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

Primary Purpose

Central Nervous System Embryonal Neoplasm, Embryonal Tumor With Multilayered Rosettes, C19MC-Altered, Germ Cell Tumor

Status

Unknown status

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Carboplatin

Mannitol

Melphalan

Quality-of-Life Assessment

Questionnaire Administration

Sodium Thiosulfate

About this trial

This is an interventional treatment trial for Central Nervous System Embryonal Neoplasm

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of Minnesota/Masonic Cancer Center
OHSU Knight Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (mannitol, melphalan, carboplatin, STS)

Arm Description

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.

Outcomes

Primary Outcome Measures

Maximum tolerated dose (Phase I)

Will be assessed based on the incidence of dose-limiting toxicity, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. All toxicities will be tabulated by event and by overall. The toxicities will also be tabulated by highest grade. The recovery from toxicities (i.e. hematologic toxicities) will also be summarized.

Response rate (Phase II)

Descriptive statistics will be estimated.

Secondary Outcome Measures

Progression free survival rate (Phase II)

Estimation made using Kaplan-Meier product limit estimation. A Cox proportional hazards regression model will be fit to the data to estimate the association of progression free survival and overall survival with baseline demographic and disease characteristics.

Overall survival rate (Phase II)

Change in neurocognitive assessment scores (Phase II)

Quantitative scores, whenever possible, will be derived from each measure and converted to measure-specific Z scores using normative data. Post-treatment Z scores will be subtracted from pre-treatment Z scores to calculate absolute change in neuropsychological test performance. Significant change will be defined as change of 1 standard deviation. These data will be summarized descriptively.

Proportion of patients with ototoxicity (Phase II)

Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Estimated using proportions with associated confidence intervals.

Full Information

NCT ID

NCT00983398

First Posted

September 23, 2009

Last Updated

October 25, 2021

Sponsor

OHSU Knight Cancer Institute

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS), Oregon Health and Science University

1. Study Identification

Unique Protocol Identification Number

NCT00983398

Brief Title

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

Official Title

Phase I/II Study of Intra-Arterial Melphalan Given With Intra-Arterial Carboplatin, Osmotic Blood-Brain Barrier Disruption and Delayed Otoprotective Sodium Thiosulfate for Patients With Recurrent or Progressive CNS Embryonal or Germ Cell Tumors

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Unknown status

Study Start Date

July 9, 2009 (Actual)

Primary Completion Date

December 31, 2021 (Anticipated)

Study Completion Date

December 31, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

OHSU Knight Cancer Institute

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS), Oregon Health and Science University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

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, 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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

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

17 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (mannitol, melphalan, carboplatin, STS)

Arm Type

Experimental

Arm Description

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)

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

Other

Intervention Name(s)

Questionnaire Administration

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

Maximum tolerated dose (Phase I)

Description

Time Frame

6 weeks

Title

Response rate (Phase II)

Description

Descriptive statistics will be estimated.

Time Frame

Up to 5 years

Secondary Outcome Measure Information:

Title

Progression free survival rate (Phase II)

Description

Time Frame

Time from first study treatment to evidence of first progression, assessed at 2 years

Title

Overall survival rate (Phase II)

Description

Time Frame

Time from time of first study treatment until death, assessed at 2 years

Title

Change in neurocognitive assessment scores (Phase II)

Description

Time Frame

Baseline to 90 days after completion of study treatment

Title

Proportion of patients with ototoxicity (Phase II)

Description

Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Estimated using proportions with associated confidence intervals.

Time Frame

Up to 30 days after completion of study treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

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

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

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