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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2016 by OHSU Knight Cancer Institute
Sponsor:
Collaborators:
National Cancer Institute (NCI)
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier:
NCT00983398
First received: September 23, 2009
Last updated: April 28, 2016
Last verified: April 2016
  Purpose
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 recurrent or progressive central nervous system (CNS) embryonal or germ cell tumors. 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.

Condition Intervention Phase
Adult Central Nervous System Germ Cell Tumor
Adult Ependymoblastoma
Adult Medulloblastoma
Adult Pineoblastoma
Adult Supratentorial Primitive Neuroectodermal Tumor
Childhood Atypical Teratoid/Rhabdoid Tumor
Childhood Central Nervous System Germ Cell Tumor
Childhood Ependymoblastoma
Medulloepithelioma
Ototoxicity
Recurrent Adult Brain Neoplasm
Recurrent Childhood Central Nervous System Embryonal Neoplasm
Recurrent Childhood Malignant Germ Cell Tumor
Recurrent Childhood Medulloblastoma
Recurrent Childhood Pineoblastoma
Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor
Drug: Carboplatin
Drug: Mannitol
Drug: Melphalan
Other: Quality-of-Life Assessment
Other: Questionnaire Administration
Drug: Sodium Thiosulfate
Phase 1
Phase 2

Study Type: Interventional
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 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

Resource links provided by NLM:


Further study details as provided by OHSU Knight Cancer Institute:

Primary Outcome Measures:
  • MTD based on the incidence of dose-limiting toxicity (DLT), graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 (Phase I) [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Descriptive statistics will be estimated.


Secondary Outcome Measures:
  • Change in neurocognitive assessment scores (Phase II) [ Time Frame: Baseline to 90 days after completion of study treatment ] [ Designated as safety issue: No ]
    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.

  • OS rate (Phase II) [ Time Frame: Time from time of first study treatment until death, assessed at 2 years ] [ Designated as safety issue: No ]
    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 PFS and OS with baseline demographic and disease characteristics.

  • Progression free survival (PFS) rate (Phase II) [ Time Frame: Time from first study treatment to evidence of first progression, assessed at 2 years ] [ Designated as safety issue: No ]
    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 PFS and overall survival (OS) with baseline demographic and disease characteristics.

  • Proportion of patients with ototoxicity, graded according to the NCI CTCAE v4.0 (Phase II) [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    Estimated using proportions with associated confidence intervals.


Estimated Enrollment: 55
Study Start Date: September 2009
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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 courses in the absence of disease progression or unacceptable toxicity.
Drug: Carboplatin
Given IA
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplat
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo
Drug: Mannitol
Given IA
Other Names:
  • D-Mannitol
  • Mannitol, D-
  • Osmitrol
  • Resectisol
Drug: Melphalan
Given IA
Other Names:
  • 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
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Other: Questionnaire Administration
Ancillary studies
Drug: Sodium Thiosulfate
Given IV
Other Names:
  • Cyanide Antidote Package
  • Disodium Thiosulfate
  • S-Hydril
  • Sodium Hyposulfate
  • Sodium Thiosulfate Pentahydrate
  • Sodium Thiosulphate
  • Sodothiol
  • Thiosulfate, Sodium, Pentahydrate
  • Thiosulfuric Acid Disodium Salt

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 courses 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.

  Eligibility

Ages Eligible for Study:   1 Year to 30 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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; tumors must be relapsed or refractory to first-line therapy; 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 must have had prior therapy according to the best available therapy as determined by their primary brain tumor specialist (to include oncology, neurosurgery and/or radiation oncology) including systemic and/or cranial or spinal radiation or chemotherapy; 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
  • 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
  • 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); the Lansky scale will be used for subjects less than 16 years of age and must be >= 50%
  • 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

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00983398

Locations
United States, Minnesota
University of Minnesota/Masonic Cancer Center Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Daniel J. Guillaume    612-624-5931    dguillau@umn.edu   
Principal Investigator: Edward A. Neuwelt         
United States, Oregon
OHSU Knight Cancer Institute Recruiting
Portland, Oregon, United States, 97239
Contact: Edward A. Neuwelt    503-494-5626    neuwelte@ohsu.edu   
Principal Investigator: Edward A. Neuwelt         
Sponsors and Collaborators
OHSU Knight Cancer Institute
National Cancer Institute (NCI)
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Principal Investigator: Edward Neuwelt OHSU Knight Cancer Institute
  More Information

Responsible Party: OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT00983398     History of Changes
Other Study ID Numbers: IRB00005056  NCI-2013-00790  OHSU-5056  MR00042551  5056  IRB00005056  P30CA069533  R01NS044687 
Study First Received: September 23, 2009
Last Updated: April 28, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasms
Neoplasms, Germ Cell and Embryonal
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Medulloblastoma
Pinealoma
Brain Neoplasms
Rhabdoid Tumor
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neoplasms, Glandular and Epithelial
Glioma
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neoplasms, Complex and Mixed
Carboplatin
Melphalan
Mechlorethamine
Nitrogen Mustard Compounds
Mannitol
Sodium thiosulfate
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 29, 2016