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

Phase 1

Completed

• Conditions: Brain and Central Nervous System Tumors
• Interventions: Drug: hydroxychloroquine; Drug: temozolomide; Other: pharmacological study; Radiation: Radiation

• Registration Number: NCT00486603
• Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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.

Study Timeline

• Study First Submitted: 2007-06-13
• Study First Submitted QC: 2007-06-13
• Study First Posted: 2007-06-14
• Study Start: 2007-10-29
• Primary Completion: 2013-06
• Study Completion: 2014-01
• Results First Submitted: 2019-05-09
• Status Verified: 2019-06
• Results First Submitted QC: 2019-06-19
• Last Update Submitted: 2019-06-19
• Results First Posted: 2019-07-10
• Last Update Posted: 2019-07-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 92

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1: RT+TMZ+HCQ 200 mg	Radiation	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)
Phase 1: RT+TMZ+HCQ 400 mg	pharmacological study	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)
Phase 1: RT+TMZ+HCQ 400 mg	Radiation	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)
Phase 2: RT + TMZ + HCQ MTD	pharmacological study	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)
Phase 1: RT+TMZ+HCQ 200 mg	pharmacological study	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)
Phase 1: RT+TMZ+HCQ 600 mg	pharmacological study	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)
Phase 1: RT+TMZ+HCQ 600 mg	Radiation	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)
Phase 1: RT+TMZ+HCQ 800 mg	pharmacological study	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)
Phase 1: RT+TMZ+HCQ 800 mg	Radiation	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)
Phase 2: RT + TMZ + HCQ MTD	Radiation	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)
Phase 1: RT+TMZ+HCQ 200 mg	hydroxychloroquine	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)
Phase 1: RT+TMZ+HCQ 200 mg	temozolomide	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)
Phase 1: RT+TMZ+HCQ 400 mg	temozolomide	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)
Phase 1: RT+TMZ+HCQ 400 mg	hydroxychloroquine	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)
Phase 1: RT+TMZ+HCQ 600 mg	hydroxychloroquine	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)
Phase 1: RT+TMZ+HCQ 600 mg	temozolomide	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)
Phase 1: RT+TMZ+HCQ 800 mg	hydroxychloroquine	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)
Phase 1: RT+TMZ+HCQ 800 mg	temozolomide	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)
Phase 2: RT + TMZ + HCQ MTD	hydroxychloroquine	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)
Phase 2: RT + TMZ + HCQ MTD	temozolomide	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)

Primary Outcome Measures

Name	Time	Method
(Phase I) Maximum Tolerated Dose (MTD) of Hydroxychloroquine (HCQ)	10 weeks	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.
(Phase II) Overall Survival	2 years	Number of months alive after end of study participation
(Phase I) Number of Participants Who Experienced Dose Limiting Toxicity (DLT)	10 weeks	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)

Secondary Outcome Measures

Name	Time	Method
(Phase II) Number of Participants With Grade 3 and 4 Toxicity	up to 2 years	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
Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition	up to 9 weeks	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.
Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition in Relation to Maximal Concentration (Cmax) of HCQ	up to 9 weeks	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.
Pharmacokinetics (PK) of Hydroxychloroquine as Measured by Lag Time (Tlag)	up to 276 days	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.
PK of Hydroxychloroquine as Measured by Oral Clearance (Liters/Hour) From Central Compartment (CL/F)	up to 276 days	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.
PK of Hydroxychloroquine as Measured by Volume of Distribution of Central Compartment (V/F)	up to 276 days	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.
PK of Hydroxychloroquine as Measured by Distribution Volume of Peripheral Compartment (V2/F)	up to 276 days	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.
PK of Hydroxychloroquine as Measured by First-order Absorption Rate Constant (Ka)	up to 276 days	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.

Trial Locations

Locations (9)

Winship Cancer Institute of Emory University; 🇺🇸 Atlanta, Georgia, United States

Case Comprehensive Cancer Center; 🇺🇸 Cleveland, Ohio, United States

Abramson Cancer Center of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, 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

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 🇺🇸 Baltimore, Maryland, United States

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

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States