A Platform Protocol to Investigate Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis in Patients With Hematologic Malignancies Undergoing Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation

NCT06859424 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: ACCELERATE
• Study Type: interventional
• Target: 358
• Locations: 1 country
• Sites: 13

Brief Summary

The purpose of this clinical trial is to compare drug combinations to learn which drugs work best to prevent graft-versus-host-disease (GVHD) in people who have received a stem cell transplant. The source of stem cells is from someone who is not related and has a different blood cell type than the study participant. The researchers will compare the new drug combination to a standard drug combination. They will also learn about the safety of each drug combination. Participants will:

• Receive the standard or new drug combination after transplant
• Visit the doctor's office for check-ups and tests after transplant that are routine for most transplant patients
• Take surveys about physical and emotional well-being
• Give blood and stool samples.

Conditions

AML (Acute Myelogenous Leukemia); Acute Lymphoid Leukemia (ALL); Acute Leukemia (Category); MDS (Myelodysplastic Syndrome); CML (Chronic Myelogenous Leukemia); Prolymphocyctic Leukemia; Chronic Myelomonocytic Leukemia (CMML); Myeloproliferative Neoplasm (MPN); Lymphoma; Myelofibrosis; CLL (Chronic Lymphocytic Leukemia)

Keywords

ACCELERATE; ACCEL-001; ACCEL-002

Outcome Measures

Primary Outcomes (2)

• Graft-versus-host disease-free, relapse-free survival (GRFS)

  To compare GRFS following transplantation of a PBSC product from a MMUD between standard-of-care PTCy-based GVHD prophylaxis (the control arm) and the combination of reduced-dose PTCy, ruxolitinib, tacrolimus, and MMF.

  1 year post-HCT

• Graft-versus-host disease-free, relapse-free survival (GRFS)

  To compare GRFS following transplantation of a PBSC product from a MMUD between standard-of-care PTCy-based GVHD prophylaxis (the control arm) and the combination of reduced-dose PTCy, abatacept, and tacrolimus.

  1 year post-HCT

Secondary Outcomes (14)

• Graft-versus-host disease-free survival (GFS)

  1 year post-HCT

• Infection-free survival (IFS)

  1 year post-HCT

• Overall survival (OS)

  1 year post-HCT

• Progression-free survival (PFS)

  1 year post-HCT

• Non-relapse mortality (NRM)

  1 year post-HCT

Study Arms (3)

Control/SOC

EXPERIMENTAL

Shared comparator control group

Drug: Conditioning Regimen A; Drug: Conditioning Regimen B; Drug: Conditioning Regimen C; Drug: Conditioning Regimen D; Drug: Conditioning Regimen E; Procedure: Hematopoietic Cell Transplantation; Drug: PTCy (50 mg/kg D3, D4); Drug: Post-transplant Tacrolimus; Drug: Post-transplant Mycophenolate mofetil; Drug: Supportive Care: Growth Factors; Procedure: Supportive Care: Blood Products; Other: Supportive Care: Infection Prophylaxis; Other: Supportive Care: Intravenous immune globulin (IVIG); Drug: Supportive Care: Seizure prophylaxis; Other: Supportive Care: Monitoring and management of CRS; Other: Study treatment compliance; Other: Prohibited Concomitant Therapy; Other: Permitted Concomitant Therapy

ACCEL-001

EXPERIMENTAL

Intervention 1

Drug: Conditioning Regimen A; Drug: Conditioning Regimen B; Drug: Conditioning Regimen C; Drug: Conditioning Regimen D; Drug: Conditioning Regimen E; Procedure: Hematopoietic Cell Transplantation; Drug: PTCy (25 mg/kg D3, D4); Drug: Post-transplant Tacrolimus; Drug: Post-transplant Abatacept; Drug: Supportive Care: Growth Factors; Procedure: Supportive Care: Blood Products; Other: Supportive Care: Infection Prophylaxis; Other: Supportive Care: Intravenous immune globulin (IVIG); Drug: Supportive Care: Seizure prophylaxis; Other: Supportive Care: Monitoring and management of CRS; Other: Supportive Care: Prophylaxis against infections; Other: Study treatment compliance; Other: Prohibited Concomitant Therapy; Other: Permitted Concomitant Therapy

ACCEL-002

EXPERIMENTAL

Intervention 2

Drug: Conditioning Regimen A; Drug: Conditioning Regimen B; Drug: Conditioning Regimen C; Drug: Conditioning Regimen D; Drug: Conditioning Regimen E; Procedure: Hematopoietic Cell Transplantation; Drug: PTCy (25 mg/kg D3, D4); Drug: Post-transplant Tacrolimus; Drug: Post-transplant Mycophenolate mofetil; Drug: Post-transplant Ruxolitinib; Drug: Supportive Care: Growth Factors; Procedure: Supportive Care: Blood Products; Other: Supportive Care: Infection Prophylaxis; Other: Supportive Care: Intravenous immune globulin (IVIG); Drug: Supportive Care: Seizure prophylaxis; Other: Supportive Care: Monitoring and management of CRS; Drug: Supportive Care: Prophylaxis against infections; Other: Supportive Care: Lipid elevations; Other: Study treatment compliance; Other: Prohibited Concomitant Therapy; Other: Permitted Concomitant Therapy

Interventions

Conditioning Regimen B DRUG

Fludarabine and TBI The recommended fludarabine plus TBI regimen is the following: * Days -7, -6 and -5: Flu (30 mg/m2/day, maximum cumulative dose, 90 mg/m2), IV * Days -4 to -1: TBI (150 cGy administered twice daily, 1200 cGy total dose) * Radiation sources, dose rates, and shielding follow institutional practice. * Although not required, it is recommended that palifermin be used to mitigate the risk of mucosal toxicity with this regimen.

ACCEL-001; ACCEL-002; Control/SOC

Conditioning Regimen C DRUG

Fludarabine and busulfan (Flu/Bu) The recommended Flu/Bu regimen is the following: * Days -6 to -2: Flu (30 mg/m2/day, recommended total dose of 150 mg/m2, but not exceeding 180 mg/m2), IV Busulfan options * Days -5 to -4: Busulfan without PK - Busulfan 3.2 mg/kg/day IV or oral equivalent; total dose of 6.4 mg/kg IV or oral equivalent respectively * Days -5 to -4: Busulfan with PK - target doses to AUC of 4000 μMol/min or BPEU of 16.43 mg x h/L (total BPEU of 65.72 mg x h/L) or less is allowed.

ACCEL-001; ACCEL-002; Control/SOC

Conditioning Regimen D DRUG

Fludarabine and melphalan (Flu/Mel) The recommended Flu/Mel regimen is the following: * Days -7 to -3: Flu (30 mg/m2/day or 25 mg/m2/day, total dose of 125-150 mg/m2), IV * Day -1: Mel (100-140 mg/m2 IV for recipients aged 18-59; dose of melphalan cannot exceed 100mg/m2 if age 60 or older or calculated glomerular filtration rate (GFR) is \<60 ml/min), IV

ACCEL-001; ACCEL-002; Control/SOC

Conditioning Regimen E DRUG

Fludarabine/cyclophosphamide/total body irradiation (Flu/Cy/TBI) The recommended Flu/Cy/TBI regimen is the following: * Days -6 to -5: Cy (14.5 mg/kg/day IV, total dose of 29 mg/kg, or single dose 50 mg/kg on Day -6 \[Minnesota regimen\]) * Days -6 to -2: Flu (30 mg/m2/day, total dose of 150 mg/m2) IV * Day -1: TBI 200 cGy single dose Hydration and Mesna may be administered per institutional standards. For recipients of RIC/NMA AND donors matched at \<7/8, consider the addition of TBI 200-300cGy for the Flu/Bu and Flu/Mel regimens to mitigate the risk of primary graft failure.

ACCEL-001; ACCEL-002; Control/SOC

Hematopoietic Cell Transplantation PROCEDURE

* On Day 0, the donor PBSC graft is infused. * Donor PBSC will be collected per NMDP/donor registry policies with a target viable CD34+ cell dose of at least 4 × 106 /kg recipient weight (actual, ideal, or adjusted ideal per institutional practice). * Dose of CD34+ cells/kg and CD3 cells/kg infused will be recorded. * If the donor PBSC graft is cryopreserved prior to the start of conditioning, follow institutional practices to ensure a sufficient cell dose is available for infusion after thawing. * The graft cannot be manipulated ex vivo to deplete T cells.

ACCEL-001; ACCEL-002; Control/SOC

PTCy (50 mg/kg D3, D4) DRUG

Cyclophosphamide (50mg/kg ideal body weight (IBW); \[if actual body weight (ABW) \< IBW, use ABW\]) will be given on Day +3 (between 60 and 72 hours after the start of the PBSC infusion) and on Day 4 post HCT (approximately 24 hours after Day +3 cyclophosphamide). Cyclophosphamide will be given as an intravenous (IV) infusion over 1-2 hours (depending on volume), or according to institutional standards. Hydration pre- and post- cyclophosphamide and Mesna administration will be given per institutional standards. No systemic immunosuppressive agents are given until at least 24 hours after the completion of the PTCy. This includes corticosteroids as anti-emetics but excludes any drugs listed in section 7.9.1. Azoles (e.g., posaconazole or voriconazole) must be delayed from beginning of conditioning through completion of Day 4 PTCy dose to avoid potential drug-drug interactions with cyclophosphamide that could lead to increased toxicity.

Control/SOC

PTCy (25 mg/kg D3, D4) DRUG

Cyclophosphamide (25mg/kg ideal body weight (IBW); \[if actual body weight (ABW) \< IBW, use ABW\]) will be given on Day +3 (between 60 and 72 hours after the start of the PBSC infusion) and on Day 4 post HCT (approximately 24 hours after Day +3 cyclophosphamide). Cyclophosphamide will be given as an intravenous (IV) infusion over 1-2 hours (depending on volume), or according to institutional standards. Hydration pre- and post- cyclophosphamide and Mesna administration will be given per institutional standards. No systemic immunosuppressive agents are given until at least 24 hours after the completion of the PTCy. This includes corticosteroids as anti-emetics but excludes any drugs listed in Table 4 and Table 5 in Section 7.1. Azoles (e.g., posaconazole or voriconazole) must be delayed from beginning of conditioning through completion of Day 4 PTCy dose to avoid potential drug-drug interactions with cyclophosphamide that could lead to increased toxicity.

ACCEL-001; ACCEL-002

Post-transplant Tacrolimus DRUG

Tacrolimus will be given per institutional practices, at a dose of 0.05 mg/kg per os (PO) or an IV dose of 0.03 mg/kg of IBW starting on Day + 5. The dose of tacrolimus may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels per institutional guidelines with a suggested range of 5-12 ng/mL. If subjects are on medications which alter the metabolism of tacrolimus (e.g., concurrent CYP3A4 inhibitors), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper is recommended to be initiated at 100 days post HCT if there is no evidence of active GVHD and ended by Day + 180 post HCT.

ACCEL-001; ACCEL-002; Control/SOC

Post-transplant Mycophenolate mofetil DRUG

MMF will be given at a dose of 15 mg/kg 3 times daily (TID) (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1g TID, IV or PO). MMF prophylaxis will start Day + 5 and continue until Day + 35 post-transplant, at which time it should be discontinued (no taper necessary). Study site investigators may modify dose/taper early if clinically indicated for the study subject. Dose rounding may be done per institutional practice.

ACCEL-002; Control/SOC

Post-transplant Abatacept DRUG

Abatacept will be given at a dose of 10 mg/kg with a maximum of 1000 mg.

ACCEL-001

Post-transplant Ruxolitinib DRUG

Ruxolitinib will be given at a dose of 5 mg/kg twice daily starting at Day 30 post HCT, provided both the absolute neutrophil count (ANC) is \> 1000/μl and platelet count is \>30,000/μl.

ACCEL-002

Supportive Care: Growth Factors DRUG

Granulocyte colony-stimulating factor (G-CSF) to accelerate neutrophil recovery should be administered starting at Day +5 with dose, route of administration, formulation, and duration of administration following institutional guidelines. Filgrastim biosimilars are permissible, but granulocyte-macrophage colony-stimulating factors are not permissible.

ACCEL-001; ACCEL-002; Control/SOC

Supportive Care: Blood Products PROCEDURE

Transfusion thresholds for blood product support will be consistent with standard institutional guidelines. All blood products must be irradiated.

ACCEL-001; ACCEL-002; Control/SOC

Supportive Care: Infection Prophylaxis OTHER

Subjects should receive infection prophylaxis according to institutional guidelines and in accordance with the Center for Disease Control (CDC) guidelines49. Infection prophylaxis will include, but is not limited to, agents or strategies (e.g., polymerase chain reaction \[PCR\] screening and preemptive therapy) to reduce the risk of bacterial, viral (e.g., adenovirus, CMV, EBV, herpes simplex), opportunistic (e.g. Pneumocystis jirovecii, Toxoplasma gondii) and fungal (yeast and mold) infections. Infection risk should assess patient-, pathogen-, and immune-related factors that increase susceptibility to infection. Minimal parameters requiring prophylaxis include but are not limited to neutropenia (ANC≤500/μL), lymphopenia (ALC≤500/μL), and exposure to immunosuppression or GvHD. Use of intravenous immunoglobulin (IVIG) should be considered for total IgG\<400 mg/dL during exposure to immunosuppression and/or GvHD.

ACCEL-001; ACCEL-002; Control/SOC

Supportive Care: Seizure prophylaxis DRUG

Subjects will receive busulfan seizure prophylaxis with levetiracetam, fosphenytoin, or lorazepam per institutional guidelines.

ACCEL-001; ACCEL-002; Control/SOC

Supportive Care: Monitoring and management of CRS OTHER

The use of HLA-mismatched PBSC has been associated with greater risk of CRS relative to bone marrow. Following the infusion of MMUD PBSC on Day 0, subjects should be monitored daily through Day 14 for the development of CRS. High index of suspicion is urged, particularly in the few days following infusion. Many sites have successfully intervened with tocilizumab in order to avoid severe or prolonged CRS. Supportive care is encouraged for CRS Grades 1-2 and tocilizumab (or alternative) is recommended for CRS grade 3-4 where subject outcome may be impacted (Appendix G - CRS Guidance and Management).

ACCEL-001; ACCEL-002; Control/SOC

Supportive Care: Prophylaxis against infections OTHER

Consider monitoring for EBV reactivation during abatacept treatment and continue for six months following HCT. Consider monitoring and prophylaxis for CMV infection/reactivation during abatacept treatment and for six months following HCT.

ACCEL-001

Supportive Care: Lipid elevations OTHER

Assess lipid levels 8-12 weeks from start of therapy with ruxolitinib and treat as needed.

ACCEL-002

Study treatment compliance OTHER

The administration of study agents must be recorded in the subject's medical chart for verification of study treatment compliance.

ACCEL-001; ACCEL-002; Control/SOC

Prohibited Concomitant Therapy OTHER

Prophylactic anti-viral cellular therapies and/or co-enrollment on studies using therapies for the prevention of GVHD is prohibited. Subjects reported to have received prohibited therapy while on this study will be withdrawn and will not be included in the primary and secondary analyses. No concomitant systemic immunosuppressive agents can be administered during PTCy (Day 3 and Day 4). If needed, administer at least 24 hours after completion of Day 4 PTCy. It is crucial that no systemic immunosuppressive agents are given until at least 24 hours after completion of the Day +4 dose of PTCy. This includes corticosteroids as anti-emetics but excludes tacrolimus and MMF. Steroid use is permitted as pre-medication prior to start of conditioning but is prohibited from Day 0 through 24 hours post Day 4 PTCy administration. If prohibited therapies are administered, these data must be reported in the study EDC on the Concomitant Medications form.

ACCEL-001; ACCEL-002; Control/SOC

Permitted Concomitant Therapy OTHER

Pre-medication and/or treatment for possible AEs related to PTCy are permitted. Subjects may continue all medications in compliance with local treatment center and local institutional guidelines, except those described in Section 7.9.1. If GVHD or infection occurs, enrollment on a clinical trial to treat infection or GVHD is permissible. At time of relapse, patients are permitted to enroll on a clinical trial or receive disease targeted therapy. The following medications/therapies must be reported on the study EDC Concomitant Medications form: * Medications taken to treat adverse events that have been reported on the study EDC Adverse Event form. * Antimicrobial prophylaxis (viral, bacterial, fungal, parasitic). * Antimicrobial pharmaceutical and cellular therapies used to treat grade II-III infections per BMT CTN grading criteria (Appendix D - BMT CTN Infection Grading). * Post HCT, primary malignant disease-directed pharmaceutical and cellular therapies. * Planned maintenance therapy

ACCEL-001; ACCEL-002; Control/SOC

Conditioning Regimen A DRUG

Busulfan and fludarabine Recommended schedule as below: * Days -6 to -3: Busulfan ≥ 9 mg/kg total dose (IV or PO) with pharmacokinetic (PK) monitoring recommended as per institutional practice to achieve a daily area under the curve (AUC) target of 4800-5300 μM\*min47 or busulfan plasma exposure units (BPEU) 19.7-21.75 mg x h/L48. * Days -6 to -2: Flu 30 mg/m2/day (adjusted for renal function) is administered over a 30-60 minute IV infusion (maximum cumulative dose, 150 mg/m2).

ACCEL-001; ACCEL-002; Control/SOC

Supportive Care: Intravenous immune globulin (IVIG) OTHER

Intravenous immune globulin (IVIG) administration will be according to local institutional standard practice for hypogammaglobulinemia but is generally not recommended.

ACCEL-001; ACCEL-002; Control/SOC

Eligibility Criteria

• Age: 18 Years - 66 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 to \< 66 years (chemotherapy-based conditioning) or \< 61 years (TBI-based conditioning) at the time of signing informed consent
• Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and institutional requirements
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Planned MAC regimen (see Table 8 in Section 7.4 for allowed MAC regimens)
• Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age 16-35
• Product planned for infusion is MMUD T-cell replete PBSC as allograft
• One of the following diagnoses:
• AML, ALL, or other acute leukemia in first remission or beyond with ≤ 5% marrow blasts and no circulating blasts or evidence of extramedullary disease. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
• Patients with MDS with no circulating blasts and with \< 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with \< 5% vs 5-10% blasts in MDS). Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
• Cardiac function: Left ventricular ejection fraction ≥ 45% based on most recent echocardiogram or multi-gated acquisition scan (MUGA) results
• Estimated creatinine clearance ≥ 45mL/min calculated by equation
• Pulmonary function: diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for hemoglobin ≥ 50% and forced expiratory volume in first second (FEV1) predicted ≥ 50% based on most recent PFT results
• Liver function acceptable per local institutional guidelines
• KPS of ≥ 70% (Appendix I - Performance Status)
• Age ≥ 18 years at the time of signing informed consent

You may not qualify if:

• Suitable HLA-matched related or 8/8 high-resolution matched unrelated donor available
• Subject unwilling or unable to give informed consent, or unable to comply with the protocol including required follow-up and testing
• Subjects with a prior allogeneic transplant
• Subjects with an autologous transplant within the past 3 months
• Subjects who are breastfeeding or pregnant
• Uncontrolled bacterial, viral or fungal infection at the time of the transplant preparative regimen
• Concurrent enrollment on a GVHD prevention clinical trial
• Subjects who undergo desensitization to reduce anti-donor HLA antibody levels prior to transplant
• Patients who are HIV-positive with persistently positive viral load. HIV-infected patients on effective anti-retroviral therapy (ART) with undetectable viral load within 6 months are eligible for this trial. Patients with well-controlled HIV are eligible provided resistance panels are negative, the patient is compliant with ART, and their disease remains well controlled.

Sponsors & Collaborators

• Center for International Blood and Marrow Transplant Research: lead
• National Marrow Donor Program: collaborator
• Incyte Corporation: collaborator

Study Sites (13)

University of Alabama Birmingham

Birmingham, Alabama, 35294, United States

RECRUITING

City of Hope

Duarte, California, 91010, United States

RECRUITING

Stanford

Palo Alto, California, 94304, United States

RECRUITING

University of Miami

Miami, Florida, 33136, United States

RECRUITING

University of Kansas Medical Center

Westwood, Kansas, 66205, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02446, United States

RECRUITING

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

RECRUITING

Memorial Sloan Kettering

New York, New York, 10065, United States

RECRUITING

University of North Carolina

Chapel Hill, North Carolina, 27514, United States

RECRUITING

Oregon Health & Science University

Portland, Oregon, 97239, United States

RECRUITING

MD Anderson

Houston, Texas, 77030, United States

RECRUITING

University of Virginia

Charlottesville, Virginia, 22903, United States

RECRUITING

Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Anemia, Refractory, with Excess of Blasts; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, B-Cell; Leukemia, Myelomonocytic, Chronic; Myeloproliferative Disorders; Lymphoma; Primary Myelofibrosis

Interventions

Stem Cell Transplantation

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Anemia, Refractory; Anemia; Myelodysplastic Syndromes; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Myelodysplastic-Myeloproliferative Diseases

Intervention Hierarchy (Ancestors)

Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative

Central Study Contacts

Leigh Anne Blackmon, MSW

CONTACT

763-406-8087; accelerate@nmdp.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: A randomized, multi-center, prospective, controlled platform trial design.

Study Record Dates

• First Submitted: February 28, 2025
• First Posted: March 5, 2025
• Study Start: July 25, 2025
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028
• Last Updated: March 17, 2026

Record last verified: 2026-03

Locations

US (13)