Carboplatin, Melphalan, Etoposide Phosphate, Mannitol, and Sodium Thiosulfate in Treating Patients With Previously Treated Brain Tumors

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of melphalan when given together with carboplatin, etoposide phosphate, mannitol, and sodium thiosulfate and to see how well they work in treating patients with previously treated brain tumors. Drugs used in chemotherapy, such as melphalan, carboplatin, and etoposide phosphate, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing, or by stopping them from spreading. Osmotic blood-brain barrier disruption (BBBD) uses mannitol to open the blood vessels around the brain and allow cancer-killing substances to be carried directly to the brain. Sodium thiosulfate may help lessen or prevent hearing loss and toxicities in patients undergoing chemotherapy with carboplatin and BBBD. Giving carboplatin, melphalan, etoposide phosphate, mannitol, and sodium thiosulfate together may be an effective treatment for brain tumors.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate toxicity and estimate the maximum tolerated dose (MTD) of melphalan (intra-arterially [i.a.]) administered in conjunction with carboplatin (i.a.) and etoposide phosphate (intravenously [i.v.]) undergoing BBBD, in subjects with anaplastic oligodendroglioma or oligoastrocytoma. (Phase I) II. To examine the efficacy (one year progression free survival [1YPFS]) of carboplatin (i.a.), melphalan (i.a.) and etoposide phosphate (i.v.) in conjunction with BBBD, in subjects with anaplastic oligodendroglioma or oligoastrocytoma. (Phase II) SECONDARY OBJECTIVES: I. To evaluate the incidence of severe neutropenia (specifically febrile neutropenia or sepsis) of carboplatin (i.a.), melphalan (i.a.) and etoposide phosphate (i.v.) in conjunction with BBBD, in subjects with anaplastic oligodendroglioma or oligoastrocytoma. II. To evaluate the overall toxicity of carboplatin (i.a.), melphalan (i.a.), and etoposide phosphate (i.v.) in conjunction with BBBD. III. To estimate the differences in tumor response, 1YPFS and survival, in subjects with allelic loss of chromosomes 1p and 19q, and tumor protein p53 (p53) immunocytochemistry, versus subjects without allelic loss. IV. To assess quality of life, cognitive function, and performance status of subjects undergoing treatment with carboplatin, melphalan and etoposide phosphate in conjunction with BBBD. V. To estimate differences in 1YPFS between subjects with anaplastic oligodendroglioma and patients with oligoastrocytoma. VI. To describe the role of biopsy versus extent of surgery (sub-maximal versus maximal safe resection) on 1YPFS and survival. VII. To describe the role of prior radiation on tumor response, 1YPFS and survival. OUTLINE: This is a phase I, dose-escalation study of melphalan followed by a phase II study. Patients receive etoposide phosphate IV over 10 minutes, mannitol IA over 30 seconds, melphalan IA over 10 minutes, and carboplatin IA over 10 minutes on days 1 and 2. Patients then receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after carboplatin. Courses repeat every 4 to 6 weeks for up to 12 months. After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Official Title
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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

Conditions
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Anaplastic Oligoastrocytoma, Anaplastic Oligodendroglioma, Mixed Glioma, Oligoastrocytoma

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Etoposide
* Drug: Etoposide Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Mannitol
* Drug: Melphalan
* Other: Quality-of-Life Assessment
* Drug: Sodium Thiosulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with pathologic evidence of an anaplastic oligodendroglioma or mixed glioma (i.e. oligoastrocytoma) are eligible; histopathologic diagnosis will be made using World Health Organization classification criteria; to qualify as a mixed tumor there must be a minimum of 25% oligodendroglial element Surgical procedure may have been complete resection, partial resection, or biopsy Subjects must have had prior treatment with temozolomide; at least 28 days must have elapsed since completion of temozolomide or other chemotherapy If subject has not undergone radiation therapy, then subject must have undergone prior consultation with a radiation oncologist (who is not an investigator on this study); if the subject has undergone radiation therapy, then at least 14 days must have elapsed since completion of radiation Subjects performance status must be (Karnofsky performance status [KPS] greater than or equal to 50; Eastern Cooperative Oncology Group [ECOG] less than or equal to 2) White blood cell count >= 2.5 x 10^3/mm^3 Absolute granulocyte count > 1.5 x 10^3/mm^3 Platelets >= 100 x 10^3/mm^3 Serum creatinine < 1.5 x upper limit of normal Bilirubin < 1.5 x upper limit of normal Subjects baseline serum glutamic oxaloacetic transaminase (SGOT)/serum glutamate pyruvate transaminase (SGPT) must be < 2.5 x institutional upper limit of normal Subjects must sign a written informed consent in accordance with institutional guidelines The effects of carboplatin, melphalan and etoposide phosphate on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because these agents as well as other therapeutic agents used in this trial are known to be teratogenic. Sexually active women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study treatment and for the duration of study treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Exclusion Criteria: Subjects with radiographic signs of excessive intracranial mass effect with associated rapid neurologic deterioration, and/or spinal cord block Subjects at significant risk for general anesthesia Subjects with uncontrolled (over the last 30 days) clinically significant confounding medical conditions Subject is pregnant, has a positive serum human chorionic gonadotropin (hCG) or is lactating Subjects who have contraindications to carboplatin, melphalan, etoposide phosphate, or sodium thiosulfate

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (etoposide, mannitol, melphalan, carboplatin, STS)<br>Patients receive etoposide phosphate IV over 10 minutes, mannitol IA over 30 seconds, melphalan IA over 10 minutes, and carboplatin IA over 10 minutes on days 1 and 2. Patients then receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after carboplatin. Courses repeat every 4 to 6 weeks for up to 12 months. | Drug: Carboplatin<br>* Given IA<br>* Other names: Ribocarbo;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Drug: Etoposide Phosphate<br>* Given IV<br>* Other names: Etopophos;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mannitol<br>* Given IA<br>* Other names: Resectisol;Drug: Melphalan<br>* Given IA<br>* Other names: WR-19813;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Sodium Thiosulfate<br>* Given IV<br>* Other names: Thiosulfuric acid disodium salt;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of melphalan, defined as one dose level below the dose that produces grade 4 toxicity in 33% of patients, graded in accordance with National Cancer Institute Common Toxicity Criteria (NCI CTC) (version 3.0) (Phase I) |  | 4 weeks | 
| Overall survival |  | 1 year | 
| Progression free survival (Phase II) | Kaplan-Meier method will be used. 95% confidence intervals estimated. Cox proportional hazards regression models will be fit to explore potential predictors. | 1 year | 
| Response rate |  | 1 year | 
| Time to best response |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional outcomes | Descriptive numeric and graphical summaries for functional status, quality of life, and cognitive function will be estimated for all subjects and separately for subjects with anaplastic oligodendrogliomas and oligoastrocytomas. | 1 year | 
| Incidence of severe neutropenia (specifically febrile neutropenia or sepsis) in accordance with NCI CTC (version 3.0) | Incidence rates of grade III/IV events and associated 95% confidence intervals will be estimated. | 1 year | 
| Rates of two year progression free survival (2YPFS) for specific tumor types | Separate estimates of 2YPFS and overall survival (and associated confidence intervals) will be made for subjects with anaplastic oligodendroglioma and for subjects with oligoastrocytoma. Confidence intervals will also be used to describe differences between this subject series and our earlier subject series. | 2 years |