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

This study has suspended participant recruitment.
(OHSU IRB closed study to further enrollment 2/17/2006)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier:
NCT00238173
First received: October 12, 2005
Last updated: September 22, 2011
Last verified: March 2011
  Purpose

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.


Condition Intervention Phase
Bone Marrow Suppression
Brain and Central Nervous System Tumors
Drug/Agent Toxicity by Tissue/Organ
Long-term Effects Secondary to Cancer Therapy in Children
Biological: filgrastim
Drug: acetylcysteine
Drug: carboplatin
Drug: cyclophosphamide
Drug: etoposide phosphate
Drug: mannitol
Drug: sodium thiosulfate
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by OHSU Knight Cancer Institute:

Primary Outcome Measures:
  • 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. [ Designated as safety issue: Yes ]

Estimated Enrollment: 30
Study Start Date: December 2004
Primary Completion Date: February 2006 (Final data collection date for primary outcome measure)
Intervention Details:
    Biological: filgrastim Drug: acetylcysteine
    administered i.v. over 30 to 60 minutes
    Drug: carboplatin
    (200 mg/m2/day; total dose 400 mg/m2) will be infused i.a. over 10 minutes, in 50-180 cc of normal saline.
    Drug: cyclophosphamide
    (330 mg/m2/day; total dose 660 mg/m2) will be infused i.v. in 25-50 cc of normal saline, over approximately 10 minutes.
    Drug: etoposide phosphate
    (200 mg/m2/day; total dose 400 mg/m2) will be infused i.v. in 25-100 cc of normal saline, over approximately 10 minutes, immediately following the cyclophosphamide.
    Drug: mannitol
    (25%) delivered i.a. at a pre-determined flow rate over 30 seconds. The flow rate will be determined by iodinated contrast injection and fluoroscopy as the lowest infusion rate in which there is retrograde flow from the arterial catheter. The rate and volume of mannitol infused will be approximately 4-12 cc/sec x 30 seconds.
    Drug: sodium thiosulfate
    STS is available as a 25% (250 mg/ml) solution. The dose of STS administered 4 hours after carboplatin is 16 gm/m2. The dose of STS administered 8 hours after carboplatin is 16 gm/m2. Actual dose to be administered will be determined and mixed with an equivalent amount of sterile water (1 ml:1 ml) for infusion.
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

Ages Eligible for Study:   1 Year to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00238173

Locations
United States, Oregon
OHSU Knight Cancer Institute
Portland, Oregon, United States, 97239-3098
Sponsors and Collaborators
OHSU Knight Cancer Institute
Investigators
Principal Investigator: Edward A. Neuwelt, MD OHSU Knight Cancer Institute
  More Information

Additional Information:
No publications provided

Responsible Party: OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT00238173     History of Changes
Other Study ID Numbers: OHSU-2050, OHSU-8522, OHSU-SOL-04085-L, OHSU-IRB-2050
Study First Received: October 12, 2005
Last Updated: September 22, 2011
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by OHSU Knight Cancer Institute:
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

Additional relevant MeSH terms:
Brain Neoplasms
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Acetylcysteine
Sodium thiosulfate
N-monoacetylcystine
Cyclophosphamide
Etoposide phosphate
Etoposide
Carboplatin
Lenograstim
Mannitol
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes
Immunosuppressive Agents

ClinicalTrials.gov processed this record on April 17, 2014