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

Primary Purpose

Anaplastic Oligoastrocytoma, Anaplastic Oligodendroglioma, Mixed Glioma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Carboplatin
Etoposide
Etoposide Phosphate
Laboratory Biomarker Analysis
Mannitol
Melphalan
Quality-of-Life Assessment
Sodium Thiosulfate
Sponsored by
OHSU Knight Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Anaplastic Oligoastrocytoma

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Minnesota/Masonic Cancer Center
  • OHSU Knight Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (etoposide, mannitol, melphalan, carboplatin, STS)

Arm Description

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.

Outcomes

Primary Outcome Measures

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)
Overall survival
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.
Response rate
Time to best response

Secondary Outcome Measures

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.
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.
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.

Full Information

First Posted
March 15, 2006
Last Updated
March 11, 2022
Sponsor
OHSU Knight Cancer Institute
Collaborators
Oregon Health and Science University
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1. Study Identification

Unique Protocol Identification Number
NCT00303849
Brief Title
Carboplatin, Melphalan, Etoposide Phosphate, Mannitol, and Sodium Thiosulfate in Treating Patients With Previously Treated Brain Tumors
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Completed
Study Start Date
September 15, 2005 (Actual)
Primary Completion Date
March 12, 2021 (Actual)
Study Completion Date
March 12, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
OHSU Knight Cancer Institute
Collaborators
Oregon Health and Science University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anaplastic Oligoastrocytoma, Anaplastic Oligodendroglioma, Mixed Glioma, Oligoastrocytoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
33 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (etoposide, mannitol, melphalan, carboplatin, STS)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Carboplatin
Other Intervention Name(s)
Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo
Intervention Description
Given IA
Intervention Type
Drug
Intervention Name(s)
Etoposide
Other Intervention Name(s)
Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Etoposide Phosphate
Other Intervention Name(s)
Etopophos
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Mannitol
Other Intervention Name(s)
D-Mannitol, Mannitol, D-, Osmitrol, Resectisol
Intervention Description
Given IA
Intervention Type
Drug
Intervention Name(s)
Melphalan
Other Intervention Name(s)
Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine mustard, L-sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813
Intervention Description
Given IA
Intervention Type
Other
Intervention Name(s)
Quality-of-Life Assessment
Other Intervention Name(s)
Quality of Life Assessment
Intervention Description
Ancillary studies
Intervention Type
Drug
Intervention Name(s)
Sodium Thiosulfate
Other Intervention Name(s)
Cyanide Antidote Package, Disodium Thiosulfate, S-Hydril, Sodium Hyposulfate, Sodium Thiosulfate Pentahydrate, Sodium Thiosulphate, Sodothiol, Thiosulfate, Sodium, Pentahydrate, Thiosulfuric acid disodium salt
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
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)
Time Frame
4 weeks
Title
Overall survival
Time Frame
1 year
Title
Progression free survival (Phase II)
Description
Kaplan-Meier method will be used. 95% confidence intervals estimated. Cox proportional hazards regression models will be fit to explore potential predictors.
Time Frame
1 year
Title
Response rate
Time Frame
1 year
Title
Time to best response
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Functional outcomes
Description
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.
Time Frame
1 year
Title
Incidence of severe neutropenia (specifically febrile neutropenia or sepsis) in accordance with NCI CTC (version 3.0)
Description
Incidence rates of grade III/IV events and associated 95% confidence intervals will be estimated.
Time Frame
1 year
Title
Rates of two year progression free survival (2YPFS) for specific tumor types
Description
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.
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Edward A Neuwelt
Organizational Affiliation
OHSU Knight Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Minnesota/Masonic Cancer Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
OHSU Knight Cancer Institute
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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