RATIONALE: Drugs used in chemotherapy, such as hydroxychloroquine and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving hydroxychloroquine together with temozolomide and radiation therapy may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of hydroxychloroquine when given together with radiation therapy and temozolomide and to see how well they work in treating patients with newly diagnosed glioblastoma multiforme.
OBJECTIVES: Primary * Determine the maximum tolerated dose of hydroxychloroquine when administered in combination with radiotherapy and temozolomide in patients with newly diagnosed glioblastoma multiforme. (Phase I) * Assess the toxicity of this regimen in these patients. (Phase I) * Determine the overall survival of patients treated with this regimen. (Phase II) Secondary * Assess the frequency of toxicity of this regimen in these patients. (Phase II) * Evaluate the pharmacokinetics and pharmacodynamics of this regimen in these patients. * Correlate the average change in autophagic vesicles from baseline with genotype, toxicity, and clinical outcomes. * Correlate the presence of TP53 and PTEN genes and BECN1 with toxicity and clinical outcomes. OUTLINE: This is a multicenter, open-label, phase I, dose-escalation study of hydroxychloroquine followed by a phase II study. * Phase I: * Initiation therapy: Patients receive oral temozolomide daily for 6 weeks and undergo conformal or intensity-modulated radiotherapy 5 days a week for 6 weeks. Patients also receive oral hydroxychloroquine daily for 10 weeks beginning concurrently with temozolomide and radiotherapy. Cohorts of 3-6 patients receive escalating doses of hydroxychloroquine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. * Maintenance therapy: Beginning 28 days after completion of radiotherapy, patients receive oral temozolomide on days 1-5 and oral hydroxychloroquine on days 1-28. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may then continue to receive hydroxychloroquine alone as above in the absence of disease progression or unacceptable toxicity. * Phase II: * Initiation therapy: Patients receive hydroxychloroquine at the MTD determined in phase I, temozolomide, and radiotherapy as in phase I. * Maintenance therapy: Patients receive hydroxychloroquine at the MTD determined in phase I and temozolomide as in phase I. Patients undergo blood and tissue sample collection periodically for pharmacological and correlative studies. Samples are analyzed for the mutational status of TP53 and PTEN genes and copy number of BECN1 via PCR; changes in autophagy protein LC3 via gel electrophoresis; and differences in the formation of LC3-II via immunoblotting. After completion of study treatment, patients are followed every 2 months.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
92
see arm description, the first 10 week cycle is call initiation cycle, Post the 10 week cycle of just HCQ, 4 week cycles are called Maintenance Cycles
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Seven samples in total will be collected baseline, initiation cycle -week3-4, week9-10, Maintenance Cycle 1 Week 4 (C1W4), Cycle2 Week4, Cycle3 Week4, Cycle6 Week4
Radiation during the first six weeks of treatment Monday-Friday
University of Alabama at Birmingham Comprehensive Cancer Center
Birmingham, Alabama, United States
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
Tampa, Florida, United States
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Josephine Ford Cancer Center at Henry Ford Hospital
Detroit, Michigan, United States
Wake Forest University Comprehensive Cancer Center
Winston-Salem, North Carolina, United States
Case Comprehensive Cancer Center
Cleveland, Ohio, United States
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
(Phase I) Maximum Tolerated Dose (MTD) of Hydroxychloroquine (HCQ)
Number of participants who tolerated doses of HCQ without dose limiting toxicity. The highest dose at which participants did not experience dose limiting toxicity was determined as the MTD.
Time frame: 10 weeks
(Phase I) Number of Participants Who Experienced Dose Limiting Toxicity (DLT)
Dose limiting toxicity defined as: Any DLT must be a toxicity considered at least possibly related to HCQ. DLTs will include any possibly, probably, or definitely HCQ-related Grade 3 or 4 toxicity. Known or reasonably suspected TMZ hematological toxicities will not be considered dose limiting unless the treating physician considers the toxicity to be exacerbated by HCQ. Nonhematological toxicities: Any Grades 3-4 severity (except nausea and vomiting without sufficient antiemetic prophylaxis)
Time frame: 10 weeks
(Phase II) Overall Survival
Number of months alive after end of study participation
Time frame: 2 years
(Phase II) Number of Participants With Grade 3 and 4 Toxicity
Number of participants experiencing Grade 3 and 4 toxicity, as defined by CTCAE v3.0, with a possible, probable or definite relationship to HCQ, TMZ or both
Time frame: up to 2 years
Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition
Number of participants with at least 2 peripheral blood mononuclear cell (PBMC) samples that were amenable to electronmicroscopy (EM) who showed an increase of autophagic vacuoles in cells.
Time frame: up to 9 weeks
Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition in Relation to Maximal Concentration (Cmax) of HCQ
Autophagy inhibition is represented by an increase in autophagic vacuoles (AV) in participants with at least 2 peripheral blood mononuclear cell samples that were amenable to EM.
Time frame: up to 9 weeks
Pharmacokinetics (PK) of Hydroxychloroquine as Measured by Lag Time (Tlag)
The population model PK parameters do not specifically represent steady-state values, as they were determined from multiple repeated single doses taken from multiple repeated doses taken by the individual patient during their period on the study. To obtain steady state PK parameters, individual estimates were simulated from the population model.
Time frame: up to 276 days
PK of Hydroxychloroquine as Measured by Oral Clearance (Liters/Hour) From Central Compartment (CL/F)
The population model PK parameters do not specifically represent steady-state values, as they were determined from multiple repeated single doses taken from multiple repeated doses taken by the individual patient during their period on the study. To obtain steady state PK parameters, individual estimates were simulated from the population model.
Time frame: up to 276 days
PK of Hydroxychloroquine as Measured by Volume of Distribution of Central Compartment (V/F)
The population model PK parameters do not specifically represent steady-state values, as they were determined from multiple repeated single doses taken from multiple repeated doses taken by the individual patient during their period on the study. To obtain steady state PK parameters, individual estimates were simulated from the population model.
Time frame: up to 276 days
PK of Hydroxychloroquine as Measured by Distribution Volume of Peripheral Compartment (V2/F)
The population model PK parameters do not specifically represent steady-state values, as they were determined from multiple repeated single doses taken from multiple repeated doses taken by the individual patient during their period on the study. To obtain steady state PK parameters, individual estimates were simulated from the population model.
Time frame: up to 276 days
PK of Hydroxychloroquine as Measured by First-order Absorption Rate Constant (Ka)
The population model PK parameters do not specifically represent steady-state values, as they were determined from multiple repeated single doses taken from multiple repeated doses taken by the individual patient during their period on the study. To obtain steady state PK parameters, individual estimates were simulated from the population model.
Time frame: up to 276 days
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