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

Brain and Central Nervous System Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00098761
• Other study ID #: CDR0000396779
• Secondary ID: PBTC-017VION-VNP
• Status: Completed
• Phase: Phase 1
• First received: December 8, 2004
• Last updated: June 29, 2011
• Start date: February 2005
• Est. completion date: February 2008

Study information

• Verified date: June 2011
• Source: Pediatric Brain Tumor Consortium
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: February 2008
• Est. primary completion date: October 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 21 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• laromustine
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.

Locations

Country	Name	City	State
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital	Houston	Texas
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	UCSF Comprehensive Cancer Center	San Francisco	California
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Pediatric Brain Tumor Consortium	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Estimate the maximum tolerated dose		First 6 weeks of therapy	Yes
Primary	Number of participants with dose limiting toxicities		First 6 weeks of therapy	Yes
Secondary	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.	Day 1 of therapy	No
Secondary	Tumor response to VNP40101M	MRI of the brain will be obtained prior to couses 3, 5, and 7 and at the end of therapy	Prior to course 3, 5, and 7 and end of therapy	No