This phase I trial tests the safety, side effects, and best dose of triapine in combination with radiation therapy in treating patients with glioblastoma or astrocytoma that has come back after a period of improvement (recurrent). Triapine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Giving triapine in combination with radiation therapy may be safe, tolerable, and/or effective in treating patients with recurrent glioblastoma or astrocytoma.
PRIMARY OBJECTIVE: I. To identify the safety and maximally tolerated dose (MTD) of oral triapine used in combination with radiation therapy for patients with recurrent glioblastoma (GBM) or astrocytoma. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To determine the pharmacokinetics of oral triapine in plasma and the central nervous system (CNS). III. To evaluate the efficacy of triapine when administered in combination with radiation therapy by assessing: IIIa. Progression-free survival (PFS); IIIb. Overall survival (OS); IIIc. The proportion of patients requiring bevacizumab for symptom control; IIId. The correlation of genetic mutations in select genes (e.g., p53, p16, KRAS, and Pi3k/mTOR/AKT) with tumor response and clinical outcomes. OUTLINE: This is a dose-escalation study of triapine in combination with radiation therapy. Patients undergo intensity-modulated radiation therapy (IMRT) once daily (QD) 5 days per week (Monday-Friday) for a total of 10 treatment days over 2 weeks and receive triapine orally (PO) 2 hours prior to IMRT on each radiation treatment day in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the study as well as blood sample collection during screening and on study. Patients may undergo cerebrospinal fluid (CSF) sample collection during screening. After completion of study treatment, patients are followed up at 2 weeks after radiation therapy, then every 3 months for up to 5 years from study treatment initiation.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Undergo blood and CSF sample collection
Undergo CT
Undergo IMRT
Undergo MRI
Given PO
City of Hope Comprehensive Cancer Center
Duarte, California, United States
RECRUITINGUCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, United States
RECRUITINGUC San Diego Moores Cancer Center
La Jolla, California, United States
RECRUITINGUC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
Incidence of dose-limiting toxicity
Will be graded in severity according to the Common Terminology Criteria for Adverse Events version 5.0. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized with descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient and frequency tables will be reviewed to determine toxicity patterns. Will employ the Backfill Bayesian Optimal Interval design to guide dose escalation and establish the maximal tolerated dose (MTD). The target toxicity rate for the MTD is = 0.25.
Time frame: Up to 28 days
Response rate
Response rate will be categorized based on the Response Assessment in Neuro-Oncology criteria, in which tumor response is based on clinical history, physical exam, and imaging findings. The total number of patients in each response category divided by the total number of evaluable patients determines response rate. An evaluable patient is defined as an eligible patient who received at least one dose of triapine. The response rates will be calculated with corresponding 95% exact Clopper-Pearson confidence intervals.
Time frame: Up to 5 years
Plasma pharmacokinetic (PK) parameters
Triapine in plasma and peri-tumoral dialysate will be quantified using a validated liquid chromatography-tandem mass spectrometry assay. Plasma PK parameters will be derived and compared to historical controls. Dialysate concentrations will be calculated at multiple time points. Exploratorily, exposure-response relationships will be evaluated.
Time frame: Up to 2 weeks
Progression-free survival
Will be estimated using Kaplan Meier curves.
Time frame: From study enrollment to date of either disease progression or death, assessed up to 5 years
Overall survival
Will be estimated using Kaplan Meier curves.
Time frame: From study enrollment to date of death, assessed up to 5 years
Proportion of patients who initiated bevacizumab for symptom control
Will be calculated using descriptive statistics.
Time frame: Up to 5 years
Tumor tissue biomarkers
The presence of genetic alterations, expression of RRM2, and other molecular gene expression signatures will be descriptive in relation to tumor response and clinical outcomes.
Time frame: Up to 5 years
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University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
RECRUITINGYale University
New Haven, Connecticut, United States
RECRUITINGSmilow Cancer Hospital Care Center-Trumbull
Trumbull, Connecticut, United States
RECRUITINGMedStar Georgetown University Hospital
Washington D.C., District of Columbia, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Coral Springs
Coral Springs, Florida, United States
RECRUITING...and 31 more locations