NCT02793544 - HLA-Mismatched Unrelated Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide | Crick

Interventions

* 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.

Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5DRUG

* 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.

Total Body Irradiation (TBI) 200cGy on Day -1RADIATION

* 200 cGy TBI is administered in a single fraction on Day -1. * Radiation sources, dose rates, and shielding follow institutional practice.

Infusion of non-T-cell depleted bone marrow on Day 0PROCEDURE

* 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.

BusulfanDRUG

* 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)

Cyclophosphamide 50mg/kg/day IV on Days -2,-1DRUG

* 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.

Cyclophosphamide 50mg/kg/day IV on Days -5,-4DRUG

* 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.

Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1RADIATION

* 200cGy TBI is administered in twice daily on Days -3, -2, and -1. * Radiation sources, dose rates, and shielding follow institutional practice.

Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4DRUG

* 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.

SirolimusDRUG

* 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.

Mycophenolate mofetilDRUG

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.

G-CSFDRUG

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.

Pre-HCT Mesna on Days -6 and -5DRUG

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.

Pre-HCT Mesna on Days -2 and -1DRUG

Pre-HCT Mesna on Days -5 and -4DRUG

Post-HCT MesnaDRUG

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.

Eligibility

Sex: ALLMin age: 15 YearsMax age: 70 Years

Medical Language ↔ Plain English

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

Locations (11)

Shands HealthCare & University of Florida

Gainesville, Florida, United States

University of Miami

Miami, Florida, United States

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

University of Maryland Greenebaum Cancer Center

Baltimore, Maryland, United States

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Karmanos Cancer Institute

Detroit, Michigan, United States

Memorial Sloan Kettering Cancer Center - Adults

New York, New York, United States

University of North Carolina Hospitals

Chapel Hill, North Carolina, United States

Ohio State Medical Center, James Cancer Center

Columbus, Ohio, United States

Virginia Commonwealth University Massey Cancer Center Bone Marrow Transplant Program

Richmond, Virginia, United States

...and 1 more locations

Outcomes

Primary Outcomes

Overall Survival

Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.

Time frame: 365 days post transplant

Secondary Outcomes

Progression-free Survival

Time from HCT until the documentation of disease progression / relapse or death due to any cause, whichever occurs first. Progression-free survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.

Time frame: 180 days and 365 days post-transplant

Transplant-related Mortality

Death without evidence of disease progression or recurrence. A cumulative incidence will be computed along with a 90% CI.

Time frame: 100 days, 180 days, and 365 days post-transplant

Cumulative Incidence of Neutrophil Recovery

Achieving a donor derived ANC ≥ 500/mm3 for 3 consecutive laboratory values on different days. A cumulative incidence will be computed along with a 90% CI.

Time frame: 100 days and 365 days post transplant

Cumulative Incidence of Platelet Recovery

Achieving a platelet count ≥ 20,000/μL for 3 consecutive laboratory values on different days (with no platelet transfusions in the preceding seven days). A cumulative incidence will be computed along with a 90% CI.

Time frame: 100 days and 365 days post transplant

Cumulative Incidence of Acute GVHD

Any skin, gastrointestinal or liver abnormalities fulfilling the BMT CTN Manual of Operations (2013) criteria of grades II-IV acute GVHD. A cumulative incidence will be computed along with a 90% CI. Any skin, gastrointestinal or liver abnormalities fulfilling the BMT CTN Manual of Operations (2013) criteria of grades III-IV acute GVHD. A cumulative incidence will be computed along with a 90% CI.

Time frame: 100 days post-transplant

Grades II-IV Acute GVHD

Any skin, gastrointestinal or liver abnormalities fulfilling the BMT CTN Manual of Operations (2013) criteria of grades II-IV acute GVHD. A cumulative incidence will be computed along with a 90% CI.

Time frame: 100 days

Grades III-IV Acute GVHD

Any skin, gastrointestinal or liver abnormalities fulfilling the BMT CTN Manual of Operations (2013) criteria of grades III-IV acute GVHD. A cumulative incidence will be computed along with a 90% CI.

Time frame: 100 days

Cumulative Incidence of Chronic GVHD

Per National Institutes of Health (NIH) Consensus Criteria and includes organ involvement and severity, and overall global composite score (mild/moderate/severe). A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.

Time frame: 180 days and 365 days post-transplant

Cumulative Incidences of Viral Reactivations and Infections: Grade 2-3 CMV Reactivation or Infection

Grade 2: Clinically active CMV infection (e.g. symptoms, cytopenias) or CMV Viremia not decreasing by at least 2/3 of the baseline value after 2 weeks of therapy; Grade 3: CMV end-organ involvement (pneumonitis, enteritis, retinitis). A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.

Time frame: 100 days, 180 days, and 365 days

Cumulative Incidences of Viral Reactivations and Infections: Grade 3 CMV Infection

CMV end-organ involvement (pneumonitis, enteritis, retinitis) ). A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.

Time frame: 100 days, 180 days, and 365 days

Cumulative Incidences of Viral Reactivations and Infections: Grade 2-3 EBV Infection

Grade 2: EBV reactivation requiring institution of therapy with rituximab; Grade 3: EBV post-transplant lymphoproliferative disorder). A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.

Time frame: 100 days, 180 days, and 365 days

Cumulative Incidences of Viral Reactivations and Infections: Grade 2 BK Virus Infection

BK viremia or viruria with clinical consequence requiring prolonged therapy and/or surgical intervention). A cumulative incidence will be computed along with a 90% CI.

Time frame: 100 days, 180 days, 365 days

Cumulative Incidences of Viral Reactivations and Infections: Grade 2-3 Adenovirus Infection

Grade 2: Adenoviral URI, viremia, or symptomatic viruria requiring treatment; Grade 3: ADV with end-organ involvement (except conjunctivitis and upper respiratory tract) ). A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.

Time frame: 100 days, 180 days, and 365 days

Cumulative Incidences of Viral Reactivations and Infections: Grade 2 HHV-6 Infection

Clinically active HHV-6 infection (e.g. symptoms, cytopenias) or HHV-6 viremia without viral load decline 0.5 log after 2 weeks of therapy). A cumulative incidence will be computed along with a 90% CI.

Time frame: 100 days, 180 days, 365 days

Cumulative Incidence of Relapse/Progression

Defined by either morphological, cytogenetic/molecular or radiological evidence of disease consistent with pre-HCT features. A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.

Time frame: 180 days and 365 days post-transplant

Cumulative Incidences of Thrombotic Microangiopathy (TMA) and Hepatic Veno-occlusive Disease (VOD)/Sinusoidal Obstruction Syndrome (SOS)

TMA is defined as (Ho et al., 2005): 1. RBC fragmentation and \>2 schistocytes per high-power field on peripheral smear 2. Concurrent increased serum LDH above institutional baseline 3. Concurrent renal and/or neurologic dysfunction without other explanation 4. Negative direct and indirect Coombs test results A cumulative incidence will be computed along with a 90% CI. VOD/SOS is defined as: In the first 20 days after HCT, the presence of ≥2 of the following: 1. Bilirubin \>2 mg/Dl, 2. Hepatomegaly or pain in right upper quadrant, 3. Weight gain (\>2% basal weight). A cumulative incidence will be computed along with a 90% CI.

Time frame: 365 days post transplant

Cumulative Incidence of Primary Graft Failure

Lack of donor-derived neutrophil engraftment. The frequency of subjects experiencing primary graft failure by 56 days will be described.

Time frame: 56 days post-transplant

Donor Chimerism

Peripheral blood chimerism (% of donor chimerism) in whole blood (unsorted). The degree of donor chimerism will be summarized using descriptive statistics.

Time frame: 28 days, 56 days, 100 days, 180 days, and 365 days post-transplant

Peripheral Blood Chimerism

The frequency of subjects with Peripheral blood (unsorted) chimerism\>95% at 56 days will be described.

Time frame: 56 days post-transplant

Proportion of Subjects Proceeding to Transplant

The proportion of subjects proceeding to HCT after informed consent.

Time frame: Pre-HCT

Time From Search to Donor Identification

Time from search to donor identification Time from preliminary search to formal donor activation.

Time frame: Pre-HCT

Donor Selection Characteristics: HLA Match

Number of matched donor and recipient HLA allele pairs. A matched donor would have 8/8 HLA allele pairs matching; mismatched donors listed below have one to four mismatched HLA allele pairs at HLA-A, -B, -C, or -DRB1.

Time frame: Pre-HCT

Donor Selection Characteristics: Donor Age

Donor age

Time frame: Pre-HCT

Donor Selection Characteristics: Donor Age, Categorical

Donor age, categorical

Time frame: Pre-HCT

Donor Selection Characteristics: Donor Weight

Donor weight

Time frame: Pre-HCT

Donor Selection Characteristics: Donor Sex

Donor sex

Time frame: Pre-HCT

Donor Selection Characteristics: Donor and Recipient Sex

Donor-recipient sex match

Time frame: Pre-HCT

Donor Selection Characteristics: Donor and Recipient CMV Serostatus

Donor-recipient Cytomegalovirus (CMV) serostatus match

Time frame: Pre-HCT

Donor Selection Characteristics: Donor and Recipient ABO Blood Match

Donor-recipient ABO group match

Time frame: Pre-HCT

Donor Clonal Hematopoiesis

The proportion of subjects developing donor clonal hematopoiesis

Time frame: 100 days and 365 days 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.

Time frame: 365 days post transplant

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

Overview

Conditions

Interventions

Eligibility

Locations (11)

Outcomes

Primary Outcomes

Secondary Outcomes