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

Overview

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.

Detailed description

This platform protocol will evaluate the safety and efficacy of post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GVHD) prophylaxis after mismatched unrelated donor (MMUD) hematopoietic cell transplant (HCT). Participants with malignant hematologic diseases eligible per inclusion criteria, receiving MMUD peripheral blood stem cells (PBSCs) after myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) will be eligible to be enrolled by participating transplant centers. The platform protocol will estimate endpoints and provide a comparator arm for investigational interventional arms (ISAs).

Two investigational ISAs are part of the platform protocol - ACCEL-001 and ACCEL-002. The ISAs describe the specific features of the intervention being studied and treatment of participants assigned to that intervention, the specific target population, sample size required based on comparison to the control arm, specific study objectives, statistical methods for evaluating the interventions, and other specific intervention-related information and assessments. Additional ISAs may be added or closed throughout the lifetime of the trial.

Interventions

• Drug Conditioning Regimen A
  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).
• Drug Conditioning Regimen B
  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.
• Drug Conditioning Regimen C
  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
• Drug Conditioning Regimen D
  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
• Drug Conditioning Regimen E
  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 200-300c
• Procedure Hematopoietic Cell Transplantation
  * 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
• Drug PTCy (50 mg/kg D3, D4)
  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 institut
• Drug PTCy (25 mg/kg D3, D4)
  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 institut
• Drug Post-transplant Tacrolimus
  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
• Drug Post-transplant Mycophenolate mofetil
  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.

Primary outcome measures

• Graft-versus-host disease-free, relapse-free survival (GRFS) [Time frame: 1 year post-HCT]
• Graft-versus-host disease-free, relapse-free survival (GRFS) [Time frame: 1 year post-HCT]

Secondary outcome measures (12)

• Graft-versus-host disease-free survival (GFS) [Time frame: 1 year post-HCT]
• Infection-free survival (IFS) [Time frame: 1 year post-HCT]
• Overall survival (OS) [Time frame: 1 year post-HCT]
• Progression-free survival (PFS) [Time frame: 1 year post-HCT]
• Non-relapse mortality (NRM) [Time frame: 1 year post-HCT]
• Cumulative incidence of relapse and disease progression [Time frame: 1 year post-HCT]
• Cumulative incidence of neutrophil engraftment [Time frame: 1 year post-HCT]
• Cumulative incidence of platelet engraftment [Time frame: 1 year post-HCT]
• Primary graft failure (PGS) and secondary graft failure (SGF) [Time frame: 1 year post-HCT]
• Incidence of ≥ grade 2 infections [Time frame: 1 year post-HCT]
• Donor cell engraftment [Time frame: 1 year post-HCT]
• Cumulative incidence of aGVHD [Time frame: 1 year post-HCT]

Eligibility criteria

Inclusion Criteria, MAC RECIPIENTS:

• 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
• HCT-CI < 5 (Appendix H - Hematopoietic Cell Transplant Comorbidity Index Scoring). The presence of prior malignancy will not be used to calculate HCT-CI for this trial, to allow for the inclusion of patients with secondary or therapy-related AML or MDS.
• 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)

Inclusion Criteria, RIC/NMA RECIPIENTS:

• Age ≥ 18 years 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 local institutional requirements
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Planned NMA/RIC regimen (see
• Table 9 in Section 7.4 for allowed NMA/RIC 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 allograft
• One of the following diagnoses:

• Patients with acute leukemia or chronic myeloid leukemia (CML) with no circulating blasts, no evidence of extramedullary disease, and with < 5% blasts in the bone marrow. 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.
• Patients with chronic lymphocytic leukemia (CLL) or other leukemias (including prolymphocytic leukemia) with chemosensitive disease at time of transplantation.
• Higher-risk chronic myelomonocytic leukemia (CMML) according to CMML-specific prognostic scoring system or high-risk MDS/myeloproliferative neoplasms (MPN) not otherwise specified are eligible, provided there is no evidence of high-grade bone marrow fibrosis or massive splenomegaly at the time of enrollment.
• Patients with lymphoma with chemosensitive disease at the time of transplantation.
• Patients with primary myelofibrosis or myelofibrosis secondary to essential thrombocythemia, polycythemia vera or MDS with grade 4 fibrosis.
• Cardiac function: Left ventricular ejection fraction ≥ 40% based on most recent echocardiogram or MUGA results with no clinical evidence of heart failure
• Estimated creatinine clearance ≥ 45mL/min calculated by equation
• Pulmonary function: DLCO corrected for hemoglobin ≥ 50% and FEV1 predicted ≥ 50% based on most recent PFT results
• Liver function acceptable per local institutional guidelines
• KPS of ≥ 60% (Appendix I - Performance Status)

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 13 centers

• University of Alabama Birmingham — Birmingham
• City of Hope — Duarte
• Stanford — Palo Alto
• University of Miami — Miami
• University of Kansas Medical Center — Westwood
• Dana-Farber Cancer Institute — Boston
• Karmanos Cancer Institute — Detroit
• Memorial Sloan Kettering — New York
• … and 5 more centers

Identifiers

NCT: NCT06859424 · ACCELERATE

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗