Hydroxychloroquine, Radiation, and Temozolomide Treating Patients With Newly Diagnosed Glioblastoma Multiforme

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II Trial of Hydroxychloroquine in Conjunction With Radiation Therapy and Concurrent and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: hydroxychloroquine
* Drug: temozolomide
* Other: pharmacological study
* Radiation: Radiation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed grade IV supratentorial astrocytoma (glioblastoma multiforme) Newly diagnosed disease Diagnosis must have been made by biopsy or resection ≤ 3 months prior to study entry INCLUSION CRITERIA: Patients must be at least 18 years of age. Patients must have histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme), established by biopsy or resection not more than 3 months prior to registration. Patients must not have received prior radiation therapy, chemotherapy, immunotherapy or therapy with biologic agents (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, TIL, LAK or gene therapy), or hormonal therapy for their brain tumor. Glucocorticoid therapy is allowed. Patients must have a Karnofsky performance status ≤ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others). Patients must have the following hematologic, renal and liver function (i.e. absolute neutrophil count > 1500/mm3, platelets > 100,000/mm3, creatinine ≤ 2 times the upper limits of normal (ULN) total bilirubin ≤ 1.5 mg/dl, ALT and AST ≤ 4 times above the upper limits of the institutional norm. Patients must be able to provide written informed consent. Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Women of childbearing potential must have a negative pregnancy test. The anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant. Patients must have a Mini Mental State Exam (MMSE) score of > 15. Patients must have tumor tissue form completed and signed by a pathologist. See section 9.5.2 for details. Prior concurrent therapy: No prior radiotherapy, chemotherapy, immunotherapy, biologic agents (e.g., immunotoxins, immunoconjugates, antisense agents, peptide receptor antagonists, interferons, interleukins, tumor-infiltrating lymphocytes, lymphokine-activated killer cell therapy, or gene therapy), or hormonal therapy for brain tumor No prior polifeprosan 20 with carmustine implant (Gliadel wafer) or GliaSite® brachytherapy No concurrent cytochrome P450 enzyme-inducing anticonvulsant drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, or oxcarbazepine) No other concurrent chemotherapeutic or investigational agents for this cancer Concurrent glucocorticoids allowed EXCLUSION CRITERIA: Patients with serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety. Patients who are pregnant or breast-feeding. Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or investigational agents). Patients with a concurrent or prior malignancy, unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin. Patients who have been free of disease (any prior malignancy) for five years are eligible for this study. Patients who have received Gliadel wafers or GliaSite brachytherapy are not eligible. Due to risk of disease exacerbation patients with porphyria are not eligible. Due to risk of disease exacerbation patients with psoriasis are ineligible unless the disease is well controlled and they are under the care of a specialist for the disorder who agrees to monitor the patient for exacerbations. Patients receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (EIADs) (i.e. phenytoin, carbamazepine, Phenobarbital, primidone or oxcarbazepine). Patients with previously documented macular degeneration or diabetic retinopathy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: RT+TMZ+HCQ 200 mg<br>Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Starting dose of HCQ is 200mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days. cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg. Other: pharmacological study (PK) pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1 Radiation (RT) | Drug: hydroxychloroquine<br>* 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<br>* Other names: HCQ;Drug: temozolomide<br>* TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)<br>* Other names: TMZ;Other: pharmacological study<br>* 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<br>* Other names: correlative studies;Radiation: Radiation<br>* Radiation during the first six weeks of treatment Monday-Friday<br>* Other names: RT;|
| Experimental: Phase 1: RT+TMZ+HCQ 400 mg<br>Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 400 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days. cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg. Other: pharmacological study (PK) pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1 Radiation (RT) | Drug: hydroxychloroquine<br>* 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<br>* Other names: HCQ;Drug: temozolomide<br>* TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)<br>* Other names: TMZ;Other: pharmacological study<br>* 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<br>* Other names: correlative studies;Radiation: Radiation<br>* Radiation during the first six weeks of treatment Monday-Friday<br>* Other names: RT;|
| Experimental: Phase 1: RT+TMZ+HCQ 600 mg<br>Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 600 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days. cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg. Other: pharmacological study (PK) pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1 Radiation (RT) | Drug: hydroxychloroquine<br>* 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<br>* Other names: HCQ;Drug: temozolomide<br>* TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)<br>* Other names: TMZ;Other: pharmacological study<br>* 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<br>* Other names: correlative studies;Radiation: Radiation<br>* Radiation during the first six weeks of treatment Monday-Friday<br>* Other names: RT;|
| Experimental: Phase 1: RT+TMZ+HCQ 800 mg<br>Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 800 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days. cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg. Other: pharmacological study (PK) pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1 Radiation (RT) | Drug: hydroxychloroquine<br>* 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<br>* Other names: HCQ;Drug: temozolomide<br>* TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)<br>* Other names: TMZ;Other: pharmacological study<br>* 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<br>* Other names: correlative studies;Radiation: Radiation<br>* Radiation during the first six weeks of treatment Monday-Friday<br>* Other names: RT;|
| Experimental: Phase 2: RT + TMZ + HCQ MTD<br>Phse 2: daily hydroxychloroquine (HCQ) (MTD 600mg) on 1st day of RT and concomitant temozolomide for 6wks during RT. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days. Other: pharmacological study (PK) Pts will continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 2 Radiation (RT) | Drug: hydroxychloroquine<br>* 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<br>* Other names: HCQ;Drug: temozolomide<br>* TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)<br>* Other names: TMZ;Other: pharmacological study<br>* 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<br>* Other names: correlative studies;Radiation: Radiation<br>* Radiation during the first six weeks of treatment Monday-Friday<br>* Other names: RT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (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. | 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) | 10 weeks | 
| (Phase II) Overall Survival | Number of months alive after end of study participation | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (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 | 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. | 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. | 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. | 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. | 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. | 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. | 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. | up to 276 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult glioblastoma, adult gliosarcoma, adult giant cell glioblastoma