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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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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

Intervention / Treatment
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* Drug: Etoposide
* Drug: Fludarabine Phosphate
* Procedure: Hematopoietic Cell Transplantation
* Biological: Lapine T-Lymphocyte Immune Globulin
* Drug: Melphalan
* Drug: Mycophenolate Mofetil
* Drug: Tacrolimus
* Drug: Thiotepa


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, HCT)<br>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<br>* Given IV<br>* Other names: VP16;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Procedure: Hematopoietic Cell Transplantation<br>* Undergo HCT<br>* Other names: stem cell transplantation;Biological: Lapine T-Lymphocyte Immune Globulin<br>* Given IV<br>* Other names: Thymoglobulin;Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Drug: Mycophenolate Mofetil<br>* Given PO or IV<br>* Other names: MMF;Drug: Tacrolimus<br>* Given IV<br>* Other names: Protopic;Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;|

What is the study measuring?
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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 |