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

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.

Study Overview

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

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.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • OHSU Knight Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

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.

Collaborators and Investigators

• Sponsor: OHSU Knight Cancer Institute
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Edward A. Neuwelt, MD, OHSU Knight Cancer Institute

Study record dates

Study Major Dates

• Study Start: December 1, 2004
• Primary Completion (Actual): February 17, 2006
• Study Completion (Actual): February 17, 2006

Study Registration Dates

• First Submitted: October 12, 2005
• First Submitted That Met QC Criteria: October 12, 2005
• First Posted (Estimate): October 13, 2005

Study Record Updates

• Last Update Posted (Actual): April 21, 2017
• Last Update Submitted That Met QC Criteria: April 19, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: untreated childhood brain stem glioma; childhood high-grade cerebral astrocytoma; bone marrow suppression; long-term effects secondary to cancer therapy in children; drug/agent toxicity by tissue/organ; childhood infratentorial ependymoma; childhood supratentorial ependymoma; childhood oligodendroglioma; recurrent childhood supratentorial primitive neuroectodermal tumor; recurrent childhood cerebellar astrocytoma; recurrent childhood cerebral astrocytoma; recurrent childhood ependymoma; recurrent childhood brain tumor; recurrent childhood brain stem glioma; recurrent childhood medulloblastoma; recurrent childhood visual pathway and hypothalamic glioma; childhood central nervous system germ cell tumor; childhood low-grade cerebral astrocytoma; 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: Chemically-Induced Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Brain Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Drug-Related Side Effects and Adverse Reactions; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Natriuretic Agents; Anti-Bacterial Agents; Diuretics, Osmotic; Diuretics; Respiratory System Agents; Antioxidants; Antidotes; Antitubercular Agents; Chelating Agents; Sequestering Agents; Free Radical Scavengers; Expectorants; Cyclophosphamide; Carboplatin; Etoposide; Etoposide phosphate; Mannitol; Acetylcysteine; N-monoacetylcystine; Sodium thiosulfate
• Other Study ID Numbers: IRB00002050; OHSU-8522; OHSU-SOL-04085-L; OHSU-IRB-2050