Clinical trial NCT00098761: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Lead sponsor: Pediatric Brain Tumor Consortium
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-12-09
Enrollment: 42
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Estimate the maximum tolerated dose
timeFrame: First 6 weeks of therapy
measure: Number of participants with dose limiting toxicities
timeFrame: First 6 weeks of therapy
Secondary outcomes:
measure: Pharmacokinetics
timeFrame: Day 1 of therapy
measure: Tumor response to VNP40101M
timeFrame: Prior to course 3, 5, and 7 and end of therapy
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
Study officials:
affiliation: Duke University
name: Sri Gururangan, MRCP (UK)
role: STUDY_CHAIR
References:
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.