Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Completed 21 and under NCI, Pharmaceutical / Industry PBTC-017 PBTC-017, VION-VNP40101M, NCT00098761

Objectives

Primary

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

Secondary

1. Determine the pharmacokinetics of this drug and its active metabolite VNP4090CE in these patients.
2. Determine the efficacy of this drug in these patients.

Entry 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

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

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 signficant 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 hemorrahge, 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

Expected Enrollment

A total of 4-60 patients (2-30 per stratum) will be accrued for this study within 18 months.

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 myelosuppresive 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.

Gururangan S, Turner CD, Stewart CF, et al.: Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors: a pediatric brain tumor consortium study. Clin Cancer Res 14 (4): 1124-30, 2008.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Pediatric Brain Tumor Consortium

Sri Gururangan, MD, Protocol chair		Ph: 919-668-6288 Email: gurur002@mc.duke.edu
Christopher Turner, MD, Protocol co-chair		Ph: 617-632-4386; 866-790-4500 Email: christopher_turner@dfci.harvard.edu

Registry Information
Official Title		Phase I Study Of Cloretazine (VNP40101M) In Children With Recurrent, Progressive Or Refractory Primary Brain Tumors
Trial Start Date		2005-02-14
Trial Completion Date		2008-02-20
Registered in ClinicalTrials.gov		NCT00098761
Date Submitted to PDQ		2004-10-07
Information Last Verified		2006-08-24
NCI Grant/Contract Number		CA81457