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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02048813
First received: January 27, 2014
Last updated: August 24, 2016
Last verified: June 2016
  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, by stopping them from dividing, or by stopping them from spreading. 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 may work better than ibrutinib and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Condition Intervention Phase
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
Drug: Cyclophosphamide
Drug: Fludarabine Phosphate
Drug: Ibrutinib
Other: Laboratory Biomarker Analysis
Other: Pharmacogenomic Study
Other: Quality-of-Life Assessment
Biological: Rituximab
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Change in quality of life assessed using Functional Assessment of Cancer Therapy -Leukemia (FACT-Leu) Trial Outcome Index (TOI) [ Time Frame: Baseline to 12 months after beginning therapy ] [ Designated as safety issue: No ]
  • PFS [ Time Frame: The time from randomization to progression or to death without documentation of progression, assessed up to 10 years ] [ Designated as safety issue: No ]
    A stratified logrank test applied to all patients as randomized will be the primary analysis, with age, ECOG performance status, disease stage, and baseline cytogenetic abnormalities as stratification factors. The same analysis applied to eligible patients only will also be performed as a sensitivity analysis. Cox proportional hazards models will be used to assess possible effects of clinical and biological characteristics on outcome, including age, gender, disease stage, cytogenetic abnormalities, ECOG performance status, and important mutations.


Secondary Outcome Measures:
  • Adherence to prescription assessed by the Moriskey Adherence Scale (Arm A only) [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    Descriptive statistics will be used to summarize trend in adherence to prescription.

  • Change in FACT-Leu TOI score [ Time Frame: Baseline to 3 months after beginning therapy ] [ Designated as safety issue: No ]
    The change in FACT-Leu TOI score will be compared between arm A and arm B to assess the short-term effect of the two therapies on QOL.

  • Change in FACT-Leu TOI score [ Time Frame: Baseline to 6 months after beginning therapy ] [ Designated as safety issue: Yes ]
    The change in FACT-Leu TOI score from the time of randomization to 6 months after beginning therapy will be compared between the two treatment arms in order to provide additional information regarding the toxicity of the different regimens.

  • Impact of CLL on QOL [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The social well-being and emotional well-being components of the FACT-General (G) will be administered at study entry. The entire FACT-Leukemia instrument (FACT-G and the leukemia subscale) at baseline will be analyzed using descriptive statistics to assess the impact of CLL on QOL independent of treatment.

  • 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 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
    The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. In addition, all adverse event data that is graded as 3, 4, or 5 will be reviewed and classified as either "unrelated or unlikely to be related" to study treatment in the event of an actual relationship developing.

  • OS [ Time Frame: Time from randomization until death due to any cause, assessed up to 10 years ] [ Designated as safety issue: No ]
    A stratified logrank test applied to all patients as randomized will be the primary analysis for OS, with age, ECOG performance status, disease stage, and baseline cytogenetic abnormalities as stratification factors. The same analysis applied to eligible patients only will also be performed as a sensitivity analysis. Cox proportional hazards models will be used to assess possible effects of clinical and biological characteristics on outcome, including age, gender, disease stage, cytogenetic abnormalities, ECOG performance status, and important mutations.


Estimated Enrollment: 519
Study Start Date: February 2014
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (ibrutinib, rituximab)
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.
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • PCI-32765
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacogenomic Study
Correlative studies
Other Name: PHARMACOGENOMIC
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Biological: Rituximab
Given IV
Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • RTXM83
Experimental: Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
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.
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-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
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacogenomic Study
Correlative studies
Other Name: PHARMACOGENOMIC
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Biological: Rituximab
Given IV
Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • RTXM83

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  • 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) aspartate transaminase (AST)/serum glutamate-pyruvate transaminase (SGPT) alanine transaminase (ALT) =< 3.0 x the institutional ULN; 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; 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; 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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02048813

  Show 784 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Tait Shanafelt ECOG-ACRIN Cancer Research Group
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02048813     History of Changes
Other Study ID Numbers: NCI-2014-00118  NCI-2014-00118  E1912  ECOG-E1912  E1912  E1912  U10CA180820  U10CA021115 
Study First Received: January 27, 2014
Last Updated: August 24, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Hot Flashes
Body Weight Changes
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Signs and Symptoms
Body Weight
Cyclophosphamide
Fludarabine phosphate
Rituximab
Fludarabine
Antibodies, Monoclonal
Antibodies
Immunoglobulins
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 24, 2016