Clinical trial NCT00238173: Acetylcysteine, Mannitol, Combination Chemotherapy, and Sodium Thiosulfate in Treating Children With Malignant Brain Tumors
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Bone Marrow Suppression
Brain and Central Nervous System Tumors
Drug/Agent Toxicity by Tissue/Organ
Long-term Effects Secondary to Cancer Therapy in Children
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
Lead sponsor: OHSU Knight Cancer Institute
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2005-10-13
Enrollment: 2
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
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.
Secondary outcomes:
Other outcomes:
Locations:
city: Portland
country: United States
facility: OHSU Knight Cancer Institute
state: Oregon
Study officials:
affiliation: OHSU Knight Cancer Institute
name: Edward A. Neuwelt, MD
role: PRINCIPAL_INVESTIGATOR
References: