Acetylcysteine, Mannitol, Combination Chemotherapy, and Sodium Thiosulfate in Treating Children With Malignant Brain Tumors
| Status: | Terminated |
|---|---|
| Conditions: | Cancer, Cancer, Brain Cancer, Brain Cancer, Brain Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 1 - 18 |
| Updated: | 4/6/2017 |
| Start Date: | December 2004 |
| End Date: | February 17, 2006 |
Phase I Dose Escalation Study of N-Acetylcysteine Administered in Conjunction With Carboplatin, Cyclophosphamide, and Etoposide Phosphate BBBD, in Children With Malignant Brain Tumors
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.
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.
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.
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.
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
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