Conditions: Brain and Central Nervous System Tumors
Keywords: adult glioblastoma adult gliosarcoma adult giant cell glioblastoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 92
Healthy volunteers: no

Brief summary:
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:
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.

Arms:
arm 1: 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) arm 2: 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) arm 3: 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) arm 4: 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) arm 5: 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)

Interventions: intervention 1: hydroxychloroquine intervention 2: temozolomide intervention 3: pharmacological study intervention 4: Radiation
Intervention descriptions: intervention 1: 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 intervention 2: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) intervention 3: 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 intervention 4: Radiation during the first six weeks of treatment Monday-Friday

Protocol document: