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ECOG 1411   |   12-690
Randomized Phase 2 Four Arm Study In Patients 60 With Previously Untreated Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By Rituximab Consolidation; Arm B = Rituximab + Bendamustine + Bortezomib Followed By Rituximab Consolidation; Arm C = Rituximab + Bendamustine Followed By Lenalidomide + Rituximab Consolidation; Arm D = Rituximab + Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation

Disease(s)
Lymphoma
Lymphoma, Mantle Cell
Lymphoma, Non - Hodgkin
Hospital(s)
Beachwood
Fairview
Hillcrest
Independence
Main Campus
North Coast Cancer
Strongsville
Wooster
Phase(s)
Phase 2
Stage(s)
Type(s)
Therapeutic
Drug(s)
Bendamustine
Bortezomib
Lenalidomide
Rituximab

Contact Information
Cancer Answer Line

866.223.8100

8:00 am - 4:30 pm, Monday - Friday


Description
Primary
  1. To determine whether the addition of bortezomib (RBV) to an induction regimen of rituximab-bendamustine (RB) improves progression-free survival (PFS) compared to RB alone in patients ≥ 60 years of age with previously untreated mantle cell lymphoma.
  2. To determine whether the addition of lenalidomide to a consolidation regimen of rituximab following an induction regimen of RB or RBV improves PFS compared to consolidation rituximab alone in this patient population.
Secondary
  1. To determine whether the addition of bortezomib to induction therapy improves the PET-documented complete response rate compared to RB alone.
  2. To determine the objective response rate (ORR) for RB and RBV.
  3. Among patients who do not have PET-documented CR at the end of induction, to determine whether the addition of lenalidomide to consolidation therapy improves CR and ORR compared with rituximab alone.
  4. To determine overall survival (OS) in the treatment arms.
  5. To determine safety, with attention to the addition of bortezomib in the induction regimen and lenalidomide-rituximab as consolidation therapy.

Inclusion Criteria
Step 1 Registration
  1. Age ≥ 18 years.
  2. Females of childbearing potential must not be pregnant or breast-feeding due to risk of fetal harm by the chemotherapeutic agents prescribed in this protocol. 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 (FCBP) is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 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).
  3. Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception.
  4. Patients must have measurable disease as defined in Section 6.
  5. Histologically confirmed untreated mantle cell lymphoma, with documented cyclin D1 by immunohistochemical stains and/or t(11;14) by cytogenetics or FISH.
  6. Patients must have at least one objective measurable disease parameter. Baseline measurements and evaluations must be obtained within 4 weeks of registration to the study. Abnormal PET scans will not constitute evaluable disease, unless verified by CT scan or other appropriate imaging. Measurable disease in the liver is required if the liver is the only site of lymphoma. If the only radiographically assessable disease is splenomegaly (without discrete measurable nodules), the patient can be enrolled, but for such patients CR cannot be differentiated from PR (per Section 6.1.3), while the spleen will be considered nodal with respect to criteria for PD (see section 6.4.5).
  7. ECOG performance status between 0-2.
  8. Hematologic parameters (unless due to marrow involvement) obtained within 4 weeks prior to registration. ANC ≥ 1500/mcL (1.5 x 10^9/L) and Platelets ≥ 100,000/mcL (100 x 10^9/L)
  9. Liver/Renal function, obtained within 4 weeks prior to registration: AST/ALT ≤ 2 x upper limit of normal (ULN), Bilirubin ≤ 2 x upper limit of normal (ULN), Calculated creatinine clearance by Cockroft-Gault formula ≥ 30 ml/min
  10. No evidence of prior malignancy except adequately treated non-melanoma skin cancer, in situ cervical carcinoma or any surgically- or radiation-cured malignancy continuously disease free for ≥ 5 years so as not to interfere with interpretation of radiographic response.
  11. No prior therapy for MCL, except < 1 week of steroid therapy for symptom control.
  12. Patient must have no CNS involvement.
  13. Patient agrees that if randomized to Arms C or D, and proceed onto Arms G or H, they must register into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist. Patients must have no medical contra-indications to, and be willing to take, DVT prophylaxis as all patients registering to the lenalidomide/rituximab Arms G and H will be required to have deep vein thrombosis (DVT) prophylaxis. Patients randomized to Arms G or H who have a history of a thrombotic vascular event will be required to have therapeutic doses of low molecular weight heparin or warfarin to maintain an INR between 2.0-3.0. Patients on Arms G and H without a history of a thromboembolic event are required to take a daily aspirin (81 mg or 325 mg) for DVT prophylaxis. Patients who are unable to tolerate aspirin should receive low molecular weight heparin therapy or warfarin treatment.Ways to minimize risk of DVT should be discussed with patients, including, but not limited to, avoiding smoking, minimizing pro-thrombotic hormone replacement, avoiding prolonged periods of inactivity (e.g. uninterrupted long car or plane trips).
  14. HIV positive patients are not excluded, but to enroll, must meet all of the below criteria: HIV is sensitive to antiretroviral therapy. Must be willing to take effective antiretroviral therapy if indicated. No history of CD4 prior to or at the time of lymphoma diagnosis < 300 cells/mm^3. 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 until at least 2 months following the completion of therapy or until the CD4 cells recover to over 250 cells/mm^3, whichever occurs later.
  15. Patients must not have grade 2 or greater peripheral neuropathy.
  16. Patients must not have NYHA Class III or IV heart failure, uncontrolled angina severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.
  17. Patients must not have hypersensitivity to bortezomib, boron or mannitol.
  18. Patients must not have a serious medical or psychiatric illness likely to interfere with study participation
  19. Patients must not be participating in any other clinical trial or taking any other experimental medications within 14 days prior to registration.
Step 2 Registration
  1. ECOG performance status between 0-2
  2. CR, PR or SD after Step 1.
  3. Prior to beginning consolidation, patients must meet the following criteria:
    • Hematologic parameters: ANC ≥ 1000 cells/mm^3 (1.0 x 10^9/L)
    • Platelets ≥ 75,000 cells/mm^3 (75 x 10^9/L)
    • AST/ALT ≤ 2 x upper limit of normal (ULN)
    • Bilirubin ≤ 2 x upper limit of normal (ULN)
    • Calculated creatinine clearance by Cockroft-Gault formula ≥ 30 ml/min
    • Patient agrees that if randomized to Arms C or D, and proceed onto Arms G or H, they must register into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist.Pregnancy tests must occur within 10 - 14 days and again within 24 hours prior to initiation of Cycle 1 of lenalidomide. *Females of childbearing potential (FCBP)* with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on lenalidomide therapy (including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide. Females with irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while on lenalidomide therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix VI: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).*Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days and again within 24 hours prior to starting Cycle 1 of lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See Appendix VI: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods, AND also Appendix XIV: Lenalidomide Information Sheet.*A female of childbearing potential is any sexually mature female, regardless of sexual orientation of whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).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/lenaliomide: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study including interruptions in therapy; 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´┐Żs 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. Women must agree to abstain from donating blood during study participation and for at least 28 days after discontinuation from protocol treatment. Males must agree to abstain from donating blood, semen, or sperm 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 all cycles of study treatment and for at least 28 days following discontinuation of protocol treatment. Patients must have no medical contra-indications to, and be willing to take, DVT prophylaxis as all patients registering to the lenalidomide/rituximab Arms G and H will be required to have deep vein thrombosis (DVT) prophylaxis. Patients randomized to Arms G or H who have a history of a thrombotic vascular event will be required to have therapeutic doses of low molecular weight heparin or warfarin to maintain an INR between 2.0 to 3.0, or any other accepted full anticoagulation regimen (e.g. direct thrombin inhibitors or Factor Xa inhibitors) with appropriate monitoring for that agent. Patients on Arms G and H without a history of a thromboembolic event are required to take a daily aspirin (81 mg or 325 mg) for DVT prophylaxis. Patients who are unable to tolerate aspirin should receive low molecular weight heparin therapy or warfarin treatment. Ways to minimize risk of DVT should be discussed with patients, including, but not limited to, avoiding smoking, minimizing pro-thrombotic hormone replacement, avoiding prolonged periods of inactivity (e.g. uninterrupted long car or plane trips).
  4. HIV positive patients are not excluded, but to enroll, must meet all of the below criteria: HIV is sensitive to antiretroviral therapy. Must be willing to take effective antiretroviral therapy if indicated. No history of CD4 prior to or at the time of lymphoma diagnosis < 300 cells/mm^3. 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 until at least 2 months following the completion of therapy or until the CD4 cells recover to over 250 cells/mm^3, which ever occurs later.

Exclusion Criteria
Exclusion Criteria Not Available

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