Clinical trial NCT04521946: 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
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: 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
Lead sponsor: M.D. Anderson Cancer Center
Sponsor class: OTHER
First posted: 2020-08-21
Enrollment: 0
Sex: ALL
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Transplant-related mortality
timeFrame: At day 30
measure: Rate of grade III or higher organ toxicity attributable to conditioning
timeFrame: Within 30 days
Secondary outcomes:
measure: Failure of platelet and neutrophil engraftment rates
timeFrame: Day 100
measure: Incidence of acute graft-versus-host (GVHD) disease
timeFrame: Up to day 100
measure: Incidence of chronic GVHD
timeFrame: At day 100 and 1 year
measure: Rate of grade II organ toxicity
timeFrame: Up to day 100
measure: Rate of graft failure (primary and secondary)
timeFrame: Up to day 100
measure: Rate of infectious complications
timeFrame: Up to day 100
measure: Progression free survival
timeFrame: At day 180
measure: Cumulative incidence of relapse
timeFrame: At day 100 and 1 year
measure: Overall survival
timeFrame: At day 100 and 1 year
measure: Progression-free survival
timeFrame: At day 100 and 1 year
Other outcomes:
Locations:
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Kris M Mahadeo, MD
role: PRINCIPAL_INVESTIGATOR
References: