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

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ClinicalTrials.gov Identifier: NCT04521946
Recruitment Status : Recruiting
First Posted : August 21, 2020
Last Update Posted : February 21, 2021
Sponsor:
Information provided by (Responsible Party):
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, 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.

Condition or disease Intervention/treatment Phase
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 Drug: Etoposide Drug: Fludarabine Phosphate Procedure: Hematopoietic Cell Transplantation Biological: Lapine T-Lymphocyte Immune Globulin Drug: Melphalan Drug: Mycophenolate Mofetil Drug: Tacrolimus Drug: Thiotepa Phase 1

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.

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Study Type : Interventional
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of Allogeneic Hematopoietic Cell Transplantation for Patients With High Grade Central Nervous System Malignancies
Actual Study Start Date : January 14, 2021
Estimated Primary Completion Date : May 9, 2025
Estimated Study Completion Date : May 9, 2025


Arm Intervention/treatment
Experimental: Treatment (chemotherapy, HCT)
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.
Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16
  • VP 16-213
  • VP-16
  • VP-16-213
  • VP16

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Procedure: Hematopoietic Cell Transplantation
Undergo HCT
Other Names:
  • HCT
  • Hematopoietic Stem Cell Transplantation
  • HSCT
  • Stem Cell Transplant
  • stem cell transplantation

Biological: Lapine T-Lymphocyte Immune Globulin
Given IV
Other Names:
  • Anti-Thymocyte Globulin Rabbit
  • Grafalon
  • Rabbit Anti-Human Thymocyte Globulin (RATG)
  • Rabbit Anti-Thymocyte Globulin
  • Rabbit Antithymocyte Globulin
  • Rabbit ATG
  • rATG
  • Thymoglobulin

Drug: Melphalan
Given IV
Other Names:
  • 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

Drug: Mycophenolate Mofetil
Given PO or IV
Other Names:
  • CellCept
  • MMF

Drug: Tacrolimus
Given IV
Other Names:
  • FK 506
  • Fujimycin
  • Hecoria
  • Prograf
  • Protopic

Drug: Thiotepa
Given IV
Other Names:
  • 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




Primary Outcome Measures :
  1. Transplant-related mortality [ Time Frame: At day 30 ]
    Will be reported together with the corresponding 95% Bayesian credible interval. Will be estimated using the method of Gooley.

  2. Rate of grade III or higher organ toxicity attributable to conditioning [ Time Frame: Within 30 days ]
    Assessed per Bearman Regimen-Related Toxicities Scale. Will be reported together with the corresponding 95% Bayesian credible interval.


Secondary Outcome Measures :
  1. Failure of platelet and neutrophil engraftment rates [ Time Frame: Day 100 ]
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.

  2. Incidence of acute graft-versus-host (GVHD) disease [ Time Frame: Up to day 100 ]
    Will be estimated using the method of Gooley.

  3. Incidence of chronic GVHD [ Time Frame: At day 100 and 1 year ]
    Will be estimated using the method of Gooley.

  4. Rate of grade II organ toxicity [ Time Frame: Up to day 100 ]
    Will be reported as counts with percentages.

  5. Rate of graft failure (primary and secondary) [ Time Frame: Up to day 100 ]
    Will be reported as counts with percentages.

  6. Rate of infectious complications [ Time Frame: Up to day 100 ]
    Will be reported as counts with percentages.

  7. Progression free survival [ Time Frame: At day 180 ]
  8. Cumulative incidence of relapse [ Time Frame: At day 100 and 1 year ]
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.

  9. Overall survival [ Time Frame: At day 100 and 1 year ]
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.

  10. Progression-free survival [ Time Frame: At day 100 and 1 year ]
    Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04521946


Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Kris M. Mahadeo    713-792-6610    kmmahadeo@mdanderson.org   
Principal Investigator: Kris M. Mahadeo         
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
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Principal Investigator: Kris M Mahadeo M.D. Anderson Cancer Center
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT04521946    
Other Study ID Numbers: 2020-0495
NCI-2020-05878 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2020-0495 ( Other Identifier: M D Anderson Cancer Center )
First Posted: August 21, 2020    Key Record Dates
Last Update Posted: February 21, 2021
Last Verified: February 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioma
Neoplasms
Ependymoma
Medulloblastoma
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Brain Neoplasms
Rhabdoid Tumor
Sarcoma, Myeloid
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms, Neuroepithelial
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neoplasms, Complex and Mixed
Leukemia, Myeloid
Leukemia
Mycophenolic Acid
Fludarabine
Fludarabine phosphate
Etoposide
Etoposide phosphate