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Phase I Dose Escalation Study of N-Acetylcysteine Administered in Conjunction With Carboplatin, Cyclophosphamide, and Etoposide Phosphate BBBD, in Children With Malignant Brain Tumors

Phase 1
1 Year
18 Years
Not Enrolling
Bone Marrow Suppression, Brain and Central Nervous System Tumors, Drug/Agent Toxicity by Tissue/Organ, Long-term Effects Secondary to Cancer Therapy in Children

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Trial Information

Phase I Dose Escalation Study of N-Acetylcysteine Administered in Conjunction With Carboplatin, Cyclophosphamide, and Etoposide Phosphate BBBD, in Children With Malignant Brain Tumors



- 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.


- 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

After completion of study treatment, patients are followed periodically.

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

Inclusion Criteria


- 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

- All tumor types, except brain stem glioma, must be recurrent

- No radiographic signs of intracranial herniation and/or spinal cord block


Performance status

- ECOG 0-2

Life expectancy

- At least 90 days


- WBC ≥ 2,500/mm^3

- Absolute granulocyte count ≥ 1,200/mm^3

- Platelet count ≥ 100,000/mm^3


- SGOT and SGPT < 2.5 times upper limit of normal

- Bilirubin < 2.0 mg/dL


- Creatinine < 1.8 mg/dL


- No history of clinically significant reactive airway disease


- 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



- At least 28 days since prior systemic chemotherapy


- At least 3 months since prior total spine radiotherapy

- At least 14 days since prior cranial radiotherapy

- Prior systemic radiotherapy allowed


- See Disease Characteristics

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Safety Issue:


Principal Investigator

Edward A. Neuwelt, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

OHSU Knight Cancer Institute


United States: Federal Government

Study ID:




Start Date:

December 2004

Completion Date:

Related Keywords:

  • Bone Marrow Suppression
  • Brain and Central Nervous System Tumors
  • Drug/Agent Toxicity by Tissue/Organ
  • Long-term Effects Secondary to Cancer Therapy in Children
  • 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
  • Brain Neoplasms
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms



OHSU Knight Cancer InstitutePortland, Oregon  97239