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

Primary Purpose

Anaplastic Ependymoma, Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Germ Cell Tumor

Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Etoposide
Fludarabine Phosphate
Hematopoietic Cell Transplantation
Lapine T-Lymphocyte Immune Globulin
Melphalan
Mycophenolate Mofetil
Tacrolimus
Thiotepa
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Anaplastic Ependymoma

Eligibility Criteria

undefined - 25 Years (Child, Adult)All SexesAccepts Healthy Volunteers

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)

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Treatment (chemotherapy, HCT)

    Arm Description

    Patients 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.

    Outcomes

    Primary Outcome Measures

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

    Secondary Outcome Measures

    Failure of platelet and neutrophil engraftment rates
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.
    Incidence of acute graft-versus-host (GVHD) disease
    Will be estimated using the method of Gooley.
    Incidence of chronic GVHD
    Will be estimated using the method of Gooley.
    Rate of grade II organ toxicity
    Will be reported as counts with percentages.
    Rate of graft failure (primary and secondary)
    Will be reported as counts with percentages.
    Rate of infectious complications
    Will be reported as counts with percentages.
    Progression free survival
    Cumulative incidence of relapse
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.
    Overall survival
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.
    Progression-free survival
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.

    Full Information

    First Posted
    August 18, 2020
    Last Updated
    October 2, 2023
    Sponsor
    M.D. Anderson Cancer Center
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04521946
    Brief Title
    Chemotherapy and Donor Stem Transplant for the Treatment of Patients With High Grade Brain Cancer
    Official Title
    A Pilot Study of Allogeneic Hematopoietic Cell Transplantation for Patients With High Grade Central Nervous System Malignancies
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    October 2023
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    No participants enrolled.
    Study Start Date
    January 14, 2021 (Actual)
    Primary Completion Date
    December 20, 2022 (Actual)
    Study Completion Date
    December 20, 2022 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    M.D. Anderson Cancer Center

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    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, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a donor stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets and may help destroy any remaining cancer cells.
    Detailed Description
    PRIMARY OBJECTIVE: I. To assess tolerability of allogenic hematopoietic cell transplantation (HCT) among patients with chemo-responsive high-grade central nervous system (CNS) malignancies as defined by transplant-related mortality (TRM) at day 30 as well as rate of grade III organ toxicity or higher (Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days. SECONDARY OBJECTIVES: I. Median time to platelet and neutrophil engraftment. II. Incidence of acute graft-versus-host disease (aGVHD) by day 100. III. Incidence of chronic GVHD at day 100 and one year. IV. Rate of grade II organ toxicity through day 100. V. Rate of graft failure (primary and secondary) through day 100. VI. Rate of infectious complications through day 100. VII. Progression free survival at day 180. VIII. Cumulative incidence of relapse, overall survival, and progression-free survival at 100 days and 1 year. OUTLINE: Patients receive thiotepa intravenously (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 orally (PO) every 8 hours or IV from days 0-40 and tapered to day 90. After completion of study treatment, patients are followed up at 100, 180, 270 and 360 days.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Anaplastic Ependymoma, Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Germ Cell Tumor, Choroid Plexus Carcinoma, Intracranial Myeloid Sarcoma, Malignant Brain Neoplasm, Malignant Glioma, Medulloblastoma, Primitive Neuroectodermal Tumor, Recurrent Anaplastic Ependymoma, Recurrent Atypical Teratoid/Rhabdoid Tumor, Recurrent Malignant Brain Neoplasm, Recurrent Malignant Glioma, Recurrent Medulloblastoma, Recurrent Primitive Neuroectodermal Tumor

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Treatment (chemotherapy, HCT)
    Arm Type
    Experimental
    Arm Description
    Patients 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.
    Intervention Type
    Drug
    Intervention Name(s)
    Etoposide
    Other Intervention Name(s)
    Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Fludarabine Phosphate
    Other Intervention Name(s)
    2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
    Intervention Description
    Given IV
    Intervention Type
    Procedure
    Intervention Name(s)
    Hematopoietic Cell Transplantation
    Other Intervention Name(s)
    HCT, Hematopoietic Stem Cell Transplantation, HSCT, Stem Cell Transplant, stem cell transplantation
    Intervention Description
    Undergo HCT
    Intervention Type
    Biological
    Intervention Name(s)
    Lapine T-Lymphocyte Immune Globulin
    Other Intervention Name(s)
    Anti-Thymocyte Globulin Rabbit, Grafalon, Rabbit Anti-Human Thymocyte Globulin (RATG), Rabbit Anti-Thymocyte Globulin, Rabbit Antithymocyte Globulin, Rabbit ATG, rATG, Thymoglobulin
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Melphalan
    Other Intervention Name(s)
    Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Mycophenolate Mofetil
    Other Intervention Name(s)
    CellCept, MMF
    Intervention Description
    Given PO or IV
    Intervention Type
    Drug
    Intervention Name(s)
    Tacrolimus
    Other Intervention Name(s)
    FK 506, Fujimycin, Hecoria, Prograf, Protopic
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Thiotepa
    Other Intervention Name(s)
    1,1'',1''''-Phosphinothioylidynetrisaziridine, Girostan, N,N'', N''''-Triethylenethiophosphoramide, Oncotiotepa, STEPA, Tepadina, TESPA, Tespamin, Tespamine, Thio-Tepa, Thiofosfamide, Thiofozil, Thiophosphamide, Thiophosphoramide, Thiotef, Tifosyl, TIO TEF, Tio-tef, Triethylene Thiophosphoramide, Triethylenethiophosphoramide, Tris(1-aziridinyl)phosphine sulfide, TSPA, WR 45312
    Intervention Description
    Given IV
    Primary Outcome Measure Information:
    Title
    Transplant-related mortality
    Description
    Will be reported together with the corresponding 95% Bayesian credible interval. Will be estimated using the method of Gooley.
    Time Frame
    At day 30
    Title
    Rate of grade III or higher organ toxicity attributable to conditioning
    Description
    Assessed per Bearman Regimen-Related Toxicities Scale. Will be reported together with the corresponding 95% Bayesian credible interval.
    Time Frame
    Within 30 days
    Secondary Outcome Measure Information:
    Title
    Failure of platelet and neutrophil engraftment rates
    Description
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.
    Time Frame
    Day 100
    Title
    Incidence of acute graft-versus-host (GVHD) disease
    Description
    Will be estimated using the method of Gooley.
    Time Frame
    Up to day 100
    Title
    Incidence of chronic GVHD
    Description
    Will be estimated using the method of Gooley.
    Time Frame
    At day 100 and 1 year
    Title
    Rate of grade II organ toxicity
    Description
    Will be reported as counts with percentages.
    Time Frame
    Up to day 100
    Title
    Rate of graft failure (primary and secondary)
    Description
    Will be reported as counts with percentages.
    Time Frame
    Up to day 100
    Title
    Rate of infectious complications
    Description
    Will be reported as counts with percentages.
    Time Frame
    Up to day 100
    Title
    Progression free survival
    Time Frame
    At day 180
    Title
    Cumulative incidence of relapse
    Description
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.
    Time Frame
    At day 100 and 1 year
    Title
    Overall survival
    Description
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.
    Time Frame
    At day 100 and 1 year
    Title
    Progression-free survival
    Description
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.
    Time Frame
    At day 100 and 1 year

    10. Eligibility

    Sex
    All
    Maximum Age & Unit of Time
    25 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    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) 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
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Kris M Mahadeo, MD
    Organizational Affiliation
    M.D. Anderson Cancer Center
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Links:
    URL
    http://www.mdanderson.org
    Description
    MD Anderson Cancer Center

    Learn more about this trial

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

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