Acetylcysteine, Mannitol, Combination Chemotherapy, and Sodium Thiosulfate in Treating Children With Malignant Brain Tumors

OHSU Knight Cancer Institute

Status and phase

Terminated

Phase 1

Conditions

Brain and Central Nervous System Tumors

Drug/Agent Toxicity by Tissue/Organ

Long-term Effects Secondary to Cancer Therapy in Children

Bone Marrow Suppression

Treatments

Biological: filgrastim

Drug: carboplatin

Drug: cyclophosphamide

Drug: sodium thiosulfate

Drug: mannitol

Drug: etoposide phosphate

Drug: acetylcysteine

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00238173

OHSU-SOL-04085-L

IRB00002050

OHSU-8522

OHSU-IRB-2050

Details and patient eligibility

About

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.

Full 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.

Enrollment

2 patients

Sex

All

Ages

1 to 18 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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