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

Study Overview
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Brief Summary
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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
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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. 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.

Official Title
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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)

Conditions
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Anemia, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine Phosphate
* Drug: Ibrutinib
* Other: Laboratory Biomarker Analysis
* Other: Pharmacogenomic Study
* Other: Quality-of-Life Assessment
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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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 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (ibrutinib, rituximab)<br>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. | Drug: Ibrutinib<br>* Given PO<br>* Other names: PCI-32765;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacogenomic Study<br>* Correlative studies<br>* Other names: PHARMACOGENOMIC;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|
| Active Comparator: Arm B (rituximab, fludarabine phosphate, cyclophosphamide)<br>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. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacogenomic Study<br>* Correlative studies<br>* Other names: PHARMACOGENOMIC;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Rate at 3 Years | 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. | Assessed every 3 months until progression up to 4 years and 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Rate at 3 Years | 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. | 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 6 Months | 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). | Assessed at 6 months | 
| The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) Trial Outcome Index (TOI) Score at 12 Months | 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). | Assessed at 12 months | 
| The Association Between Baseline Rai Stage and Complete Response (CR) Rate | 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. | Assessed at baseline, every 3 months for the first 2 years, and every 6 months for years 3-5 | 
| Progression-free Survival (PFS) by Measurable Residual Disease (MDR) Status at 2 Years | 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. | Assessed every 3 months until progression up to 5 years |