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
Condition: Lymphoma
MeSH terms: Lymphoma; Lymphoma, Follicular
Intervention: rituximab; Bendamustin; bortezomib; lenalidomide
Intervention description: Given IV; Given IV; Given IV; Given orally
Intervention MeSH terms: Rituximab; Lenalidomide; Bortezomib; Bendamustine Hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 289.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: contiguous stage II grade 1 follicular lymphoma; contiguous stage II grade 2 follicular lymphoma; contiguous stage II grade 3 follicular lymphoma; noncontiguous stage II grade 1 follicular lymphoma; noncontiguous stage II grade 2 follicular lymphoma; noncontiguous stage II grade 3 follicular lymphoma; stage III grade 1 follicular lymphoma; stage III grade 2 follicular lymphoma; stage III grade 3 follicular lymphoma; stage IV grade 1 follicular lymphoma; stage IV grade 2 follicular lymphoma; stage IV grade 3 follicular lymphoma

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria (Induction):

          -  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 lactate dehydrogenase (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

          -  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

          -  ECOG performance status 0-2

          -  Absolute neutrophil count (ANC) ≥ 1,500/mm³ (includes neutrophils and bands)

          -  Platelet count ≥ 100,000/mm³

          -  Creatinine ≤ 2.0 mg/dL

          -  Aspartate aminotransferase (AST) and alanine transaminase (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)

          -  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

          -  Must register into the mandatory RevAssist® program and be willing and able to comply
             with the requirements of RevAssist® (for patients randomized to arm C and proceed onto
             arm F)

        Exclusion Criteria (Induction):

          -  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

          -  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

          -  Pregnant or nursing

          -  Active, uncontrolled infections (afebrile for > 48 hours off antibiotics)

          -  ≥ grade 2 neuropathy

          -  Myocardial infarction within the past 6 months

          -  NYHA class III-IV heart failure, uncontrolled angina, severe uncontrolled ventricular
             arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction
             system abnormalities

          -  Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study

          -  Known hypersensitivity to boron or mannitol

          -  Chronic carriers of hepatitis B virus (HBV) with positive hepatitis surface antigen
             (HBsAg +)

        Inclusion Criteria (Continuation):

          -  Patient must have improved their response or have had no interval change in their
             tumor measurements with restaging from Induction cycle 3 to 6 as determined at Cycle 6
             restaging.

          -  Adequate organ function

          -  ECOG performance status 0-2

          -  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

          -  Additional requirements for Arm C induction patients registering to arm F:

               -  Patients must be willing to take deep vein thrombosis (DVT) prophylaxis. Subjects
                  with a history of a thrombotic vascular event will be required to have full
                  anticoagulation, therapeutic doses of low molecular weight heparin or warfarin to
                  maintain an INR between 2.0 - 3.0, or any other accepted full anticoagulation
                  regimen (e.g. direct thrombin inhibitors or Factor Xa inhibitors) with
                  appropriate monitoring for that agent. Subjects without a history of a
                  thromboembolic event are required to take a daily aspirin (81 mg or 325 mg) for
                  DVT prophylaxis. Subjects who are unable to tolerate aspirin should receive low
                  molecular weight heparin therapy or warfarin treatment or another accepted full
                  anticoagulation regimen.

               -  Females of childbearing potential (FCBP) must agree to use two reliable forms of
                  contraception simultaneously or to practice complete abstinence from heterosexual
                  intercourse during the following time periods related to this study/lenalidomide:
                  1) for at least 28 days before starting lenalidomide; 2) while participating in
                  the study; and 3) for at least 28 days after discontinuation/stopping
                  lenalidomide. The two methods of reliable contraception must include one highly
                  effective method (i.e. intrauterine device (IUD), hormonal [birth control pills,
                  injections, or implants], tubal ligation, partner's vasectomy) and one additional
                  effective (barrier) method (i.e. latex condom, diaphragm, cervical cap). FCBP
                  must be referred to a qualified provider of contraceptive methods if needed.

               -  Patient must agree to abstain from donating blood during study participation and
                  for at least 28 days after discontinuation from protocol treatment.

               -  All males, regardless of whether they have undergone a successful vasectomy, must
                  agree to use a latex condom during sexual contact with a female of childbearing
                  potential, or to practice complete abstinence from heterosexual intercourse with
                  any female of childbearing potential during the cycles of continuation therapy of
                  which lenalidomide are taken and for at least 28 days after
                  discontinuation/stopping lenalidomide. Patient must agree to abstain from
                  donating blood, semen, or sperm during study participation and for at least 28
                  days after discontinuation from protocol treatment.

               -  Must register into the mandatory RevAssist® program and be willing and able to
                  comply with the requirements of RevAssist®

        Exclusion Criteria (Continuation):

          -  Active, uncontrolled infections (afebrile for > 48 hours off antibiotics)

          -  ≥ grade 2 neuropathy

          -  Additional requirements for Arm C induction patients registering to arm F:

               -  Not pregnant or breast-feeding