Clinical Trials /

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

NCT02048813

Description:

This randomized 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. Drugs used in chemotherapy, 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. Monoclonal antibodies, such as rituximab, interfere with the ability of cancer cells to grow and spread. 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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Ibrutinib</span> and <span class="go-doc-concept go-doc-intervention">Rituximab</span> Compared With <span class="go-doc-concept go-doc-intervention">Fludarabine Phosphate</span>, <span class="go-doc-concept go-doc-intervention">Cyclophosphamide</span>, and <span class="go-doc-concept go-doc-intervention">Rituximab</span> in Treating Patients With Untreated <span class="go-doc-concept go-doc-disease">Chronic Lymphocytic Leukemia</span> or Small Lymphocytic Lymphoma

Title

  • Brief Title: Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
  • Official Title: 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)
  • Clinical Trial IDs

    NCT ID: NCT02048813

    ORG ID: NCI-2014-00118

    NCI ID: NCI-2014-00118

    Trial Conditions

    Anemia

    Fever, Sweat, and Hot Flashes

    Stage I Chronic Lymphocytic Leukemia

    Stage I Small Lymphocytic Lymphoma

    Stage II Chronic Lymphocytic Leukemia

    Stage II Small Lymphocytic Lymphoma

    Stage III Chronic Lymphocytic Leukemia

    Stage III Small Lymphocytic Lymphoma

    Stage IV Chronic Lymphocytic Leukemia

    Stage IV Small Lymphocytic Lymphoma

    Weight Change

    Trial Interventions

    Drug Synonyms Arms
    Cyclophosphamide (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, CYCLOPHOSPHAMIDE, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719 Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
    Fludarabine Phosphate 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, FLUDARABINE PHOSPHATE, Oforta, SH T 586 Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
    Ibrutinib BTK Inhibitor PCI-32765, CRA-032765, IBRUTINIB, PCI-32765 Arm A (ibrutinib, rituximab)

    Trial Purpose

    This randomized 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. Drugs used in
    chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to
    stop the growth of cancer cells, either by killing the cells or by stopping them from
    dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different
    ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help
    kill them or carry cancer-killing substances to them. It is not yet known whether
    fludarabine phosphate, cyclophosphamide, and rituximab are more effective than ibrutinib and
    rituximab in treating patients with untreated chronic lymphocytic leukemia or small
    lymphocytic lymphoma.

    Detailed Description

    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.

    Trial Arms

    Name Type Description Interventions
    Arm A (ibrutinib, rituximab) Experimental Patients receive ibrutinib PO QD on days 1-28. Beginning course 2, patients also receive rituximab 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. Ibrutinib
    Arm B (rituximab, fludarabine phosphate, cyclophosphamide) Experimental 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. Cyclophosphamide, Fludarabine Phosphate

    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 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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 70 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Change in quality of life assessed using Functional Assessment of Cancer Therapy -Leukemia (FACT-Leu) Trial Outcome Index (TOI)

    PFS

    Secondary Outcome Measures

    Adherence to prescription assessed by the Moriskey Adherence Scale (Arm A only)

    Change in FACT-Leu TOI score

    Change in FACT-Leu TOI score

    Impact of CLL on QOL

    Incidence of toxicity, defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment, graded according to NCI Common Terminology for Adverse Events version 4.0

    OS

    Trial Keywords