Version Date: April 13, 2017 NCI Update Date: August 23, Addendum #1 Prior to Activation SWOG / SWOG

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1 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 STUDY CHAIR: SWOG CO-CHAIR: ALLIANCE CO-CHAIR: NCIC CTG CO-CHAIR: LABORATORY CO-CHAIR: RADIOLOGY CO-CHAIR: STUDY STATISTICIAN: LYMPHOMA COMMITTEE CHAIR: TRANSPLANT COMMITTEE CHAIR: BMT CTN CHAIR: Timothy S. Fenske, MD, MS Brian Till, MD Kristie Blum, MD Michael Crump, MD David Scott, MBChB PhD Lale Kostakoglu, MD Fangxin Hong, PhD Brad Kahl, MD Hillard Lazarus, MD Matt Lunning, MD Version Date: April 13, 2017 STUDY PARTICIPANTS ACTIVATION DATE ALLIANCE / Alliance for Clinical Trials in Oncology August 29, 2017 NRG / NRG Oncology Addendum #1 Prior to Activation SWOG / SWOG Update #1 Prior to Activation NCTN GROUP STUDY CHAMPIONS ALLIANCE: Kristie Blum, MD SWOG: Brian Till, MD Agents IND# NSC# Supply Rituximab Commercial 1

2 Table of Contents Schema Introduction Evolution of induction regimens and consolidation therapy for initial treatment of MCL Rituximab maintenance in MCL Prognostic importance of minimal residual disease (MRD) in MCL Recent data evaluating auto-hct when applied later in the MCL disease course Objectives Primary Endpoints Secondary Endpoints Selection of Patients Eligibility Criteria for Screening (STEP 0 - Preregistration) Eligibility Criteria for Treatment Assignment (STEP 1) Registration and Randomization Procedures Preregistration (Step 0) Registration to Treatment (Step 1) Treatment Plan Administration Schedule Autologous Hematopoietic Cell Transplantation (HCT) Adverse Event Reporting Requirements Dose Modifications Supportive Care Duration of Therapy Duration of Follow-up Measurement of Effect Schedule of Evaluations: Measurement of Treatment/Intervention Effect Definitions of analysis variables Study Parameters Drug Formulation and Procurement Rituximab Statistical Considerations Accrual Randomized Scheme Sample Size Calculation Statistical Analysis Plan Safety Monitoring Analysis for reporting of initial transplant effect Gender and Ethnicity

3 10. Biological Specimen Submissions Specimen Collection and Submission Schedule ECOG-ACRIN Sample Tracking System Use of Specimens in Research Sample Inventory Submission Guidelines Integral Biomarker Studies ClonoSEQ Assay Lab Data Transfer Guidelines Electronic Data Capture Patient Consent and Peer Judgment References Appendix I Pathology Submission Guidelines Appendix II Patient Thank You Letter Appendix III ECOG Performance Status Appendix IV Adaptive Biotechnologies Forms

4 STUDY CHAIR Timothy S. Fenske, MD, MS Medical College of Wisconsin 9200 W. Wisconsin Avenue Milwaukee, WI Tel: Fax: STUDY CHAIR LIAISON (SCL) Arielle E. Baim, BA Medical College of Wisconsin 9200 W. Wisconsin Avenue Milwaukee, WI Tel: Fax:

5 CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION To submit site registration documents: For patient enrollments: Submit study data CTSU Regulatory Office 1818 Market Street, Suite 1100 Philadelphia, PA Phone CTSU Fax (for submitting regulatory documents only) Please refer to the patient enrollment section of the protocol for instructions on using the Oncology Patient Enrollment Network (OPEN) which can be accessed at or Contact the CTSU Help Desk with any OPEN-related questions at Data collection for this study will be done exclusively through Medidata Rave. Please see the data submission section of the protocol for further instructions. The most current version of the study protocol and all supporting documents must be downloaded from the protocol-specific Web page of the CTSU Member Web site located at Access to the CTSU members website is managed through the Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username and password. For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the Coordinating Group. For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data submission) contact the CTSU Help Desk by phone or CTSU General Information Line , or ctsucontact@westat.com. All calls and correspondence will be triaged to the appropriate CTSU representative. The CTSU Web site is located at 5

6 Schema STEP 1 STEP 0 P R E - R E G I S T R A T I O N 1 Submit Tumor Tissue to Adaptive Biotechnologies for clonal marker testing Clonal Marker Present? Eligibility: Restaging indicates PR or CR status Yes 2 No informative marker: MRD indeterminate Post Induction Restaging: Submit blood to Adaptive Biotechnologies for MRD assessment 2 MRD neg CR MRD pos PR or CR MRD neg PR MRD indeterminate Stratify 4 MIPI-c score Intensive vs. nonintesive induction STEP 1 R E G I S T R A T I O N R A N D O M I Z A T I O N ARM C Auto-HCT +Rituximab 3 ARM D Auto-HCT +Rituximab 3 ARM A Auto-HCT +Rituximab 3 ARM B +Rituximab 3 Day 100 Submit blood for MRD 1. Patients may be pre-registered to STEP 0 and tumor tissue submitted for determination of the clonal marker during induction or within 60 days following completion of induction. Patients who are pre-registered after induction must have a PR or CR status. 2. Sites will be notified of the results of the clonal assessment. Patients for whom a marker exists and at restaging are found to have complete or partial response (CR or PR), blood must be submitted for determination of minimal residual disease (MRD) status. Blood must be collected at time of or after restaging and should not be submitted until after notification of clonal marker status. If blood was submitted at the same time the tumor tissue was submitted for clonal marker evaluation, only blood from patients with a clonal marker signature will be evaluated. 3. Rituximab maintenance: 375 mg/m2 IV q 8 weeks x 3 years 4. Patients will be stratified by induction regimen and MIPI-c score. For induction regimen there will be two categories: containing high-dose cytarabine versus lacking high-dose cytarabine. For MIPI-c score there will be four categories: low, low/intermediate, high/intermediate + high, and not determined. 6

7 1. Introduction 1.1 Evolution of induction regimens and consolidation therapy for initial treatment of MCL Mantle cell lymphoma (MCL) is a distinct subset of B-cell non-hodgkin lymphoma characterized by the (11;14) translocation resulting in a IGH/CCND1 fusion gene. It was first recognized as a distinct clinicopathological entity approximately 20 years ago, and initial therapy utilized the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone. (1) Following the introduction of the anti- CD20 monoclonal antibody rituximab into clinical practice, the German Low Grade Lymphoma Study Group conducted a randomized phase III trial comparing induction therapy with CHOP or CHOP plus rituximab (R-CHOP) for MCL. (2) This study revealed a superior time to treatment failure (TTF) following R-CHOP compared with CHOP; however, the median progression-free survival (PFS) with R-CHOP was only approximately 18 months. As a result, several different approaches have subsequently been evaluated as intensification of therapy as a strategy to improve on these outcomes. A regimen of cyclophosphamide, vincristine, doxorubicin, and dexamethasone, delivered in a hyperfractionated manner and alternating with high doses of cytarabine and methotrexate, (HyperCVAD/MTX-Ara-c) was developed. (3) This regimen, when combined with rituximab (R-HyperCVAD), appeared in two singlearm studies to improve outcomes compared with historical, with a median TTF/PFS of years, although a large percentage of patients were not able to complete the full scheduled course of therapy due to toxicity. (4,5) A parallel strategy of intensive therapy was developed in Europe that also involved augmentation of R-CHOP drugs but involved a shorter course of induction therapy followed by consolidative high-dose therapy and autologous stem cell transplantation. The Nordic MCL-1 trial involved 4 cycles of doseintensified CHOP without rituximab followed by autologous hematopoietic cell transplantation (auto-hct), and the failure-free survival was only about 2.5 years. (6) This study was followed by the Nordic MCL-2 trial, in which patients received 6 cycles of augmented R-maxi-CHOP alternating with high-dose cytarabine and rituximab followed by autologous hematopoietic cell transplantation (auto-hct). Although this was a single arm trial, the addition of rituximab and high-dose cytarabine improved outcomes compared with historical (MCL-1) patients, with a median PFS of more than 7 years. (7) Similar regimens incorporating rituximab and high-dose cytarabine have been developed by other groups. The Groupe d Etude des Lymphomes de l Adulte (GELA) published a study using 2 cycles of CHOP, followed by 1 cycle of R- CHOP and 3 cycles of R-DHAP (dexamethasone, high-dose cytarabine, and cisplatin) followed by auto-hct, which yielded a median event-free survival of nearly 7 years. (8) The CALGB trial treated patients with 2-3 cycles of augmented R-CHOP combined with methotrexate followed by intensification with high-dose cytarabine and etoposide combined with rituximab, followed by auto- HCT, and patients achieved a median PFS of more than 5 years. (9) The European MCL Network conducted a randomized phase III trial in which patients were randomized to receive 6 cycles of either R-CHOP or alternating R- 7

8 CHOP and R-DHAP, both followed by auto-hct. This study demonstrated a statistically significantly longer TTF (88 months vs. 46 months) in favor of the RCHOP/RDHAP arm. (10) This European MCL Network trial and the Nordic trial, both demonstrated a median PFS/TTF of over 7 years which are the best results reported to date in younger MCL patients. As a result, induction strategies which incorporate high dose cytarabine followed by auto-hct have become common world wide standards. Although treatment of younger patients with MCL has focused on intensive regimens and consolidation with auto-hct, recent data suggest that other novel regimens could be effective in this population. The bendamustine plus rituximab (BR) regimen yields high response rates in the non-transplant setting and led to superior PFS (35 vs. 22 months) compared with R-CHOP in a the subset of MCL patients of a randomized phase 3 trial by the German Study Group Indolent Lymphomas (StiL). (11) A recent randomized phase II SWOG trial (S1106) evaluated whether the BR regimen could be an effective induction platform for younger MCL patients prior to auto-hct in comparison with R-HyperCVAD. (12) The study was closed early due to a high rate of patients coming off study in the R-HyperCVAD arm, due primarily to hematologic toxicity and failure to collect an adequate HPC (stem cell) product. Although the limited number of evaluable patients treated in this trial prevented an adequately powered comparison, the PFS and OS curves were overlapping for the 2 groups, suggesting that BR may be an acceptable induction regimen, potentially sparing patients the toxicity of more intensive regimens. While most large prospective clinical trials for younger, fit patients with MCL in the last decade have incorporated auto-hct as post-induction consolidation, the data supporting the superiority of auto-hct over other strategies such as maintenance therapy are lacking. For example, in E1405, following induction therapy with the VcR-CVAD regimen, patients could be assigned to auto-hct or to maintenance rituximab. (13) The patient assigned to MR had comparable PFS and OS, despite having less favorable disease characteristics. There has been only one randomized trial testing auto-hct vs. non-transplant strategies, in which patients who responded to CHOP-like induction therapy were randomized to auto-hct or interferon-alpha (IFN-α) maintenance therapy. The patients who received auto-hct had a longer PFS (39 vs. 17 months) but no difference in OS compared with the IFN-α arm. (14) In recent years several novel induction regimens have been evaluated, or are under evaluation as first-line therapy of MCL. For example, lenalidomide and rituximab was evaluated in 38 patients (median age 65; age range 42-86) and was found to produce a 2 year PFS of 85% and 2 year survival of 97%. (15) An ongoing Intergroup study of first-line therapy of MCL in older patients is evaluating bendamustine + rituximab +/- bortezomib induction followed by rituximab +/- lenalidomide as maintenance therapy, without a plan for auto-hct (ClinicalTrials.gov NCT ). It is not known whether auto-hct confers a survival benefit following highly active induction regimens such as those containing rituximab and high-dose cytarabine, or bendamustine, or other, newer agents such as proteasome inhibitors, immune-modulatory drugs, or B cell receptor signaling pathway inhibitors. 8

9 1.2 Rituximab maintenance in MCL A prospective randomized trial of patients over age 60 (median age of 70), who were not felt to be candidates for high dose therapy and auto-hct, was conducted to evaluate the impact of rituximab maintenance following rituximabbased induction therapy. Among patients who responded to R-CHOP, rituximab maintenance improved overall survival compared to interferon alfa (4 year survival 87% vs. 63%, respectively). (16) In a retrospective study of 157 consecutive patients from the Fred Hutchinson Cancer Research Center, improved overall survival was seen at 5 years following auto-hct, even after multivariate adjustment for confounding factors. (18) In ECOG 1405, 75 MCL patients were treated with a novel regimen consisting of 6 cycles of rituximab, bortezomib, modified hyperfractionated cyclophosphamide, doxorubicin, and vincristine (VcR-CVAD). Transplant-eligible patients then had the option of consolidation with auto-hct versus 2 years of maintenance rituximab. 22 patients underwent auto-hct, while 44 patients received maintenance rituximab. Even after adjustment for MIPI prognostic factors and response to induction therapy (CR vs. PR), no significant differences were seen in PFS (76% vs. 79% at 2 years) or OS between the auto-hct and maintenance rituximab groups (100% vs. 93% at 2 years), respectively. (13) This study, while not randomized, suggests that the benefit (if any) of auto-hct in first remission for MCL may be modest, particularly when compared with a modern induction regimen followed by maintenance rituximab. The LYSA group (Lymphoma Study Association) recently presented the final results of the LyMa trial. In this study, newly diagnosed patients with MCL aged 65 and younger were treated with 4 courses of R-DHAP followed by auto-hct. Patients were then randomized to either observation or maintenance rituximab (375 mg/m2 every 2 months for 3 years). Of 290 enrolled patients, 240 underwent randomization in a 1:1 fashion. At a median follow up of 50 months from randomization, a significant benefit was observed in favor or maintenance rituximab in terms of 4 year PFS (82.2% vs. 64.4%) and 4 year OS (88.7% vs. 81.4%). This prospective validation of the previous retrospective studies establishes maintenance rituximab as a standard following auto-hct. 1.3 Prognostic importance of minimal residual disease (MRD) in MCL MCL patients nearly universally relapse despite achieving a clinical CR, suggesting that a small number of chemotherapy-resistant lymphoma cells (below the limit of detection by conventional imaging and laboratory/ histopathologic analysis) remain in the marrow or lymph nodes after treatment. In recent years, it has become feasible to quantify minimal residual disease (MRD) using highly sensitive assays based on polymerase chain reaction, flow cytometry or deep sequencing techniques. Using such technology, it is now feasible to use MRD to predict clinical relapse and also to rationally risk-stratify patients to receive additional therapy. The first large study to show a correlation between MRD status and outcome was reported by Pott et al in a post-hoc analysis of a subset of patients from the European MCL Younger and MCL Elderly studies. (19) In this study, real-time quantitative PCR (RQ-PCR) for clonal IgH or Bcl-1/IgH was performed on 259 patients with diagnostic material available. A suitable molecular marker for RQ- 9

10 PCR could be detected from diagnostic specimens in approximately 90% of patients. In the MCL Younger study, the rates of MRD-negative status after induction (prior to auto-hct) for patients who received R-CHOP were 68% in the peripheral blood and 37% in the bone marrow. The MRD-negative rates after induction for patients who received R-CHOP/R-DHAP were 83% in the peripheral blood and 70% in the bone marrow. The presence of MRD was associated with an inferior 2-year remission duration of both young and elderly patients. A longer term follow up of patients from these trials, excluding patients who did not have a CR or PR at 6 months after auto-hct, was recently reported and in a landmark analysis, patients who were MRD-negative at one year after completing therapy had a median PFS of 6.8 years, compared with 3 years for patients who developed detectable MRD within 1 year. (19) The prognostic importance of MRD status after therapy was also evaluated by the Nordic group in a population of younger patients receiving intensive induction therapy and auto-hct. (20) MRD was assessed using standard nested PCR in 160 patients to detect either Bcl-1/IgH translocation or a clonal IgH band. Following auto-hct in the MCL-2 study, 92% of patients were in a molecular CR. Patients who developed PCR-detectable disease within the first year after auto- HCT had a median PFS of 1.5 years. Those who had MRD relapse after 1 year had a median PFS of 5 years, and those who were continuously MRD-negative had a median PFS that was not reached. A subsequent study from the Nordic group (MCL-3) differed from MCL-2 in that responding patients not in CR after induction received ibritumomab one week prior to auto-hct. Following induction therapy, 53% of patients had achieved MRD-negativity, which improved to 83% following auto-hct. The 5-year PFS of patients who were MRD-negative post-auto-hct was approximately 80%, compared with only approximately 30% for patients who still had measurable disease by PCR. (21) Recent data from the French LyMa trial confirmed the importance of pre-auto- HCT MRD status. In this study, patients received 4 cycles of R-DHAP induction followed by auto-hct, and were then randomized to 3 years of rituximab maintenance or observation. (22) Following induction, the rate of MRD-negativity was 66% in the marrow and 80% in the peripheral blood. Patients who achieved an MRD-negative status after induction in either the marrow or blood had a longer PFS, whether they received maintenance rituximab or observation postauto-hct. In the CALGB study, which added post-auto-hct bortezomib in two different extended dosing schedules to the CALGB induction backbone described above, the 5-year PFS was 93% for patients who were MRD-negative after induction and 51% for patients who were MRD-positive. (23) A recent study from the Seattle group reported on the prognostic impact of pre-transplant MRD status. In this study, patients who were MRD-negative prior to auto-hct had a 5 year OS of 82% and a 5 year PFS of 75%, versus approximately 50% and 30%, respectively, for those that were MRD-positive. (24) In a subset analysis of patients in the S1106 trial who were treated with BR prior to auto-hct, 8 of 9 evaluable patients were found to have achieved an MRDnegative CR following induction therapy. (12) 10

11 Thus, a variety of induction regimens are capable of inducing MRD-negative remission rates of approximately 70% in the marrow in 80% in the peripheral blood. Given the excellent outcomes of patients who achieve a molecular complete remission, including in patients not treated with auto-hct, a question that naturally follows is whether auto-hct is beneficial or necessary for patients who achieve an MRD-negative first complete remission with induction therapy. 1.4 Recent data evaluating auto-hct when applied later in the MCL disease course A Center for International Blood and Marrow Research (CIBMTR) study evaluated outcomes in chemo-sensitive MCL patients undergoing auto-hct or allo-hct early vs. late in the disease course. For patients who underwent auto- HCT late in the disease course (after a relapse or after 3 or more regimens), the median PFS was between 2-3 years, with median survival from the time of transplantation of approximately 4 years. (25) Similar results were reported in a retrospective study from the MD Anderson group, with median PFS between 2-3 years and median survival between 4-5 years for relapsed / refractory MCL patients undergoing auto-hct. (26) The Fred Hutchinson Cancer Research group performed a retrospective analysis of patients with relapsed or refractory MCL who underwent auto-hct. Certain factors were independently associated with PFS such as MIPI score at transplant, B symptoms at diagnosis, and remission quotient (calculated by dividing the time in months from diagnosis to auto-hct, by the number of regimens received prior to auto-hct). Using these factors it was possible to construct a prognostic score which identified a group of patients with a 58% chance of being progression-free at 5 years. (27) These studies indicate that MCL patients may derive considerable benefit from auto-hct later in the disease course, which is an important consideration for the proposed study which aims to randomly assign patients to consolidation with auto-hct versus maintenance rituximab. These data indicate that, for the patients assigned to maintenance rituximab, auto-hct may be an effective option later in the disease course. Since auto-hct in first remission has not been shown to improve overall survival in a randomized study, and since the outcomes of patients who achieve MRDnegative status is excellent without auto-hct consolidation, we consider rituximab maintenance only to be an acceptable standard of care for these patients. We plan to test whether the addition of auto-hct as part of frontline therapy significantly improves 5-year overall survival in such patients. 11

12 2. Objectives 2.1 Primary Endpoints To compare overall survival in MCL patients in MRD-negative first complete remission (CR) who undergo auto-hct followed by maintenance rituximab vs. maintenance rituximab alone (without auto- HCT). 2.2 Secondary Endpoints To compare progression-free survival in MCL patients in MRDnegative CR who undergo auto-hct followed by maintenance rituximab vs. maintenance rituximab alone To define the overall survival and progression-free survival at 2 and 5 years of chemosensitive but MRD-positive CR patients who undergo auto-hct followed by 3 years of maintenance rituximab To define the overall survival and progression-free survival at 2 and 5 years of chemosensitive but MRD-positive PR patients who undergo auto-hct followed by 3 years of maintenance rituximab To define the overall survival and progression-free survival at 2 and 5 years of MRD-negative PR patients who undergo auto-hct followed by 3 years of maintenance rituximab To define the overall survival and progression-free survival at 2 and 5 years of MRD-indeterminate patients who undergo auto-hct followed by 3 years of maintenance rituximab To describe the rate of complications (serious infection, hospitalization, need for intravenous immune globulin) in MCL patients undergoing maintenance rituximab following auto-hct To determine the prognostic impact of MRD status at day 100, in MCL patients who were MRD-positive (including MRD-positive CR and MRD-positive PR) prior to auto-hct. 12

13 3. Selection of Patients This study requires the submission of the original diagnostic tumor biopsy to Adaptive Biotechnologies for ClonoSEQ ID molecular marker testing. Tumor tissue requirements for preregistration are outlined in Section 10. Tumor tissue is to be submitted from patients meeting preregistration criteria and submitted during induction or within two (2) months following completion of induction. Patients who are preregistered after completion of induction must have partial response (PR) or complete response (CR) status. Institutions will be notified of the results of the clonal marker assessment. Peripheral blood must be submitted to Adaptive Biotechnologies from patients for whom the clonal marker exists, and at restaging are in CR or PR, for determination of minimal residual disease (MRD) assessment for treatment assignment. Peripheral blood requirements are outlined in Section 10. Peripheral blood is to be submitted from patients meeting preregistration criteria and must be collected at the time of or after restaging and should not be submitted until after notification of clonal marker status. If peripheral blood was submitted at the same time as the tumor tissue for clonal marker testing, only peripheral blood from patients with the clonal marker signature will be evaluated. Institutions will be notified of the results of the MRD assessment. Each of the criteria in the checklist that follows must be met in order for a patient to be considered eligible for this study. Use the checklist to confirm a patient s eligibility. For each patient, this checklist must be photocopied, completed and maintained in the patient s chart. NOTE: Before submitting specimens, physicians must first register with Adaptive Biotechnologies. Please refer to Section 10 for instructions. In calculating days of tests and measurements, the day a test or measurement is done is considered Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later would be considered Day 28. ECOG-ACRIN Patient No. Patient s Initials (L, F, M) Physician Signature and Date NOTE: CTEP Policy does not allow for the issuance of waivers to any protocol specified criteria ( Therefore, all eligibility criteria listed in Section 3 must be met, without exception. The registration of individuals who do not meet all criteria listed in Section 3 can result in the participant being censored from the analysis of the study, and the citation of a major protocol violation during an audit. All questions regarding clarification of eligibility criteria must be directed to the Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). NOTE: Institutions may use the eligibility checklist as source documentation if it has been reviewed, signed, and dated prior to registration/randomization by the treating physician. 13

14 3.1 Eligibility Criteria for Screening (STEP 0 - Preregistration) Age 18 and 65 years Patients must have histologically confirmed mantle cell lymphoma, with documented CD19 or CD20 expression and cyclin D1 (BCL1) by immunohistochemical stains and/or t(11;14) by cytogenetics or FISH. The diagnosis must be confirmed by formal hematopathology review at the enrolling center, including assessment of Ki-67 proliferation index ( 30% versus > 30% versus indeterminate 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 For patients who have completed induction therapy, restaging evaluation must show status of partial (PR) or complete response (CR). Post-induction patients 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. Overall, a partial response needs to have been achieved (using studies at the time of diagnosis as the baseline). 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 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 (as defined in Section 10.1) available for submission to Adaptive Biotechnologies for ClonoSEQ ID molecular marker identification of unique clonal immunoglobulin DNA sequence. Adaptive Biotechnologies will forward results within fourteen (14) days of receipt of the tumor tissue specimen to the submitting institution and to the ECOG-ACRIN Operations Office. 14

15 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. Adaptive Biotechnologies will forward results within seven (7) days of receipt of the peripheral blood specimen to the submitting institution and to the ECOG-ACRIN Operations Office. 3.2 Eligibility Criteria for Treatment Assignment (STEP 1) Patients must have met eligibility criteria for the screening step (3.1) 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 registration to Step 1, AND no more than 300 days may have elapsed from the first dose of induction chemotherapy (C1D1) 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 (see Section 6.2.2). (28) Patients must meet institutional eligibility requirements for stem cell transplant, including cardiac, renal, liver, and pulmonary requirements. 15

16 3.2.6 Patients have an ECOG performance status of 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 that has minimal overlapping toxicity and pharmacokinetic interactions with protocol therapy No history of HIV-related opportunistic disease or AIDSdefining conditions within past 12 months other than historic CD4+ T-cell counts below 200 cells/mm Expected long-term survival if lymphoma were not present 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 due to the potential for congenital abnormalities and of harm to nursing infants due to the treatment regimens used. 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). Female? (Yes or No) Date of blood test or urine study: 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 and for 12 months post rituximab treatment. Physician Signature Date OPTIONAL: This signature line is provided for use by institutions wishing to use the eligibility checklist as source documentation. 16

17 4. Registration and Randomization Procedures CTEP Investigator Registration Procedures Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all investigators participating in any NCI-sponsored clinical trial to register and to renew their registration annually. Registration requires the submission of: a completed Statement of Investigator Form (FDA Form 1572) with an original signature a current Curriculum Vitae (CV) a completed and signed Supplemental Investigator Data Form (IDF) a completed Financial Disclosure Form (FDF) with an original signature Fillable PDF forms and additional information can be found on the CTEP website at < For questions, please contact the CTEP Investigator Registration Help Desk by at <pmbregpend@ctep.nci.nih.gov>. CTEP Associate Registration Procedures / CTEP-IAM Account The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) application is a web-based application intended for use by both Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored clinical trials). Associates will use the CTEP-IAM application to register (both initial registration and annual re-registration) with CTEP and to obtain a user account. Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP Investigator Registration Procedures above for information on registering with CTEP as an Investigator, which must be completed before a CTEP-IAM account can be requested.) An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications, including the CTSU members website. Additional information can be found on the CTEP website at < For questions, please contact the CTEP Associate Registration Help Desk by at <ctepreghelp@ctep.nci.nih.gov>. CTSU Registration Procedures This study is supported by the NCI Cancer Trials Support Unit (CTSU). IRB Approval: Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can be approved to enroll patients. Assignment of site registration status in the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory criteria including but 17

18 not limited to: an active Federal Wide Assurance (FWA) number, an active roster affiliation with the Lead Network or a participating organization, a valid IRB approval, and compliance with all protocol specific requirements. Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally. The CIRB s approval of the SSW is then communicated to the CTSU Regulatory Office. In order for the SSW approval to be processed, the Signatory Institution must inform the CTSU which CIRB-approved institutions aligned with the Signatory Institution are participating in the study. Downloading Site Registration Documents: Site registration forms may be downloaded from the protocol page located on the CTSU members website. Go to and log in to the members area using your CTEP-IAM username and password Click on the Protocols tab in the upper left of your screen Click on the (state organization type e.g. P2C, CITN, NCTN Groupname) link to expand, then select trial protocol #[NCI Protocol #] Click on the Site Registration Documents link Requirements For Site Registration: CTSU IRB Certification (for sites not participating via the NCI CIRB) CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI CIRB) If applicable, add to this bulleted list any other protocol-specific documents or requirements (e.g., site or investigator specialized credentialing; evidence of training; study-specific regulatory forms) needed for site registration. Include any processing instructions, or reference the location in the protocol or appendices where further instructions can be found. Submitting Regulatory Documents Submit completed forms along with a copy of your IRB Approval and Model Informed Consent to the CTSU Regulatory Office, where they will be entered and tracked in the CTSU RSS. CTSU Regulatory Office 1818 Market Street, Suite 1100 Philadelphia, PA Phone: FAX: (215) CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) Required Protocol Specific Regulatory Documents 1. CTSU Regulatory Transmittal Form. 2. Copy of IRB Informed Consent Document. 18

19 NOTE: Any deletion or substantive modification of information concerning risks or alternative procedures contained in the sample informed consent document must be justified in writing by the investigator and approved by the IRB. 3. A. CTSU IRB Certification Form. OR B. Signed HHS OMB No (replaces Form 310). OR C. IRB Approval Letter NOTE: The above submissions must include the following details: Indicate all sites approved for the protocol under an assurance number. OHRP assurance number of reviewing IRB Full protocol title and number Version Date Type of review (full board vs. expedited) Date of review. Signature of IRB official Checking Your Site s Registration Status: Check the status of your site s registration packets by querying the RSS site registration status page of the members section of the CTSU website. NOTE: Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office. Go to and log in to the members area using your CTEP-IAM username and password Click on the Regulatory tab at the top of your screen Click on the Site Registration tab Enter your 5-character CTEP Institution Code and click on Go Patient Enrollment Patients must not start protocol treatment prior to registration to Step 1. Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access OPEN, the site user must have an active CTEP-IAM account (check at < >) and a 'Registrar' role on either the LPO or participating organization roster. All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise System for regulatory and roster data {add if a Rave study: and, upon enrollment, initializes the patient in the Rave database.}. OPEN can be accessed at or from the OPEN tab on the CTSU members side of the website at Prior to accessing OPEN, site staff should verify the following: All eligibility criteria have been met within the protocol stated timeframes. 19

20 All patients have signed an appropriate consent form and HIPAA authorization form (if applicable). NOTE: The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records. Further instructional information is provided on the OPEN tab of the CTSU members side of the CTSU website at or at For any additional questions contact the CTSU Help Desk at or ctsucontact@westat.com. 4.1 Preregistration (Step 0) At the time of preregistration, the following information will be collected: Protocol Number Investigator Identification Institution and affiliate name Investigator s name Patient Identification Patient s initials (first and last) Patient s Hospital ID and/or Social Security number Patient demographics Gender Birth date (mm/yyyy) Race Ethnicity Nine-digit ZIP code Method of payment Country of residence Eligibility Verification Patients must meet all of the eligibility requirements listed in Section Additional Requirements Patients must provide a signed and dated, written informed consent form. NOTE: Copies of the consent are not collected by the ECOG-ACRIN Operations Office Boston Biological specimens must be submitted to Adaptive Biotechnologies following preregistration as indicated in Section 10: Archived FFPE diagnostic tumor tissue must be submitted following preregistration for determination of the ClonoSEQ ID molecular marker. 20

21 Peripheral blood must be submitted for MRD assessments from patients for whom (a) ClonoSEQ ID molecular marker is identified, (b) induction therapy is complete, and (c) restaging indicates partial or complete response to therapy. NOTE: Before submitting specimens, physicians must first register with Adaptive Biotechnologies. Please refer to Section 10 for instructions Data collection for this study will be done exclusively through the Medidata Rave clinical data management system. Access to the trial in Rave is granted through the imedidata application to all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave via imedidata, the site user must have an active CTEP-IAM account (check at < >) and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on either the LPO or participating organization roster at the enrolling site. 4.2 Registration to Treatment (Step 1) Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the appropriate roster will be sent a study invitation from imedidata. To accept the invitation, site users must log into the Select Login ( using their CTEP-IAM user name and password, and click on the accept link in the upper right-corner of the imedidata page. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (elearnings), and can be accessed by clicking on the link in the upper right pane of the imedidata screen. Users that have not previously activated their imedidata/rave account at the time of initial site registration approval for the study in RSS will also receive a separate invitation from imedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on imedidata/rave is available on the CTSU members website under the Rave tab at or by contacting the CTSU Help Desk at or by at ctsucontact@westat.com. Patients must not start protocol treatment prior to registration to Step 1. 21

22 At the time of registration, the following information will be collected: Protocol Number Investigator Identification Institution and affiliate name Investigator s name Patient Identification Patient s initials (first and last) Patient s Hospital ID and/or Social Security number Patient demographics Gender Birth date (mm/yyyy) Race Ethnicity Nine-digit ZIP code Method of payment Country of residence Classification Factors ClonoSEQ ID molecular marker identified: Dominant Sequences Identified [Yes] v. Polyclonality [No] v. Indeterminate [No] MRD Detected Status: MRD- [No] v. MRD+ [Yes] v. MRD Indeterminate PR v. CR Stratification Factors (Arms A and B only) Patients will be stratified by induction regimen and MIPI-c score. For induction regimen there will be two categories: containing high-dose cytarabine versus lacking high-dose cytarabine. For MIPI-c score there will be four categories: low, low/intermediate, high/intermediate + high, and not determined Eligibility Verification Patients must meet all of the eligibility requirements listed in Section Additional Requirements Peripheral blood is required to be submitted for MRD assessments for patients on Arm C only as indicated in Section 10. Adaptive Biotechnologies will forward MRD results to the submitting institution to inform them of the patient s disease status. 22

23 Data collection for this study will be done exclusively through the Medidata Rave clinical data management system. Access to the trial in Rave is granted through the imedidata application to all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave via imedidata, the site user must have an active CTEP-IAM account (check at < >) and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on either the LPO or participating organization roster at the enrolling site. Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the appropriate roster will be sent a study invitation from imedidata. To accept the invitation, site users must log into the Select Login ( using their CTEP-IAM user name and password, and click on the accept link in the upper right-corner of the imedidata page. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (elearnings), and can be accessed by clicking on the link in the upper right pane of the imedidata screen. Users that have not previously activated their imedidata/rave account at the time of initial site registration approval for the study in RSS will also receive a separate invitation from imedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on imedidata/rave is available on the CTSU members website under the Rave tab at or by contacting the CTSU Help Desk at or by at ctsucontact@westat.com Instructions for Patients who Do Not Start Assigned Protocol Treatment If a patient does not receive any assigned protocol treatment, baseline and follow-up data will still be collected and must be submitted through Medidata Rave according to the schedule in the Forms Completion Guidelines. 23

24 5. Treatment Plan 5.1 Administration Schedule Remission Induction Therapy is not considered an aspect of protocol therapy, but the therapy may impact the patient s eligibility to register to treatment: Any standard-of-care remission induction regimen (up to two distinct regimens) is acceptable and may be given under the direction of the patient s community oncologist, or at the enrolling center. Investigational remission induction regimens are also acceptable. Up to two distinct induction chemotherapy regimens are allowed as long as a continuous response was ongoing throughout therapy, i.e. patients with evidence of disease progression or relapse during induction are not eligible. 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. NOTE: If rituximab is administered at a site other than the enrolling center, the enrolling center will be responsible for collecting the information regarding doses given and, in cases where doses were reduced, delayed, or omitted. Patient treatment assignment per induction response status, clonal molecular marker identified, and MRD status is as follows: Clonal molecular marker identified + blood MRD negative + Complete response per Lugano criteria (Section 6.2.2): Randomized to Arms A or B Clonal molecular marker identified + blood MRD positive + Complete or Partial response per Lugano criteria (Section 6.2.2): Arm C No clonal molecular marker identified OR Clonal molecular marker + blood MRD negative + Partial response per Lugano criteria (Section 6.2.2): Arm D Arm A Arm B Autologous Hematopoietic cell transplantation (HCT): See Section 5.2 Rituximab maintenance: 375 mg/m 2 IV every 8 weeks (± 1 week) x 18 doses (approximately 3 years). Rituximab should begin days after transplant. Rituximab maintenance: 375 mg/m 2 IV every 8 weeks (± 1 week) x 18 doses (approximately 3 years). Rituximab should begin days after completion of induction therapy. 24

25 5.1.3 Arm C Autologous Hematopoietic cell transplantation (HCT): See Section 5.2 NOTE: Arm D Blood must be submitted to Adaptive Biotechnologies at Day 100 (+/- 5 days) post-transplant for MRD assessments. Rituximab maintenance: 375 mg/m 2 IV every 8 weeks (± 1 week) x 18 doses (approximately 3 years). Rituximab should begin days after transplant. Autologous Hematopoietic cell transplantation (HCT): See Section 5.2 Rituximab maintenance: 375 mg/m 2 IV every 8 weeks (± 1 week) x 18 doses (approximately 3 years). Rituximab should begin days after transplant. 5.2 Autologous Hematopoietic Cell Transplantation (HCT) All aspects of the autologous hematopoietic cell transplant (HCT) procedure, including stem cell mobilization, stem cell collection, highdose chemotherapy, HCT infusion, and post-transplant supportive care will be performed as per institutional guidelines. Several preparative regimens will be allowed (see Section 5.2.3). Management of post-transplant complications will also be as per institutional standard of care Hematopoietic Progenitor Cell (HPC) Mobilization and Collection. This will be performed as per the standard-of-care at the transplant (enrolling) center. Growth factor, plerixafor, or chemotherapy-based mobilization is acceptable Preparative Regimen and Autologous Hematopoietic Cell Transplantation (Auto-HCT). Any of the following preparative regimens will be acceptable, and may be given as per the standardof-care at the transplant (enrolling) institution: BEAM (carmustine, etoposide, cytarabine, melphalan); BEAC (carmustine, etoposide, cytarabine, cyclophosphamide); CBV (cyclophosphamide, carmustine, etoposide); BVAC (carmustine, etoposide, cytarabine, cyclophosphamide, and BEP (carmustine, etoposide, cisplatin). Investigational preparative regimens are not allowed. If less than 1.5 million CD34 + cells per kg of patient body weight are successfully collected (after pooling up to 3 mobilization attempts), the patient will be considered to have discontinued protocol therapy Autologous Hematopoietic Cell Transplantation (Auto-HCT) and posttransplant supportive care Autologous HCT and post-transplant supportive care will be performed as per the standard of care at the transplant (enrolling) institution. NOTE: For patients who do not undergo HCT, data is to be submitted per and are treated per physician 25

26 5.3 Adverse Event Reporting Requirements Purpose discretion with the recommendation that they receive maintenance Rituximab. Adverse event (AE) data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of the patients enrolled, as well as those who will enroll in future studies using similar agents. For this study, the SAE reporting period will commence with the initiation of Step 1 (Arms A, B, C, and D). Please note that for patients undergoing autotransplant, expected transplant-related AEs are not to be reported. Routine reporting: Adverse events are reported in a routine manner at scheduled times during a trial using Medidata Rave. Expedited reporting: In addition to routine reporting, certain adverse events must be reported in an expedited manner for timelier monitoring of patient safety and care. The following sections provide information and instructions regarding expedited adverse event reporting Terminology Adverse Event (AE): Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Attribution: An assessment of the relationship between the adverse event and the protocol treatment, using the following categories. ATTRIBUTION Unrelated Unlikely Possible Probable Definite DESCRIPTION The AE is clearly NOT related to treatment. The AE is doubtfully related to treatment. The AE may be related to treatment. The AE is likely related to treatment. The AE is clearly related to treatment. CTCAE: The NCI Common Terminology Criteria for Adverse Events provides a descriptive terminology that is to be utilized for AE reporting. A grade (severity) is provided for each AE term. Expectedness: Expected events are those that have been previously identified as resulting from administration of the agent. An adverse event is considered unexpected, for expedited 26

27 reporting purposes, when either the type of event or the severity of the event is NOT listed in the protocol or drug package insert Reporting Procedure This study requires that expedited adverse event reporting use CTEP s Adverse Event Reporting System (CTEP-AERS). The CTEP s guidelines for CTEP-AERS can be found at A CTEP-AERS report must be submitted electronically to ECOG-ACRIN and the appropriate regulatory agencies via the CTEP-AERS Webbased application located at In the rare event when Internet connectivity is disrupted a 24-hour notification is to be made by telephone to the AE Team at ECOG-ACRIN ( ) the FDA (1-800-FDA-1088) An electronic report MUST be submitted immediately upon reestablishment of internet connection. Supporting and follow up data: Any supporting or follow up documentation must be uploaded to the Supplemental Data Folder in Medidata Rave within hours. In addition, supporting or follow up documentation must be faxed to the and FDA ( ) in the same timeframe. CTEP Technical Help Desk: For any technical questions or system problems regarding the use of the CTEP-AERS application, please contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov or by phone at Determination of Reporting Requirements Many factors determine the reporting requirements of each individual protocol, and which events are reportable in an expeditious manner, including: the phase (0, 1, 2, or 3) of the trial whether the patient has received an investigational or commercial agent or both the Common Terminology Criteria for Adverse Events (CTCAE) grade the relationship to the study treatment (attribution) the expectedness of the adverse event Using these factors, the instructions and tables in the following sections have been customized for protocol and outline the specific expedited adverse event reporting requirements for study. 27

28 5.3.5 Steps to determine if an event is to be reported in an expedited manner Identify the type and grade of the event using CTCAE v4.0. Determine if the event is related to the protocol treatment (attribution). Determine the expectedness of the event. An unexpected event is defined as one where the type of severity of the event is not listed in the investigator s brochure, package insert or protocol. With this information, review the chart in Section to determine if event is reportable via CTEP-AERS. Is the event reportable? Yes No Refer to footnote b in Section to determine if the event meets the protocol specific reporting requirements for this study. If so, report the event via CTEP-AERS. Report the event via CTEP-AERS. 28

29 5.3.6 Expedited Reporting Requirements for Arm A, B, C, and D on protocol Commercial Agents: Rituximab Expedited reporting requirements for adverse events experienced by patients on arms with commercial agents only Arms A, D, C, and D. Attribution Unrelated or Unlikely Possible, Probable, Definite Grade 4 Grade 5 a Unexpected Expected Unexpected Expected 7 calendar days 7 calendar days 7 calendar days 7 calendar days 7 calendar days ECOG-ACRIN and Protocol-Specific Requirements See footnote (b) for special requirements. 7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the event. a b This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE: Any death that occurs > 30 days after the last dose of treatment and is attributed possibly, probably, or definitely to the treatment must be reported within 7 calendar days of learning of the event. Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited reporting for this trial: Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth defects must be reported via CTEP-AERS within 7 calendar days of learning of the event. For instructions on how to specifically report these events via CTEP-AERS, please contact the AEMD Help Desk at aemd@tech-res.com or This will need to be discussed on a case-by-case basis Other recipients of adverse event reports and supplemental data Adverse events determined to be reportable via CTEP-AERS must also be reported by the institution, according to the local policy and procedures, to the Institutional Review Board responsible for oversight of the patient Second Primary Cancer Reporting Requirements All cases of second primary cancers, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), that occur following treatment on NCI-sponsored trials must be reported to ECOG-ACRIN using Medidata Rave A second malignancy is a cancer that is UNRELATED to any prior anti-cancer treatment (including the treatment on this protocol). Second malignancies require ONLY routine reporting as follows: 1. Complete a Second Primary Form in Medidata Rave within 14 days. 2. Upload a copy of the pathology report to ECOG-ACRIN via Medidata Rave confirming the diagnosis. 29

30 3. If the patient has been diagnosed with AML/MDS, upload a copy of the cytogenetics report (if available) to ECOG-ACRIN via Medidata Rave. A secondary malignancy is a cancer CAUSED BY any prior anticancer treatment (including the treatment on this protocol). Secondary malignancies require both routine and expedited reporting as follows: 1. Complete a Second Primary Form in Medidata Rave within 14 days. 2. Report the diagnosis via CTEP-AERS at Report under a.) leukemia secondary to oncology chemotherapy, b.) myelodysplastic syndrome, or c.) treatment related secondary malignancy 3. Upload a copy of the pathology report to ECOG-ACRIN via Medidata Rave and submit a copy to NCI/CTEP confirming the diagnosis. 4. If the patient has been diagnosed with AML/MDS, upload a copy of the cytogenetics report (if available) to ECOG-ACRIN via Medidata Rave and submit a copy to NCI/CTEP. NOTE: NOTE: NOTE: 5.4 Dose Modifications The ECOG-ACRIN Second Primary Form and the CTEP- AERS report should not be used to report recurrence or development of metastatic disease. If a patient has been enrolled in more than one NCIsponsored study, the ECOG-ACRIN Second Primary Form must be submitted for the most recent trial. ECOG-ACRIN must be provided with a copy of the form and the associated pathology report and cytogenetics report (if available) even if ECOG-ACRIN was not the patient's most recent trial. Once data regarding survival and remission status are no longer required by the protocol, no follow-up data should be submitted via CTEP-AERS or by the ECOG-ACRIN Second Primary Form. Remission induction therapy. All treatment (chemotherapy, biological therapies, immunotherapies) given as induction therapy will be given as nonprotocol treatment. As such, dosing will be determined off protocol and toxicities from that phase of therapy will not be captured as part of this protocol. However, the induction regimens used (up to 2), total number of cycles, and dates of administration must be provided. HPC mobilization therapy. All treatment (growth factors, plerixafor, chemotherapy, immunotherapy) given for the purposes of HPC mobilization will be given as non-protocol treatment. As such, dosing will be determined off protocol and toxicities from that phase of therapy will not be captured as part of this protocol. However, the mobilization regimens, number of mobilization attempts, and total CD34 + stem cell yield will be collected on case report forms. 30

31 Preparative regimen, autologous HPC infusion, and post-transplant supportive care. High dose therapy, autologous hematopoietic cell transplantation and the immediate post-transplant supportive care will be delivered as per standard of care at the transplant center. As such, dosing will be determined off protocol and toxicities from that phase of therapy will not be captured as part of this protocol. Post-transplant maintenance rituximab. Post-transplant maintenance rituximab will be delivered as per standard of care, either through the patient s primary hematologist/oncologist, or at the enrolling center. NOTE: There are no prescribed dose modifications for rituximab. If, however, a patient has grade 3 or 4 neutropenia in the absence of other grade 3 or 4 cytopenias, consider the possibility of late onset neutropenia associated with rituximab. Manage per institutional standards. Often, myeloid growth factor is administered and per investigator s choice rituximab may be administered on schedule or delayed by 1 week intervals with repeat CBC to ensure resolution of neutropenia, and then start the new cycle. If not recovered by 4 weeks despite growth factor, it recommended that rituximab be discontinued. All toxicity grades below are described using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website ( 5.5 Supportive Care All supportive measures, including administration of growth factors and IV immune globulin replacement, will be administered according to standard of care and institutional guidelines Hypersensitivity and Infusion Reactions Available at the bedside prior to rituximab administration will be epinephrine for subcutaneous injection, diphenhydramine hydrochloride for IV injection, and resuscitation equipment for the emergency management of anaphylactoid reactions. Rituximab should be administered intravenously through a dedicated line at an initial rate of 50 mg/hr. If hypersensitivity or infusion-related events do not occur, escalate the infusion rate in 50 mg/hr increments every 30 minutes, to a maximum of 300 mg/hr. If hypersensitivity or infusion-related events develop, the infusion should be temporarily slowed or interrupted. The patient should be treated according to the appropriate standard of care. The infusion can be continued at onehalf the previous rate when symptoms abate. Subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, and increased at 30-minute intervals by 100 mg/hr increments to a maximum of 400 mg/hr. 31

32 Rituximab Infusion Rate Adjustments Infusion Rate 5.6 Duration of Therapy Fever Rigors Mucosal Congestion/ Edema (or) (or) Hypotension Decrease ½ > 38.0ºC Mild Mild Mild Interrupt > 39.0ºC Moderate Moderate Mild to Moderate During the rituximab infusion, the patient's vital signs (blood pressure, pulse, respiration, temperature) should be monitored at least every 15 minutes x 4 and then hourly until the infusion is discontinued. Following the antibody infusion, the intravenous line should be maintained for medications as needed. If there are no complications after one hour of observation, the intravenous line may be discontinued. Patients will receive protocol therapy unless: Extraordinary Medical Circumstances: If at any time the constraints of this protocol are detrimental to the patient's health, protocol treatment should be discontinued. In this event submit forms according to the instructions in the Forms Packet. Patient withdraws consent. Patient experiences unacceptable toxicity. Patient experiences progression of lymphoma prior to completion of protocol therapy (for example, during the maintenance rituximab). Non-protocol therapies are administered. Patient becomes pregnant. 5.7 Duration of Follow-up For this protocol, all patients, including those who discontinue protocol therapy early, will be followed for response until progression, even if non-protocol therapy is initiated, and for survival for 10 years from the date of randomization (for Arm A and Arm B patients) or 10 years from Step 1 registration (for Arm C and D patients). All patients must also be followed through completion of all protocol therapy and all patients must be followed for survival for at least 10 years even if progression occurs prior to the 10-year point. 32

33 6. Measurement of Effect Response and progression will be evaluated in this study using the revised international working group guidelines (Lugano classification) (28). For patients who achieve a CR with induction therapy, no baseline lesions are required to be reported. If patients continue to be in CR, no lesion measurements are needed. Once a patient (who entered transplant in CR) relapses, measurements of lesions will be reported. For patients who achieved a PR with induction therapy, baseline lesions will be reported and tracked at each disease reassessment. 6.1 Schedule of Evaluations: For patients who entered transplant with a negative (Deauville score of 1-3) PET scan, a diagnostic CT of the chest, abdomen, and pelvis with contrast (or PET/CT scan with or without contrast) will be repeated at 12, 24, 36, 48, and 60 months (+/- 1 month) post-transplant. For patients in Arm B a similar scan schedule should be followed but using the end of induction therapy as the reference point (i.e., 12, 24, 36, 48, and 60 months (+/- 1 month) post completion of induction therapy. Additional scans may be performed at the discretion of the treating physician for surveillance or if disease progression is suspected based on clinical assessment. For patients who entered transplant with a positive (Deauville score of 4) PET scan, a PET/CT scan should be repeated days post-transplant. Following this, diagnostic CT of the chest, abdomen, and pelvis (or PET/CT scan with or without contrast) will be repeated at 12, 24, 36, 48, and 60 months (+/- 1 month) post-transplant. Again, additional scans may be performed at the discretion of the treating physician for surveillance or if disease progression is suspected based on clinical assessment. 6.2 Measurement of Treatment/Intervention Effect Target Lesions & Target Lymph Nodes Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 33

34 abdominal masses, and other lesions that cannot be confirmed and followed by imaging Initial response post-transplant. This response is to be performed between days 60 and 99 [for patients in Arm C who did not achieve a CR after induction therapy], with the preferred mode of evaluation being PET/CT scan (see Section 6.1) Complete Metabolic Response (CR): 1) Deauville Score of 1, 2, or 3 with or without a residual mass or nodal lesion: a. 1, no FDG uptake above background; b. 2, FDG uptake mediastinum; c. 3, FDG uptake > mediastinum but liver; d. 4, FDG uptake moderately > liver; e. 5, FDG uptake markedly higher than liver and/or new lesions; f. X, new areas of uptake unlikely to be related to lymphoma. 2) In Waldeyer s ring or extranodal sites with high physiologic uptake or with activation within spleen or marrow (e.g., with chemotherapy or myeloid colony-stimulating factors), uptake may be greater than normal mediastinum and/or liver. In this circumstance, complete metabolic response may be inferred if uptake at sites of initial involvement is no greater than surrounding normal tissue even if the tissue has high physiologic uptake. 3) No new lesions. 4) No evidence of FDG avid disease in marrow unless as noted in (2). Partial Response (PR): 1) Deauville Score of 4 or 5 with reduced uptake compared to baseline and residual mass(es) of any size. 2) No new lesions. 3) Residual marrow uptake higher than uptake in normal marrow but reduced compared with baseline (diffuse uptake compatible with reactive changes from chemotherapy allowed). If there are persistent focal changes in the marrow in the context of a nodal response, consideration should be given to further evaluation with a BM biopsy. Stable Disease (SD): 1) Score 4 or 5 with no significant change in FDG uptake from baseline or end of induction treatment. 2) No new lesions. 3) No change in marrow uptake from baseline. Progressive Disease (PD): 1) Score 4 or 5 with an increase in intensity of uptake from baseline. 2) New FDG-avid foci consistent with lymphoma. 34

35 3) New or recurrent FDG-avid foci in the bone marrow Follow-Up Assessment [at 12, 24, 36, 48, and 60 months (+/- 1 month) and thereafter] These measurements are based on the post induction or day measured lesions on CT or PET/CT. Again, lesion measurements do not need to be reported for patients who achieved CR with induction therapy, until the patient relapses. For patients who achieved PR with induction therapy, lesions need to be measured and reported at each follow-up assessment. Complete Remission (CR): All of the following must be true: 1) For previously measured lesions: Target nodes/nodal masses must regress to < 1.5 cm in LDi. No extralymphatic sites of disease NOTE: LDi, longest transverse diameter 2) Spleen or other organ enlargement must have regressed to normal size. 3) For previously non-measured lesions: Absent. 4) No new lesions. 5) No marrow involvement. Partial Remission (PR): All of the following must be true: 1) For previously measured lesions: 50% decrease in the SPD of up to 6 target measurable nodes and extranodal sites. When a lesion is too small to measure on CT, assign 5mm x 5 mm as the default value. When the lesions is no longer visible, assign 0 x 0 mm. For a node > 5 mm x 5 mm, but smaller than normal, use actual measurement for calculation NOTE: SPD, sum of the product of the perpendicular diameters for multiple lesions 2) Spleen must have regressed by > 50% in length beyond normal. 3) For previously non-measured lesions: Absent, normal, regressed, but no increase. 4) No new lesions. 5) No new or recurrent marrow involvement. Stable Disease (SD): All of the following must be true 1) For previously measured lesions: < 50% decrease in the SPD of up to 6 dominant, measurable nodes and extranodal sites, no criteria for progressive disease met. NOTE: SPD, sum of the product of the perpendicular diameters for multiple lesions 2) No organ enlargement/splenomegaly consistent with progression. 3) For previously non-measured lesions: No increase consistent with progression. 35

36 4) No new lesions. 5) No new or recurrent marrow involvement. Progressive Disease (PD): At least one of the following must be true: 1) For previously measured lesions: An individual node/lesion must be abnormal with: LDi >1.5 cm AND increase by 50% from PPD nadir AND an increase in LDi or SDi from nadir by 0.5 cm for lesions 2 cm or 1.0 cm for lesions > 2 cm. NOTE: PPD, product of perpendicular diameters; LDi, longest transverse diameter; SDi, shortest axis perpendicular to the LDi 2) New lesions: A new node > 1.5 cm in any axis OR a new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any axis, its presence must be unequivocal and must be attributable to lymphoma. 3) New or clear progression of pre-existing unmeasured lesions. 4) New or recurrent splenomegaly: In the setting of splenomegaly, the splenic length must increase by > 50% of the extent of its prior increase beyond baseline (e.g., a 15-cm spleen must increase to > 16 cm). If no prior splenomegaly, must increase by at least 2 cm from baseline 5) New or recurrent marrow involvement. 6.3 Definitions of analysis variables PFS is defined as the time between randomization and progressive disease or death, whichever comes first. Patients alive with no history of relapse/progression are censored at the time of the last observation. Overall Survival is defined as the time between randomization and death from any cause. Patients alive at the time of last observation are censored at the time of the last observation. 36

37 7. Study Parameters Following preregistration Screening Post-induction restaging (PR or CR) Pretransplant Biological Specimen Submissions: MANDATORY for Molecular Marker Testing and Minimal Residual Disease Assessments Tumor Tissue 1,2,3 X Day 100 post auto- HCT Peripheral Blood, EDTA 10 ml purple top tube 1,3 X Arm C 9 Therapeutic Parameters History and Physical examination Hematopathology review including calculation of Ki-67% (< 30% vs 30% or indeterminate) PET/CT scan with Deauville score X X 8 X 8 Bone marrow aspirate and biopsy X 6 Performance Status X X X Post Step 1 Years CBC and differential (can be done locally) X X (Q 2 months) 7 Serum or Urine Pregnancy Test 5 CD4 count and HIV viral load (HIV + patients only) Stem cell collection X X Arms A,C,D Enrolling center to complete follow up form (can be follow up appt at enrolling center, or completed by telephone follow up to patient s local X (Q 6 months) oncologist s office) CT N-C-A-P X 8 Quantitative immunoglobulin levels (can be done locally) X (Q 6 months) 1. All specimens submitted must be entered and tracked via the online ECOG-ACRIN Sample Tracking System (STS). See Section Representative tumor tissue specimen and related pathology reports must be submitted for molecular marker testing following preregistration (Step 0) as outlined in Section 10. Failure to submit the required pathology materials will render the patient ineligible for participation in the trial. 3. Kits are available for the collection and shipment of the tumor tissue and peripheral blood specimens See Section 10 for instructions. 4. Follow-up should be completed with the enrolling center once every 6 months, at either q6 months post-transplant or q6 months postassignment to Arm B. It is preferred the follow-up visit occur at the enrolling center, however, if insurance will not cover this, follow-up may occur via telephone with the patient s local oncologist. 5. Baseline pregnancy test much be done within 2 weeks prior to the Step 1 registration. For Arms A, C, and D, a pregnancy test must be done within 2 weeks prior to starting auto-hct. 6. Bone marrow aspirate and biopsy should be performed within 90 days prior to post-induction restaging. 37

38 7. CBC and differential should be conducted q2 months during rituximab administration, but these tests do not need to be conducted during follow-up. 8. For patients who entered the study PET-positive and received auto-hct, a PET/CT scan should be conducted between days posttransplant. For patients who entered the study PET-negative and received auto-hct, a CT or PET/CT scan does not need to be conducted at days post auto-hct, but a CT NCAP (or PET/CT scan, at the treating physician s discretion) should be conducted on an annual basis throughout follow-up, even though follow-up forms are completed every 6 months post step All patients on Arm C should receive MRD assessment on day 100 after auto-hct via the ClonoSEQ assay with the peripheral blood submission. 38

39 8. Drug Formulation and Procurement 8.1 Rituximab Other Names IDEC-C2B8, Chimeric anti-cd20 monoclonal antibody, Rituxan Classification Antibody Mode of Action Rituximab is a chimeric murine/human gamma 1 kappa monoclonal antibody (Chinese hamster ovary [CHO] transfectoma). It recognizes the CD20 antigen expressed on normal B cells and most malignant B- cell lymphomas. It binds with high affinity to CD20-positive cells, performs human effector functions in vitro, and depletes B cells in vivo. The Fab domain of rituximab binds to the CD20 antigen on B- lymphocytes and the Fc domain recruits immune effector functions to mediate Bcell lysis in vitro. The biological effect is manifested by B- cell depletion in peripheral blood, lymph nodes, and bone marrow Storage and Stability Intact vials of rituximab are stored at refrigerated temperatures of 2 degrees to 8 degrees Celsius (36 degrees to 46 degrees Fahrenheit). Protect vials from direct sunlight. Once diluted to a concentration of 1 to 4 mg/ml in polyvinylchloride or polyolefin IV bags containing normal saline or 5% dextrose, the product is stable for up to 24 hours at 2 degrees to 8 degrees Celsius, and at room temperature for an additional 12 hours after refrigeration (for a maximum period of 36 hours) if protected from light Dose Specifics Rituxumab will be administered at 375 mg/m² intravenously every 8 weeks ( +/- 1 week) Preparation Withdraw the necessary amount of rituximab and dilute to a final concentration of 1 to 4 mg/ml into an infusion bag containing either 0.9% Sodium Chloride or 5% Dextrose in Water. Gently invert the bag to mix the solution. Caution should be taken during the preparation of the drug, as shaking can cause aggregation and precipitation of the antibody Route of Administration Rituximab is administered intravenously. An in-line filter is not required. The initial rate is 50 mg/hr for the first hour, or slower if clinically indicated. If no toxicity is seen, the rate may be escalated gradually in 50 mg/hour increments at 30-minute intervals to a maximum of 300mg/hr. If the first dose is well tolerated, the initial rate for subsequent dose is 100mg/hr, increased gradually in 100 mg/hr 39

40 increments at 30-minute intervals, not to exceed 400 mg/hr. If the patient experiences fever and rigors, the antibody infusion is discontinued. The severity of the side effects should be evaluated. If the symptoms improve, the infusion is continued initially at one-half the previous rate. Following the antibody infusion, the intravenous line should be maintained for medications as needed. Oral pre-medication (650 to 1000 mg of acetaminophen and 25 to 50 mg diphenhydramine) or equivalent will be administered 30 to 60 minutes prior to starting each infusion of rituximab. The patient should be treated according to the best available local practices and procedures. In patients with detectable circulating lymphoma cells, it is often recommended that the initial infusion rate be reduced to 25 mg/hr; these patients may experience more frequent and severe transient fever and rigors, shortness of breath, and hypotension. NOTE: Incompatibilities In addition, alternative rituximab infusion rates (i.e., rapid rituximab infusion ) can be used per institutional guidelines as long as the total number of milligrams of rituximab is the same and that rapid infusion is not administered with the patient s first rituximab cycle. Further, a rituximab infusion should never be given over less than 90 minutes (common infusion time for rapid infusion is 20% of the bag volume over 30 minutes, and then 80% of the remaining bag volume over 60 minutes). Do not mix or dilute rituximab with other drugs. No incompatibilities between rituximab and polyvinylchloride or polyethylene bags have been observed Availability Commercially available: Preservative-free injection 10mg/mL, in 10 and 50 ml single-unit vials. Please see Package Insert for further information Side Effects Please refer to Package Insert Nursing/Patient Implications 1. Monitor blood pressure, pulse, respiration, and temperature every 15 minutes x 4 or until stable and then hourly until the infusion is discontinued. 2. Have epinephrine for subcutaneous injections, diphenhydramine for intravenous injection, and resuscitation equipment for emergency management of anaphylactoid reactions available. 3. Monitor and alter infusion rates in the presence of toxicities. 40

41 References Product Information: rituximab. IDEC Corporation, December, Reff ME et al. Depletion of B cell in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994; 83:

42 9. Statistical Considerations This is a randomized phase III study to evaluate the benefit of auto-hct followed by maintenance rituximab in patients that achieved a MRD-negative complete remission (CR) following induction therapy. Patients eligibile for randomization will be treated with either auto-hct followed by maintenance rituximab vs. maintenance rituximab alone (without auto-hct). Patients with MRD-negative partial remission (PR), MRD-positive after ID testing or with no informative marker (MRD-indeterminate) will also be enrolled to the study and assigned to auto-hct followed by maintenance rituximab. A total of 412 eligible MRD-negative CR patients will be randomized at a 1:1 ratio to the experimental arm with auto-hct followed by maintenance rituximab vs. the standard arm with maintenance rituximab alone, stratified on the (a) MIPI-c score and (b) type of induction regimen ( intensive induction contains high dose cytarabine such as R-CHOP/R-DHAP, Nordic, CALGB 59909, or R-HyperCVAD/MTX/araC vs. non-intensive regimens). To account for potentially ineligible patients, we will increase the total accrual by 5% to a total number of 434 MRD-negative CR patients. Approximately 186 patients with MRDnegtive PR or MRD-positive CR/PR, and 69 patients who are MRD-indeterminate will be enrolled, which leads to a total accrual of approximately 689 patients. The primary objective is to compare overall survival (OS) between auto-hct followed by maintenance rituximab and maintenance rituximab alone. With the planned sample size and follow-up time, adjusted for sequential monitoring described below, the study will have 80% power to detect a 45% reduction (Hazard ratio of 0.55) in the OS hazard rate in the experimental arm compared with the standard arm, at a one-sided significance level of with a stratified log-rank test. With an exponential distribution assumption for OS, this translates into a 10% improvement in 6-year OS rate from 76% to 86% with the addition of auto-hct. The number of events needed at full information time is 99. The secondary objectives include progression-free survival (PFS) for MRD-negative patients, PFS and OS for MRD-positive patients (or patients in PR) who undergo auto- HCT followed maintenance rituximab, and MRD status at day 100 in MRD-positive patients prior to auto-hct. The study has a planned preliminary analysis with 4-years additional follow-up. The effect of transplant on progression-free survival (PFS) will be tested, and the estimates together with 95% confidence intervals will be reported publically. This preliminary outcome analysis is not data-driven and will be carried out independently of the protocolspecified interim and final analyses for overall survival (OS). The study-level conclusions will be made based on the primary analysis of OS with 6 years additional follow-up. 9.1 Accrual A recent CIBMTR query shows that approximately 375 first remission auto transplants occur in the U.S. yearly. A conservative estimate of an additional 75 patients per year in Canada gives a total figure of 450 patients transplanted per year in the U.S. and Canada. Assuming 90% of patients have a positive MRD ID test (representing a useful marker of disease) and that 70% of patients achieve MRD-negative CR status, then leaves 284 potentially eligible patients per year. Assuming 40% of these patients are actually enrolled, would yield 113 patients enrolled yearly and therefore 9.4 patients enrolled per month. Accrual would then take approximately 46 months to enroll 434 MRD-negative CR patients. Approximately 186 MRD-positive patients will be enrolled during the accrual 42

43 duration, as well as 69 MRD-indeterminate patients, which leads to a total accrual of approximately 689 (= ) patients. 9.2 Randomized Scheme Randomization to treatment will be determined using permuted blocks within strata with dynamic balancing on main ECOG-ACRIN institutions plus affiliates. The randomization and the primary test will be stratified by (a) MIPI-c score and (b) type of induction regimen ( intensive induction contains high dose cytarabine such as R-CHOP/R-DHAP, Nordic, CALGB 59909, or R-HyperCVAD/MTX/ara-C vs. non-intensive regimens). 9.3 Sample Size Calculation The primary objective is to compare overall survival (OS) between auto-hct followed by maintenance rituximab and maintenance rituximab alone. OS is defined as the time from the date of randomization/registration to death from any cause, or censoring at the time of being last known alive. We assume a 6-year OS rate of 76% in the standard rituximab maintenance arm, and target to detect a 10% improvement to 86% at 6 years with the addition of auto-hct. With an exponential distribution assumption for OS, this translates into a 45% hazard reduction (Hazard ratio of 0.55). Adjusted for sequential monitoring described below, with 412 patients accrued over 46 months, the study will have 80% power to detect such a difference using a one-sided log rank test at the one-sided significance level of and assuming 6 years of additional follow-up. The number of events needed at full information time is Statistical Analysis Plan The analytical population is defined based on an intent-to-treat principal includes all randomized and pathologically eligible patients. Patients who are ineligible for other reasons and patients who did not receive the assigned treatment will be included in the analytical population. The eligible subset includes all randomized eligible patients. The per-protocol population is defined as randomized eligible patients receiving planned protocol treatment. The toxicity population is defined as all patients who receive any protocol treatment regardless of eligibility. Primary and secondary objectives will be analyzed using the analytical population. The potential impact of ineligible patients (and other major deviations) will be assessed through secondary analyses using the eligible subset. In addition,analyses using the per-protocol population may also be examined. MRD status, including the rate of MRD-negative CR, MRD-negative PR, MRDpositive CR, MRD-positive PR and MRD-indeterminate, at the time of registration will be reported together with 95% confidence interval. For the primary objective, the Kaplan-Meier method will be used to estimate OS for each arm, including medians and confidence intervals. Comparison of OS between treatment arms will be conducted using a one-sided log-rank test stratified with MIPI-c score and induction regimen. Cox proportional hazards models will be used to assess possible effects of baseline clinical and biological characteristics on outcome. Treatment and covariate interactions will also be examined. 43

44 The first secondary objective (2.2.1) will compare progression-free survival (PFS) in MRD-negative CR patients who undergo auto-hct followed by maintenance rituximab vs. maintenance rituximab alone. PFS is defined as the time from randomization to the earliest time of documented disease progression or death without progression. Cases with incomplete follow-up or without adequate disease evaluation will be censored at the date they were last documented to be progression free. We assume a 4-year PFS rate of 70% in the standard rituximab maintenance arm; we target to detect an 11% improvement to 81% with the addition of auto-hct. With an exponential distribution assumption for PFS, this translates into a 41% hazard reduction (Hazard ratio of 0.59). With 412 patients accrued over 46 months, the study will have 84% power to detect such a difference using a one-sided log rank test at the one-sided significance level of and assuming 4 years of additional follow-up. 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. The other secondary objectives include progression-free survival (PFS) and OS for the other patients enrolled but not randomized. There are 4 groups of patients under this analysis, including MRD-negative PR patients, MRD-positive CR patients, MRD-positive PR patients and MRD-indeterminate patients. All of these 4 groups of patients will undergo auto-hct followed by maintenance rituximab, while only MRD-positive CR and MRD-positive PR patients will have MRD status reassessed at day 100 post auto-hct. The analysis on PFS and OS will be conducted individually within each of the 4 groups, although combining some groups of patients will also be considered. The Kaplan-Meier method will be used to estimate PFS and OS with median and confidence intervals. MRD status at day 100 after auto-hct will be assessed in MRD-positive CR/PR patients prior to auto-hct and the conversion rate will be reported together with confidence intervals. To check the prognostic value of 100-day MRD status, PFS and OS will be estimated separately and compared for patients who become MRD-negative or remain MRD-positive. In this case, a landmark analysis approach will be used. Patients who survived 100-days post auto-hct will be included in the analysis, and PFS and OS are defined as starting from day 100 after auto-hct. Due to the limited sample size, the comparison will be underpowered and thus will be mainly descriptive (e.g., median and confidence intervals). The analysis will be conducted for MRD-negative CR and MRDnegative PR patients separately and jointly. The primary safety analysis, including rate of complications, will be based on the toxicity population, and the analysis will be performed according to treatment received. To further verify the prognostic effect of MRD status, we will compare PFS and OS between MRD-negative CR patients who are randomized to auto-hct followed maintenance rituximab and MRD-positive CR patients who are assigned to auto-hct followed by maintenance rituximab. There will be about 206 MRDnegative CR patients that are randomized to auto-hct followed by 3 years of maintenance rituximab (arm A). Out of the 186 other patients, it is estimated that about 74 of them will be eligible MRD-positive CR patients that are assigned to auto-hct followed by maintenance rituximab (arm C). This study will have 86% power to detect a 5-year OS rate of 89% in the MRD-negative CR patients vs. 44

45 77% in the MRD-positive CR patients, at a one-sided significance level. If the 5-year OS rate is 79% in the MRD-positive CR patients, the power is 74%. 9.5 Safety Monitoring This study will be monitored by the ECOG ACRIN Data Safety Monitoring Committee for efficacy, harm, inefficacy, and safety. Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN studies. Reports of these analyses are sent to the ECOG-ACRIN Principal Investigator or Senior Investigator at the participating institutions. Expedited reporting of certain adverse events is required, as described in Section 5.3. Interim efficacy analyses of OS is planned twice per year for all semi-annual ECOG-ACRIN Data Safety Monitoring Committee (DSMC) meetings unless small increments of information (< 10%) are gained during six months. Based on the estimation, it takes 12 month to achieve 10% or more information increment, therefore, the interim analysis will take place every 12 month. The interim efficacy analysis will begin when 25 events, that is, approximately 25% of the planned full information has occurred, and continue until either criteria for early stopping are met or full information is reached. The final interim analysis will occur at approximately 9.75 years (117 months) after activation (99 OS events, under the alternative hypothesis). To preserve the overall type I error rate, critical values at the interim analyses will be determined using a truncated version of the O Brien-Fleming group sequential boundary adjusts for the sequential testing. And the use function methodology of Lan and DeMets will be employed to adjust the boundaries if the actual interim analyses do not correspond with the projected information times provided. If at one of the scheduled interim analyses, it has crossed the upper boundary, the study may be stopped in favor of the alternative by the ECOG-ACRIN DSMC. More details of the planned interim analyses for OS can be found in Table 1. Table1: Interim and Final Analyses Characteristics for OS Interim and Final Analysis Approximate time since study start (months) % information Estimated Upper Boundary Estimated Number of Events % % % % % % Final % This study will also be monitored for early stopping for harm and futility using the methodology of Freidlin, Korn and Gray (Clinical Trials, 2010). This method allows for the study to stop early if the results are not consistent with at least a small trend in favor of the alternative hypothesis at a given information time. At 25% information, the DSMC may consider stopping the study for harm if the low bound of a 95% confidence interval in the hazard ratio (for the auto-hct arm 45

46 versus the non-transplant arm) is above 1. Inefficacy monitoring is scheduled to start approximately after 49% of the full information becomes available with repeated analyses at each semi-annual DSMC meeting. If there is not at least a 10% increment in information, an interim analysis for inefficacy will not be conducted. Linear 20% Inefficacy Boundary (LIB20) will be used. Table 2 lists the analysis plan with cut-off values. At each interim analysis, if the estimated hazard ratio is larger than the cut-off value given in the LIB20 boundary, the DSMC may recommend that the study be terminated for futility. In practice actual analysis times may vary, therefore the cutoff values will be recomputed accordingly. Table2: Futility Monitoring Analyses information time and cut-off value % OS Information Approximate time since study start (months) Cut-off for Log OS HR Cut-off for OS HR 49% % % % % Analysis for reporting of initial transplant effect This study has a planned preliminary analysis on progression-free survival (PFS) at 4 years after last patient is enrolled, unless the study is stopped earlier. All patients should already have been randomly assigned and off treatment armspecific therapy by then. PFS will be compared on the analytical population defined in Section 9.4 between two randomized arms using a log-rank test stratified on MIPI-c score and induction regimen. Hazard ratios will be estimated with a stratified Cox proportional hazard model. We will tabulate all cases entered, and those excluded from the analyses along with the reasons, the distribution of the baseline patient characteristics, and important prognostic factors. We will also report treatment information (the proportion of patients receiving their assigned treatment) and toxicity data collected as of the reporting time. The outcome data will be reported to the public through publications in journals and presentations at professional meetings. This preliminary outcome analysis is not data-driven and will be carried out independently of the protocol-specified interim and final analyses for overall survival (OS). However, the study-level conclusions will be made based on the primary analysis on OS with 6-years additional follow-up. 9.7 Gender and Ethnicity Based on previous data, the anticipated accrual in subgroups defined by gender and race is shown in the following table. Mantle cell lymphoma is more common in males, and based on published research (Armitage et al, 1998) and accrual to previous studies, we expect accrual to reflect this higher prevalence. 46

47 Gender and Minority Accrual Estimates for Proposed Study (Total accrual Goal=689) Racial Categories DOMESTIC PLANNED ENROLLMENT REPORT Not Hispanic or Latino Ethnic Categories Hispanic or Latino Female Male Female Male American Indian/ Alaska Native Asian Native Hawaiian or Other Pacific Islander Black or African American White More Than One Race Total Total The accrual targets in individual cells are not large enough for definitive treatment comparisons to be made within these subgroups. Therefore, overall accrual to the study will not be extended to meet individual subgroup accrual targets. Study Monitoring This study will be monitored by the ECOG-ACRIN Data Safety Monitoring Committee (DSMC). The DSMC meets twice each year. For each meeting, all monitored studies are reviewed for safety and progress toward completion. When appropriate, the DSMC will also review interim analyses of outcome data. Copies of the toxicity reports prepared for the DSMC meetings are included in the study reports prepared for the ECOG-ACRIN group meeting (except that for double blind studies, the DSMC may review unblinded toxicity data, while only pooled or blinded data will be made public). These group meeting reports are made available to the local investigators, who may provide them to their IRBs. Only the study statistician and the DSMC members will have access to interim analyses of outcome data. Prior to completion of this study, any use of outcome data will require approval of the DSMC. Any DSMC recommendations for changes to this study will be circulated to the local investigators in the form of addenda to this protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be obtained from the ECOG-ACRIN Operations Office Boston. 47

48 10. Biological Specimen Submissions Following preregistration (Step 0), original diagnostic tumor biopsy specimen from previously collected tissue must be submitted during induction (dominant sequences identified), or within 60 days of the last dose of induction therapy (patient must have CR or PR status) to Adaptive Biotechnologies for the mandatory molecular marker ID testing described in Section 11. The institution and ECOG-ACRIN Operations Office will be notified of the results within fourteen (14) days of receipt of the tumor tissue specimen. Peripheral blood specimens must be submitted to Adaptive Biotechnologies from patients for whom the molecular marker was identified, and at restaging have CR or PR status, for the mandatory minimal residual disease (MRD) assessment described in Section 11. The institution and ECOG-ACRIN Operations Office will be notified of the results within seven (7) days of receipt of the peripheral blood. Peripheral blood must be submitted for the MRD assessment 100 (+/- 5 days) days post auto-hct for patients on Arm C only. The institution will be notified of the MRD results to inform them of the patient s disease status. Before submitting specimens, physicians or authorized persons (per state law) must register and create an account with Adaptive Biotechnologies by completing the Physician Registration Form referenced in Appendix IV Multi-Site Clinical Trial Physician-Institution Registration Form (form can be downloaded ECOG-ACRIN and CTSU web pages) and ing to clinicalservices@adaptivebiotech.com in order to gain access to the online ClonoSEQ secure portal for ordering tests and accessing test results. Appendix IV also includes Adaptive Biotechnologies: Registration Form Helpful Hints which summarizes how to complete the physician registration form (posted on ECOG-ACRIN and CTSU web pages). Once Adaptive receives the completed form, turnaround time to establish the account is usually within 24 hours. When setting up your account, you can choose how to be notified when results are available (via to online portal or fax) as well as designate others within your institution to have access to the account. Requesting kits can be done by ing clinicalservices@adaptivebiotech.com. An initial order of three (3) collection kits will be sent upon receipt of the physician registration form. Kits are to be used for both tissue and blood submissions. Physicians or authorized persons (per state law) can order tests by manually signing and submitting the fully completed portal-generated ClonoSEQ Test Requisition Form (TRF) along with the specimens. The TRF must contain two unique identifiers, ECOG- ACRIN Patient Sequence Number and Date of Birth. NOTE: Physicians and authorized persons (per state law) are the only ones allowed to create an account with Adaptive and to sign the TRF. Even if you already have an account with Adaptive Biotechnologies, you must create one specific to this trial. If you have any questions about setting up your account, please contact Adaptive Biotechnologies Clinical Services at (888) Appendix IV Adaptive Biotechnologies: Process Flow contains an overview of the various steps involved for registering, submitting tests, and retrieving results (guide is posted on ECOG-ACRIN and CTSU web pages). Appendix IV Adaptive Biotechnologies Diagnostic Portal is an overview of how to submit test orders via the online portal (posted on ECOG-ACRIN and CTSU web pages). 48

49 Please note within the portal, under Create New Patient under First name enter the ECOG-ACRIN Five-Digit Patient Sequence Number-Patient Initials and under Last name enter -NCI-CTEP Institution Code. These documents may be downloaded by accessing It is required that all specimens submitted on this trial be entered and tracked using the ECOG-ACRIN Sample Tracking System (see Section 10.2). An STS Shipping Manifest Form is to be included with every submission. All specimens must be labeled clearly with the ECOG-ACRIN protocol number (), ECOG-ACRIN patient sequence number, patient s initials, date of birth, date of collection and specimen type Specimen Collection and Submission Schedule Kits are available to order for the collection and shipment of the tumor tissue and peripheral blood specimens and will contain the supplies and instructions for collecting, processing, and shipping the specimens, including the 10mL EDTA tube and prepaid, preaddressed FedEx Clinical Pak. An initial order of three (3) collection kits will be sent upon receipt of the physician registration form. Additional kits can be ordered by ing clinicalservices@adaptivebiotech.com. Kits will generally arrive within one (1) week from when the order was placed. Kits will be shipped via ground shipping unless otherwise specified. Specimens must be submitted as follows: MANDATORY: Original diagnostic tumor tissue biopsy must be submitted following preregistration (Step 0) during induction or within two (2) months following completion of induction (patient must have CR or PR status), see Section MANDATORY: Peripheral blood specimens must be submitted following preregistration (Step 0) from patients for whom the clonal marker exists and have CR or PR status and 100 days (+/- 5 days) post auto-hct (Arm C only) on the day of collection, see Section Peripheral blood should not be submitted until after notification of the clonal marker status. If peripheral blood was submitted at the same time as the tumor tissue for clonal marker testing, only peripheral blood from patients with the clonal marker signature will be evaluated Tumor Tissue Submission Submitting pathologist and clinical research associate may refer to Appendix I, which outlines the Pathology Submission Guidelines. Submission of pathology specimens from all patients is mandatory. Questions are to be directed to Adaptive Biotechnologies Clinical Services at (888) The tumor tissue specimens are to be labeled with the institution s assigned pathology ID as well as the information above. 49

50 Required Materials Forms: Must be submitted with all tumor tissue submissions. STS generated Shipping Manifest Form Copy of the institutional pathology report Test Requisition Form Pathological Material Submission: Representative diagnostic formalin-fixed paraffinembedded (FFPE) tumor tissue specimen NOTE: All tissue scrolls and slides must be adequately labeled, with slides numbered sequentially in the order cut. Five (5) to Ten (10) 5 µm tissue scrolls placed into an Eppendorf tube or Three (3) 10 µm tissue scrolls placed into an Eppendorf tube or Three to Five (3-5) unstained air dried plus slides Peripheral Blood Submissions Peripheral blood specimens should be shipped the day they are drawn at the time of or after restaging and 100 days (+/- 5 days) post auto-hct [for patients on Arm C only]. If you have any questions concerning collection and shipment of the peripheral blood please contact Adaptive Biotechnologies Clinical Services at (888) Sample Preparation Guidelines Shipping Procedures Peripheral blood specimens should be shipped the day they are drawn at room temperature (do not freeze). Peripheral Blood: Draw 10 ml of whole blood into one (1) EDTA purple top tube (provided in the kit). Please completely fill all blood tubes as full as possible. Ship day of collection. Invert the tube eight times prior to shipment. Pathology materials are to be shipped overnight at ambient temperature following preregistration (Step 0). Peripheral blood specimens should be mailed the day they are obtained and shipped overnight to arrive during normal working hours. The laboratory is open to receive shipments Monday through Saturday. Follow packing guidelines listed in the kit. 50

51 PREHOLIDAY SHIPMENTS SHOULD BE AVOIDED Please Adaptive Biotechnologies at to notify the laboratory when tumor tissue and peripheral blood specimens are being shipped. Indicate the ECOG-ACRIN protocol number (), the FedEx tracking number, and the name and phone number of the contact person. Ship to: Adaptive Biotechnologies 1551 Eastlake Avenue E Suite #200 Seattle, WA (888) An STS Shipping Manifest Form and Adaptive Biotechnologies Test Requisition Form must be generated and shipped with all specimen submissions Results Reporting from Adaptive Biotechnologies Adaptive will forward clonal marker status results within fourteen (14) days of receipt of the tumor tissue. Results will be reported as: Dominant Sequences Identified [Clonal Marker Identified Submit Peripheral Blood for MRD Testing] Polyclonality [No Clonal Marker Identified Do Not Submit Peripheral Blood for MRD Testing] Indeterminate [No Clonal Marker Identified Do Not Submit Peripheral Blood for MRD Testing] Adaptive will forward MRD status results within seven (7) days of receipt of the peripheral blood. Results will be reported as: Yes [MRD Detected] No [MRD Not Detected] Indeterminate [MRD Indeterminate] NOTE: 10.2 ECOG-ACRIN Sample Tracking System Patients with no clonal marker identified are considered MRD indeterminate. It is required that all specimens submitted on this trial be entered and tracked using the ECOG-ACRIN Sample Tracking System (STS). The software will allow the use of either 1) an ECOG-ACRIN user name and password previously assigned (for those already using STS), or 2) a CTSU username and password. When you are ready to log the collection and/or shipment of the specimens required for this study, please access the Sample Tracking System software by clicking Important: Please note that the STS software creates popup windows, so you will need to enable pop-ups within your web browser while using 51

52 the software. A user manual and interactive demo are available by clicking this link: Please take a moment to familiarize yourself with the software prior to using the system. An STS generated Shipping Manifest Form must be shipped with all specimen submissions. Please direct your questions or comments pertaining to the STS to ecog.tst@jimmy.harvard.edu Study Specific Notes Generic Specimen Submission Form (#2981) is required to be submitted with the shipment if STS is unavailable at the time of specimen submission. Indicate the appropriate Lab on the submission form. Retroactively enter all specimen collection and shipping information when STS is available Use of Specimens in Research Residual tumor tissue (including DNA) and peripheral blood will be forwarded to the ECOG-ACRIN Central Biorepository and Pathology Facility to be stored for future research studies. Specimens from patients who consented to allow their specimens to be used for future ECOG-ACRIN approved research studies will be retained in an ECOG- ACRIN designated central repository. Specimens submitted will be processed to maximize their utility for current and future research projects. Tissue processing may include, but not limited to, extraction of DNA and RNA and construction of tissue microarrays (TMAs). DNA and plasma (if appropriate) will be isolated from the submitted peripheral blood specimens. Any residual tissue blocks will be available for purposes of individual patient management on specific written request. If future use is denied or withdrawn by the patient, the specimens will be removed from consideration for use in any future research study. Pathology materials may be retained for documentation purposes or returned to the institution. All other specimens will be destroyed per guidelines of the respective repository Sample Inventory Submission Guidelines Inventories of all specimens submitted from institutions will be tracked via the ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory. Inventories of specimens forwarded and utilized for approved laboratory research studies will be submitted by the investigating laboratories to the ECOG-ACRIN Operations Office Boston on a monthly basis in an electronic format defined by the ECOG-ACRIN Operations Office Boston. 52

53 11. Integral Biomarker Studies 11.1 ClonoSEQ Assay The ClonoSEQ assay by Adaptive Biotechologies (South San Francisco, CA), developed by Sequenta and previously called ClonoSIGHT, will be used to identify clonal immunoglobulin DNA sequences unique to a patient s lymphoma, which will then be used to determine the existence of minimal residual disease (MRD) in the peripheral blood of patients following induction. ClonoSEQ is a novel, deep sequencing-based method to identify cells with specific molecular signatures. This will be used to determine the patients response to therapy and to determine eligibility for this clinical trial. The patient-specific rearrangement can be determined from a sample with high disease load, e.g., the diagnostic sample. The level of the specific clone can then be determined with high sensitivity and specificity in different samples in the patient. Detection of minimal residual disease can help inform the patient s response as well as detection of relapse. The assay is highly sensitive and specific and has been shown to be reliable in predicting lymphoma relapse ( molecular relapse ) prior to relapse being detectable by conventional radiographic and clinical methods [1-2]. MRD status will be used to assign patients to treatment on the trial, as well as serve as an integrated biomarker in a subset of patients. For patients who are MRD-positive following induction, one additional MRD assessment will be performed around day 100 (+/- 5 days) post auto-hct. This information will be used for a post-hoc analysis of the predictive value of MRD status post-transplant on PFS and OS, in patients who were MRD-positive pre-transplant. The method employs consensus primers to universally amplify rearranged immunoglobulin gene segments in a sample and relies on high-throughput sequencing and specifically designed algorithms to identify clonal gene rearrangements in diagnostic samples and quantify these rearrangements in follow-up MRD samples. The follow up samples are derived from peripheral blood for this clinical trial. Detailed studies defining the test characteristics have been performed both for identifying the tumor clone from tumor derived DNA as well as for the follow-up samples derived from circulating DNA. The technical performance has been reported for ALL (Faham et al, Blood; 2012; 120(26): , DOI: [12]. The assay was shown to have high precision and is highly quantitative at clonotype frequencies at or above 3 X Random error increased at clonotype frequencies below For each clonotype, the assay showed high r 2 values with a range of to (mean and median 0.991) between each of the expected and measured clonotype frequencies. The slopes ranged from to 1.14 (mean 1.00 and median 0.977), illustrating the quantitative nature of the assay over at least 3 orders of magnitude. The Sequenta/Adaptive laboratories have fully performed studies defining the accuracy, precision and reportable range. They have performed tests of preanalytic interference (e.g. substance that can interfere with the test). All the experiments that were done with input DNA amount 150ng-15,000ng passed the determined QC metric. 53

54 Briefly, since PCR inhibition is often found in FFPE samples, and this inhibition can detrimentally affect the results of the ClonoSEQ test, the lab developed an algorithmic approach to assess whether PCR inhibition is present in a sample. They utilize the qpcr method to measure DNA concentration using a stock and a 1:10 dilution. After adjusting for the 10-fold concentration difference, they measure the difference in DNA concentration between the stock and 1:10 dilution. If a 3-fold difference is observed, that is considered evidence of inhibition, and workflows are initiated to mitigate this PCR inhibition. Therefore, the ability to assess inhibition using the qpcr method is critical for ClonoSEQ sample QC and important for establishing the tumor clone that will be measured for MRD. Using this qpcr QC metric, they have validated the DNA extraction methods for each of the new sample types, which include FFPE slices, FFPE slides, bone marrow aspiration slides and bone marrow aspiration cover slips. This new QC method can be universally applied to any sample type. The detection limit was determined to be between 10-5 and 10-6 for the majority of challenged receptors. As there are a very large number of possible primer pair combinations, it is not possible to test them all. However, based on this study, the detection limit was determined to be 10-5 to A pooled high and low cell-line control will be utilized for all validation runs and clinical sample batches. This control will be used to assess linearity and assay performance for each individual run. High Level Control: The high level control will be comprised of the 12 cell-lines spiked at different concentrations into a normal control DNA sample comprised of one or more normal individuals. Each cell line has one or more clonotypes so that each of the 6 assays has at least 2 clonotypes among the 12 cell lines. The concentration of the lowest clonotype is about 5x10-5 and the highest clonotype is higher than 1%. Low Level Control: The low level control will be comprised of the 12 cell-lines spiked at different concentrations into a normal control DNA sample comprised of one or more normal individuals. Each cell line has one or more clonotypes so that each of the 6 assays has at least 2 clonotypes among the 12 cell lines. The concentration of the lowest clonotype is about 2.5x10-5 and the highest clonotype is higher than 0.1%. As shown in Figure 1, the slope for Plate 1 is and the slope for Plate 2 is Each of these slopes meets the validation criteria. In summary all positive control samples passed the validation criteria. 54

55 Validation results are summarized in Figure 2 below. R 2 = 0.93 which demonstrates excellent concordance between the biological replicates. Additionally, these results validate that the range of incubation time (1-24 hours) for the proteinase K incubation generates highly concordant results. A quantitative analysis between the 36 biological replicates was performed. R2 between the DNA concentrations (ng/ul) measured using QPCR for Rep 1 and Rep 2 was calculated in log space and plotted. 55

56 Median ratio of observed clone molecules per million leukocytes among the cell line clones in each of the ClonoSIGHT 1.1 validation plates vs. the observed values obtained in the Adaptive/Sequenta CLIA lab over the previous 10 weeks using the 1.0 assay. Bars on box plots indicate minimum and maximum median ratios (Figure 3). Cell line clones for all assays (i.e. IGH-VDJ, IGH-DJ, IGK, TRB, TRD and TRG) are included. In addition, the variation in the ratio of the high and low cell line controls on each plate was assessed. The controls are designed to be 10 fold apart in the clone molecules per million leukocytes. Figure 4 shows the fidelity of the assay in measuring the fold difference between the two controls. Figure 4. Median ratio of clone molecules per million leukocytes among the cell line clones in the high DNA vs. low DNA cell line samples using the ClonoSIGHT 1.1 assay. Bars on box plots indicate minimum and maximum median ratios. Cell line clones for each assay (i.e. IGH- VDJ, IGH-DJ, IGK, TRB, TRD and TRG) are shown as separate box plots. 56

57 Later investigated was the variation in the level of each clone among the 9 replicate experiments in the 9 plates. As shown in Figure 5, the estimates of the clone molecules per million leukocytes are highly repeatable. Figure 5. Molecules per million leukocytes for each cell line clone sequence among 9 replicate experiments in the 9 plates. Data for each assay (i.e. IGH-VDJ, IGH-DJ, IGK, TRB, TRD and TRG) are shown as separate plots. Individual clone sequences are shown in each column, with the median across all clone sequences in the last column of each plot. The assay performance and failure form the validation criteria: (1) No false positives; (2) > 85% qualitative concordance between clonality results obtained 57

58 by ClonoSIGHT 1.0 and 1.1 (Run 1) at the sample level. No false positives were observed. 100% qualitative concordance was achieved between the ClonoSIGHT 1.0 and 1.1 assays when analyzing the 500 pg/ul dilutions Lab Data Transfer Guidelines The data collected on the above mentioned laboratory research studies will be submitted electronically using a secured data transfer to the ECOG-ACRIN Operations Office - Boston by the investigating laboratories on a quarterly basis or per joint agreement between ECOG-ACRIN and the investigator. The quarterly cut-off dates are March 31, June 30, September 30, and December 31. Data is due at the ECOG-ACRIN Operations Office - Boston 1 week after these cut-off dates. 58

59 12. Electronic Data Capture Please refer to the Forms Completion Guidelines for the forms submission schedule. Data collection will be performed exclusively in Medidata Rave. This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations Office Boston to CTEP by electronic means. Reports are due January 31, April 30, July 31 and October 31 Instructions for submitting data using the CDUS can be found on the CTEP Web site 13. Patient Consent and Peer Judgment Current FDA, NCI, state, federal and institutional regulations concerning informed consent will be followed. 14. References 1. Fisher RI, Dahlberg S, Nathwani BN, Banks PM, Miller TP, Grogan TM. A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study. Blood 1995; 85: Lenz G, Dreyling M, Hoster E, Wormann B, Duhrsen U, Metzner B, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2005; 23: Romaguera JE, Khouri IF, Kantarjian HM, Hagemeister FB, Rodriguez MA, McLaughlin P, et al. Untreated aggressive mantle cell lymphoma: results with intensive chemotherapy without stem cell transplant in elderly patients. Leuk Lymphoma 2000; 39: Romaguera JE, Fayad LE, Feng L, Hartig K, Weaver P, Rodriguez MA, et al. Tenyear follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol 2010; 150: Bernstein SH, Epner E, Unger JM, Leblanc M, Cebula E, Burack R, et al. A phase II multicenter trial of hypercvad MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG Ann Oncol 2013; 24: Andersen NS, Pedersen L, Elonen E, Johnson A, Kolstad A, Franssila K, et al. Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: outcome related to remission pretransplant. Eur J Haematol 2003; 71: Geisler CH, Kolstad A, Laurell A, Jerkeman M, Raty R, Andersen NS, et al. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem- 59

60 cell support: still very long survival but late relapses do occur. Br J Haematol 2012; 158: Delarue R, Haioun C, Ribrag V, Brice P, Delmer A, Tilly H, et al. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'etude des Lymphomes de l'adulte. Blood 2013; 121: Damon LE, Johnson JL, Niedzwiecki D, Cheson BD, Hurd DD, Bartlett NL, et al. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB J Clin Oncol 2009; 27: Hermine O, Hoster E, Walewski J, Bosly A, Stilgenbauer S, Thieblemont C, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stemcell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomized, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet 2016; [Epub ahead of print] 11. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013; 381: Chen R, Li H, Bernstein SH, Rimsza LM, Forman S, Constine LS, et al. Results of a randomized phase II trial of R-HCVAD versus R-Bendamustine followed by autologous stem cell transplants for patients with mantel cell lymphoma: US Intergroup S1106. International Conference on Malignant Lymphoma (Lugano, Switzerland) 2015; Abstract 062:. 13. Chang JE, Li H, Smith MR, Gascoyne RD, Paietta EM, Yang DT, et al. Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405). Blood 2014; 123: Dreyling M, Lenz G, Hoster E, Van Hoof A, Gisselbrecht C, Schmits R, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood 2005; 105: Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, et al. Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma. N Engl J Med 2015; 373: Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med 2012; 367: Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Gyan E, et al. Rituximab maintenance after autologous stem cell transplantation prolongs survival in younger patients with mantle cell lymphoma: final results of the randomized phase 3 LyMa trial of the Lysa/Goelams group. American Society of Hematology Annual Meeting 2016: Abstract

61 18. Graf SA, Stevenson PA, Holmberg LA, Till BG, Press OW, Chauncey TR, et al. Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma. Ann Oncol 2015; 26: Pott C, Hoster E, Delfau-Larue MH, Beldjord K, Bottcher S, Asnafi V, et al. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study. Blood 2010; 115: Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, et al. Long-term progression-free survival of mantle cell lymphoma after intensive frontline immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood 2008; 112: Kolstad A, Laurell A, Jerkeman M, Gronbaek K, Elonen E, Raty R, et al. Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-cr patients before transplant in mantle cell lymphoma. Blood 2014; 123: Callanan MB, Delfau MH, Macintyre E, Thieblemont C, Oberic L, Gyan E, et al. Predictive Power of Early, Sequential MRD Monitoring in Peripheral Blood and Bone Marrow in Patients with Mantle Cell Lymphoma Following Autologous Stem Cell Transplantation with or without Rituximab Maintenance ; Interim Results from the LyMa-MRD Project, Conducted on Behalf of the Lysa Group. American Society of Hematology Annual Meeting 2015; Abstract Kaplan LD, Jung SH, Stock W, Bartlett N, Pitcher B, Byrd JC, et al. Bortezomib Maintenance (BM) Versus Consolidation (BC) Following Aggressive Immunochemotherapy and Autologous Stem Cell Transplant (ASCT) for Untreated Mantle Cell Lymphoma (MCL): CALGB (Alliance) American Society of Hematology Annual Meeting 2015; Abstract Cowan AJ, Stevenson PA, Cassaday RD, Graf SA, Fromm JR, Wu D, et al. Pretransplantation Minimal Residual Disease Predicts Survival in Patients with Mantle Cell Lymphoma Undergoing Autologous Stem Cell Transplantation in Complete Remission. Biol Blood Marrow Transplant 2016; 22: Fenske TS, Zhang MJ, Carreras J, Ayala E, Burns LJ, Cashen A, et al. Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: analysis of transplantation timing and modality. J Clin Oncol 2014; 32: Tam CS, Bassett R, Ledesma C, Korbling M, Alousi A, Hosing C, et al. Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood 2009; 113: Cassaday RD, Guthrie KA, Budde EL, Thompson L, Till BG, Press OW, et al. Specific features identify patients with relapsed or refractory mantle cell lymphoma benefitting from autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 2013; 19: Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging and response assessment of Hodgkin and non-hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014; 32:

62 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 Appendix I Pathology Submission Guidelines The following items are included in Appendix I: 1. Guidelines for Submission of Pathology Materials (instructional sheet for Clinical Research Associates [CRAs]) 2. Instructional memo to submitting pathologists 3. ECOG-ACRIN Generic Specimen Submission Form (#2981) 62

63 : 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 Guidelines for Submission of Pathology Materials The following materials must be submitted following preregistration (Step 0): 1. Pathology Submission (MANDATORY): Representative diagnostic formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen NOTE: All tissue scrolls and slides must be adequately labeled, with slides numbered sequentially in the order cut. Five (5) to ten (10) 5 µm tissue scrolls placed into an Eppendorf tube or Three (3) 10 µm tissue scrolls placed into an Eppendorf tube or Three to Five (3-5) unstained air dried plus slides 2. Forms and Reports: The following items are to be included with the pathology materials: Copy of institutional pathology report STS generated Shipping Manifest Form NOTE: Adequate patient identifying information must be included with every submission. It is strongly recommended that full patient names be provided. The information will be used only to identify patient materials, and will help to expedite any required communications with the institution (including pathologists). 3. Mail pathology materials to: Adaptive Biotechnologies 1551 Eastlake Avenue E Suite #200 Seattle, WA (888) If you have any questions concerning the above instructions or if you anticipate any problems in submitting the required pathology materials, contact Adaptive Biotechnologies Client Services at: (888)

64 TO: FROM: DATE: SUBJECT: MEMORANDUM (Submitting Pathologist) Stanley Hamilton, M.D., Chair ECOG-ACRIN Laboratory Science and Pathology Committee Submission of Pathology Materials for : 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 The patient named on the attached request has been entered onto an ECOG-ACRIN protocol by (ECOG-ACRIN Investigator). This protocol requires the submission of pathology materials for molecular marker ID testing. Keep a copy of the submission for your records and return any relevant completed forms, the surgical pathology report(s), the slides and/or scrolls and any other required material to the Clinical Research Associate (CRA). The CRA will forward all required pathology material to Adaptive Biotechnologies. Scrolls and/or slides submitted for this study will be retained at the ECOG-ACRIN Central Biorepository and Pathology Facility for future undefined research studies. If you have any questions regarding this request, please contact Adaptive Biotechnologies Clinical Services at (888) The ECOG-ACRIN CRA at your institution is: Name: Address: Phone: Thank you. 64

65 ECOG-ACRIN Generic Specimen Submission Form Form No. 2981v3 Page 1 of 1 Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. Protocol Number Patient ID Patient Initials Last First Date Shipped Courier Courier Tracking Number Shipped To (Laboratory Name) Date CRA will log into STS FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. Required fields for all samples Additional fields for tissue submissions Completed by Protocol Specified Timepoint: Receiving Lab Sample Type (fluid or fresh tissue, include collection tube type) Quantity Collection Date and Time 24 HR Surgical or Sample ID Anatomic Site Disease Status (e.g., primary, mets, normal) Stain or Fixative Lab ID Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. Leukemia/Myeloma Studies: Study Drug Information: Diagnosis Intended Treatment Trial Peripheral WBC Count (x1000) Peripheral Blasts % Lymphocytes % Therapy Drug Name Date Drug Administered Start Time 24 HR Stop Time 24HR Caloric Intake: Date of Last Caloric Intake Time of Last Caloric Intake 24HR CRA Name CRA Phone CRA Comments 9/12/14 65

66 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 Appendix II Patient Thank You Letter We ask that the physician use the template contained in this appendix to prepare a letter thanking the patient for enrolling in this trial. The template is intended as a guide and can be downloaded from the web site at As this is a personal letter, physicians may elect to further tailor the text to their situation. This small gesture is a part of a broader program being undertaken by ECOG-ACRIN and the NCI to increase awareness of the importance of clinical trials and improve accrual and follow-through. We appreciate your help in this effort. [PATIENT NAME] [PATIENT ADDRESS] [DATE] Dear [PATIENT SALUTATION], Thank you for agreeing to take part in this important research study. Many questions remain unanswered in cancer. With the participation of people like you in clinical trials, we hope to improve treatment and quality of life for those with your type of cancer. We believe you will receive high quality, complete care. I and my research staff will maintain very close contact with you. This will allow me to provide you with the best care while learning as much as possible to help you and other patients. On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to helping you. Sincerely, [PHYSICIAN NAME] 66

67 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 Appendix III ECOG Performance Status PS 0 PS 1 PS 2 PS 3 PS 4 Fully active, able to carry on all pre-disease performance without restriction Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature e.g., light house work, office work. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 67

68 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 Appendix IV Adaptive Biotechnologies Forms This appendix contains examples of the Multi-Site Clinical Trial Physician-Institution Registration Form, Adaptive Biotechnologies Registration Form Helpful Hints, Adaptive Biotechnologies Process Flow, and Adaptive Biotechnologies Diagnostic Portal documents, provided by Adaptive Biotechnologies. These forms may be downloaded by accessing the ECOG-ACRIN website ( or CTSU website ( Multi-Site Clinical Trial Physician-Institution Registration Form THIS IS AN EXAMPLE FORM. PLEASE DO NOT USE. 68

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71 Adaptive Biotechnologies Registration Form Helpful Hints 71

72 Adaptive Biotechnologies Process Flow 72

73 Adaptive Biotechnologies Diagnostic Portal 73

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