Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01886872
First received: June 24, 2013
Last updated: August 26, 2014
Last verified: June 2014
  Purpose

This randomized phase III trial studies rituximab with bendamustine hydrochloride or ibrutinib to see how well they work compared to ibrutinib alone in treating older patients with previously untreated chronic lymphocytic leukemia. Monoclonal antibodies, such as rituximab, can block cancer growth in difference ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet know whether rituximab with bendamustine hydrochloride is more effective than rituximab and ibrutinib or ibrutinib alone in treating chronic lymphocytic leukemia.


Condition Intervention Phase
Stage I Chronic Lymphocytic Leukemia
Stage II Chronic Lymphocytic Leukemia
Stage III Chronic Lymphocytic Leukemia
Stage IV Chronic Lymphocytic Leukemia
Drug: ibrutinib
Biological: rituximab
Drug: bendamustine hydrochloride
Other: laboratory biomarker analysis
Other: quality-of-life assessment
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase III Study of Bendamustine Plus Rituximab Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in Untreated Older Patients (≥ 65 Years of Age) With Chronic Lymphocytic Leukemia (CLL)

Resource links provided by NLM:


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

Primary Outcome Measures:
  • PFS [ Time Frame: Time from study entry to the time of documented disease progression or death, assessed up to 10 years ] [ Designated as safety issue: No ]
    Log-rank statistics will be used to compare the PFS distributions of the different treatment arms. The methods of Kaplan and Meier will be used to estimate PFS for the treatment arms. For each of the planned comparisons, we will assess the corresponding hazard ratios, 2-year PFS estimates, and PFS medians along with their 95% confidence intervals.


Secondary Outcome Measures:
  • OS [ Time Frame: From the date of registration to the date of death, assessed up to 10 years ] [ Designated as safety issue: No ]
    The Kaplan-Meier method will be used to estimate OS distributions in this CLL population.

  • Time to progression [ Time Frame: From the date of registration to the date of disease progression, assessed up to 10 years ] [ Designated as safety issue: No ]
    The Kaplan-Meier method will be used to estimate time to progression distributions in this CLL population.

  • Duration of response (CR, nPR, and PR) [ Time Frame: From the date at which the patient's objective status is first noted to be a response to the date that progression or death is documented (if one has occurred) or to the date of last follow-up, assessed up to 10 years ] [ Designated as safety issue: No ]
    The Kaplan-Meier method will be used to estimate the duration of response in the CLL population.

  • Proportion of patients achieving any response to treatment (ORR [PR +nPR+ CR]) [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Estimated using the number of patients with the type of response of interest divided by the total number of patients randomized to that treatment arm. Corresponding exact binomial 95% confidence intervals for true response rates will be calculated.

  • Proportion of patients achieving a biopsy-proven CR [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Estimated using the number of patients with the type of response of interest divided by the total number of patients randomized to that treatment arm. Corresponding exact binomial 95% confidence intervals for true response rates will be calculated

  • Complete and nPR rate [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Estimated using the number of patients with the type of response of interest divided by the total number of patients randomized to that treatment arm. Corresponding exact binomial 95% confidence intervals for true response rates will be calculated

  • Proportion of patients who attain MRD negative status [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Estimated using the number of patients who achieve minimal residual disease divided by the total number randomized to that treatment arm. Corresponding exact binomial 95% confidence intervals for MRD rates will be calculated.

  • Toxicity, calculated according to the frequency and severity of adverse events per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 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.

  • Proportion of patients who experience grade 3 or higher non-hematologic toxicities [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
  • Tolerability assessed by the number of patients requiring dose modifications and/or dose delays [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Tolerability measures will be assessed within each of the treatment arms.

  • Proportion of patients who go off treatment due to adverse reactions or refuse further treatment for lesser toxicities that inhibit their willingness to continue participation [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Tolerability measures will be assessed within each of the treatment arms.

  • Geriatric functional status (optional) [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Assessed using assessed by the Older Americans' Resources and Services Multidimensional Functional Assessment Questionnaire, Activities of Daily Living, Medical Outcomes Study physical functioning, Karnofsky performance status rated by a health care professional, Karnofsky performance status rated by the patient, timed "Up and Go", and number of falls in the last six months.

  • Quality of life [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Assessed using the Geriatric Assessment Survey.


Estimated Enrollment: 523
Study Start Date: December 2013
Estimated Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (rituximab, bendamustine hydrochloride)
Patients receive rituximab IV on day 1 (day 0 course 1) and bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm II.
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: bendamustine hydrochloride
Given IV
Other Names:
  • bendamustin hydrochloride
  • bendamustine
  • cytostasan hydrochloride
  • Treanda
Other: laboratory biomarker analysis
Correlative studies
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Experimental: Arm II (ibrutinib)
Patients receive ibrutinib PO daily. Treatment continuous in the absence of disease progression or unacceptable toxicity.
Drug: ibrutinib
Given PO
Other Names:
  • Bruton's tyrosine kinase inhibitor PCI-32765
  • BTK inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765
Other: laboratory biomarker analysis
Correlative studies
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Experimental: Arm III (ibrutinib, rituximab)
Patients receive ibrutinib as in Arm II. Patients receive rituximab IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: ibrutinib
Given PO
Other Names:
  • Bruton's tyrosine kinase inhibitor PCI-32765
  • BTK inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Other: laboratory biomarker analysis
Correlative studies
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   65 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must be diagnosed with CLL in accordance with International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria that includes all of the following:

    • >= 5 x10^9 B lymphocytes (5000/uL) in the peripheral blood
    • On morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes
    • CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell population, which express the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5; patients with bright surface immunoglobulin expression or lack of CD23 expression in > 10% of cells must lack t(11;14) translocation by interphase cytogenetics
  • Patients must be intermediate or high-risk Rai stage CLL

    • Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus enlarged lymph nodes at any site, with or without hepatomegaly or splenomegaly
    • High risk (formerly Rai stage III/IV) is defined by fulfilling criteria for intermediate risk disease plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia
  • Patients must meet criteria for treatment as defined by IWCLL 2008 guidelines which includes at least one of the following criteria:

    • Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia)
    • Massive (>= 6 cm below the costal margin), progressive or symptomatic splenomegaly
    • Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy
    • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy
    • Constitutional symptoms, which include any of the following:

      • Unintentional weight loss of 10% or more within 6 months
      • Significant fatigue
      • Fevers > 100.5 degrees F for 2 weeks or more without evidence of infection
      • Night sweats > 1 month without evidence of infection
  • Prior Treatment

    • Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids)
    • Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment; palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Patients with active hepatitis B defined by hepatitis B surface antigen positivity or core antibody positivity in the presence of hepatitis B DNA are not eligible for this study; patients with a positive hepatitis B core antibody but with negative hepatitis B DNA may participate, but must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician

    • Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B serology; if patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, but should have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician
  • Patients must not be receiving active systemic anticoagulation with heparin or warfarin; patients must be off warfarin therapy for at least 30 days prior to enrollment
  • Patients with class III or class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligible
  • Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 6 months are not eligible
  • Patients with human immunodeficiency virus (HIV) are eligible if their CD4 count is >= 350 cells/mm^3 and if they are not taking prohibited cytochrome (CYP)-interacting medications
  • Patients must not have any history of Richter's transformation or prolymphocytic leukemia (prolymphocytes in blood > 55%)
  • Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily
  • Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics
  • Patients must not have continued requirement for therapy with a strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitor or inducer
  • Patients must not have a known allergy to mannitol
  • Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions)
  • Patients may not have had major surgery within 10 days of enrollment, or minor surgery within 7 days of enrollment; examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint; the decision about whether a surgery is major or minor can be made at the discretion of the treating physician
  • Absolute neutrophil count (ANC) >= 1,000/uL unless due to bone marrow involvement
  • Aspartate aminotransferase (AST) or alanine aminotransferase (AST) =< 2.5 x upper limits of normal except if due to disease
  • Bilirubin =< 1.5 x upper limits of normal (unless due to liver involvement, hemolysis, or Gilbert's disease)
  • Creatinine clearance >= 40 mL/min

    • To be calculated by modified Cockcroft-Gault formula
  • Platelet count (untransfused) >= 30,000/uL
  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: NCT01886872

  Show 571 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Jennifer Woyach Alliance for Clinical Trials in Oncology
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01886872     History of Changes
Other Study ID Numbers: NCI-2013-01220, NCI-2013-01220, ALLIANCE A041202, A041202, A041202, U10CA031946, U10CA180821
Study First Received: June 24, 2013
Last Updated: August 26, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Leukemia, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antibodies, Monoclonal
Rituximab
Bendamustine
Nitrogen Mustard Compounds
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Antirheumatic Agents

ClinicalTrials.gov processed this record on August 28, 2014