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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00983398
Recruitment Status : Active, not recruiting
First Posted : September 24, 2009
Last Update Posted : October 26, 2021
Sponsor:
Collaborators:
National Institute of Neurological Disorders and Stroke (NINDS)
Oregon Health and Science University
Information provided by (Responsible Party):
Edward Neuwelt, OHSU Knight Cancer Institute

Tracking Information
First Submitted Date  ICMJE September 23, 2009
First Posted Date  ICMJE September 24, 2009
Last Update Posted Date October 26, 2021
Actual Study Start Date  ICMJE July 9, 2009
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 15, 2020)
  • Maximum tolerated dose (Phase I) [ Time Frame: 6 weeks ]
    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) [ Time Frame: Up to 5 years ]
    Descriptive statistics will be estimated.
Original Primary Outcome Measures  ICMJE
 (submitted: September 23, 2009)
PHASE I: PRIMARY OBJECTIVE To determine the maximum tolerated dose (MTD) of IA melphalan given with IA carboplatin, osmotic BBBD and delayed IV STS in subjects with recurrent or progressive embryonal and germ cell tumors of the CNS. [ Time Frame: 2 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 15, 2020)
  • Progression free survival rate (Phase II) [ Time Frame: Time from first study treatment to evidence of first progression, assessed at 2 years ]
    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) [ Time Frame: Time from time of first study treatment until death, assessed at 2 years ]
    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.
  • Change in neurocognitive assessment scores (Phase II) [ Time Frame: Baseline to 90 days after completion of study treatment ]
    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) [ Time Frame: Up to 30 days after completion of study treatment ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2009)
  • PHASE II: PRIMARY OBJECTIVE 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. [ Time Frame: 2 years ]
  • 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. [ Time Frame: 2 years ]
  • 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 [ Time Frame: 2 years ]
  • 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. [ Time Frame: 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Melphalan, Carboplatin, Mannitol, and Sodium Thiosulfate in Treating Patients With Recurrent or Progressive CNS Embryonal or Germ Cell Tumors
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Carboplatin
    Given IA
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • 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
Study Arms  ICMJE 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 cycles in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: Carboplatin
  • Drug: Mannitol
  • Drug: Melphalan
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
  • Drug: Sodium Thiosulfate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 26, 2021)
17
Original Estimated Enrollment  ICMJE
 (submitted: September 23, 2009)
55
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00983398
Other Study ID Numbers  ICMJE IRB00005056
NCI-2013-00790 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
OHSU-5056
MR00042551
5056
IRB00005056 ( Other Identifier: OHSU Knight Cancer Institute )
R01NS044687 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Edward Neuwelt, OHSU Knight Cancer Institute
Original Responsible Party Edward A. Neuwelt, M.D., Professor, Oregon Health & Science University
Current Study Sponsor  ICMJE OHSU Knight Cancer Institute
Original Study Sponsor  ICMJE Oregon Health and Science University
Collaborators  ICMJE
  • National Institute of Neurological Disorders and Stroke (NINDS)
  • Oregon Health and Science University
Investigators  ICMJE
Principal Investigator: Edward A Neuwelt OHSU Knight Cancer Institute
PRS Account OHSU Knight Cancer Institute
Verification Date October 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP