Melphalan, Carboplatin, and Sodium Thiosulfate for Patients With Central Nervous System (CNS) Embryonal or Germ Cell Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by OHSU Knight Cancer Institute
Sponsor:
Information provided by (Responsible Party):
OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier:
NCT00983398
First received: September 23, 2009
Last updated: May 2, 2014
Last verified: May 2014
  Purpose
  • The purpose of this study is to determine the safety and effectiveness of the chemotherapy drugs called carboplatin and melphalan, when they are given into an artery, in patients with malignant brain tumors (called embryonal and germ cell tumors). The carboplatin and melphalan will be given during a procedure called blood-brain barrier disruption (BBBD). When used to treat this type of brain tumor, BBBD treatment is experimental and not approved by the FDA. Patients also receive a drug called sodium thiosulfate in a vein, in order to protect against carboplatin-induced hearing loss.
  • Participants will be admitted to the hospital every four weeks for approximately three days. The patient will be put to sleep with general anesthesia, and a tube will be placed in an artery in the groin. Mannitol (a sugar solution) will be given into the tube in the groin artery; this procedure is called blood-brain barrier disruption (BBBD). Next, the carboplatin and melphalan chemotherapy drugs will be given into the artery. The BBBD procedure is done on two days in a row, every four weeks. The patient will undergo monthly MRI scans of the head, monthly hearing evaluation, as well as weekly blood tests. The patient will also have memory testing done. Treatment will last for up to 12 months.

Condition Intervention Phase
Central Nervous System Embryonal Tumor
Germ Cell Tumors
Drug: Melphalan
Drug: Carboplatin
Drug: Sodium thiosulfate
Drug: Filgrastim
Drug: Pegfilgrastim
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:
  • 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: Up to 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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: Up to 2 years ] [ Designated as safety issue: No ]
  • 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: Up to 2 years ] [ Designated as safety issue: No ]
  • 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: Up to 2 years ] [ Designated as safety issue: No ]
  • 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: Up to 2 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 55
Study Start Date: September 2009
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Melphalan, Mannitol, Carboplatin

The rate and volume of mannitol infused will be 1.5-12 ml/s x 30 seconds.

melphalan (dose to be determined by the dose escalation algorithm) will be infused IA over 10 minutes, in 50-180 cc of normal saline.

carboplatin (200 mg/m2/day; total dose 400 mg/m2) will be infused IA over 10 minutes, in 50-180 cc of normal saline.

Drug: Melphalan

intra-arterial

Dose Level / Dose

  1. 4 mg/m2 daily X 2 days (8 mg/m2/course)
  2. 6 mg/m2 daily X 2 days (12 mg/m2/course)
  3. 8 mg/m2 daily X 2 days (16 mg/m2/course)
  4. 10 mg/m2 daily X 2 days (20 mg/m2/course)
Drug: Carboplatin
intra-arterial 200mg/m2/day x 2 days
Drug: Sodium thiosulfate

20 gm/m2 at 4 hours post carboplatin

16 gm/m2 at 8 hours post carboplatin

Other Name: STS
Drug: Filgrastim
5 micrograms/kg/day subcutaneous (SC) beginning 24-48 hrs after chemotherapy
Other Name: G-CSF
Drug: Pegfilgrastim
6 mg SC 24-48 hrs after chemotherapy
Other Name: Neulasta

Detailed Description:

PHASE I PRIMARY OBJECTIVE To determine the maximum tolerated dose (MTD) of Intra-arterial (IA) melphalan given with IA carboplatin, osmotic BBBD and delayed IV sodium thiosulfate (STS) in subjects with recurrent or progressive embryonal and germ cell tumors of the CNS.

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.

SECONDARY OBJECTIVES

  • 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.
  • 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.
  • 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.
  Eligibility

Ages Eligible for Study:   1 Year to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects with histologically confirmed CNS embryonal tumor (PNET, medulloblastoma, atypical teratoid/rhabdoid tumor (ATRT), medulloepithelioma, pineoblastoma or ependymoblastoma), or germ cell tumor
  • 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 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 must have a consultation with a radiation oncologist or providers must have a discussion in the context of Neuro-Oncology Tumor Board within 28 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 per Section 8.4. Subjects who have had radiation to all sites of disease are not eligible unless there has been documented radiographic progression of tumors subsequent to radiation
  • Age greater or equal to 1 year and less than 30 years of age
  • Baseline laboratory data should be the following:

    • Glomerular filtration rate (GFR) greater than 30
    • Absolute granulocyte count greater or equal to 1.0 x 103/mm3
    • Platelets greater or equal to 100 x 103/mm3
    • Creatinine < 1.5
    • Total Bilirubin < 2.0
    • Aspartate aminotransferase-Alanine aminotransferase (AST/ALT) < 2.5x upper limits of normal
  • Karnofsky Performance Status (KPS) must be greater than or equal to 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.

Exclusion Criteria:

  • radiographic signs of excessive intracranial mass effect with associated rapid neurologic deterioration and/or spinal cord block
  • significant risk with general anesthesia
  • uncontrolled (over the last 30 days) clinically significant confounding medical conditions
  • pregnant or lactating
  • 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

Contacts
Contact: Edward A Neuwelt, MD 503-494-5626 neuwelte@ohsu.edu
Contact: Cynthia A Lacy, BSN 503-494-5626 lacyc@ohsu.edu

Locations
United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Dan Guillaume, MD    612-624-5931    dguillau@umn.edu   
Contact: Tammie Dahlheimer, NP    612-626-2629    tdahlheimer@umphysicians.umn.edu   
Sub-Investigator: Dan Guillaume, MD         
United States, Oregon
Oregon Health & Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Edward A Neuwelt, MD    503-494-5626    neuwelte@ohsu.edu   
Contact: Cynthia A Lacy, BSN    503-494-5626    lacyc@ohsu.edu   
Principal Investigator: Edward A Neuwelt, MD         
Sponsors and Collaborators
OHSU Knight Cancer Institute
Investigators
Principal Investigator: Edward A Neuwelt, MD Oregon Health and Science University
  More Information

No publications provided

Responsible Party: OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT00983398     History of Changes
Other Study ID Numbers: OHSU-5056, SOL-08131-L, OHSU-5056
Study First Received: September 23, 2009
Last Updated: May 2, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by OHSU Knight Cancer Institute:
CNS embryonal tumor
cognitive/functional effects
drug toxicity
response rate
survival times
maximum tolerated dose (MTD) of IA melphalan/IA carboplatin
2-year progression-free survival (PFS) and overall survival (OS) rates

Additional relevant MeSH terms:
Neoplasms
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Carboplatin
Melphalan
Sodium thiosulfate
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antidotes
Protective Agents
Antioxidants
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Chelating Agents
Sequestering Agents

ClinicalTrials.gov processed this record on September 18, 2014