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VNP40101M in Treating Young Patients With Recurrent, Progressive, or Refractory Primary Brain Tumors

Primary Purpose

Brain and Central Nervous System Tumors

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
laromustine
Sponsored by
Pediatric Brain Tumor Consortium
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Brain and Central Nervous System Tumors focused on measuring recurrent childhood brain stem glioma, recurrent childhood visual pathway and hypothalamic glioma, recurrent childhood cerebellar astrocytoma, recurrent childhood cerebral astrocytoma, recurrent childhood ependymoma, recurrent childhood medulloblastoma, recurrent childhood supratentorial primitive neuroectodermal tumor, childhood central nervous system germ cell tumor, childhood choroid plexus tumor, childhood craniopharyngioma, childhood infratentorial ependymoma, childhood grade I meningioma, childhood grade II meningioma, childhood grade III meningioma, childhood high-grade cerebral astrocytoma, childhood low-grade cerebral astrocytoma

Eligibility Criteria

undefined - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

DISEASE CHARACTERISTICS: Histologically confirmed* primary brain tumor, including benign brain tumors (e.g., low-grade glioma) Recurrent or progressive disease OR refractory to standard therapy NOTE: *Patients with intrinsic brain stem or diffuse optic pathway tumors do not require histological confirmation, but must have clinical and/or radiographic evidence of disease progression No bone marrow disease PATIENT CHARACTERISTICS: Age 21 and under Performance status Karnofsky 50-100% (for patients > 16 years of age) OR Lansky 50-100% (for patients ≤ 16 years of age) Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 1,000/mm^3* Platelet count ≥ 100,000/mm^3* Hemoglobin ≥ 8 g/dL* NOTE: *Unsupported Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT and AST ≤ 2.5 times ULN No overt hepatic disease Renal BUN < 25 mg/dL Creatinine ≤ 1.5 times ULN for age OR Glomerular filtration rate > 70 mL/min No overt renal disease Cardiovascular Shortening fraction ≥ 30% by echocardiogram OR Ejection fraction ≥ 50% by gated radionucleotide study No clinically significant cardiac arrhythmia by EKG No overt cardiac disease Pulmonary DLCO ≥ 60% of predicted Chest X-ray normal (defined as absence of pulmonary infiltrates, pneumonitis, pleural effusion, pulmonary hemorrhage, or fibrosis) AND a resting pulse oximetry reading of > 94% in room air (for patients who cannot perform the DLCO) No overt pulmonary disease Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Neurologic deficits allowed provided there has been no deficit progression for ≥ 1 week before study entry No uncontrolled infection No known hypersensitivity to polyethylene glycol PRIOR CONCURRENT THERAPY: Biologic therapy At least 6 months since prior allogeneic bone marrow or stem cell transplantation At least 3 months since prior autologous bone marrow or stem cell transplantation More than 1 week since prior colony-stimulating factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa) At least 3 weeks since prior myelosuppressive anticancer biologic therapy No concurrent routine colony-stimulating factors Chemotherapy At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered Endocrine therapy Concurrent corticosteroids allowed provided dose is stable or decreasing for ≥ 1 week before study entry Radiotherapy At least 3 months since prior craniospinal irradiation ≥ 18 Gy At least 2 weeks since prior focal irradiation to the primary tumor and/or symptomatic metastatic sites Surgery Not specified Other At least 7 days since prior nonmyelosuppressive anticancer therapy At least 7 days since prior investigational agents Concurrent enzyme-inducing anticonvulsant drugs allowed No other concurrent anticancer or experimental agents or therapies

Sites / Locations

  • UCSF Comprehensive Cancer Center
  • Children's National Medical Center
  • Children's Memorial Hospital - Chicago
  • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Duke Comprehensive Cancer Center
  • Children's Hospital of Philadelphia
  • Children's Hospital of Pittsburgh
  • St. Jude Children's Research Hospital
  • Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
  • Children's Hospital and Regional Medical Center - Seattle

Outcomes

Primary Outcome Measures

Estimate the maximum tolerated dose
Number of participants with dose limiting toxicities

Secondary Outcome Measures

Pharmacokinetics
Plasma samples for pharmacokinetic studies will be collected with the first dose of the study drug pre-infusion, and 5, 15, and 30 minutes, 1 hour, 2 hours, and 4 hours after the end of infusion. VNP40101M plasma concentration-time data will be modeled and the individual pharmacokinetic pararmeters volume of the central compartment, elimination rate constant, and half-life will be estimated.
Tumor response to VNP40101M
MRI of the brain will be obtained prior to couses 3, 5, and 7 and at the end of therapy

Full Information

First Posted
December 8, 2004
Last Updated
June 29, 2011
Sponsor
Pediatric Brain Tumor Consortium
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00098761
Brief Title
VNP40101M in Treating Young Patients With Recurrent, Progressive, or Refractory Primary Brain Tumors
Official Title
Phase I Study Of Cloretazine (VNP40101M) In Children With Recurrent, Progressive Or Refractory Primary Brain Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
June 2011
Overall Recruitment Status
Completed
Study Start Date
February 2005 (undefined)
Primary Completion Date
October 2006 (Actual)
Study Completion Date
February 2008 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Pediatric Brain Tumor Consortium
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
RATIONALE: Drugs used in chemotherapy, such as VNP40101M, work in different ways to stop tumor cells from dividing so they stop growing or die. PURPOSE: This phase I trial is studying the side effects and best dose of VNP40101M in treating young patients with recurrent, progressive, or refractory primary brain tumors.
Detailed Description
OBJECTIVES: Primary Determine the maximum tolerated dose and dose-limiting toxicity of VNP40101M in pediatric patients with recurrent, progressive, or refractory primary brain tumors. Secondary Determine the pharmacokinetics of this drug and its active metabolite VNP4090CE in these patients. Determine the efficacy of this drug in these patients. OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to receiving ≥ 1 of the following prior therapies: craniospinal irradiation (yes vs no), autologous bone marrow transplant (yes vs no), and > 2 myelosuppressive chemotherapy or myelosuppressive biologic therapy regimens (yes vs no). Patients receive VNP40101M IV over 30 minutes on days 1-5. Treatment repeats every 42 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 2-6 patients per stratum receive escalating doses of VNP40101M until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 25% of patients experience dose-limiting toxicity. A total of 12 patients are treated at the MTD. Patients are followed for 3 months. PROJECTED ACCRUAL: A total of 4-60 patients (2-30 per stratum) will be accrued for this study within 18 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain and Central Nervous System Tumors
Keywords
recurrent childhood brain stem glioma, recurrent childhood visual pathway and hypothalamic glioma, recurrent childhood cerebellar astrocytoma, recurrent childhood cerebral astrocytoma, recurrent childhood ependymoma, recurrent childhood medulloblastoma, recurrent childhood supratentorial primitive neuroectodermal tumor, childhood central nervous system germ cell tumor, childhood choroid plexus tumor, childhood craniopharyngioma, childhood infratentorial ependymoma, childhood grade I meningioma, childhood grade II meningioma, childhood grade III meningioma, childhood high-grade cerebral astrocytoma, childhood low-grade cerebral astrocytoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
42 (Actual)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
laromustine
Other Intervention Name(s)
Cloretazine, VNP40101M
Intervention Description
This is a dose escalation study. Participants receive 20, 30, 45, 60, 78, 103, 137, 182, or 242 mg/m2/day intravenously over 30 minutes for 5 consecutive days every 6 weeks up to 48 weeks.
Primary Outcome Measure Information:
Title
Estimate the maximum tolerated dose
Time Frame
First 6 weeks of therapy
Title
Number of participants with dose limiting toxicities
Time Frame
First 6 weeks of therapy
Secondary Outcome Measure Information:
Title
Pharmacokinetics
Description
Plasma samples for pharmacokinetic studies will be collected with the first dose of the study drug pre-infusion, and 5, 15, and 30 minutes, 1 hour, 2 hours, and 4 hours after the end of infusion. VNP40101M plasma concentration-time data will be modeled and the individual pharmacokinetic pararmeters volume of the central compartment, elimination rate constant, and half-life will be estimated.
Time Frame
Day 1 of therapy
Title
Tumor response to VNP40101M
Description
MRI of the brain will be obtained prior to couses 3, 5, and 7 and at the end of therapy
Time Frame
Prior to course 3, 5, and 7 and end of therapy

10. Eligibility

Sex
All
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS: Histologically confirmed* primary brain tumor, including benign brain tumors (e.g., low-grade glioma) Recurrent or progressive disease OR refractory to standard therapy NOTE: *Patients with intrinsic brain stem or diffuse optic pathway tumors do not require histological confirmation, but must have clinical and/or radiographic evidence of disease progression No bone marrow disease PATIENT CHARACTERISTICS: Age 21 and under Performance status Karnofsky 50-100% (for patients > 16 years of age) OR Lansky 50-100% (for patients ≤ 16 years of age) Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 1,000/mm^3* Platelet count ≥ 100,000/mm^3* Hemoglobin ≥ 8 g/dL* NOTE: *Unsupported Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT and AST ≤ 2.5 times ULN No overt hepatic disease Renal BUN < 25 mg/dL Creatinine ≤ 1.5 times ULN for age OR Glomerular filtration rate > 70 mL/min No overt renal disease Cardiovascular Shortening fraction ≥ 30% by echocardiogram OR Ejection fraction ≥ 50% by gated radionucleotide study No clinically significant cardiac arrhythmia by EKG No overt cardiac disease Pulmonary DLCO ≥ 60% of predicted Chest X-ray normal (defined as absence of pulmonary infiltrates, pneumonitis, pleural effusion, pulmonary hemorrhage, or fibrosis) AND a resting pulse oximetry reading of > 94% in room air (for patients who cannot perform the DLCO) No overt pulmonary disease Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Neurologic deficits allowed provided there has been no deficit progression for ≥ 1 week before study entry No uncontrolled infection No known hypersensitivity to polyethylene glycol PRIOR CONCURRENT THERAPY: Biologic therapy At least 6 months since prior allogeneic bone marrow or stem cell transplantation At least 3 months since prior autologous bone marrow or stem cell transplantation More than 1 week since prior colony-stimulating factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa) At least 3 weeks since prior myelosuppressive anticancer biologic therapy No concurrent routine colony-stimulating factors Chemotherapy At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered Endocrine therapy Concurrent corticosteroids allowed provided dose is stable or decreasing for ≥ 1 week before study entry Radiotherapy At least 3 months since prior craniospinal irradiation ≥ 18 Gy At least 2 weeks since prior focal irradiation to the primary tumor and/or symptomatic metastatic sites Surgery Not specified Other At least 7 days since prior nonmyelosuppressive anticancer therapy At least 7 days since prior investigational agents Concurrent enzyme-inducing anticonvulsant drugs allowed No other concurrent anticancer or experimental agents or therapies
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sri Gururangan, MRCP (UK)
Organizational Affiliation
Duke University
Official's Role
Study Chair
Facility Information:
Facility Name
UCSF Comprehensive Cancer Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010-2970
Country
United States
Facility Name
Children's Memorial Hospital - Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Duke Comprehensive Cancer Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104-4318
Country
United States
Facility Name
Children's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-2399
Country
United States
Facility Name
Children's Hospital and Regional Medical Center - Seattle
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
18281546
Citation
Gururangan S, Turner CD, Stewart CF, O'Shaughnessy M, Kocak M, Poussaint TY, Phillips PC, Goldman S, Packer R, Pollack IF, Blaney SM, Karsten V, Gerson SL, Boyett JM, Friedman HS, Kun LE. Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors: a pediatric brain tumor consortium study. Clin Cancer Res. 2008 Feb 15;14(4):1124-30. doi: 10.1158/1078-0432.CCR-07-4242.
Results Reference
result

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VNP40101M in Treating Young Patients With Recurrent, Progressive, or Refractory Primary Brain Tumors

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