HLA-Mismatched Unrelated Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide

A Multi-Center, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide for Patients With Hematologic Malignancies

This is a multi-center, single arm Phase II study of hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)-mismatched unrelated bone marrow transplantation donors and post-transplantation cyclophosphamide (PTCy), sirolimus and mycophenolate mofetil (MMF) for graft versus host disease (GVHD) prophylaxis in patients with hematologic malignancies.

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia (CLL); Myelodysplastic Syndrome (MDS); Acute Myelogenous Leukemia (AML); Chemotherapy-sensitive Lymphoma; Acute Lymphoblastic Leukemia (ALL)/T Lymphoblastic Lymphoma; Acute Biphenotypic Leukemia (ABL); Acute Undifferentiated Leukemia (AUL)
• Intervention / Treatment: Drug: Fludarabine; Drug: Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5; Radiation: Total Body Irradiation (TBI) 200cGy on Day -1; Procedure: Infusion of non-T-cell depleted bone marrow on Day 0; Drug: Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4; Drug: Sirolimus; Drug: Mycophenolate mofetil; Drug: G-CSF; Drug: Pre-HCT Mesna on Days -6 and -5; Drug: Post-HCT Mesna; Drug: Busulfan; Drug: Cyclophosphamide 50mg/kg/day IV on Days -2,-1; Drug: Pre-HCT Mesna on Days -2 and -1; Drug: Cyclophosphamide 50mg/kg/day IV on Days -5,-4; Radiation: Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1; Drug: Pre-HCT Mesna on Days -5 and -4

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • Shands HealthCare & University of Florida
    • Miami, Florida, United States, 33136
      • University of Miami
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Greenebaum Cancer Center
    • Baltimore, Maryland, United States, 21287
      • The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center - Adults
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Hospitals
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State Medical Center, James Cancer Center
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Massey Cancer Center Bone Marrow Transplant Program
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Memorial Lutheran Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 70 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 15 years and < 71 years at the time of signing the informed consent form
2. Partially HLA-mismatched unrelated donor: HLA typing will be performed at high resolution (allele level) for the HLA-A, -B, -C, and -DRB1 loci; a minimum match of 4/8 at HLA-A, -B, -C, and -DRB1 is required
3. Product planned for infusion is bone marrow

4. Disease and disease status:

   1. Acute Leukemias or T lymphoblastic lymphoma in 1st or subsequent complete remission (CR): Acute lymphoblastic leukemia (ALL)/T lymphoblastic lymphoma; acute myelogenous leukemia (AML); acute biphenotypic leukemia (ABL); acute undifferentiated leukemia (AUL)
   2. Myelodysplastic Syndrome (MDS), fulfilling the following criteria: Subjects 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; Subjects must have < 20% bone marrow blasts, assessed within 60 days of informed consent; Subjects may have received prior therapy for the treatment of MDS prior to enrollment
   3. Chronic Lymphocytic Leukemia (CLL) in CR if RIC is to be used; in CR or partial response (PR) if FIC is to be used
   4. Chronic myeloid leukemia (CML) in 1st or subsequent chronic phase characterized by <10% blasts in the blood or bone marrow.
   5. Chemotherapy-sensitive lymphoma in status other than 1st CR
5. Performance status: Karnofsky or Lansky score ≥ 60% (Appendix A)

6. Adequate organ function defined as:

   1. Cardiac: left ventricular ejection fraction (LVEF) at rest ≥ 35% (RIC cohort) or LVEF at rest ≥ 40% (FIC cohort), or left ventricular shortening fraction (LVFS) ≥ 25%
   2. Pulmonary: diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume (FEV1), forced vital capacity (FVC) ≥ 50% predicted by pulmonary function tests (PFTs)
   3. Hepatic: total bilirubin ≤ 2.5 mg/dL, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) < 5 x upper limit of (ULN) (unless disease related)
   4. Renal: serum creatinine (SCr) within normal range for age (see table 2.3). If SCr is outside normal range for age, creatinine clearance (CrCl) > 40 mL/min/1.73m2 must be obtained (measured by 24-hour (hr) urine specimen or nuclear glomerular filtration rate (GFR), or calculated GFR (by Cockcroft-Gault formula for those aged ≥ 18 years; by Original Schwartz estimate for those < 18 years))
7. Subjects ≥ 18 years of age must have the ability to give informed consent according to applicable regulatory and local institutional requirements. Legal guardian permission must be obtained for subjects < 18 years of age. Pediatric subjects will be included in age appropriate discussion in order to obtain assent.

8. Subjects with documentation of confirmed HIV-1 infection (i.e. HIV-positive), and a hematologic malignancy who meets all other eligibility requirements must:

   1. Receive only RIC regimen (i.e. Regimen A)
   2. Be willing to comply with effective antiretroviral therapy (ARV)
   3. Have achieved a sustained virologic response for 12 weeks after cessation of hepatitis C antiviral treatment (in HIV-positive subjects with hepatitis C)

Exclusion Criteria:

1. HLA-matched related or 8/8 allele matched (HLA-A, -B, -C, -DRB1) unrelated donor available. This exclusion does not apply to HIV-positive subjects who have a CCR5delta32 homozygous donor.
2. Autologous HCT < 3 months prior to the time of signing the informed consent form
3. Females who are breast-feeding or pregnant

4. HIV-positive subjects:

   1. Acquired immunodeficiency syndrome (AIDS) related syndromes or symptoms that may pose an excessive risk for transplantation-related morbidity as determined by the Treatment Review Committee (see Appendix D).
   2. Untreatable HIV infection due to multidrug ARV resistance. Subjects with a detectable or standard viral load > 750 copies/mL should be evaluated with an HIV drug resistance test (HIV-1 genotype). The results should be included as part of the ARV review (described in Appendix D).
   3. May not be currently prescribed ritonavir, cobacistat and/or zidovudine
5. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings)
6. Prior allogeneic HCT
7. History of primary idiopathic myelofibrosis
8. MDS subjects may not receive RIC and must be < 50 years of age at the time of signing the informed consent form

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Regimen A (RIC: Flu/Cy/TBI); Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2; Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5; Total Body Irradiation (TBI) 200cGy on Day -1; Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.	Drug: Fludarabine; Fludarabine 30 mg/m2/day (adjusted for renal function) is administered over a 30-60 minute IV infusion on Days -6 through -2 (maximum cumulative dose, 150 mg/m2).; The body surface area (BSA) for fludarabine dosing is based on adjusted ideal body weight (IBW) (Appendix K).; creatinine clearance may change during the days fludarabine is given. Adjustment in fludarabine dose due to creatinine changes during conditioning is permitted.; Other Names: Fludara®; Drug: Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5; Cy 14.5 mg/kg/day is administered as a 1-2 hour IV infusion on Days -6 and -5 after hydration.; Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.; Hydration prior to Cy may be given according to institutional guideline.; Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual weight.; Other Names: Cytoxan®; Radiation: Total Body Irradiation (TBI) 200cGy on Day -1; 200 cGy TBI is administered in a single fraction on Day -1.; Radiation sources, dose rates, and shielding follow institutional practice.; Procedure: Infusion of non-T-cell depleted bone marrow on Day 0; On Day 0, the harvested bone marrow is infused.; Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated cells/kg recipient weight.; The lowest acceptable nucleated cells yield is 1.5 x 108 cells/kg recipient weight.; Drug: Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4; Cy 50mg/kg IV, over 1-2 hours (depending on volume), is given on Day+3 (ideally between 60 and 72 hours after bone marrow infusion) and on Day+4 (approximately 24 hours after Day+3 Cy).; Hydration with Cy, management of volume status, and monitoring for hemorrhagic cystitis will follow institutional standards.; Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.; Cy is dosed according to IBW, unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual body weight.; Drug: Sirolimus; Sirolimus dosing is based on adjusted IBW (Appendix K).; Sirolimus prophylaxis is discontinued after the last dose on Day+180, or may be continued if there is GVHD. For subjects ≥ 18 years old: A one-time sirolimus loading dose, 6 mg PO, is given on Day+5, at least 24 hours after Cy completion.; Sirolimus is then continued at a maintenance dose (starting dose 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by high performance liquid chromatography (HPLC) or immunoassay. For subjects < 18 years old: A one-time sirolimus loading dose, 3 mg/m2 PO with the dose not to exceed 6 mg, is given on Day+5, at least 24 hours after Cy completion.; Sirolimus is then continued at a maintenance dose (starting dose 1 mg/m2 PO QD, maximum 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by HPLC or immunoassay.; Other Names: rapamycin; Rapamune®; Drug: Mycophenolate mofetil; MMF begins on Day+5, at least 24 hours after completion of PTCy. MMF dose is 15 mg/kg PO TID (adjusted IBW (Appendix K)) with total daily dose not to exceed 3 grams (i.e. maximum 1 g PO TID). An equivalent IV dose (1:1 conversion) may instead be given. MMF prophylaxis is discontinued after the last dose on Day+35, or may be continued if there is GVHD.; Other Names: MMF; Cellcept®; Drug: G-CSF; Granulocyte-colony stimulating factor (G-CSF): filgrastim or a biosimilar begins on Day+5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously (SC) (rounding to the nearest vial dose is allowed), until the absolute neutrophil count (ANC) is ≥ 1,000/mm3 over the course of 3 consecutive days. Additional G-CSF may be administered as warranted.; Other Names: filgrastim; Drug: Pre-HCT Mesna on Days -6 and -5; Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy. Mesna is dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual weight.; Drug: Post-HCT Mesna; Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy on Day+3 and Day+4. Mesna is dosed according to IBW, unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual body weight.
ACTIVE_COMPARATOR: Regimen B 2a (FIC: Bu/Cy); Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO); Cyclophosphamide 50mg/kg/day IV on Days -2,-1; Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.	Procedure: Infusion of non-T-cell depleted bone marrow on Day 0; On Day 0, the harvested bone marrow is infused.; Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated cells/kg recipient weight.; The lowest acceptable nucleated cells yield is 1.5 x 108 cells/kg recipient weight.; Drug: Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4; Cy 50mg/kg IV, over 1-2 hours (depending on volume), is given on Day+3 (ideally between 60 and 72 hours after bone marrow infusion) and on Day+4 (approximately 24 hours after Day+3 Cy).; Hydration with Cy, management of volume status, and monitoring for hemorrhagic cystitis will follow institutional standards.; Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.; Cy is dosed according to IBW, unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual body weight.; Drug: Sirolimus; Sirolimus dosing is based on adjusted IBW (Appendix K).; Sirolimus prophylaxis is discontinued after the last dose on Day+180, or may be continued if there is GVHD. For subjects ≥ 18 years old: A one-time sirolimus loading dose, 6 mg PO, is given on Day+5, at least 24 hours after Cy completion.; Sirolimus is then continued at a maintenance dose (starting dose 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by high performance liquid chromatography (HPLC) or immunoassay. For subjects < 18 years old: A one-time sirolimus loading dose, 3 mg/m2 PO with the dose not to exceed 6 mg, is given on Day+5, at least 24 hours after Cy completion.; Sirolimus is then continued at a maintenance dose (starting dose 1 mg/m2 PO QD, maximum 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by HPLC or immunoassay.; Other Names: rapamycin; Rapamune®; Drug: Mycophenolate mofetil; MMF begins on Day+5, at least 24 hours after completion of PTCy. MMF dose is 15 mg/kg PO TID (adjusted IBW (Appendix K)) with total daily dose not to exceed 3 grams (i.e. maximum 1 g PO TID). An equivalent IV dose (1:1 conversion) may instead be given. MMF prophylaxis is discontinued after the last dose on Day+35, or may be continued if there is GVHD.; Other Names: MMF; Cellcept®; Drug: G-CSF; Granulocyte-colony stimulating factor (G-CSF): filgrastim or a biosimilar begins on Day+5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously (SC) (rounding to the nearest vial dose is allowed), until the absolute neutrophil count (ANC) is ≥ 1,000/mm3 over the course of 3 consecutive days. Additional G-CSF may be administered as warranted.; Other Names: filgrastim; Drug: Post-HCT Mesna; Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy on Day+3 and Day+4. Mesna is dosed according to IBW, unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual body weight.; Drug: Busulfan; Busulfan ≥ 9mg/kg total dose (IV or PO) on Days -6, -5, -4, -3 (PK monitoring required to achieve a daily area under the curve (AUC) target of 4800-5300 μM*min (Perkins et al., 2012)); Busulfan dosing is based on adjusted IBW (Appendix K); Other Names: Busulfex®; Drug: Cyclophosphamide 50mg/kg/day IV on Days -2,-1; Cy 50mg/kg/day is administered as a 1-2 hour IV infusion on Days -2 and -1 after hydration.; Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.; Hydration prior to Cy may be given according to institutional guideline.; Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual weight.; Other Names: Cytoxan®; Drug: Pre-HCT Mesna on Days -2 and -1; Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy. Mesna is dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual weight.
ACTIVE_COMPARATOR: Regimen B 2b (FIC: Bu/Flu); Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO); Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2; Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.	Drug: Fludarabine; Fludarabine 30 mg/m2/day (adjusted for renal function) is administered over a 30-60 minute IV infusion on Days -6 through -2 (maximum cumulative dose, 150 mg/m2).; The body surface area (BSA) for fludarabine dosing is based on adjusted ideal body weight (IBW) (Appendix K).; creatinine clearance may change during the days fludarabine is given. Adjustment in fludarabine dose due to creatinine changes during conditioning is permitted.; Other Names: Fludara®; Procedure: Infusion of non-T-cell depleted bone marrow on Day 0; On Day 0, the harvested bone marrow is infused.; Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated cells/kg recipient weight.; The lowest acceptable nucleated cells yield is 1.5 x 108 cells/kg recipient weight.; Drug: Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4; Cy 50mg/kg IV, over 1-2 hours (depending on volume), is given on Day+3 (ideally between 60 and 72 hours after bone marrow infusion) and on Day+4 (approximately 24 hours after Day+3 Cy).; Hydration with Cy, management of volume status, and monitoring for hemorrhagic cystitis will follow institutional standards.; Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.; Cy is dosed according to IBW, unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual body weight.; Drug: Sirolimus; Sirolimus dosing is based on adjusted IBW (Appendix K).; Sirolimus prophylaxis is discontinued after the last dose on Day+180, or may be continued if there is GVHD. For subjects ≥ 18 years old: A one-time sirolimus loading dose, 6 mg PO, is given on Day+5, at least 24 hours after Cy completion.; Sirolimus is then continued at a maintenance dose (starting dose 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by high performance liquid chromatography (HPLC) or immunoassay. For subjects < 18 years old: A one-time sirolimus loading dose, 3 mg/m2 PO with the dose not to exceed 6 mg, is given on Day+5, at least 24 hours after Cy completion.; Sirolimus is then continued at a maintenance dose (starting dose 1 mg/m2 PO QD, maximum 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by HPLC or immunoassay.; Other Names: rapamycin; Rapamune®; Drug: Mycophenolate mofetil; MMF begins on Day+5, at least 24 hours after completion of PTCy. MMF dose is 15 mg/kg PO TID (adjusted IBW (Appendix K)) with total daily dose not to exceed 3 grams (i.e. maximum 1 g PO TID). An equivalent IV dose (1:1 conversion) may instead be given. MMF prophylaxis is discontinued after the last dose on Day+35, or may be continued if there is GVHD.; Other Names: MMF; Cellcept®; Drug: G-CSF; Granulocyte-colony stimulating factor (G-CSF): filgrastim or a biosimilar begins on Day+5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously (SC) (rounding to the nearest vial dose is allowed), until the absolute neutrophil count (ANC) is ≥ 1,000/mm3 over the course of 3 consecutive days. Additional G-CSF may be administered as warranted.; Other Names: filgrastim; Drug: Post-HCT Mesna; Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy on Day+3 and Day+4. Mesna is dosed according to IBW, unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual body weight.; Drug: Busulfan; Busulfan ≥ 9mg/kg total dose (IV or PO) on Days -6, -5, -4, -3 (PK monitoring required to achieve a daily area under the curve (AUC) target of 4800-5300 μM*min (Perkins et al., 2012)); Busulfan dosing is based on adjusted IBW (Appendix K); Other Names: Busulfex®
ACTIVE_COMPARATOR: Regimen C (FIC: Cy/TBI); Cyclophosphamide 50mg/kg/day IV on Days -5,-4; Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1; Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.	Procedure: Infusion of non-T-cell depleted bone marrow on Day 0; On Day 0, the harvested bone marrow is infused.; Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated cells/kg recipient weight.; The lowest acceptable nucleated cells yield is 1.5 x 108 cells/kg recipient weight.; Drug: Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4; Cy 50mg/kg IV, over 1-2 hours (depending on volume), is given on Day+3 (ideally between 60 and 72 hours after bone marrow infusion) and on Day+4 (approximately 24 hours after Day+3 Cy).; Hydration with Cy, management of volume status, and monitoring for hemorrhagic cystitis will follow institutional standards.; Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.; Cy is dosed according to IBW, unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual body weight.; Drug: Sirolimus; Sirolimus dosing is based on adjusted IBW (Appendix K).; Sirolimus prophylaxis is discontinued after the last dose on Day+180, or may be continued if there is GVHD. For subjects ≥ 18 years old: A one-time sirolimus loading dose, 6 mg PO, is given on Day+5, at least 24 hours after Cy completion.; Sirolimus is then continued at a maintenance dose (starting dose 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by high performance liquid chromatography (HPLC) or immunoassay. For subjects < 18 years old: A one-time sirolimus loading dose, 3 mg/m2 PO with the dose not to exceed 6 mg, is given on Day+5, at least 24 hours after Cy completion.; Sirolimus is then continued at a maintenance dose (starting dose 1 mg/m2 PO QD, maximum 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by HPLC or immunoassay.; Other Names: rapamycin; Rapamune®; Drug: Mycophenolate mofetil; MMF begins on Day+5, at least 24 hours after completion of PTCy. MMF dose is 15 mg/kg PO TID (adjusted IBW (Appendix K)) with total daily dose not to exceed 3 grams (i.e. maximum 1 g PO TID). An equivalent IV dose (1:1 conversion) may instead be given. MMF prophylaxis is discontinued after the last dose on Day+35, or may be continued if there is GVHD.; Other Names: MMF; Cellcept®; Drug: G-CSF; Granulocyte-colony stimulating factor (G-CSF): filgrastim or a biosimilar begins on Day+5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously (SC) (rounding to the nearest vial dose is allowed), until the absolute neutrophil count (ANC) is ≥ 1,000/mm3 over the course of 3 consecutive days. Additional G-CSF may be administered as warranted.; Other Names: filgrastim; Drug: Post-HCT Mesna; Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy on Day+3 and Day+4. Mesna is dosed according to IBW, unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual body weight.; Drug: Cyclophosphamide 50mg/kg/day IV on Days -5,-4; Cy 50mg/kg/day is administered as a 1-2 hour IV infusion on Days -5 and -4 after hydration.; Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.; Hydration prior to Cy may be given according to institutional guideline.; Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual weight.; Other Names: Cytoxan®; Radiation: Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1; 200cGy TBI is administered in twice daily on Days -3, -2, and -1.; Radiation sources, dose rates, and shielding follow institutional practice.; Drug: Pre-HCT Mesna on Days -5 and -4; Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy. Mesna is dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual weight.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	1 year post transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival		180 days and 365 days post-transplant
Transplant-related mortality		100 days, 180 days, and 365 days post-transplant
Cumulative incidence of neutrophil recovery		1 year post transplant
Cumulative incidence of platelet recovery		1 year post transplant
Cumulative incidence of primary graft failure		56 days post-transplant
Donor Chimerism	Peripheral blood chimerism (% of donor chimerism) in whole blood (unsorted)	28 days, 56 days, 100 days, 180 days, and 365 days post-transplant
Peripheral blood chimerism	The percentage of subjects with peripheral blood (unsorted) chimerism>95%	56 days post-transplant
Cumulative incidence of acute GVHD		100 days post-transplant
Cumulative incidence of chronic GVHD		180 days and 365 days post-transplant
Cumulative incidences of viral reactivations and infections		100 days, 180 days and 365 days post-transplant
Cumulative incidence of relapse/progression		180 days and 365 days post-transplant
Cumulative incidences of thrombotic microangiopathy (TMA) and hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS)		1 year post transplant
Proportion of subjects proceeding to transplant		1 year post transplant
Donor Selection Characteristics	number of mismatches at HLA-A, -B, -C, -DRB1, -DQB1, -DPB1, donor age, donor-recipient CMV serostatus match, donor weight, donor-recipient sex match and donor-recipient ABO group match	1 year post transplant
Time from search to donor identification		1 year post transplant
Subgroup analysis of HIV-positive subjects	If CCR5delta32 homozygous donors are successfully found and used for one or more HIV-positive subjects, a descriptive analysis of baseline characteristics and outcomes for those HIV-positive subjects will be conducted, including the viral load detected over time obtained from collected samples.	1 year post transplant
Donor clonal hematopoiesis	The proportion of subjects developing donor clonal hematopoiesis	100 days and 365 days post-transplant

Collaborators and Investigators

• Sponsor: Center for International Blood and Marrow Transplant Research
• Collaborators: National Marrow Donor Program
• Investigators: Study Chair: Javier Bolaños Meade, MD, Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins; Study Chair: Bronwen E. Shaw, MD, PhD, CIBMTR/Medical College of Wisconsin

Publications and helpful links

General Publications

• Shaw BE, Jimenez-Jimenez AM, Burns LJ, Logan BR, Khimani F, Shaffer BC, Shah NN, Mussetter A, Tang XY, McCarty JM, Alavi A, Farhadfar N, Jamieson K, Hardy NM, Choe H, Ambinder RF, Anasetti C, Perales MA, Spellman SR, Howard A, Komanduri KV, Luznik L, Norkin M, Pidala JA, Ratanatharathorn V, Confer DL, Devine SM, Horowitz MM, Bolanos-Meade J. National Marrow Donor Program-Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide. J Clin Oncol. 2021 Jun 20;39(18):1971-1982. doi: 10.1200/JCO.20.03502. Epub 2021 Apr 27.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2016
• Primary Completion (ACTUAL): March 1, 2020
• Study Completion (ACTUAL): March 1, 2020

Study Registration Dates

• First Submitted: May 31, 2016
• First Submitted That Met QC Criteria: June 2, 2016
• First Posted (ESTIMATE): June 8, 2016

Study Record Updates

• Last Update Posted (ACTUAL): December 2, 2020
• Last Update Submitted That Met QC Criteria: November 30, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Leukemia, Lymphoid; Leukemia, B-Cell; Lymphoma; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Biphenotypic, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Cyclophosphamide; Fludarabine; Mycophenolic Acid; Sirolimus; Busulfan; Mesna
• Other Study ID Numbers: 15-MMUD