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)


Phoenix/Scottsdale, Ariz., Rochester, Minn.

Trial status:

Open for Enrollment

Why is this study being done?

PRIMARY OBJECTIVES: 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 course 2, patients also receive rituximab intravenously (IV) over 4 hours on day 1 (days 1 and 2 of course 2 only). Treatment repeats every 28 days for 7 courses. In the absence of disease progression, patients may continue ibrutinib PO QD. ARM B: Patients receive rituximab as seen in Arm A and fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 courses. After completion of study treatment, patients are followed up for 10 years.

Who is eligible to participate?

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 x10^9/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 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 - Total bilirubin =< 2.5 x upper limit of normal (ULN) 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) =< 2.5 x ULN; 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 28 days prior to registration or minor surgery within the last 5 days - 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: - New York Heart Association class III or IV heart disease - Recent myocardial infarction (=< 3 months) - Uncontrolled infection - Cerebral vascular accident or intracranial bleed within the last 6 months - Infection with known chronic, active hepatitis C - Positive serology for hepatitis B defined as a positive test for hepatitis B surface antigen (HBsAg); in addition, if negative for HBsAg but hepatitis B core antibody (HBcAb) positive (regardless of HBsAb status), a hepatitis B deoxyribonucleic acid (DNA) test will be performed and, if positive the subject will be ineligible - Patients are not eligible if they require chronic use of strong or moderate cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)/5 inhibitors or inducers at the time of registration - 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; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: - Has not undergone a hysterectomy or bilateral oophorectomy; or - Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - 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 the duration of their participation in the study

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