Chemotherapy and Donor Stem Transplant for the Treatment of Patients With High Grade Brain Cancer

Registration Number
NCT04521946
Lead Sponsor
M.D. Anderson Cancer Center
Brief Summary

This phase I trial investigates the side effects and effectiveness of chemotherapy followed by a donor (allogeneic) stem cell transplant when given to patients with high grade brain cancer. Chemotherapy drugs, such as fludarabine, thiotepa, etoposide, melphalan, and rabbit anti-thymocyte globulin, work in different ways to stop the growth of tumor cells, eit...

Detailed Description

PRIMARY OBJECTIVE:
...

Recruitment & Eligibility

Status
WITHDRAWN
Sex
All
Target Recruitment
Not specified
Inclusion Criteria
  • Pathological criteria for any high grade primary or recurrent malignant brain tumor - medulloblastoma (patients who are ineligible for tandem autologous transplants or who are at least 3 months post autologous HCT), primitive neuroectodermal tumor (PNET), atypical teratoid rhabdoid tumor (ATRT), malignant glioma, CNS germ cell tumor, intracranial sarcomas, choroid plexus carcinoma, anaplastic ependymoma. High grade tumors defined as those that are grade III or higher based on World Health Organization (WHO) classification grading system or for medulloblastoma: group 3 and 4 molecular subtypes

  • Patients have to be in at least, a chemo-responsive disease status

  • Available suitable HCT donor

  • Creatinine clearance or glomerular filtration rate (GFR) >= 50 ml/min/1.73m^2, and not requiring dialysis

  • Diffusion capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) >= 50% predicted. If unable to perform pulmonary function tests, then O2 saturation >= 92% in room air

  • Bilirubin =< 3x upper limit of normal (ULN) (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome)

  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5x for age

  • DONOR: HCT will be done using stem cell sources in the following order of preference (and fulfilling minimal cell dose requirements per institutional standards):

    • Matched related donor bone marrow (10 of 10 human leukocyte antigen [HLA] alleles [HLA-A, B, C, DR, and DQ]). Matched related donor peripheral blood stem cell (PBSC) is allowed only if collection of bone marrow (BM) is not available or refused by guardian/donor

    • Matched allogeneic umbilical cord blood: related

      • High-resolution matching at A,B, DRB1 (minimum 4/6)
      • Killer-cell immunoglobulin-like receptor (KIR) major histocompatibility complex (MHC) class 1 preferential mismatch (minimum 4/6)
    • Matched allogeneic umbilical cord blood: unrelated

      • High-resolution matching at A,B, DRB1(minimum 4/6)
      • KIR MHC class 1 preferential mismatch (minimum 4/6)
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Exclusion Criteria
  • Lack of histocompatible suitable graft source
  • End-organ failure that precludes the ability to tolerate the transplant procedure, including conditioning regimen
  • Renal failure requiring dialysis
  • Congenital heart disease resulting in congestive heart failure
  • Ventilatory failure: requires invasive mechanical ventilation
  • Human immunodeficiency virus (HIV) infection
  • Uncontrolled bacterial, viral, or fungal infections
  • A female of reproductive potential who is pregnant, planning to become pregnant during the study, or is nursing a child
  • Any patient who does not fulfill inclusion criteria listed above
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Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Treatment (chemotherapy, HCT)Hematopoietic Cell TransplantationPatients receive thiotepa IV over 2-4 hours and etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3. Patients receiving umbilical cord transplant only also receive lapine T-lymphocyte immune globulin IV over 4-12 hours on days -4 and -3. Patients then undergo HCT on day 0. Patients also receive tacrolimus IV or cyclosporine IV beginning on day -2 to and mycophenolate mofetil PO every 8 hours or IV from days 0-40 and tapered to day 90.
Treatment (chemotherapy, HCT)Lapine T-Lymphocyte Immune GlobulinPatients receive thiotepa IV over 2-4 hours and etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3. Patients receiving umbilical cord transplant only also receive lapine T-lymphocyte immune globulin IV over 4-12 hours on days -4 and -3. Patients then undergo HCT on day 0. Patients also receive tacrolimus IV or cyclosporine IV beginning on day -2 to and mycophenolate mofetil PO every 8 hours or IV from days 0-40 and tapered to day 90.
Treatment (chemotherapy, HCT)Fludarabine PhosphatePatients receive thiotepa IV over 2-4 hours and etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3. Patients receiving umbilical cord transplant only also receive lapine T-lymphocyte immune globulin IV over 4-12 hours on days -4 and -3. Patients then undergo HCT on day 0. Patients also receive tacrolimus IV or cyclosporine IV beginning on day -2 to and mycophenolate mofetil PO every 8 hours or IV from days 0-40 and tapered to day 90.
Treatment (chemotherapy, HCT)EtoposidePatients receive thiotepa IV over 2-4 hours and etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3. Patients receiving umbilical cord transplant only also receive lapine T-lymphocyte immune globulin IV over 4-12 hours on days -4 and -3. Patients then undergo HCT on day 0. Patients also receive tacrolimus IV or cyclosporine IV beginning on day -2 to and mycophenolate mofetil PO every 8 hours or IV from days 0-40 and tapered to day 90.
Treatment (chemotherapy, HCT)MelphalanPatients receive thiotepa IV over 2-4 hours and etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3. Patients receiving umbilical cord transplant only also receive lapine T-lymphocyte immune globulin IV over 4-12 hours on days -4 and -3. Patients then undergo HCT on day 0. Patients also receive tacrolimus IV or cyclosporine IV beginning on day -2 to and mycophenolate mofetil PO every 8 hours or IV from days 0-40 and tapered to day 90.
Treatment (chemotherapy, HCT)Mycophenolate MofetilPatients receive thiotepa IV over 2-4 hours and etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3. Patients receiving umbilical cord transplant only also receive lapine T-lymphocyte immune globulin IV over 4-12 hours on days -4 and -3. Patients then undergo HCT on day 0. Patients also receive tacrolimus IV or cyclosporine IV beginning on day -2 to and mycophenolate mofetil PO every 8 hours or IV from days 0-40 and tapered to day 90.
Treatment (chemotherapy, HCT)TacrolimusPatients receive thiotepa IV over 2-4 hours and etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3. Patients receiving umbilical cord transplant only also receive lapine T-lymphocyte immune globulin IV over 4-12 hours on days -4 and -3. Patients then undergo HCT on day 0. Patients also receive tacrolimus IV or cyclosporine IV beginning on day -2 to and mycophenolate mofetil PO every 8 hours or IV from days 0-40 and tapered to day 90.
Treatment (chemotherapy, HCT)ThiotepaPatients receive thiotepa IV over 2-4 hours and etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3. Patients receiving umbilical cord transplant only also receive lapine T-lymphocyte immune globulin IV over 4-12 hours on days -4 and -3. Patients then undergo HCT on day 0. Patients also receive tacrolimus IV or cyclosporine IV beginning on day -2 to and mycophenolate mofetil PO every 8 hours or IV from days 0-40 and tapered to day 90.
Primary Outcome Measures
NameTimeMethod
Transplant-related mortalityAt day 30

Will be reported together with the corresponding 95% Bayesian credible interval. Will be estimated using the method of Gooley.

Rate of grade III or higher organ toxicity attributable to conditioningWithin 30 days

Assessed per Bearman Regimen-Related Toxicities Scale. Will be reported together with the corresponding 95% Bayesian credible interval.

Secondary Outcome Measures
NameTimeMethod
Failure of platelet and neutrophil engraftment ratesDay 100

Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.

Overall survivalAt day 100 and 1 year

Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.

Progression free survivalAt day 180
Cumulative incidence of relapseAt day 100 and 1 year

Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.

Progression-free survivalAt day 100 and 1 year

Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.

Incidence of acute graft-versus-host (GVHD) diseaseUp to day 100

Will be estimated using the method of Gooley.

Rate of grade II organ toxicityUp to day 100

Will be reported as counts with percentages.

Rate of graft failure (primary and secondary)Up to day 100

Will be reported as counts with percentages.

Rate of infectious complicationsUp to day 100

Will be reported as counts with percentages.

Incidence of chronic GVHDAt day 100 and 1 year

Will be estimated using the method of Gooley.

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