Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Supportive care, Treatment	Closed	1 to 18	NCI	OHSU-8522 OHSU-SOL-04085-L, NCT00238173

Objectives

Primary

1. 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

1. Determine the blood/bone marrow toxicity of this regimen in these patients.
2. Determine tumor response in patients treated with this regimen.

Entry 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

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

Patient Characteristics:

Performance status

• ECOG 0-2

Life expectancy

• At least 90 days

Hematopoietic

• WBC ≥ 2,500/mm³
• Absolute granulocyte count ≥ 1,200/mm³
• Platelet count ≥ 100,000/mm³

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

Expected Enrollment

A total of 30 patients will be accrued for this study.

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.

Trial Contact Information

Trial Lead Organizations

Knight Cancer Institute at Oregon Health and Science University

Edward Neuwelt, MD, Principal investigator		Ph: 503-494-5626; 800-494-1234 Email: Neuwelte@ohsu.edu

Registry Information
Official Title		Phase I Dose Escalation Study of N-Acetylcysteine Administered in Conjunction with Carboplatin, Cyclophosphamide, and Etoposide Phosphate BBBD, in Children with Malignant Brain Tumors
Trial Start Date		2004-12-03
Registered in ClinicalTrials.gov		NCT00238173
Date Submitted to PDQ		2005-08-11
Information Last Verified		2006-04-05
NCI Grant/Contract Number		CA69533, NS44687