Melphalan, Carboplatin, Mannitol, and Sodium Thiosulfate in Treating Patients With Recurrent or Progressive CNS Embryonal or Germ Cell Tumors

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE1/PHASE2

Total Enrollment

17 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-07-09

Study Completion Date

2022-12-31

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, mannitol, and sodium thiosulfate, and to see how well they work in treating patients with central nervous system (CNS) embryonal or germ cell tumors that is growing, spreading, or getting worse (progressive) or has come back (recurrent). Drugs used in chemotherapy, such as melphalan and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, 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 melphalan together with carboplatin, mannitol, and sodium thiosulfate may be an effective treatment for recurrent or progressive CNS embryonal or germ cell tumors.

Detailed Description

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PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of intra-arterial (IA) melphalan given with IA carboplatin, osmotic BBBD and delayed intravenous (IV) sodium thiosulfate (STS) in subjects with recurrent or progressive embryonal and germ cell tumors of the CNS. (Phase I) II. To estimate the response rate in subjects with recurrent or progressive CNS embryonal and germ cell tumors treated with IA carboplatin, IA melphalan, osmotic BBBD and delayed IV STS. (Phase II)

SECONDARY OBJECTIVES:

I. To describe 2-year progression-free survival (PFS) and overall survival (OS) rates in subjects with recurrent or progressive CNS embryonal and germ cell tumors treated with IA carboplatin, IA melphalan, osmotic BBBD and delayed IV STS. (Phase II) II. To describe neuropsychological and audiology outcomes in subjects with recurrent or progressive CNS embryonal and germ cell tumors treated with IA carboplatin, IA melphalan, osmotic BBBD and delayed IV STS. (Phase II) III. To describe the overall toxicity of IA carboplatin and IA melphalan in conjunction with osmotic BBBD and delayed STS chemoprotection in subjects with recurrent or progressive CNS embryonal or germ cell tumors. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of melphalan followed by a phase II study.

Patients receive mannitol IA over 30 seconds, melphalan IA over 10 minutes, and carboplatin IA over 10 minutes. Patients then receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after carboplatin. Treatment repeats every 4-6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 1 year, and then annually for 3 years.

Conditions

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Central Nervous System Embryonal Neoplasm Embryonal Tumor With Multilayered Rosettes, C19MC-Altered Germ Cell Tumor Medulloblastoma Medulloepithelioma Primitive Neuroectodermal Tumor Recurrent Childhood Central Nervous System Embryonal Neoplasm Recurrent Malignant Germ Cell Tumor Recurrent Medulloblastoma Recurrent Primitive Neuroectodermal Tumor

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Treatment (mannitol, melphalan, carboplatin, STS)

Patients receive mannitol IA over 30 seconds, melphalan IA over 10 minutes, and carboplatin IA over 10 minutes. Patients then receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after carboplatin. Treatment repeats every 4-6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Group Type EXPERIMENTAL

Carboplatin

Intervention Type DRUG

Given IA

Mannitol

Intervention Type DRUG

Given IA

Melphalan

Intervention Type DRUG

Given IA

Quality-of-Life Assessment

Intervention Type OTHER

Ancillary studies

Questionnaire Administration

Intervention Type OTHER

Ancillary studies

Sodium Thiosulfate

Intervention Type DRUG

Given IV

Interventions

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Carboplatin

Given IA

Intervention Type DRUG

Mannitol

Given IA

Intervention Type DRUG

Melphalan

Given IA

Intervention Type DRUG

Quality-of-Life Assessment

Ancillary studies

Intervention Type OTHER

Questionnaire Administration

Ancillary studies

Intervention Type OTHER

Sodium Thiosulfate

Given IV

Intervention Type DRUG

Other Intervention Names

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Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo D-Mannitol Mannitol, D- Osmitrol Resectisol 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 Quality of Life Assessment Cyanide Antidote Package Disodium Thiosulfate S-Hydril Sodium Hyposulfate Sodium Thiosulfate Pentahydrate Sodium Thiosulphate Sodothiol Thiosulfate, Sodium, Pentahydrate Thiosulfuric Acid Disodium Salt

Eligibility Criteria

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Inclusion Criteria

* Subjects with histologically confirmed CNS embryonal tumor (primitive neuroectodermal tumor \[PNET\], medulloblastoma, atypical teratoid rhabdoid tumor \[ATRT\], medulloepithelioma, pineoblastoma or ependymoblastoma), or germ cell tumor, are eligible; subjects may be enrolled on study as first-line treatment; diagnosis will be made on the basis of computed tomography (CT)-assisted or stereotactic biopsy, open biopsy, surgical resection, cerebrospinal fluid (CSF) cytology, or elevated tumor markers
* Subjects may be enrolled as part of first-line treatment; those subjects who enroll as first-line treatment will not be restricted from traditional treatments in the future; at least 14 days must have elapsed since completion of cranial radiotherapy and 28 days since completion of chemotherapy; at least 28 days must have elapsed since completion of total spine radiotherapy
* Subjects with no previous radiotherapy treatment must have a consultation with a radiation oncologist or providers must have a discussion in the context of Neuro-Oncology Tumor Board within 60 days prior to start of IA/BBBD chemotherapy to determine the need for radiotherapy prior to or after IA/BBBD
* Glomerular filtration rate (GFR) or creatinine clearance (CrCl) (24 hour urine) greater than 30 ml/min corrected for body surface area
* Absolute granulocyte count \>= 1.0 x 10\^3/mm\^3
* Platelets \>= 100 x 10\^3/mm\^3
* Creatinine \< 1.5
* Total bilirubin \< 2.0 mg/dl
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \< 2.5 x upper limits of normal
* Subject's Karnofsky performance status (KPS) must be \>= 50% (Eastern Cooperative Oncology Group \[ECOG\] performance score \< 3)
* Subjects or their legal guardian must sign a written informed consent in accordance with institutional guidelines
* 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 female become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
* For the phase II portion of the study, subjects must have disease that is evaluable for response; subjects who have had radiation to all sites of disease are not eligible unless there is imaging evidence of active tumor, ie: increased blood volume

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 with general anesthesia
* Subjects with uncontrolled (over the last 30 days) clinically significant confounding medical conditions
* Subject is pregnant or is lactating
* Subjects who have contraindications to carboplatin, melphalan, or STS

Minimum Eligible Age

18 Years

Maximum Eligible Age

45 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Edward Neuwelt

Principal Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Edward A Neuwelt

Role: PRINCIPAL_INVESTIGATOR

OHSU Knight Cancer Institute

Locations

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University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota, United States

Site Status

OHSU Knight Cancer Institute

Portland, Oregon, United States

Site Status

Countries

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United States