Rituximab With or Without Stem Cell Transplant in Treating Patients With Minimal Residual Disease-Negative Mantle Cell Lymphoma in First Complete Remission

Study Overview
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Brief Summary
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This randomized phase III trial studies rituximab after stem cell transplant and to see how well it works compared with rituximab alone in treating patients with in minimal residual disease-negative mantle cell lymphoma in first complete remission. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Giving chemotherapy before a stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Giving rituximab with or without stem cell transplant may work better in treating patients with mantle cell lymphoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare overall survival in mantle cell lymphoma (MCL) patients in minimal residual disease (MRD)-negative first remission who undergo autologous hematopoietic stem cell transplantation (auto-HCT) followed by maintenance rituximab versus (vs.) maintenance rituximab alone (without auto-HCT). SECONDARY OBJECTIVES: I. To compare progression-free survival in MCL patients in MRD-negative first remission who undergo auto-HCT followed by maintenance rituximab vs. maintenance rituximab alone. II. To define the overall survival and progression-free survival at 2 and 5 years of chemosensitive but MRD-positive (or MRD-indeterminate) patients who undergo auto-HCT followed by 2 years of maintenance rituximab. III. To describe the rate of complications (serious infection, hospitalization, need for intravenous immune globulin) in MCL patients undergoing maintenance rituximab following auto-HCT. IV. To determine the prognostic impact of MRD status at day 100, in MCL patients who were MRD-positive prior to auto-HCT. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive standard of care preparative chemotherapy and undergo auto-HCT. Beginning 60-120 days after transplant, patients receive rituximab intravenously (IV) once every 8 weeks for up to 18 courses in the absence of disease progression or unacceptable toxicity. GROUP II: Patients receive standard of care induction chemotherapy. Beginning 40-120 days after completion of chemotherapy, patients receive rituximab as in Group I. After completion of study treatment, patients are followed up every 3 and 6 months for 10 years.

Official Title
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A Randomized Phase III Trial of Consolidation With Autologous Hematopoietic Cell Transplantation Followed by Maintenance Rituximab vs. Maintenance Rituximab Alone for Patients With Mantle Cell Lymphoma in Minimal Residual Disease-Negative First Complete Remission

Conditions
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CD20 Positive, Mantle Cell Lymphoma

Intervention / Treatment
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* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Other: Laboratory Biomarker Analysis
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: INCLUSION CRITERIA FOR SCREENING (STEP 0 - PREREGISTRATION) Patients must have histologically confirmed mantle cell lymphoma, with cyclin D1 by immunohistochemical stains and/or t(11;14) by cytogenetics or FISH. If patient has cyclin D1 negative mantle cell lymphoma with classical morphology and an expression profile (including SOX11+) that is otherwise indistinguishable from mantle cell lymphoma, communication with investigator is required for consideration of enrollment. The proliferation rate, using Ki-67 or MIB-1, should also be determined, but is not required until Step 1 registration. Patients may register to Step 0 without a documented Ki-67 index. Patients should be deemed to be potentially eligible and willing candidates for auto-HCT by the enrolling physician Patient may be receiving or have completed induction therapy within 60 days prior to preregistration to step 0; no more than 300 days may have passed between the first day of induction therapy and preregistration to step 0 For patients who have completed induction therapy, restaging evaluation must show status of partial (PR) or complete response (CR); patients preregistered post-induction with evidence of clinical disease progression are not eligible for preregistration Up to two regimens of chemotherapy are allowed as long as a continuous response was ongoing throughout therapy NOTE: For example, a patient who started treatment with rituximab/bendamustine and was then switched to rituximab(R)-cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) (due to insufficient response or excessive toxicity) would be counted as having received 2 regimens; however, R-CHOP alternating with R-dexamethasone, high-dose cytarabine, and cisplatin (DHAP) as a planned induction regimen would count as one regimen Patient does not have any documented history of central nervous system (CNS) involvement by mantle cell lymphoma; this includes no evidence of parenchymal brain, spinal cord, or cerebrospinal fluid involvement; radiculopathy symptoms from nerve root compression by lymphoma do not constitute CNS involvement Patient must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the original diagnostic biopsy available for submission to Adaptive Biotechnologies for ClonoSEQ ID molecular marker identification of unique clonal immunoglobulin deoxyribonucleic acid (DNA) sequence NOTE: Patients for whom the molecular marker is identified will have peripheral blood collected after completion of induction (patient?s disease status is PR or CR) and submitted to Adaptive Biotechnologies for minimal residual disease (MRD) assessment INCLUSION CRITERIA FOR TREATMENT ASSIGNMENT (STEP 1) Patients must have met eligibility criteria for the screening step Institution has received results from Adaptive Biotechnologies as defined by one of the following criteria: Patients are ?MRD Indeterminate?: ClonoSEQ ID molecular marker assessment did not identify any unique clonal immunoglobulin DNA sequence OR ClonoSEQ ID molecular marker assessment identified unique clonal immunoglobulin DNA sequence and MRD assessment is completed Patients must have completed induction therapy within 120 days prior to preregistration to step 0, AND no more than 300 days may have elapsed from the first dose of induction chemotherapy (cycle 1 [C1] day 1 [D1]) given, until the last day of induction chemotherapy administered; for those assigned to Arms A, C, or D, the date of transplant (?day 0?) must not be greater than 365 days after the first dose of induction chemotherapy (C1D1) given Patient must have received at least four (4) cycles of induction therapy Up to two regimens of chemotherapy are allowed as long as a continuous response was ongoing throughout therapy NOTE: For example, a patient who started treatment with rituximab/bendamustine and was then switched to R-CHOP (due to insufficient response or excessive toxicity) would be counted as having received 2 regimens; however, R-CHOP alternating with R-DHAP as a planned induction regimen would count as one regimen Patients must have achieved a radiologic complete or partial remission as defined by the Lugano criteria Patients must meet institutional eligibility requirements for stem cell transplant, including cardiac, renal, liver, and pulmonary requirements Patients have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Human immunodeficiency virus (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/mm^3 No history of acquired immune deficiency syndrome (AIDS)-defining conditions Patient must be disease-free >= 3 years of prior malignancies with the exception of adequately treated non-melanoma skin cancer, adequately treated in situ carcinoma, low grade prostate carcinoma (Gleason grade =< 6) managed with observation that has been stable for at least 6 months Women must not be pregnant or breast-feeding 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 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) Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Group I (auto-HCT, rituximab)<br>Patients receive standard of care preparative chemotherapy and undergo auto-HCT. Beginning 60-120 days after transplant, patients receive rituximab IV once every 8 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo HCT<br>* Other names: autologous stem cell transplantation;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Rituximab<br>* Given IV<br>|
| Experimental: Group II (rituximab alone)<br>Patients receive standard of care induction chemotherapy. Beginning 40-120 days after completion of chemotherapy, patients receive rituximab as in Group I. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Rituximab<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) in MCL patients in MRD-negative first remission who undergo auto-HCT followed by rituximab vs. maintenance rituximab alone | The Kaplan-Meier method will be used to estimate OS, including medians and confidence intervals. Comparison of OS between treatment arms will be conducted using a one-sided log-rank test stratified with mantle cell lymphoma International Prognostic Index (MIPI)-c score and induction regimen. | Time between randomization and death from any cause, assessed up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | The primary safety analysis will be based on the toxicity population, and the analysis will be performed by treatment received. | Up to 10 years | 
| MRD status in MCL patients who were MRD-positive prior to auto-HCT | Will be reported together with confidence intervals. | At 100 days | 
| OS in MRD-positive patients (or patients in PR) who undergo auto-HCT followed by rituximab | Will be estimated by the method of Kaplan and Meier. | Time between randomization and death from any cause, assessed up to 10 years | 
| PFS in MRD-positive patients (or patients in PR) who undergo auto-HCT followed by rituximab | Will be estimated by the method of Kaplan and Meier. | From randomization to the earliest of documented disease progression or death without progression, assessed up to 10 years | 
| Progression-free survival (PFS) in MCL patients in MRD-negative first remission who undergo auto-HCT followed by rituximab vs rituximab alone | The method of Kaplan and Meier will be used to estimate PFS, and stratified log-rank test will be used to compare PFS between two arms. | From randomization to the earliest of documented disease progression or death without progression, assessed up to 10 years | 
| Rate of complications in MCL patients undergoing maintenance rituximab |  | Up to 10 years |