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

Pediatric Brain Tumor Consortium

Status and phase

Completed

Phase 1

Conditions

Brain and Central Nervous System Tumors

Treatments

Drug: laromustine

Study type

Interventional

Funder types

NETWORK

NIH

Identifiers

NCT00098761

CDR0000396779

VION-VNP40101M

PBTC-017

Details and patient eligibility

About

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.

Full 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.

Enrollment

42 patients

Sex

All

Ages

Under 21 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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