Brief Summary
RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as bendamustine hydrochloride, also work in different ways to kill cancer cells or stop them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may stop the growth of mantle cell lymphoma by blocking blood flow to the cancer. It is not yet known whether giving rituximab together with bendamustine and bortezomib is more effective than rituximab and bendamustine, followed by rituximab alone or with lenalidomide in treating mantle cell lymphoma.
PURPOSE: This randomized phase II trial studies rituximab, bortezomib, bendamustine, and lenalidomide in treating previously untreated older patients with mantle cell lymphoma.
PURPOSE: This randomized phase II trial studies rituximab, bortezomib, bendamustine, and lenalidomide in treating previously untreated older patients with mantle cell lymphoma.
Brief Title
Rituximab, Bendamustine Hydrochloride, and Bortezomib Followed by Rituximab and Lenalidomide in Treating Older Patients With Previously Untreated Mantle Cell Lymphoma
Detailed Description
OBJECTIVES:
Primary
* 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 with previously untreated mantle cell lymphoma.
* 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
* To determine whether the addition of bortezomib to induction therapy improves the positron emission tomography (PET)-documented complete response (CR) rate compared to RB alone.
* To determine the objective response rate (ORR) for RB and RBV.
* 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.
* To determine overall survival (OS) in the treatment arms.
* To determine safety, with attention to the addition of bortezomib in the induction regimen and lenalidomide-rituximab (LR) as consolidation therapy.
Laboratory
* To collect paraffin-embedded tissue for creation of tissue microarray.
* To collect and bank serum and blood mononuclear cells for future studies.
* To collect formalin-fixed paraffin-embedded (FFPE) tissue to analyze potential prognostic factors (Ki-67 proliferation index by immunohistochemistry and correlation with proposed 5-gene set of proliferation markers analyzed by RNA PCR; SOX 11 expression by immunohistochemistry; and Micro-RNA levels by microarray).
Quality of Life
* Using patient-reported outcomes data, to determine the extent and severity of neuropathy associated with the addition of bortezomib to induction treatment.
* Using patient-reported outcomes data, to determine the extent and severity of fatigue associated with the addition of lenalidomide to consolidation treatment.
* To evaluate the effects of the addition of bortezomib and lenalidomide on patient-reported health-related quality of life.
* To evaluate the effects of bortezomib-related neuropathy on patient-reported health-related quality of life.
* To evaluate the response of lymphoma-specific symptoms to treatment.
* Using longitudinal patient-reported outcomes data, to describe the trajectory of lymphoma symptoms, neuropathy, fatigue, and overall health-related quality of life prior to, during, and following treatment among older adults with MCL.
Imaging
* To assess the proportion of patients up and down staging when fludeoxyglucose F 18- (FDG) PET/CT is added to standard Ann Arbor staging.
* To assess the ability of pre-treatment FDG-PET/CT (SUVmax) to predict response rate and PFS.
* Among patients with interim (post-cycle 3) FDG-PET/CT imaging, to assess the correlation of interim FDG-PET/CT imaging with response rate and PFS both during induction and consolidation therapy.
* To assess standard FDG-PET/CT metrics including SUVmax, tumor metabolic burden, total tumor burden, and association with pathology features (blastoid variant vs other, and Ki67) in the setting of MCL.
* To assess differences in overall and CR rates when using Deauville vs International Harmonization Project FDG-PET/CT interpretation criteria.
* To determine whether there is a correlation between FDG-PET/CT response and residual disease assessment by molecular and/or flow cytometric techniques.
Residual Disease Assessment by Molecular and Flow Cytometric Techniques
* To determine whether the number of malignant cells in circulation predict the number of cells in marrow.
* To determine whether the number of malignant cells in circulation/in marrow at the end of induction correlate with CR and 2-year PFS.
* To determine whether there is a higher rate of minimal residual disease (MRD) negativity among patients randomized to RBV as compared with RB, and among patients treated with LR maintenance compared with rituximab.
* To compare the two methods of MRD detection - molecular techniques and flow cytometry - as prognostic markers for outcome.
OUTLINE: This is a multicenter study. Patients are stratified according to mantle cell lymphoma International Prognostic Index risk score (low vs intermediate vs high). Patients are randomized to 1 of 4 treatment arms.
* Arm A: Patients receive induction therapy comprising rituximab IV on day 1 and bendamustine hydrochloride IV over 60 minutes on days 1-2. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
* Arm E: Patients receive consolidation therapy comprising rituximab IV on day 1. Courses repeat every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
* Arm B: Patients receive induction therapy comprising bortezomib IV or subcutaneously (SC) on days 1, 4, 8, and 11 and rituximab and bendamustine hydrochloride as patients in arm A. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
* Arm F: Patients receive consolidation therapy comprising rituximab IV on day 1. Courses repeat every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
* Arm C: Patients receive induction therapy comprising rituximab and bendamustine hydrochloride as patients in arm A. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
* Arm G: Patients receive consolidation therapy comprising lenalidomide orally (PO) daily on days 1-21 every 4 weeks and rituximab IV every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
* Arm D: Patients receive bortezomib, rituximab, and bendamustine hydrochloride as patients in arm B. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
* Arm H: Patients receive consolidation therapy comprising lenalidomide PO daily on days 1-21 every 4 weeks and rituximab IV every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
Patients may undergo blood and bone marrow sample collection at baseline and during treatment for correlative studies.
Patients complete the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym), the FACT/GOG-Neurotoxicity scale (FACT/GOG-Ntx), FACT-Fatigue, and FACT-General questionnaires at baseline and periodically during study and follow up.
After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 10 years.
Primary
* 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 with previously untreated mantle cell lymphoma.
* 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
* To determine whether the addition of bortezomib to induction therapy improves the positron emission tomography (PET)-documented complete response (CR) rate compared to RB alone.
* To determine the objective response rate (ORR) for RB and RBV.
* 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.
* To determine overall survival (OS) in the treatment arms.
* To determine safety, with attention to the addition of bortezomib in the induction regimen and lenalidomide-rituximab (LR) as consolidation therapy.
Laboratory
* To collect paraffin-embedded tissue for creation of tissue microarray.
* To collect and bank serum and blood mononuclear cells for future studies.
* To collect formalin-fixed paraffin-embedded (FFPE) tissue to analyze potential prognostic factors (Ki-67 proliferation index by immunohistochemistry and correlation with proposed 5-gene set of proliferation markers analyzed by RNA PCR; SOX 11 expression by immunohistochemistry; and Micro-RNA levels by microarray).
Quality of Life
* Using patient-reported outcomes data, to determine the extent and severity of neuropathy associated with the addition of bortezomib to induction treatment.
* Using patient-reported outcomes data, to determine the extent and severity of fatigue associated with the addition of lenalidomide to consolidation treatment.
* To evaluate the effects of the addition of bortezomib and lenalidomide on patient-reported health-related quality of life.
* To evaluate the effects of bortezomib-related neuropathy on patient-reported health-related quality of life.
* To evaluate the response of lymphoma-specific symptoms to treatment.
* Using longitudinal patient-reported outcomes data, to describe the trajectory of lymphoma symptoms, neuropathy, fatigue, and overall health-related quality of life prior to, during, and following treatment among older adults with MCL.
Imaging
* To assess the proportion of patients up and down staging when fludeoxyglucose F 18- (FDG) PET/CT is added to standard Ann Arbor staging.
* To assess the ability of pre-treatment FDG-PET/CT (SUVmax) to predict response rate and PFS.
* Among patients with interim (post-cycle 3) FDG-PET/CT imaging, to assess the correlation of interim FDG-PET/CT imaging with response rate and PFS both during induction and consolidation therapy.
* To assess standard FDG-PET/CT metrics including SUVmax, tumor metabolic burden, total tumor burden, and association with pathology features (blastoid variant vs other, and Ki67) in the setting of MCL.
* To assess differences in overall and CR rates when using Deauville vs International Harmonization Project FDG-PET/CT interpretation criteria.
* To determine whether there is a correlation between FDG-PET/CT response and residual disease assessment by molecular and/or flow cytometric techniques.
Residual Disease Assessment by Molecular and Flow Cytometric Techniques
* To determine whether the number of malignant cells in circulation predict the number of cells in marrow.
* To determine whether the number of malignant cells in circulation/in marrow at the end of induction correlate with CR and 2-year PFS.
* To determine whether there is a higher rate of minimal residual disease (MRD) negativity among patients randomized to RBV as compared with RB, and among patients treated with LR maintenance compared with rituximab.
* To compare the two methods of MRD detection - molecular techniques and flow cytometry - as prognostic markers for outcome.
OUTLINE: This is a multicenter study. Patients are stratified according to mantle cell lymphoma International Prognostic Index risk score (low vs intermediate vs high). Patients are randomized to 1 of 4 treatment arms.
* Arm A: Patients receive induction therapy comprising rituximab IV on day 1 and bendamustine hydrochloride IV over 60 minutes on days 1-2. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
* Arm E: Patients receive consolidation therapy comprising rituximab IV on day 1. Courses repeat every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
* Arm B: Patients receive induction therapy comprising bortezomib IV or subcutaneously (SC) on days 1, 4, 8, and 11 and rituximab and bendamustine hydrochloride as patients in arm A. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
* Arm F: Patients receive consolidation therapy comprising rituximab IV on day 1. Courses repeat every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
* Arm C: Patients receive induction therapy comprising rituximab and bendamustine hydrochloride as patients in arm A. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
* Arm G: Patients receive consolidation therapy comprising lenalidomide orally (PO) daily on days 1-21 every 4 weeks and rituximab IV every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
* Arm D: Patients receive bortezomib, rituximab, and bendamustine hydrochloride as patients in arm B. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
* Arm H: Patients receive consolidation therapy comprising lenalidomide PO daily on days 1-21 every 4 weeks and rituximab IV every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
Patients may undergo blood and bone marrow sample collection at baseline and during treatment for correlative studies.
Patients complete the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym), the FACT/GOG-Neurotoxicity scale (FACT/GOG-Ntx), FACT-Fatigue, and FACT-General questionnaires at baseline and periodically during study and follow up.
After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 10 years.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Lymphoma
Mantle Cell Lymphoma
Eligibility Criteria
Step 1 (Induction) Inclusion Criteria:
* Mantle Cell Lymphoma International Prognostic Index (MIPI) score must be calculated and entered in OPEN
* Histologically confirmed untreated mantle cell lymphoma (MCL), with documented cyclin D1 by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescence in situ hybridization (FISH)
* Patients must have at least one objective measurable disease parameter
* Negative pregnancy test
* Women of childbearing potential and sexually active males use an accepted and effective method of contraception
* ECOG performance status 0-2
* Absolute neutrophil count (ANC) ≥ 1,500/mcL (1.5 x 10\^9/L)
* Platelets ≥ 100,000/mcL (100 x 10\^9/L)
* Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2 times upper limit of normal (ULN)
* Bilirubin ≤ 2 times ULN
* Calculated creatinine clearance by Cockroft-Gault formula ≥ 30 mL/min
* Patient agrees that if randomized to Arms C or D, and proceeding 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 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. 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 or another accepted full anticoagulation regimen. Ways to minimize risk of DVT should be discussed with patients, including, but not limited to, avoiding smoking, minimizing prothrombotic hormone replacement, avoiding prolonged periods of inactivity (e.g. uninterrupted long car or plane trips).
* 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
* CD4 count at screening \>= 300 cells/mm³
* 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/mm³, whichever occurs later
Step 1 (Induction) Exclusion Criteria:
* Women (sexually mature female) must not be pregnant or breast-feeding
* Evidence of prior malignancy except adequately treated non-melanoma skin cancer, in situ cervical carcinoma, low grade prostate carcinoma (Gleason grade ≤ 6) managed with observation that has been stable for at least 6 months, or any malignancy treated with curative intent continuously disease free for \>=3 years so as not to interfere with interpretation of radiographic response
* Prior therapy for MCL, except: \< 2 weeks of steroid therapy for symptom control or local radiation therapy for symptom control if there is measurable disease outside the radiation portal. Patients may be on chronic steroids for non-malignant disease if on a stable dose equivalent to ≤ 20 mg prednisone per day.
* CNS involvement
* History of AIDS-defining conditions
* Grade 2 or greater peripheral neuropathy.
* NYHA Class III or IV heart failure, uncontrolled angina severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia
* Hypersensitivity to bortezomib, boron or mannitol
* A serious medical or psychiatric illness likely to interfere with study participation
* Participating in any other therapeutic clinical trial or taking any other experimental medications within 14 days prior to registration.
Step 2 (Maintenance) Inclusion Criteria:
* ECOG performance status between 0-2
* Complete response, partial response or stable disease after Step 1
* ANC \>= 1000 cells/mm3 (1.0 x 10\^9/L)
* Platelets \>= 75,000 cells/mm3 (75 x 10\^9/L)
* AST/ALT \<= 2 x upper limit of normal (ULN)
* Total bilirubin \<= 2 x upper limit of normal (ULN) or, if total elevated, direct 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 proceeding onto Arms G or H, they must register into the mandatory REMS program, and be willing and able to comply with the requirements of REMS.
* 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.
* 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'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.
* 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 full anticoagulation, 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, 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 or another accepted full anticoagulation regimen. 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).
* Mantle Cell Lymphoma International Prognostic Index (MIPI) score must be calculated and entered in OPEN
* Histologically confirmed untreated mantle cell lymphoma (MCL), with documented cyclin D1 by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescence in situ hybridization (FISH)
* Patients must have at least one objective measurable disease parameter
* Negative pregnancy test
* Women of childbearing potential and sexually active males use an accepted and effective method of contraception
* ECOG performance status 0-2
* Absolute neutrophil count (ANC) ≥ 1,500/mcL (1.5 x 10\^9/L)
* Platelets ≥ 100,000/mcL (100 x 10\^9/L)
* Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2 times upper limit of normal (ULN)
* Bilirubin ≤ 2 times ULN
* Calculated creatinine clearance by Cockroft-Gault formula ≥ 30 mL/min
* Patient agrees that if randomized to Arms C or D, and proceeding 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 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. 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 or another accepted full anticoagulation regimen. Ways to minimize risk of DVT should be discussed with patients, including, but not limited to, avoiding smoking, minimizing prothrombotic hormone replacement, avoiding prolonged periods of inactivity (e.g. uninterrupted long car or plane trips).
* 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
* CD4 count at screening \>= 300 cells/mm³
* 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/mm³, whichever occurs later
Step 1 (Induction) Exclusion Criteria:
* Women (sexually mature female) must not be pregnant or breast-feeding
* Evidence of prior malignancy except adequately treated non-melanoma skin cancer, in situ cervical carcinoma, low grade prostate carcinoma (Gleason grade ≤ 6) managed with observation that has been stable for at least 6 months, or any malignancy treated with curative intent continuously disease free for \>=3 years so as not to interfere with interpretation of radiographic response
* Prior therapy for MCL, except: \< 2 weeks of steroid therapy for symptom control or local radiation therapy for symptom control if there is measurable disease outside the radiation portal. Patients may be on chronic steroids for non-malignant disease if on a stable dose equivalent to ≤ 20 mg prednisone per day.
* CNS involvement
* History of AIDS-defining conditions
* Grade 2 or greater peripheral neuropathy.
* NYHA Class III or IV heart failure, uncontrolled angina severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia
* Hypersensitivity to bortezomib, boron or mannitol
* A serious medical or psychiatric illness likely to interfere with study participation
* Participating in any other therapeutic clinical trial or taking any other experimental medications within 14 days prior to registration.
Step 2 (Maintenance) Inclusion Criteria:
* ECOG performance status between 0-2
* Complete response, partial response or stable disease after Step 1
* ANC \>= 1000 cells/mm3 (1.0 x 10\^9/L)
* Platelets \>= 75,000 cells/mm3 (75 x 10\^9/L)
* AST/ALT \<= 2 x upper limit of normal (ULN)
* Total bilirubin \<= 2 x upper limit of normal (ULN) or, if total elevated, direct 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 proceeding onto Arms G or H, they must register into the mandatory REMS program, and be willing and able to comply with the requirements of REMS.
* 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.
* 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'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.
* 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 full anticoagulation, 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, 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 or another accepted full anticoagulation regimen. 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).
Inclusion Criteria
Inclusion Criteria:
* Mantle Cell Lymphoma International Prognostic Index (MIPI) score must be calculated and entered in OPEN
* Histologically confirmed untreated mantle cell lymphoma (MCL), with documented cyclin D1 by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescence in situ hybridization (FISH)
* Patients must have at least one objective measurable disease parameter
* Negative pregnancy test
* Women of childbearing potential and sexually active males use an accepted and effective method of contraception
* ECOG performance status 0-2
* Absolute neutrophil count (ANC) ≥ 1,500/mcL (1.5 x 10\^9/L)
* Platelets ≥ 100,000/mcL (100 x 10\^9/L)
* Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2 times upper limit of normal (ULN)
* Bilirubin ≤ 2 times ULN
* Calculated creatinine clearance by Cockroft-Gault formula ≥ 30 mL/min
* Patient agrees that if randomized to Arms C or D, and proceeding 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 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. 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 or another accepted full anticoagulation regimen. Ways to minimize risk of DVT should be discussed with patients, including, but not limited to, avoiding smoking, minimizing prothrombotic hormone replacement, avoiding prolonged periods of inactivity (e.g. uninterrupted long car or plane trips).
* 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
* CD4 count at screening \>= 300 cells/mm³
* 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/mm³, whichever occurs later
Step 1 (Induction)
* Mantle Cell Lymphoma International Prognostic Index (MIPI) score must be calculated and entered in OPEN
* Histologically confirmed untreated mantle cell lymphoma (MCL), with documented cyclin D1 by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescence in situ hybridization (FISH)
* Patients must have at least one objective measurable disease parameter
* Negative pregnancy test
* Women of childbearing potential and sexually active males use an accepted and effective method of contraception
* ECOG performance status 0-2
* Absolute neutrophil count (ANC) ≥ 1,500/mcL (1.5 x 10\^9/L)
* Platelets ≥ 100,000/mcL (100 x 10\^9/L)
* Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2 times upper limit of normal (ULN)
* Bilirubin ≤ 2 times ULN
* Calculated creatinine clearance by Cockroft-Gault formula ≥ 30 mL/min
* Patient agrees that if randomized to Arms C or D, and proceeding 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 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. 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 or another accepted full anticoagulation regimen. Ways to minimize risk of DVT should be discussed with patients, including, but not limited to, avoiding smoking, minimizing prothrombotic hormone replacement, avoiding prolonged periods of inactivity (e.g. uninterrupted long car or plane trips).
* 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
* CD4 count at screening \>= 300 cells/mm³
* 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/mm³, whichever occurs later
Step 1 (Induction)
Gender
All
Gender Based
false
Keywords
Lymphoma
Mantle Cell Lymphoma
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
120 Years
Minimum Age
18 Years
NCT Id
NCT01415752
Org Class
Network
Org Full Name
Eastern Cooperative Oncology Group
Org Study Id
E1411
Overall Status
Active, not recruiting
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Intergroup 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 (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation (RBV → LR)
Primary Outcomes
Outcome Description
PFS is defined as time from randomization to lymphoma progression or death. Progression is defined as:
* Appearance of any new lesion \>1.5 cm in any axis during or at the end of therapy
* \>=50% increase from nadir in the sum of products of the diameters (SPD) of any previously involved nodes or extranodal masses, or in a single involved node or extranodal mass, or the size of other lesions.
* \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis.
* Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems
* Appearance of any new lesion \>1.5 cm in any axis during or at the end of therapy
* \>=50% increase from nadir in the sum of products of the diameters (SPD) of any previously involved nodes or extranodal masses, or in a single involved node or extranodal mass, or the size of other lesions.
* \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis.
* Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems
Outcome Measure
Progression-free Survival (PFS) for Induction Phase
Outcome Time Frame
Assessed at baseline, every 3 months for 2.5 years, every 6 months up to 10 years from end of treatment, and then annually up to 10 years and 6 months
Outcome Description
PFS is defined as time from Step 2 registration to lymphoma progression or death. Progression is defined as:
* Appearance of any new lesion \>1.5 cm in any axis during or at the end of therapy
* \>=50% increase from nadir in the sum of products of the diameters (SPD) of any previously involved nodes or extranodal masses, or in a single involved node or extranodal mass, or the size of other lesions.
* \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis.
* Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems
* Appearance of any new lesion \>1.5 cm in any axis during or at the end of therapy
* \>=50% increase from nadir in the sum of products of the diameters (SPD) of any previously involved nodes or extranodal masses, or in a single involved node or extranodal mass, or the size of other lesions.
* \>=50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis.
* Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems
Outcome Measure
Progression-free Survival (PFS) for Maintenance Phase (Step 2)
Outcome Time Frame
Assessed at registration to step 2, cycles 6, 12, 18, treatment completion, then every 3 months for 2.5 years, every 6 months up to 10 years from end of treatment, and then annually up to 10 years and 6 months
Secondary Ids
Secondary Id
NCI-2011-02980
Secondary Id
CDR0000707057
Secondary Outcomes
Outcome Description
Objective response is defined as either complete response (CR) or partial response (PR).
CR is defined as disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy.
PR is defined as:
* ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses
* No increase in the size of other nodes, liver or spleen.
* Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior to treatment. However, if positive, the cell type should be specified, e.g. large-cell lymphoma or small cleaved cell lymphoma.
* No new sites of disease.
* Patients who achieve a CR but have persistent morphologic bone marrow involvement will be considered partial responders.
* When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients are considered partial responders.
CR is defined as disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy.
PR is defined as:
* ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses
* No increase in the size of other nodes, liver or spleen.
* Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior to treatment. However, if positive, the cell type should be specified, e.g. large-cell lymphoma or small cleaved cell lymphoma.
* No new sites of disease.
* Patients who achieve a CR but have persistent morphologic bone marrow involvement will be considered partial responders.
* When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients are considered partial responders.
Outcome Time Frame
Assessed at baseline and 24 weeks (end of cycle 6)
Outcome Measure
Objective Response for Induction Phase (Step 1)
Outcome Description
Complete response is defined as disappearance of all detectable clinical evidence of disease.
Outcome Time Frame
Assessed at baseline and 24 weeks (end of cycle 6)
Outcome Measure
PET-documented Complete Response for Induction Phase (Step 1)
Outcome Description
OS is defined as the time from registration of Step 2 (maintenance) until death from any cause or last know alive. The Kaplan-Meier estimate of 5-year OS rate is reported.
Outcome Time Frame
Assessed every 3 months for 2.5 years, every 6 months for years 2.5-5
Outcome Measure
Overall Survival (OS) Rate at 5 Years Since Maintenance (Step 2)
Outcome Description
Objective response is defined as either complete response (CR) or partial response (PR).
CR is defined as disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy.
PR is defined as:
* ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses
* No increase in the size of other nodes, liver or spleen.
* Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior to treatment. However, if positive, the cell type should be specified, e.g. large-cell lymphoma or small cleaved cell lymphoma.
* No new sites of disease.
* Patients who achieve a CR but have persistent morphologic bone marrow involvement will be considered partial responders.
* When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients are considered partial responders.
CR is defined as disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy.
PR is defined as:
* ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses
* No increase in the size of other nodes, liver or spleen.
* Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior to treatment. However, if positive, the cell type should be specified, e.g. large-cell lymphoma or small cleaved cell lymphoma.
* No new sites of disease.
* Patients who achieve a CR but have persistent morphologic bone marrow involvement will be considered partial responders.
* When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients are considered partial responders.
Outcome Time Frame
Assessed at baseline and every 4 months for 2 years
Outcome Measure
Objective Response for Maintenance (Step 2) Among Patients Without PET-documented CR at the End of Induction
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
120
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Aditi Shastri
Investigator Email
ASHASTRI@montefiore.org
Investigator Phone
718-920-4826