Rituximab, Bendamustine Hydrochloride, and Bortezomib Followed by Rituximab and Lenalidomide in Treating Older Patients With Previously Untreated Mantle Cell Lymphoma

Study Overview
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Brief Summary
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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.

Detailed Description
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OBJECTIVES: Primary To determine whether the addition of bortezomib (RBV) to an induction regimen of rituximab-bendamustine hydrochloride (RB) improves progression-free survival (PFS) compared to RB alone in patients ≥ 60 years of age 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. 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). 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. Tertiary 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. 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.

Official Title
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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)

Conditions
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Lymphoma, Neurotoxicity, Therapy-related Toxicity

Intervention / Treatment
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* Biological: rituximab
* Drug: bendamustine hydrochloride
* Drug: bortezomib
* Drug: lenalidomide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: 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 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 Patient must have no CNS involvement PATIENT CHARACTERISTICS: ECOG performance status 0-2 ANC ≥ 1,500/mcL (1.5 x 10^9/L)* Platelets ≥ 100,000/mcL (100 x 10^9/L)* NOTE: *Unless due to marrow involvement. AST/ALT ≤ 2 times upper limit of normal (ULN) Bilirubin ≤ 2 times ULN Calculated creatinine clearance by Cockroft-Gault formula ≥ 30 mL/min Women (sexually mature female) must not be pregnant or breast-feeding Negative pregnancy test Women of childbearing potential and sexually active males use an accepted and effective method of contraception Men must agree to use a latex condom during sexual contact with a female of child-bearing potential, 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 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 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, deep vein thrombosis (DVT) prophylaxis as all patients registering to the lenalidomide/rituximab Arms G and H will be required to have 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 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 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/mm³ 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/mm³, whichever occurs later Patients must not have grade 2 or greater peripheral neuropathy Patients must not have NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia Patients must not have hypersensitivity to bortezomib, boron, or mannitol Patients must not have a serious medical or psychiatric illness likely to interfere with study participation PRIOR CONCURRENT THERAPY: No prior therapy for MCL, except < 1 week of steroid therapy for symptom control HIV-positive patients are not excluded, but to enroll, must meet all of the below criteria: Must be willing to take effective antiretroviral therapy if indicated If on antiretroviral therapy, must not be taking zidovudine or stavudine Patients must not be participating in any other clinical trial or taking any other experimental medications within 14 days prior to registration

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>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. Patients then proceed to arm E. | Biological: rituximab<br>* Given IV<br>Drug: bendamustine hydrochloride<br>* Given IV<br>|
| Experimental: Arm B<br>Patients receive induction therapy comprising bortezomib IV 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. Patients then proceed to arm F. | Biological: rituximab<br>* Given IV<br>Drug: bendamustine hydrochloride<br>* Given IV<br>Drug: bortezomib<br>* Given IV or SC<br>|
| Experimental: Arm C<br>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. Patients then proceed to arm G. | Biological: rituximab<br>* Given IV<br>Drug: bendamustine hydrochloride<br>* Given IV<br>Drug: lenalidomide<br>* Given PO<br>|
| Experimental: Arm D<br>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. Patients then proceed to arm H. | Biological: rituximab<br>* Given IV<br>Drug: bendamustine hydrochloride<br>* Given IV<br>Drug: bortezomib<br>* Given IV or SC<br>Drug: lenalidomide<br>* Given PO<br>|
| Experimental: Arm E<br>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. | Biological: rituximab<br>* Given IV<br>|
| Experimental: Arm F<br>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. | Biological: rituximab<br>* Given IV<br>|
| Experimental: Arm G<br>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. | Biological: rituximab<br>* Given IV<br>Drug: lenalidomide<br>* Given PO<br>|
| Experimental: Arm H<br>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. | Biological: rituximab<br>* Given IV<br>Drug: lenalidomide<br>* Given PO<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year PFS rate of patients treated with RBV to an induction regimen of RB compared to RB alone |  |  | 
| PFS improvement of patients treated with lenalidomide added to a consolidation regimen |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PET-documented CR rate |  |  | 
| Response rate to RB and RBV |  |  | 
| Toxicity |  |  | 
| Quality of life |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV mantle cell lymphoma, neurotoxicity, therapy-related toxicity, contiguous stage II mantle cell lymphoma, noncontiguous stage II mantle cell lymphoma, stage I mantle cell lymphoma, stage III mantle cell lymphoma