Bone Marrow Suppression, Brain and Central Nervous System Tumors, Drug/Agent Toxicity by Tissue/Organ, Long-term Effects Secondary to Cancer Therapy in Children
Conditions
Keywords
drug/agent toxicity by tissue/organ, bone marrow suppression, long-term effects secondary to cancer therapy in children, recurrent childhood brain stem glioma, untreated childhood brain stem glioma, childhood central nervous system germ cell tumor, recurrent childhood supratentorial primitive neuroectodermal tumor, recurrent childhood visual pathway and hypothalamic glioma, recurrent childhood brain tumor, recurrent childhood cerebellar astrocytoma, childhood high-grade cerebral astrocytoma, childhood low-grade cerebral astrocytoma, recurrent childhood cerebral astrocytoma, recurrent childhood medulloblastoma, childhood oligodendroglioma, childhood infratentorial ependymoma, childhood supratentorial ependymoma, recurrent childhood ependymoma, childhood central nervous system choriocarcinoma, childhood central nervous system embryonal tumor, childhood central nervous system germinoma, childhood central nervous system mixed germ cell tumor, childhood central nervous system teratoma, childhood central nervous system yolk sac tumor, recurrent childhood central nervous system embryonal tumor
Brief summary
RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide, etoposide phosphate, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Mannitol may help chemotherapy work better by making it easier for these drugs to get to the tumor. Chemoprotective drugs, such as acetylcysteine and sodium thiosulfate, may protect normal cells from the side effects of chemotherapy. Giving acetylcysteine together with mannitol, combination chemotherapy, and sodium thiosulfate may be an effective treatment for malignant brain tumors. PURPOSE: This phase I trial is studying the side effects and best dose of acetylcysteine when given together with mannitol, combination chemotherapy, and sodium thiosulfate in treating children with malignant brain tumors.
Detailed description
OBJECTIVES: Primary * Determine the toxicity and maximum tolerated dose of acetylcysteine when given in combination with blood-brain barrier disruption treatment with mannitol, combination chemotherapy comprising cyclophosphamide, etoposide phosphate, and carboplatin, and delayed high-dose sodium thiosulfate in pediatric patients with malignant brain tumors. Secondary * Determine the blood/bone marrow toxicity of this regimen in these patients. * Determine tumor response in patients treated with this regimen. OUTLINE: This is a dose-escalation study of acetylcysteine. Patients receive acetylcysteine IV over 30-60 minutes followed, at least 15 minutes later, by x-ray-guided femoral artery catheterization under general anesthesia on days 1 and 2. After placement of the catheter, patients receive cyclophosphamide IV over 10 minutes, etoposide phosphate IV over 10 minutes, mannitol intra-arterially (IA) over 30 seconds, and carboplatin IA over 10 minutes also on days 1 and 2. Patients then receive high-dose sodium thiosulfate IV over 15 minutes 4 hours after completion of carboplatin. Some patients may receive a second dose of sodium thiosulfate 8 hours after completion of carboplatin. Beginning 48 hours after the last dose of chemotherapy on day 2, patients receive filgrastim (G-CSF) subcutaneously once daily for 7-10 days or until blood counts recover. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of acetylcysteine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 3 patients are treated at the MTD. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.
Interventions
DRUGetoposide phosphate
(200 mg/m2/day; total dose 400 mg/m2) will be infused i.v. in 25-100 cc of normal saline, over approximately 10 minutes, immediately following the cyclophosphamide.
BIOLOGICALfilgrastim
DRUGacetylcysteine
administered i.v. over 30 to 60 minutes
DRUGcarboplatin
(200 mg/m2/day; total dose 400 mg/m2) will be infused i.a. over 10 minutes, in 50-180 cc of normal saline.
DRUGcyclophosphamide
(330 mg/m2/day; total dose 660 mg/m2) will be infused i.v. in 25-50 cc of normal saline, over approximately 10 minutes.
DRUGmannitol
(25%) delivered i.a. at a pre-determined flow rate over 30 seconds. The flow rate will be determined by iodinated contrast injection and fluoroscopy as the lowest infusion rate in which there is retrograde flow from the arterial catheter. The rate and volume of mannitol infused will be approximately 4-12 cc/sec x 30 seconds.
DRUGsodium thiosulfate
STS is available as a 25% (250 mg/ml) solution. The dose of STS administered 4 hours after carboplatin is 16 gm/m2. The dose of STS administered 8 hours after carboplatin is 16 gm/m2. Actual dose to be administered will be determined and mixed with an equivalent amount of sterile water (1 ml:1 ml) for infusion.
Sponsors
National Cancer Institute (NCI)
OHSU Knight Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed brain tumors, including any of the following: * Brain stem glioma * Primitive neuroectodermal tumor * CNS germ cell tumor * Malignant glioma * Diagnosis based on any of the following: * CT-assisted or stereotactic biopsy * Open biopsy * Surgical resection * Cerebrospinal fluid cytology * Elevated tumor markers * Unequivocal radiographic changes (for patients with brain stem glioma or optic glioma) * All tumor types, except brain stem glioma, must be recurrent * No radiographic signs of intracranial herniation and/or spinal cord block PATIENT CHARACTERISTICS: Performance status * ECOG 0-2 Life expectancy * At least 90 days Hematopoietic * WBC ≥ 2,500/mm\^3 * Absolute granulocyte count ≥ 1,200/mm\^3 * Platelet count ≥ 100,000/mm\^3 Hepatic * SGOT and SGPT \< 2.5 times upper limit of normal * Bilirubin \< 2.0 mg/dL Renal * Creatinine \< 1.8 mg/dL Pulmonary * No history of clinically significant reactive airway disease Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No significant risk for general anesthesia * No uncontrolled, clinically significant, confounding medical condition within the past 30 days * No contraindication to study drugs PRIOR CONCURRENT THERAPY: Chemotherapy * At least 28 days since prior systemic chemotherapy Radiotherapy * At least 3 months since prior total spine radiotherapy * At least 14 days since prior cranial radiotherapy * Prior systemic radiotherapy allowed Surgery * See Disease Characteristics
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To assess toxicity and the maximally tolerated dose of N-acetylcysteine administered in conjunction with carboplatin, cyclophosphamide and etoposide phosphate BBBD, and delayed high dose sodium thiosulfate, in children with malignant brain tumors. | — |
Countries
United States
Outcome results
None listed