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Phase I Study Of Cloretazine (VNP40101M) In Children With Recurrent, Progressive Or Refractory Primary Brain Tumors

Phase 1
21 Years
Not Enrolling
Brain and Central Nervous System Tumors

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Trial Information

Phase I Study Of Cloretazine (VNP40101M) In Children With Recurrent, Progressive Or Refractory Primary Brain Tumors



- Determine the maximum tolerated dose and dose-limiting toxicity of VNP40101M in
pediatric patients with recurrent, progressive, or refractory primary brain tumors.


- 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.

Inclusion Criteria


- 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



- 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


- Absolute neutrophil count ≥ 1,000/mm^3*

- Platelet count ≥ 100,000/mm^3*

- Hemoglobin ≥ 8 g/dL* NOTE: *Unsupported


- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT and AST ≤ 2.5 times ULN

- No overt hepatic disease


- BUN < 25 mg/dL

- Creatinine ≤ 1.5 times ULN for age OR

- Glomerular filtration rate > 70 mL/min

- No overt renal disease


- Shortening fraction ≥ 30% by echocardiogram OR

- Ejection fraction ≥ 50% by gated radionucleotide study

- No clinically significant cardiac arrhythmia by EKG

- No overt cardiac disease


- 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


- 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


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


- 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


- 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


- Not specified


- 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Estimate the maximum tolerated dose

Outcome Time Frame:

First 6 weeks of therapy

Safety Issue:


Principal Investigator

Sri Gururangan, MRCP (UK)

Investigator Role:

Study Chair

Investigator Affiliation:

Duke University


United States: Food and Drug Administration

Study ID:




Start Date:

February 2005

Completion Date:

February 2008

Related Keywords:

  • Brain and Central Nervous System Tumors
  • 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
  • Brain Neoplasms
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms



Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
Duke Comprehensive Cancer Center Durham, North Carolina  27710
Children's National Medical Center Washington, District of Columbia  20010-2970
Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania  15213
Children's Hospital and Regional Medical Center - Seattle Seattle, Washington  98105
Children's Memorial Hospital - Chicago Chicago, Illinois  60614
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute Boston, Massachusetts  02115
St. Jude Children's Research Hospital Memphis, Tennessee  38105-2794
UCSF Comprehensive Cancer Center San Francisco, California  94115
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital Houston, Texas  77030-2399