Allo vs Hypomethylating/Best Supportive Care in MDS (BMTCTN1102)

Study Overview
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Brief Summary
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This study is designed as a multicenter trial, with biological assignment to one of two study arms; Arm 1: Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT), Arm 2: Non-Transplant Therapy/Best Supportive Care.

Detailed Description
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Background: MDS is a clonal disorder of hematopoietic precursors and stem cells, which may evolve to a terminal phase resembling acute leukemia. A subject of clinical urgency for researchers, clinicians, patients, and health care underwriters such as Medicare, is the role of allogeneic hematopoietic cell transplantation (alloHCT) in the treatment of older patients with higher risk myelodysplastic syndromes (MDS). The use of reduced intensity conditioning (RIC) regimens has extended HCT to the care of older patients with acute myelogenous leukemia (AML) and lymphoma and a number of retrospective and phase II trials for patients with MDS now show the curative potential of RIC alloHCT in selected patients. This protocol is designed to evaluate the relative benefits of RIC alloHCT compared to non-transplant therapies focusing on overall survival. This will be done by having patients biologically assigned to the alloHCT arm or the hypomethylating therapy/best supportive care arm and following them for survival at 3 years.

Official Title
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A Multi-Center Biologic Assignment Trial Comparing Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients w/Intermediate-2 & High Risk Myelodysplastic Syndrome (BMTCTN1102)

Conditions
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MDS

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Cell Transplant
* Procedure: Hypomethylating Therapy / Best Supportive Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients fulfilling the following criteria will be eligible for entry into this study: Patients with de novo MDS who have, or have previously had, Intermediate-2 or High risk disease as determined by the International Prognostic Scoring System (IPSS). Current Intermediate-2 or High risk disease is NOT a requirement. Patients must have an acceptable MDS subtype: Refractory cytopenia with unilineage dysplasia (RCUD) (includes refractory anemia (RA)) Refractory anemia with ringed sideroblasts (RARS) Refractory anemia with excess blasts (RAEB-1) Refractory anemia with excess blasts (RAEB-2) Refractory cytopenia with multilineage dysplasia (RCMD) Myelodysplastic syndrome with isolated del(5q) (5q-syndrome) Myelodysplastic syndrome (MDS), unclassifiable Patients must have fewer than 20% marrow blasts within 60 days of consent. Patients may have received prior therapy for the treatment of MDS, including but not limited to: growth factor, transfusion support, immunomodulatory (IMID) therapy, DNA hypomethylating therapy, or cytotoxic chemotherapy prior to enrollment. Age 50.0-75.0 years. Karnofsky performance status > 70 or Eastern Cooperative Oncology Group (ECOG) ≤ 1. Patients are eligible if no formal unrelated donor search has been activated prior to date of consent. A formal unrelated donor search begins at the time at which samples are requested from potential National Marrow Donor Program (NMDP) donors. Patients who have started a sibling donor search or who have found a matched sibling donor are eligible. Patients and physicians must be willing to comply with treatment assignment: No intent to proceed with alloHCT using donor sources not specified in this protocol, including human leukocyte antigen (HLA)-mismatched related or unrelated donors (< 6/6 HLA related matched or < 8/8 HLA unrelated matched) or umbilical cord blood unit(s). No intent to use myeloablative conditioning regimens. Intent to proceed with RIC alloHCT if a matched sibling or matched unrelated donor is identified. There is no requirement as to the timing of the transplantation. Patients must be considered to be suitable RIC alloHCT candidates at the time of enrollment based on medical history, physical examination, and available laboratory tests. Specific testing for organ function is not required for eligibility but, if available, these tests should be used to judge eligibility. Signed informed consent Exclusion Criteria: Patients with the following will be ineligible for registration onto this study: Therapy-related MDS (defined as the occurrence of MDS due to prior exposure to systemic chemotherapy and/or radiation for malignancy) Current or prior diagnosis of AML Chronic myelomonocytic leukemia or myelodysplastic/myeloproliferative neoplasm (unacceptable MDS subtypes); uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression or no clinical improvement) at time of enrollment. Patients with prior malignancies, except treated non-melanoma skin cancer or treated cervical carcinoma in situ. Cancer treated with curative surgery without chemotherapy/radiation therapy > 5 years previously will be allowed. Cancer treated with curative surgery < 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs. Prior autologous or allogeneic HCT Human Immunodeficiency Virus (HIV) infection Patients of childbearing potential unwilling to use contraceptive techniques Patients with psychosocial conditions that would prevent study compliance

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two arms will enroll and have data collected on them simultaneously.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Transplant<br>Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) | Procedure: Allogeneic Hematopoietic Cell Transplant<br>* Bone marrow or peripheral blood stem cell transplant.from a fully matched related (6/6) or unrelated (8/8) donor. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity.<br>* Other names: RIC alloHCT;|
| Active Comparator: Hypomethylating Therapy / Best Supportive Care<br>The specific non-transplant treatment regimen will be at the discretion of the treating physician. | Procedure: Hypomethylating Therapy / Best Supportive Care<br>* The specific non-transplant treatment regimen will be at the discretion of the treating physician.<br>* Other names: Non-transplant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Survival (OS) | The primary endpoint for this study is overall survival (OS) at three years post-consent. Death from any cause will be considered an event for this endpoint. Surviving participants are censored at the time of last follow-up. Three year OS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy. The results posted are from the February 2020 interim analysis per protocol study design. Two interim analyses for efficacy were performed previously in January and November 2019 and presented to the Data and Safety Monitoring Board (DSMB). Results at the second analysis was crossing the efficacy boundary. Subsequently, the DSMB approved early release of study data as of February 2020. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Leukemia-free Survival (LFS) | LFS is defined as the time from the date of patient consent to the date of progression to AML or death from any cause, whichever comes first. Progression to AML is defined as > 20% leukemic blasts in bone marrow or in the peripheral blood. Death from any cause or transformation of MDS to AML are considered events for this endpoint. Participants without either event are censored at the time of last follow-up. Three year leukemia-free survival probability estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy. | 3 years | 
| Quality of Life (QOL) - Functional Assessment of Cancer Therapy-General (FACT-G) | QOL will be compared between the 2 arms using the FACT-G instrument. FACT-G evaluates the health-related quality of life (HQL) of patients receiving treatment for cancer. FACT-G consists of four subscales developed and normed in cancer patients: Physical Well-being, Social/Family Well-being, Emotional Well-being, and Functional Well-being. The FACT-G score ranges 0-108. Each subscale is positively scored, with higher scores indicating better functioning. The self-reported questionnaire will be completed at enrollment and at 6, 12, 18, 24, and 36 months from consent. Results shown are FACT-G total scores. | 3 years | 
| Quality of Life (QOL) - Medical Outcomes Study Short Form (MOS SF-36) | SF36 is being used in this protocol as a generic measure of quality of life (QOL). The self-reported questionnaires are completed at enrollment and at 6, 12, 18, 24, and 36 months from consent. The MOS SF-36 instrument is a general assessment of health QOL with eight components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social Functioning, Role Emotional, and Mental Health Index. The sub scores for each of the eight components were computed based on the raw categorical values from the survey and range 0-100 with higher scores indicating better outcomes for each domain. Then overall Physical Component Summary (PCS) and Mental Component Summary (MCS) are computed using standardized algorithm for SF36. MCS and PCS scores range 0-100 with higher score indicating positive outcome. To facilitate comparison of the results with published norms, PCS and MCS are used as the outcome measures in summarizing the SF-36 data. | 3 years | 
| Quality of Life (QOL) - EQ-5D | QOL will be compared between the 2 arms using the EQ-5D survey. The EQ-5D contains a five-item survey with three response levels per item measuring mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D takes approximately 1 minute to complete (Agency for Healthcare Research and Quality, 2005). The EQ-5D score ranges -0.224 to 1. The maximum score of 1 indicates the best health state, by contrast with the scores of individual questions, where higher scores indicate more severe or frequent problems. The self-reported questionnaire will be completed at enrollment and at 6, 12, 18, 24, and 36 months from consent. | 3 years | 
| Percentage of Participants With Overall Survival (OS) in As-treated Population | Time to event outcomes will be analyzed from the time of consent. Death from any cause will be considered an event for this endpoint. Surviving participants are censored at the time of last follow-up. Three-year OS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy. | 3 years | 
| Percentage of Participants With Leukemia-free Survival (LFS) in As-treated Population | LFS is defined as the time from the date of patient consent to the date of progression to AML or death from any cause, whichever comes first. Progression to AML is defined as > 20% leukemic blasts in bone marrow or in the peripheral blood. Death from any cause or transformation of MDS to AML are considered events for this endpoint. Participants without either event are censored at the time of last follow-up. Three year leukemia-free survival probability estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy. | 3 years | 
| Percentage of Participants on HCT Arm With Overall Survival (OS) | The time to event outcomes is evaluated from the time of transplant. Death from any cause will be considered an event for this endpoint. Surviving participants are censored at the time of last follow-up. OS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy. | 27 months post-transplant | 
| Percentage of Participants on HCT Arm With Disease Relapse | Outcome Measure Description: The time to event outcomes is evaluated from the time of transplant. Disease relapse is defined as: Satisfying criteria for evolution into acute leukemia; or reappearance of pre-transplant morphologic abnormalities, detected in bone marrow specimens; or reappearance of pre-transplant cytogenetic abnormality in at least one metaphase on each of two separate consecutive examinations at least one month apart, regardless of the number of metaphases analyzed; or institution of any therapy to treat relapsed disease (institution of any therapy not meant for maintenance or prevention), including withdrawal of immunosuppressive therapy or DLI. Relapse estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy. | 27 months post-transplant | 
| Percentage of Participants on HCT Arm With Disease-free Survival (DFS) | The time to event outcomes is evaluated from the time of transplant. Death or disease relapse/progression will be considered as events for this endpoint. Surviving participants are censored at the time of last follow-up. DFS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy. | 27 months post-transplant | 
| Percentage of Participants on HCT Arm With Treatment-related Mortality | The time to event outcomes is evaluated from the time of transplant. The events are deaths prior to disease relapse. TRM estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy. | 27 months post-transplant | 
| Percentage of Participants on HCT Arm With Grade II-IV Acute GVHD (aGVHD) | Grade II-IV aGVHD is the event. aGVHD will be graded according to the BMT CTN Manual of Procedures (MOP). Staging for skin: Stage 1. <25% rash; 2. 25-50%; 3. >50%; 4. generalized erythroderma with bullae. Staging for GI: Stage 1. Diarrhea>500ml/d or persistent nausea; 2. >1000ml/d; 3. >1500ml/d; 4. Large volume diarrhea and severe abdominal pain +- ileus. Staging for Liver: Stage 1. bilirubin 2-3mg/dl; 2. bilirubin 3-6 mg/dl; 3. bilirubin 6-15 mg/dl; 4. bilirubin>15mg/dl. aGVHD grading is performed by the consensus conference criteria (Przepiorka et al. 1995). Grade I aGVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. | 27 months post-transplant | 
| Percentage of Participants on HCT Arm With Grade III-IV Acute GVHD | The time to event outcomes is evaluated from the time of transplant. Grade III-IV Acute GVHD will be considered as events for this endpoint. | 27 months post-transplant | 
| Percentage of Participants on HCT Arm With Chronic GVHD | The time to event outcomes is evaluated from the time of transplant. Chronic GVHD will be considered as events for this endpoint. Data will be collected and reviewed according to the recommendations of the NIH Consensus Criteria. Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will also be recorded. This secondary endpoint of chronic GVHD will include mild, moderate and severe chronic GVHD based on NIH Consensus Criteria. | 27 months post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelodysplastic Syndrome