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

NCT ID: NCT02120157

Last Updated: 2021-11-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-07-02
• Study Completion Date: 2020-10-01

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%.

Detailed Description

This is a phase II prospective study designed to evaluate the incidence of 6 month non- relapse mortality, safety, and feasibility of haploidentical bone marrow transplantation (BMT) after myeloablative conditioning with post-transplant Cy. Conditioning regimens include a total body irradiation (TBI)-based prep for lymphoid leukemias and a chemotherapy based prep for myeloid leukemias.

To estimate the incidence of non-relapse mortality at 180 days following myeloablative haploidentical BMT for children and young adults with high risk hematologic malignancies.

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Haploidentical BMT with PTCy for acute leukemias and MDS

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

Group Type: EXPERIMENTAL

Cyclophosphamide

Intervention Type: DRUG

Chemotherapy administration

TBI

Intervention Type: RADIATION

Radiation Therapy

Busulfan

Intervention Type: DRUG

Chemotherapy Administered

Unmanipulated Bone Marrow

Intervention Type: OTHER

Bone Marrow Transplant

Tacrolimus

Intervention Type: DRUG

Immunosuppressive Drug Administered

Mycophenolate mofetil

Intervention Type: DRUG

Immunosuppressive Drug Administered

Interventions

Cyclophosphamide

Chemotherapy administration

Intervention Type: DRUG

TBI

Radiation Therapy

Intervention Type: RADIATION

Busulfan

Chemotherapy Administered

Intervention Type: DRUG

Unmanipulated Bone Marrow

Bone Marrow Transplant

Intervention Type: OTHER

Tacrolimus

Immunosuppressive Drug Administered

Intervention Type: DRUG

Mycophenolate mofetil

Immunosuppressive Drug Administered

Intervention Type: DRUG

Other Intervention Names

Cy; Bu; tacro; MMF

Eligibility Criteria

Inclusion Criteria

• 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.
• Acute Leukemia - Remission is defined as morphology with < 5% blasts with no morphological characteristics of acute leukemia (e.g., Auer Rods) in a bone marrow with > 20% cellularity.

Exclusion Criteria

• 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

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 25 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Heather Symons, MD, MHS

Role: PRINCIPAL_INVESTIGATOR

SKCCC Johns Hopkins Hospital

Locations

Children's Hospital of Colorado

Aurora, Colorado, United States

Nemours Alfred I. DuPont Hospital for Children

Wilmington, Delaware, United States

All Children's Hospital Johns Hopkins Medicine

St. Petersburg, Florida, United States

Johns Hopkins Hospital

Baltimore, Maryland, United States

Washington University in St. Louis

St Louis, Missouri, United States

Levine Cancer Center

Charlotte, North Carolina, United States

Medical University of South Carolina

Charleston, South Carolina, United States

British Columbia Children's Hospital

Vancouver, British Columbia, Canada

Hospital for Sick Children

Toronto, Ontario, Canada

Countries

United States; Canada

References

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.

Reference Type: DERIVED

PMID: 37257193 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NA_00091665

Identifier Type: OTHER

Identifier Source: secondary_id

J13161

Identifier Type: -

Identifier Source: org_study_id