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

A Pilot Study of Allogeneic Hematopoietic Cell Transplantation for Patients With High Grade Central Nervous System Malignancies

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.

Study Overview

• Status: Withdrawn
• Conditions: Malignant Glioma; Medulloblastoma; Anaplastic Ependymoma; Recurrent Malignant Glioma; Recurrent Medulloblastoma; Atypical Teratoid/Rhabdoid Tumor; Primitive Neuroectodermal Tumor; Choroid Plexus Carcinoma; Recurrent Atypical Teratoid/Rhabdoid Tumor; Malignant Brain Neoplasm; Central Nervous System Germ Cell Tumor; Intracranial Myeloid Sarcoma; Recurrent Anaplastic Ependymoma; Recurrent Malignant Brain Neoplasm; Recurrent Primitive Neuroectodermal Tumor
• Intervention / Treatment: Drug: Etoposide; Drug: Melphalan; Procedure: Hematopoietic Cell Transplantation; Drug: Fludarabine Phosphate; Drug: Tacrolimus; Biological: Lapine T-Lymphocyte Immune Globulin; Drug: Thiotepa; Drug: Mycophenolate Mofetil

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.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • M D Anderson Cancer Center
      • Contact: Kris M. Mahadeo; Phone Number: 713-792-6610; Email: kmmahadeo@mdanderson.org
      • Principal Investigator: Kris M. Mahadeo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: Melphalan; Given IV; Other Names: CB-3025; L-PAM; L-Sarcolysin; Alanine Nitrogen Mustard; L-Phenylalanine Mustard; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; Procedure: Hematopoietic Cell Transplantation; Undergo HCT; Other Names: HSCT; HCT; Hematopoietic Stem Cell Transplantation; stem cell transplantation; Stem Cell Transplant; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Tacrolimus; Given IV; Other Names: Prograf; Hecoria; FK 506; Fujimycin; Protopic; Biological: Lapine T-Lymphocyte Immune Globulin; Given IV; Other Names: Thymoglobulin; Anti-Thymocyte Globulin Rabbit; Grafalon; Rabbit Anti-Human Thymocyte Globulin (RATG); Rabbit Anti-Thymocyte Globulin; Rabbit Antithymocyte Globulin; Rabbit ATG; rATG; Drug: Thiotepa; Given IV; Other Names: Tepadina; Oncotiotepa; STEPA; TESPA; Tespamin; TSPA; Girostan; Tespamine; Thio-Tepa; Thiofosfamide; Thiofozil; Thiophosphamide; Thiophosphoramide; Thiotef; Tifosyl; TIO TEF; Tio-tef; Triethylene Thiophosphoramide; Triethylenethiophosphoramide; Tris(1-aziridinyl)phosphine sulfide; WR 45312; 1,1'',1''''-Phosphinothioylidynetrisaziridine; N,N'', N''''-Triethylenethiophosphoramide; Drug: Mycophenolate Mofetil; Given PO or IV; Other Names: CellCept; MMF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transplant-related mortality	Will be reported together with the corresponding 95% Bayesian credible interval. Will be estimated using the method of Gooley.	At day 30
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.	Within 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Failure of platelet and neutrophil engraftment rates	Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.	Day 100
Incidence of acute graft-versus-host (GVHD) disease	Will be estimated using the method of Gooley.	Up to day 100
Incidence of chronic GVHD	Will be estimated using the method of Gooley.	At day 100 and 1 year
Rate of grade II organ toxicity	Will be reported as counts with percentages.	Up to day 100
Rate of graft failure (primary and secondary)	Will be reported as counts with percentages.	Up to day 100
Rate of infectious complications	Will be reported as counts with percentages.	Up to day 100
Progression free survival		At day 180
Cumulative incidence of relapse	Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.	At day 100 and 1 year
Overall survival	Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.	At day 100 and 1 year
Progression-free survival	Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.	At day 100 and 1 year

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Investigators: Principal Investigator: Kris M Mahadeo, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2021
• Primary Completion (Actual): December 20, 2022
• Study Completion (Actual): December 20, 2022

Study Registration Dates

• First Submitted: August 18, 2020
• First Submitted That Met QC Criteria: August 18, 2020
• First Posted (Actual): August 21, 2020

Study Record Updates

• Last Update Posted (Actual): October 26, 2024
• Last Update Submitted That Met QC Criteria: October 23, 2024
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neoplasms by Site; Disease Attributes; Neoplasms by Histologic Type; Hematologic Diseases; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Leukemia, Myeloid; Nervous System Neoplasms; Sarcoma; Neoplasms, Connective and Soft Tissue; Leukemia; Central Nervous System Neoplasms; Neoplasms, Complex and Mixed; Neoplasms; Recurrence; Glioma; Brain Neoplasms; Ependymoma; Medulloblastoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Rhabdoid Tumor; Sarcoma, Myeloid; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Topoisomerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Keratolytic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Antibiotics, Antitubercular; Antitubercular Agents; Calcineurin Inhibitors; Fludarabine; Melphalan; Etoposide; Antibodies; Immunoglobulins; Mycophenolic Acid; Tacrolimus; Fludarabine phosphate; Etoposide phosphate; Podophyllotoxin; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin; Mechlorethamine; Nitrogen Mustard Compounds; Thiotepa; Antilymphocyte Serum; Thymoglobulin
• Other Study ID Numbers: 2020-0495 (M D Anderson Cancer Center); NCI-2020-05878 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No