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Trial of Myeloablative Conditioning & Transplantation of Partially Human Leukocyte Antigen (HLA)-Mismatched Marrow With Post-transplant Cyclophosphamide for Peds Pts w/ Hematologic Malignancies

NCT02120157

Description:

We propose a multi-institutional phase II haplo-identical 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%.

Related Conditions:
  • Acute Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Juvenile Myelomonocytic Leukemia
  • Mixed Phenotype Acute Leukemia
  • Myelodysplastic Syndromes
  • Natural Killer Cell Lymphoblastic Leukemia/Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Trial of Myeloablative Conditioning & Transplantation of Partially HLA-mismatched Marrow With Post-transplant Cyclophosphamide for Peds Pts w/ Hematologic Malignancies
  • Official Title: Pediatric Blood & Marrow Transplant Consortium (PBMTC) Multi-center Phase II Pilot Trial of Myeloablative Conditioning and Transplantation of Partially HLA-mismatched T Cell Replete Bone Marrow With Post-transplantation Cyclophosphamide for Pediatric Patients With Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: J13161
  • SECONDARY ID: NA_00091665
  • NCT ID: NCT02120157

Conditions

  • Myeloablative Conditioning
  • HLA-mismatched Bone Marrow Transplantation
  • Graft Survival
  • Transplantion, Bone Marrow

Interventions

DrugSynonymsArms
Cyclophosphamide1: Acute Lymphoblastic Leukemia/Lymphoma
Busulfan1: Acute Lymphoblastic Leukemia/Lymphoma
Tacrolimus1: Acute Lymphoblastic Leukemia/Lymphoma
Mycophenolate mofetilMMF1: Acute Lymphoblastic Leukemia/Lymphoma

Purpose

We propose a multi-institutional phase II haplo-identical T cell replete BMT study in children with high-risk leukemias. The myeloablative conditioning regimen prescribed will be TBI-based for lymphoid leukemias and busulfan-based for myeloid leukemias. 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, 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-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.
    

Trial Arms

NameTypeDescriptionInterventions
1: Acute Lymphoblastic Leukemia/LymphomaExperimentalDays -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+ 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
  • Cyclophosphamide
  • Busulfan
  • Tacrolimus
  • Mycophenolate mofetil
2: Acute Lymphocytic Leukemia/LymphomaExperimentalDays -5 through -4: Cyclophosphamide 50mg/kg/day IV q24h x 2 days+Mesna 40 mg/kg/day IV+ Days -3 through -1: TBI 200 cGy twice a day for 3 days 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
  • Cyclophosphamide
  • Tacrolimus
  • Mycophenolate mofetil

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
             (criteria are meant to complement existing criteria within COG protocols):

          -  Acute lymphocytic leukemia (ALL) in CR1* as defined by at least one of the following:

        hypodiploidy, induction failure, 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 COG AAML1031 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 Leukemias in 2nd or subsequent CR (CR>2)

          -  Mixed phenotype/Undifferentiated Leukemias in 1st or subsequent CR*

          -  Secondary or therapy related leukemias in CR > 1

          -  NK cell lymphoblastic leukemia CR > 1

          -  Myelodysplastic syndrome (MDS)

          -  JMML (patients are eligible if they are not eligible for COG1221)

          -  Prior transplant eligible if < 18yo, >6 months has elapsed since BMT, and patient is
             off immunosuppression for > 3 months with no GVHD

          -  No known active 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:

          -  Patients will not be excluded on the basis of sex, racial or ethnic background.

          -  Poor cardiac function: left ventricular ejection fraction <45% as determined by MUGA
             or ECHO. For pediatric patients LVEF <45% or a shortening fraction below normal limits
             for age.

          -  Symptomatic pulmonary disease. Poor pulmonary function: FEV1, FVC, and 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
             PFTs because of developmental stage pulse oximetry < 92% on RA.

          -  Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary
             malignancy). ALT or 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: CrCl will be
             estimated by the Schwartz formula. A measured CrCl or a 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 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
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:6 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Mortality
Time Frame:Day 180
Safety Issue:
Description:To estimate the incidence of non-relapse mortality at 180 days following myeloablative, HLA-mismatched BMT for patients with high risk hematologic malignancies

Secondary Outcome Measures

Measure:Donor Cell Engraftment
Time Frame:Day 60
Safety Issue:
Description:Estimate the incidence of donor cell engraftment at Day 60 following myeloablative, HLA-mismatched BMT. Estimate the time to neutrophil and platelet recovery. Estimate the incidence of primary and secondary graft failure. Estimate the cumulative incidence of acute GVHD grades 2-4 and grades 3-4 using competing risk analysis Estimate the cumulative incidence of chronic GVHD using competing risk analysis. Characterize the duration of use, number, and type of steroid and non-steroid immunosuppressants used to treat GVHD. Estimate overall survival (OS), relapse, progression-free survival, disease-free survival, event-free survival, and relapse-free GVHD-free survival in patients receiving myeloablative, HLA-mismatched BMT for patients with high risk hematologic malignancies at 1 year and 2 years. Assess hematologic and non-hematologic toxicities of myeloablative haploidentical BMT. Characterize immune reconstitution post myeloablative haploidentical BMT with PT/Cy.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

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

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