Combination Chemotherapy With BBBD Followed By Sodium Thiosulfate in Treating Patients With Anaplastic Oligodendroglioma or Oligoastrocytoma
RATIONALE: Drugs used in chemotherapy, such as etoposide, carboplatin, and melphalan, 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. Chemoprotective drugs, such as sodium thiosulfate, may protect normal cells from the side effects of chemotherapy. Blood-brain barrier disruption uses certain drugs, such as mannitol, to open the blood vessels around the brain and allow chemotherapy to be carried directly to the brain tumor. Giving combination chemotherapy together with blood-brain barrier disruption may kill more tumor cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of melphalan when given together with etoposide, carboplatin and blood-brain barrier disruption followed by sodium thiosulfate and to see how well they work in treating patients with anaplastic oligodendroglioma or oligoastrocytoma.
Brain and Central Nervous System Tumors
Drug: Etoposide phosphate
Drug: Sodium thiosulfate
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Study of Carboplatin, Melphalan and Etoposide Phosphate in Conjunction With Osmotic Opening of the Blood-Brain Barrier and Delayed Intravenous Sodium Thiosulfate Chemoprotection, in Previously Treated Subjects With Anaplastic Oligodendroglioma or Oligoastrocytoma|
- Maximum tolerated dose (MTD) of melphalan as measured by NCI Common Terminology Criteria (CTC) v3 (Phase I) [ Time Frame: Completed ] [ Designated as safety issue: Yes ]
MTD = 1 dose level below dose level that produces grade 4 toxicity attributable to the chemotherapy regimen that occurs during cycle one of chemotherapy, in 33% of subjects.
The Melphalan MTD when given with this combination chemotherapy has been determined to be 4mg/m2/day x 2 days.
- Progression-free survival as measured by radiographic response at one year progression free survival (1YPFS) (Phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
- Incidence of neutropenia as measured by complete blood cell count lab values done weekly during study treatment [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]Evaluate incidence of severe neutropenia (febrile neutropenia or sepsis) of carboplatin, melphalan, and etoposide phosphate in conjunction with BBBD
- Overall toxicity of chemotherapy as measured by NCI CTC v3 during study treatment [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
- Estimate differences in tumor response, 1YPFS, and survival in patients with and without allelic loss as measured by lab assays before study treatment [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]Evaluation of allelic loss by lab assays testing for chromosomes 1p and 19q and p53 immunocytochemistry
- Quality of life (QOL) as measured by European Organisation for Research and Treatment of Cancer (EORTC) QOL [ Time Frame: Up to 3 years plus follow up ] [ Designated as safety issue: No ]Every 3 months during treatment and within 30 days of final treatment. After final treatment, QOL assessment annually.
- Estimate differences in 1YPFS between subjects with anaplastic oligodendroglioma and oligoastrocytoma [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
- Describe role of biopsy vs extent of surgery on 1YPFS and survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]Role of biopsy versus extent of surgery (sub-maximal versus maximal safe resection)on 1YPFS and survival
- Role of prior radiation on tumor response, 1YPFS, and survival. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]Describe role of prior radiation on tumor response, 1YPFS, and survival.
|Study Start Date:||September 2005|
|Estimated Study Completion Date:||December 2016|
|Estimated Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
|Experimental: All subjects||
Drug: Etoposide phosphate
Dose: 200mg/m2/day x 2 days; Every 4 weeks for up to one year
Etoposide may be substituted
Dose: 4mg/m2/day x 2 days; Every 4 weeks for up to one year.Drug: Carboplatin
Dose: 200mg/m2/day x 2 days; Every 4 weeks for up to one yearDrug: Sodium thiosulfate
Dose: 4 hrs post carboplatin = 20gm/m2
Dose: 8 hrs post carboplatin = 16gm/m2
Every 4 weeks for up to one year
Other Name: STSDrug: Filgrastim
48 hrs after last dose of carboplatin, every day (QD) x 7-10 days until white blood cells (WBC) greater than 5000. Dose based on weight of subject.
Pegfilgrastim (Neulasta) may be given instead.
Other Names:Drug: Pegfilgrastim
Dose: 6mg, 24-72 hrs after chemotherapy.
Filgrastim (Neupogen) may be given instead
- Evaluate toxicity and estimate the maximum tolerated dose (MTD) of melphalan administered in conjunction with carboplatin and etoposide phosphate in combination with blood-brain barrier disruption (BBBD) with mannitol and delayed sodium thiosulfate, in patients with anaplastic oligodendroglioma or oligoastrocytoma. (phase I)
- Examine the efficacy, in terms of 1-year progression-free survival (1YPFS), in patients treated with this regimen. (phase II)
- Evaluate the incidence of severe neutropenia (specifically febrile neutropenia or sepsis) in patients treated with this regimen.
- Evaluate the overall toxicity of this regimen.
- Compare tumor response, 1YPFS, and survival in patients with vs without allelic loss of chromosomes 1p and 19q and p53 immunocytochemistry.
- Assess quality of life, cognitive function, and performance status in these patients.
- Estimate differences in 1YPFS between patients with anaplastic oligodendroglioma and patients with oligoastrocytoma.
- Describe the role of biopsy versus extent of surgery (sub-maximal versus maximal safe resection) on 1YPFS and survival.
- Describe the role of prior radiotherapy on tumor response, 1YPFS, and survival.
OUTLINE: This is a multi-center, phase I dose-escalation study of melphalan followed by a phase II study.
- Phase I: Patients receive etoposide phosphate IV over 10 minutes, mannitol intra-arterially (IA), carboplatin IA over 10 minutes, and melphalan IA over 10 minutes on days 1 and 2 and sodium thiosulfate IV over 15 minutes beginning 4 and 8 hours after completion of chemotherapy on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 4 and continuing until blood counts recover OR a small dose of pegfilgrastim SC on day 2. Treatment repeats every 4 weeks for up to 12 monthly courses in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of melphalan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
- Phase II: Patients receive etoposide phosphate, mannitol, carboplatin, melphalan at the MTD, sodium thiosulfate, and G-CSF or pegfilgrastim as in phase I. Treatment repeats every 4 weeks for up to 12 monthly courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed every 3 months for one year; every 6 months for the next two years; then annually.
PROJECTED ACCRUAL: Up to 60 patients will be accrued for this study.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00303849
|Contact: Edward A Neuwelt, MDfirstname.lastname@example.org|
|Contact: Cynthia A Lacy, BSNemail@example.com|
|United States, Minnesota|
|University of Minnesota||Recruiting|
|Minneapolis, Minnesota, United States, 55455|
|Contact: Matthew Hunt, MD 612-626-0975 firstname.lastname@example.org|
|Contact: Natalie Brandt, BSN 612-624-8117 email@example.com|
|Principal Investigator: Matthew Hunt, MD|
|United States, Oregon|
|Knight Cancer Institute at Oregon Health and Science University||Recruiting|
|Portland, Oregon, United States, 97239-3098|
|Contact: Clinical Trials Office - Knight Cancer Institute at Oregon Hea 503-494-1080 firstname.lastname@example.org|
|Contact: Edward A Neuwelt, MD 503-494-5626 email@example.com|
|Principal Investigator: Edward A Neuwelt, MD|
|Principal Investigator:||Edward A. Neuwelt, MD||OHSU Knight Cancer Institute|