Myeloablative Haploidentical BMT With Post-transplant Cyclophosphamide for Pediatric Patients With Hematologic Malignancies

NCT02120157 | Completed Phase 2 Results DMC

• 2 other identifiers: J13161NA_00091665
• Study Type: interventional
• Target: 35
• Locations: 2 countries
• Sites: 9

Brief Summary

This is a multi-institutional phase II haploidentical T cell replete bone marrow transplant (BMT) study in children with high-risk leukemia. The myeloablative conditioning regimen prescribed will be Total body irradiation (TBI)-based for lymphoid leukemia and busulfan-based for myeloid leukemia. Our goal is to establish an easily exportable, inexpensive platform for haplotransplantation that has a safety profile equivalent to matched related and unrelated BMTs. The primary objective will be to estimate the incidence of 6-month non-relapse mortality (NRM), hypothesizing that NRM is \< 18%.

Conditions

Myeloablative Conditioning; HLA-mismatched Bone Marrow Transplantation; Graft Survival; Transplantation, Bone Marrow

Keywords

Acute lymphoblastic leukemia; Acute myeloid leukemia; Juvenile myelomonocytic leukemia; Treatment related leukemia; Biphenotypic leukemia

Outcome Measures

Primary Outcomes (1)

• Cumulative Incidence of Non-relapse Mortality

  Cumulative incidence (measured as a percentage) of non-relapse mortality at 180 days following myeloablative, Human Leukocyte Antigen (HLA)-mismatched bone marrow transplant (BMT) for patients with high risk hematologic malignancies.

  Day 180

Secondary Outcomes (11)

• Number of Participants With Donor Cell Engraftment

  Day 60

• Cumulative Incidence of Acute Graft Versus Host Disease (GVHD) Grades 2-4 and Grades 3-4

  100 days

• Cumulative Incidence of Chronic GVHD

  2 years

• Primary and Secondary Graft Failure

  2 years

• Steroid and Non-steroid Immunosuppressants

  Two Years

Study Arms (1)

Haploidentical BMT with PTCy for acute leukemias and MDS

EXPERIMENTAL

Patients with AML and MDS: Days -6 through -3: Busulfan q 5-6h IV q24h x 4 days Days -2 and -1: Cyclophosphamide 50mg/kg/day IV x 2 days+ Mesna 40 mg/kg/day IV For patients with ALL and lymphoblastic lymphoma: Days -5 through -4: Cyclophosphamide 50mg/kg/day IV q24h x 2 days+Mesna 40 mg/kg/day IV Days -3 through -1: TBI 200 Centigray (cGy) twice a day for 3 days All patients Day 0: Infuse unmanipulated bone marrow Day +3 and +4: Cyclophosphamide 50 mg/kg/day IV + Mesna 40 mg/kg IBW/day IV Day +5: Begin tacrolimus 0.015mg/kg IBW/dose IV over 4 hours q 12h and mycophenolate mofetil (MMF)15mg/kg po/IV tid with maximum daily dose 3 gm/day Day +30: Assess chimerism and disease status in bone marrow Day +35: Discontinue MMF Day +60: Assess chimerism and disease status in bone marrow Day 180: Discontinue tacrolimus

Drug: Cyclophosphamide; Radiation: TBI; Drug: Busulfan; Other: Unmanipulated Bone Marrow; Drug: Tacrolimus; Drug: Mycophenolate mofetil

Interventions

Cyclophosphamide DRUG

Chemotherapy administration

Also known as: Cy

Haploidentical BMT with PTCy for acute leukemias and MDS

TBI RADIATION

Radiation Therapy

Haploidentical BMT with PTCy for acute leukemias and MDS

Busulfan DRUG

Chemotherapy Administered

Also known as: Bu

Haploidentical BMT with PTCy for acute leukemias and MDS

Unmanipulated Bone Marrow OTHER

Bone Marrow Transplant

Haploidentical BMT with PTCy for acute leukemias and MDS

Tacrolimus DRUG

Immunosuppressive Drug Administered

Also known as: tacro

Haploidentical BMT with PTCy for acute leukemias and MDS

Mycophenolate mofetil DRUG

Immunosuppressive Drug Administered

Also known as: MMF

Haploidentical BMT with PTCy for acute leukemias and MDS

Eligibility Criteria

• Age: 6 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patient age 0.5-25years
• Patients must have a first-degree related donor or half-sibling who is at minimum HLA haploidentical. The donor and recipient must be identical at at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype.
• An unrelated donor search is not required for a patient to be eligible for this protocol, or a donor search and donor mobilization may be abandoned if the clinical situation dictates an urgent transplant. Clinical urgency is defined as 6-8 weeks from referral to transplant or a low-likelihood of finding a matched, unrelated donor. Patients with an eligible HLA-matched RELATED should not be enrolled on this trial.
• Patients must have at least one of the following high-risk conditions listed below:
• Acute lymphocytic leukemia (ALL) in CR1\* as defined by at least one of the following:
• hypodiploidy, induction failure,Minimal residual disease (MRD) after consolidation
• \- Acute myeloid leukemia (AML) in CR1 with high risk features defined as: High allelic ratio FLT3/ITD+, Monosomy 7, Del (5q), Standard risk cytogenetics with positive minimal residual disease at the end of Induction I chemotherapy (for patients being treated on or according to Children's Oncology Group (COG) AAML1031 study who have had MRD studies sent to Seattle or performed at their local institution where the flow assay is sensitive enough to detect \> 0.1% blasts)
• Acute Leukemia in 2nd or subsequent CR (CR\>2)
• Mixed phenotype/Undifferentiated Leukemia in 1st or subsequent CR\*
• Secondary or therapy related leukemia in CR \> 1
• Natural Killer (NK) cell lymphoblastic leukemia CR \> 1
• Myelodysplastic syndrome (MDS)
• Juvenile myelomonocytic leukemia (JMML) (patients are eligible if they are not eligible for COG1221 study)
• Prior transplant eligible if \< 18yo, \>6 months has elapsed since BMT, and patient is off immunosuppression for \> 3 months with no Graft versus host disease (GVHD)
• No known active Central nervous system (CNS) involvement or extramedullary involvement by malignancy. Such disease treated into remission is permitted.

You may not qualify if:

• Poor cardiac function: left ventricular ejection fraction \<45% as determined by Multigated acquisition scan (MUGA) or Echocardiogram (ECHO). For pediatric patients Left ventricular ejection fraction (LVEF) \<45% or a shortening fraction below normal limits for age.
• Symptomatic pulmonary disease. Poor pulmonary function: Forced expiratory volume (FEV1), Forced vital capacity (FVC), and Diffusing capacity for carbon monoxide (DLCO) \<50% predicted (corrected for hemoglobin) for patients who have not received thoracic or mantle irradiation. For patients who have received thoracic or mantle irradiation, FEV1 and FVC \<70% predicted or DLCO \< 50 of predicted. For children unable to perform Pulmonary function tests (PFTs) because of developmental stage pulse oximetry \< 92% on Room air (RA).
• Poor liver function: bilirubin \>2 mg/dl (not due to hemolysis, Gilbert's or primary malignancy). Alanine aminotransferase (ALT) or Aspartate transaminase (AST) \> 3 x laboratory upper normal limits.
• Poor renal function: Creatinine \>2.0mg/dl or creatinine clearance (calculated creatinine clearance is permitted) \< 60 mL/min based on Traditional Cockcroft-Gault formula: 140 - age (yrs) x Smaller of Actual Weight vs. Ideal Body Weight (kg) / 72 x Serum creatinine (mg/dl) Multiply by another factor of 0.85 if female Intended for ages 18-110, serum creatinine 0.6-7 mg/dl For patients \<18 years: creatinine clearance (CrCl) will be estimated by the Schwartz formula. A measured CrCl or a Glomerular filtration rate (GFR) may be substituted to determine the subject's CrCl.
• Schwartz equation: CrCl (ml/min/1.73m2)=\[length (cm) x k\] /serum creatinine K = 0.45 for infants 1 to 52 weeks old k = 0.55 for children 1 to 13 years old k = 0.55 for adolescent females 13-18 years old k = 0.7 for adolescent males 13-18 years old
• HIV-positive
• Positive leukocytotoxic crossmatch Specifically, complement dependent cytotoxicity and flow cytometric crossmatch assays must be negative, and the mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay should be \<3000. Consult with PI for the clinical significance of any anti-donor antibody.
• Women of childbearing potential who currently are pregnant (HCG+) or who are not practicing adequate contraception or who are breastfeeding
• Uncontrolled viral, bacterial, or fungal infections (currently taking medication and have progression of clinical symptoms)
• Patients with symptoms consistent with Respiratory syncytial virus (RSV), influenza A, B, or parainfluenza at the time of enrollment will be assayed for the above viruses and if positive are not eligible for the trial until they are no longer symptomatic (patients may have continued assay positivity for a period of time post resolution of symptoms secondary to the nature of the assay

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead

Study Sites (9)

Children's Hospital of Colorado

Aurora, Colorado, 80045, United States

Location

Nemours Alfred I. DuPont Hospital for Children

Wilmington, Delaware, 19803, United States

Location

All Children's Hospital Johns Hopkins Medicine

St. Petersburg, Florida, 33701, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Washington University in St. Louis

St Louis, Missouri, 63110, United States

Location

Levine Cancer Center

Charlotte, North Carolina, 28203, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29423, United States

Location

British Columbia Children's Hospital

Vancouver, British Columbia, V6H 3V4, Canada

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (1)

• Fierro-Pineda JC, Tsai HL, Blackford A, Cluster A, Caywood E, Dalal J, Davis J, Egeler M, Huo J, Hudspeth M, Keating A, Kelly SS, Krueger J, Lee D, Lehmann L, Madden L, Oshrine B, Pulsipher MA, Fry T, Symons HJ. Prospective PTCTC trial of myeloablative haplo-BMT with posttransplant cyclophosphamide for pediatric acute leukemias. Blood Adv. 2023 Sep 26;7(18):5639-5648. doi: 10.1182/bloodadvances.2023010281.

  PMID: 37257193 DERIVED

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Juvenile

Interventions

Cyclophosphamide; Busulfan; Tacrolimus; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Macrolides; Lactones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Results Point of Contact

• Title: Heather Symons, MD
• Organization: Johns Hopkins University

hsymons2@jhmi.edu

410-502-9961

Study Officials

• Heather Symons, MD, MHS

  SKCCC Johns Hopkins Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 16, 2014
• First Posted: April 22, 2014
• Study Start: July 2, 2015
• Primary Completion: June 15, 2018
• Study Completion: October 1, 2020
• Last Updated: November 26, 2021
• Results First Posted: April 18, 2019

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (7); CA (2)