Bendamustine Hydrochloride and Rituximab With or Without Bortezomib Followed by Rituximab With or Without Lenalidomide in Treating Patients With High-Risk Stage II, Stage III, or Stage IV Follicular Lymphoma

This study is currently recruiting participants.
Verified December 2012 by National Cancer Institute (NCI)
Sponsor:
Collaborator:
Information provided by:
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01216683
First received: October 6, 2010
Last updated: December 7, 2012
Last verified: December 2012

October 6, 2010
December 7, 2012
December 2010
August 2016   (final data collection date for primary outcome measure)
  • Complete remission (CR) rate after induction therapy [ Designated as safety issue: No ]
  • 1-year post-induction disease-free survival rate [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT01216683 on ClinicalTrials.gov Archive Site
  • Progression-free survival at 3 years [ Designated as safety issue: No ]
  • Overall survival at 5 years [ Designated as safety issue: No ]
  • Effect of continuation therapy in converting partial response or stable disease from induction into CR [ Designated as safety issue: No ]
  • Association of the original FLIPI-1 score with the recently reported FLIPI-2 score [ Designated as safety issue: No ]
  • Relationship between FLIPI-2 score and outcome [ Designated as safety issue: No ]
  • Overall health-related quality of life and disease-related symptoms as assessed by the FACT-Lymphoma subscale (FACTLym) [ Designated as safety issue: No ]
  • Treatment-related symptoms as assessed by the 13-item FACT-Fatigue scale and the 11-item FACT/GOG-Neurotoxicity scale [ Designated as safety issue: No ]
  • Disease-related symptoms and distress as assessed by the patient self-report assessment [ Designated as safety issue: No ]
  • Number of co-morbidities as assessed by the Cumulative Illness Rating Scale (CIRS) at 2 years [ Designated as safety issue: No ]
  • Relationship between CIRS score and outcome [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Bendamustine Hydrochloride and Rituximab With or Without Bortezomib Followed by Rituximab With or Without Lenalidomide in Treating Patients With High-Risk Stage II, Stage III, or Stage IV Follicular Lymphoma
A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by Lenalidomide/Rituximab in High Risk Follicular Lymphoma

RATIONALE: 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. Monoclonal antibodies, such as rituximab, can block cancer growth in different 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. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether giving bendamustine hydrochloride and rituximab together alone is more effective than giving bendamustine hydrochloride and rituximab together with bortezomib or lenalidomide in treating follicular lymphoma.

PURPOSE: This randomized phase II trial is studying giving bendamustine hydrochloride and rituximab together with or without bortezomib followed by rituximab with or without lenalidomide to see how well they work in treating patients with high-risk stage II, stage III, or stage IV follicular lymphoma.

OBJECTIVES:

Primary

  • To compare the complete remission rate in patients with high-risk follicular lymphoma receiving induction therapy comprising bendamustine hydrochloride and rituximab with vs without bortezomib.
  • To compare the 1-year post-induction disease-free survival rate in patients receiving continuation therapy comprising rituximab with vs without lenalidomide.

Secondary

  • To determine the 3-year progression-free survival and the 5-year overall survival of these patients.
  • To evaluate patient-reported outcomes at baseline and during treatment to determine differences in symptom palliation, treatment-related symptoms, and overall health-related quality of life.
  • To examine the association between baseline FLIPI information and outcome of these patients.
  • To examine the association between baseline and end-of-treatment patient comorbidities assessed by the Cumulative Illness Rating Scale (CIRS) and outcome.
  • To create an image and tissue bank including serial PET/CT scans, diagnostic paraffin-embedded tissue, germline DNA, and serial blood and bone marrow samples sufficient to support proposed and future studies of tumor and host characteristics that may predict for clinical outcome, including treatment arm effects, and enhance existing prognostic indices. (exploratory)

OUTLINE: Patients are stratified according to FLIPI-1score (1 or 2 vs 3 vs 4 or 5) and GELF tumor burden (low vs high). Patients are randomized to 1 of 3 treatment arms.

  • Arm I: Patients receive rituximab IV on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Beginning 4 weeks after the completion of induction therapy, patients receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

  • Arm II: Patients receive rituximab IV on day 1; bortezomib IV on days 1, 4, 8, and 11; and bendamustine hydrochloride IV over 1 hour on days 1 and 4. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Beginning 4 weeks after the completion of induction therapy, patients receive rituximab as in arm I.

  • Arm III: Patients receive rituximab IV on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Immediately after completing induction therapy, patients receive oral lenalidomide on days 1-21. Treatment repeats every 4 weeks for 13 courses in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after the completion of induction therapy, patients receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

Quality of life (including fatigue, neurotoxicity, anxiety, and depression) is assessed by questionnaire at baseline and periodically during study therapy.

Blood, bone marrow, and tissue samples may be collected periodically for correlative studies and for a repository.

After completion of study therapy, patients are followed up periodically for 15 years.

Interventional
Phase 2
Allocation: Randomized
Masking: Open Label
Primary Purpose: Treatment
Lymphoma
  • Biological: rituximab
    Given IV
  • Drug: bendamustine hydrochloride
    Given IV
  • Drug: bortezomib
    Given IV
  • Drug: lenalidomide
    Given orally
  • Experimental: Arm I
    Patients receive rituximab IV on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after the completion of induction therapy, patients receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: rituximab
    • Drug: bendamustine hydrochloride
  • Experimental: Arm II
    Patients receive rituximab IV on day 1, bortezomib IV on days 1, 4, 8, and 11, and bendamustine hydrochloride IV over 1 hour on days 1 and 4. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after the completion of induction therapy, patients receive rituximab as in arm I.
    Interventions:
    • Biological: rituximab
    • Drug: bendamustine hydrochloride
    • Drug: bortezomib
  • Experimental: Arm III
    Patients receive rituximab IV on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Immediately after completing induction therapy, patients receive oral lenalidomide on days 1-21. Treatment repeats every 28 days for 13 courses in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after the completion of induction therapy, patients receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: rituximab
    • Drug: bendamustine hydrochloride
    • Drug: lenalidomide
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
250
Not Provided
August 2016   (final data collection date for primary outcome measure)

DISEASE CHARACTERISTICS:

  • Histologically confirmed (biopsy-proven) diagnosis of follicular B-cell non-Hodgkin lymphoma with no evidence of transformation to large cell histology

    • Patients having both diffuse and follicular architectural elements are eligible if the histology is predominantly follicular (i.e., ≥ 50% of the cross-sectional area) and there is no evidence of transformation to a large cell histology
    • Diagnostic confirmation (i.e., core needle or excisional lymph node biopsy) required if the interval since tissue diagnosis of low-grade malignant lymphoma is > 24 months

      • Bone marrow biopsy alone not acceptable
  • Stage II, III, or IV AND grade 1, 2, or 3a disease
  • Must meet criteria for High Tumor Burden (higher risk) as defined by either the Groupe D'Etude des Lymphomes Follicularies (GELF) criteria OR the follicular lymphoma international prognostic index (FLIPI) as defined below:

    • Patient must meet ≥ 1 of the following GELF criteria:

      • Nodal or extranodal mass ≥ 7 cm
      • At least 3 nodal masses > 3.0 cm in diameter
      • Systemic symptoms due to lymphoma or B symptoms
      • Splenomegaly with spleen > 16 cm by CT scan
      • Evidence of compression syndrome (e.g., ureteral, orbital, gastrointestinal) or pleural or peritoneal serous effusion due to lymphoma (irrespective of cell content)
      • Leukemic presentation (≥ 5.0 x 10^9/L malignant circulating follicular cells)
      • Cytopenias (polymorphonuclear leukocytes < 1.0 X 10^9/L, hemoglobin < 10 g/dL, and/or platelets < 100 x 10^9/L)
    • Patient must have a FLIPI-1 score of 3, 4, or 5 (1 point per criterion below):

      • Age ≥ 60 years
      • Stage III-IV disease
      • Hemoglobin level < 12 g/dL
      • > 4 nodal areas
      • Serum LDH level above normal
  • At least 1 objective measurable disease parameter

    • Baseline measurements and evaluations (PET and CT) obtained within 6 weeks of randomization
    • Measurable disease in the liver is required if the liver is the only site of lymphoma

PATIENT CHARACTERISTICS:

  • See Disease Characteristics
  • ECOG performance status 0-2
  • ANC ≥ 1,500/mm³ (includes neutrophils and bands)
  • Platelet count ≥ 100,000/mm³
  • Creatinine ≤ 2.0 mg/dL
  • AST and ALT ≤ 5 x upper limit of normal (ULN)
  • Alkaline phosphatase ≤ 5 x ULN
  • Total bilirubin ≤ 1.5 x ULN (patients with known Gilbert disease should contact the study PI)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use 2 effective methods (1 highly effective and 1 additional effective method) of contraception ≥ 28 days before, during, and for ≥ 28 days after completing study treatment
  • HIV-positive patients must meet all of the following criteria:

    • HIV is sensitive to antiretroviral therapy
    • Must be willing to take effective antiretroviral therapy if indicated
    • No history of CD4 < 300 cells/mm³ prior to or at the time of lymphoma diagnosis
    • No history of AIDS-defining conditions
    • If on antiretroviral therapy, must not be taking zidovudine or stavudine
    • Must be willing to take prophylaxis for Pneumocystis jiroveci pneumonia (PCP) during therapy and ≥ 2 months following completion of study therapy or until the CD4 cells recover to over 250 cells/mm³
  • No recent history of malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for ≥ 2 years
  • No active, uncontrolled infections (afebrile for > 48 hours off antibiotics)
  • No ≥ grade 2 neuropathy
  • No myocardial infarction within the past 6 months
  • No NYHA class III-IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
  • No serious medical or psychiatric illness likely to interfere with participation in this clinical study
  • No known hypersensitivity to boron or mannitol
  • No chronic carriers of hepatitis B virus (HBV) with positive hepatitis surface antigen (HBsAg +)

    • Patients with a prior history of HBV infection, but immune, with only IgG hepatitis core antibody positive (HBcAb+), must receive antiviral prophylaxis (e.g., lamivudine 100 mg po daily) for ≥ 1 week prior to course 1 and throughout induction and continuation therapy and for ≥ 12 months after the last rituximab dose
  • Must register into the mandatory RevAssist® program and be willing and able to comply with the requirements of RevAssist® (for patients randomized to arm III)

PRIOR CONCURRENT THERAPY:

  • No prior chemotherapy, radiotherapy, or immunotherapy for lymphoma

    • Prednisone or other corticosteroids used for non-lymphomatous conditions will not be considered as prior chemotherapy
    • A prior/recent short course (< 2 weeks) of steroids for symptom relief of lymphoma-related symptoms is allowed
Both
18 Years and older
No
Not Provided
United States
 
NCT01216683
CDR0000683312, ECOG-E2408
Not Provided
Robert L. Comis, ECOG Group Chair's Office
Eastern Cooperative Oncology Group
National Cancer Institute (NCI)
Principal Investigator: Andrew M. Evens, DO, MS Robert H. Lurie Cancer Center
National Cancer Institute (NCI)
December 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP