * If value is higher due to hepatic involvement by CLL, patient is eligible * No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment; patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation * No current use of corticosteroids; EXCEPTION: low doses of steroids (\< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted * No previous use of corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL; prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed * No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =\< 2 years; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy for their cancer) * Able to adhere to the study visit schedule and other protocol requirements * No major surgery within the last 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug * No radiation therapy =\< 4 weeks prior to registration * Patients with human immunodeficiency virus (HIV) infection may be eligible provided they meet the following criteria: * CD4-positive cell count \>= lower limit of institutional normal * HIV viral load \< 10,000 copies HIV ribonucleic acid (RNA)/mL (if not on anti-HIV therapy) OR \< 50 copies HIV RNA/mL (if on anti-HIV therapy) * No evidence of hepatitis B or C infection * No evidence of resistant strains of HIV * No history of acquired immune deficiency syndrome (AIDS)-defining condition * Patients must not have any of the following conditions: * Congestive heart failure or New York Heart Association Functional Classification III or IV congestive heart failure * History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration * Recent infections requiring systemic treatment; need to have completed anti-biotic therapy \> 14 days before the first dose of study drug * Cerebral vascular accident or intracranial bleed within the last 6 months * Infection with known chronic, active hepatitis C * Serologic status reflecting active hepatitis B or C infection; patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment (PCR positive patients will be excluded) * Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) family 3, subfamily A (3A) inhibitor * Patients may not be on any other investigational agents * Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days * Women must not be pregnant or breast-feeding since this study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown; female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to registration to rule out pregnancy; female patients who are of non-reproductive potential are those who are post-menopausal by history (i.e. no menses for \>= 1 year); OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy) * Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for 90 days after the last dose of study drug * Patient must be able to swallow capsules and not have the following conditions: * Disease significantly affecting gastrointestinal function * Resection of the stomach or small bowel * Symptomatic inflammatory bowel disease * Ulcerative colitis * Partial or complete bowel obstruction * Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug * Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug * Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or hemophilia * Patient must not have currently active, clinically significant hepatic impairment (\>= moderate hepatic impairment according to the NCI/Child Pugh)
healthy Volunteers: false
maximum Age: 70 Years
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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 Names
Drug: Ibrutinib
Other: Laboratory Biomarker Analysis
Other: Pharmacogenomic Study
Other: Quality-of-Life Assessment
Biological: Rituximab
label
Arm A (ibrutinib, rituximab)
type
EXPERIMENTAL
description
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 Names
Drug: Cyclophosphamide
Drug: Fludarabine Phosphate
Other: Laboratory Biomarker Analysis
Other: Pharmacogenomic Study
Other: Quality-of-Life Assessment
Biological: Rituximab
label
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
type
ACTIVE_COMPARATOR

interventions

arm Group Labels
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
description
Given IV
name
Cyclophosphamide
other Names
(-)-Cyclophosphamide
2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
Asta B 518
B 518
B-518
B518
Carloxan
Ciclofosfamida
Ciclofosfamide
Cicloxal
Clafen
Claphene
type
DRUG
arm Group Labels
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
description
Given IV
name
Fludarabine Phosphate
other Names
2-F-ara-AMP
9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
Beneflur
Fludara
SH T 586
type
DRUG
arm Group Labels
Arm A (ibrutinib, rituximab)
description
Given PO
name
Ibrutinib
other Names
BTK Inhibitor PCI-32765
CRA 032765
CRA-032765
CRA032765
Imbruvica
PCI 32765
PCI-32765
PCI32765
type
DRUG
arm Group Labels
Arm A (ibrutinib, rituximab)
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
description
Correlative studies
name
Laboratory Biomarker Analysis
type
OTHER
arm Group Labels
Arm A (ibrutinib, rituximab)
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
description
Correlative studies
name
Pharmacogenomic Study
other Names
PHARMACOGENOMIC
type
OTHER
arm Group Labels
Arm A (ibrutinib, rituximab)
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
description
Ancillary studies
name
Quality-of-Life Assessment
other Names
Quality of Life Assessment
type
OTHER
arm Group Labels
Arm A (ibrutinib, rituximab)
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
description
Given IV
name
Rituximab
other Names
ABP 798
ABP-798
ABP798
BI 695500
BI-695500
BI695500
Blitzima
C2B8 Monoclonal Antibody
Chimeric Anti-CD20 Antibody
CT P10
CT-P10
CTP10
type
BIOLOGICAL

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 529
type: ACTUAL

Registered outcome plans (not posted results)

other Outcomes

description
Genetic abnormalities are assessed at baseline and longitudinally during treatment as well as after treatment. Distribution of genetic abnormalities are reported.
measure
Distribution of Genetic Abnormalities Before and After Treatment
time Frame
Assessed at baseline, and 3, 6, 12, 15, 18, 24, 36 months
description
T-cell counts will be measured at 12 months.
measure
T-cell Counts at 12 Months
time Frame
Assessed at 12 months
description
PFS was defined as time from randomization to 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 ≥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 progression. * Transformation to a more aggressive histology. 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. The distribution of PFS by SNPs will be reported.
measure
Association Between Single Nucleotide Polymorphisms (SNPs) and PFS
time Frame
Assessed every 3 months until progression; after progression, assessed every 3 months for first 2 years, every 6 months for years 3-5
description
A prognostic model that incorporates clinical and biologic characters to predict PFS will be developed.
measure
Prognostic Model to Predict PFS
time Frame
Assessed every 3 months until progression; after progression, assessed every 3 months for first 2 years, every 6 months for years 3-5
description
Evaluation of signaling networks downstream of the B-cell receptor in patients receiving Ibrutinib-based therapy.
measure
Signaling Networks Downstream of the B-cell Receptor
time Frame
Assessed at baseline and 3, 6, 12, 15, 18, 24, 36 months
description
Collection of relapse samples to study mechanisms of resistance to protocol treatments.
measure
Collection of Relapse Samples
time Frame
Assessed at relapse

primary Outcomes

description
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.
measure
Progression-free Survival (PFS) Rate at 3 Years
time Frame
Assessed every 3 months until progression up to 4 years and 8 months

secondary Outcomes

description
Overall survival was defined as time from randomization to death from any cause or date last known alive. Overall survival rate at 3 years was estimated using the method of Kaplan-Meier.
measure
Overall Survival (OS) Rate at 3 Years
time Frame
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
description
The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) is comprised of the physical well-being (PWB) and functional well-being (FWB) components of the FACT-General (FACT-G) and the leukemia subscale. The FACT-Leu TOI contains a total of 31 items, with scores ranging from 0 to 124. The higher the score, the better the quality of life (QOL).
measure
The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) Score at 6 Months
time Frame
Assessed at 6 months
description
The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) is comprised of the physical well-being (PWB) and functional well-being (FWB) components of the FACT-General (FACT-G) and the leukemia subscale. The FACT-Leu TOI contains a total of 31 items, with scores ranging from 0 to 124. The higher the score, the better the quality of life (QOL).
measure
The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) Score at 12 Months
time Frame
Assessed at 12 months
description
Patients are classified as stage 0-IV according to the Rai system and categorized into one of the three risk groups: Low risk - Stage 0 Intermediate risk - Stage I or II High risk - Stage III or IV CR requires all of the following for at least 2 months: * Absence of lymphadenopathy by physical examination on 2 occasions at least 4 weeks apart and appropriate radiographic techniques. For patients whose only measurable disease at the time of enrollment is on CT scan, a CT scan is required and all lymph nodes must be ≤ 1.5 cm before classifying the patient a CR. * Absence of hepatomegaly or splenomegaly by physical examination * Absence of constitutional symptoms due to disease * Normal complete blood count * One marrow aspirate and biopsy should be performed 52 weeks after Day 1 of cycle 1 among patients with clinical and laboratory evidence of a CR to document a CR. The marrow sample must be at least normocellular with \< 30% of nucleated cells being lymphocytes.
measure
The Association Between Baseline Rai Stage and Complete Response (CR) Rate
time Frame
Assessed at baseline, every 3 months for the first 2 years, and every 6 months for years 3-5
description
PFS was defined as time from randomization to progression or death. Progression is characterized by any of the following: * ≥ 50% increase from nadir since start of treatment (tx) in the sum of the products of ≥ 2 lymph nodes on 2 consecutive exams 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 progression. * Transformation to a more aggressive histology. For patients with 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. MRD status was evaluated at 2 years and samples with \<=20 monotypic events or an MRD level of \<10\^-4 were classified as undetectable MRD.
measure
Progression-free Survival (PFS) by Measurable Residual Disease (MDR) Status at 2 Years
time Frame
Assessed every 3 months until progression up to 5 years

Full study description

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.

Source references

references

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