Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	ABTC-0603 NABTT-0603, 0603, NCT00486603

Objectives

Primary

1. Determine the maximum tolerated dose of hydroxychloroquine when administered in combination with radiotherapy and temozolomide in patients with newly diagnosed glioblastoma multiforme. (Phase I)
2. Assess the toxicity of this regimen in these patients. (Phase I)
3. Determine the overall survival of patients treated with this regimen. (Phase II)

Secondary

1. Assess the frequency of toxicity of this regimen in these patients. (Phase II)
2. Evaluate the pharmacokinetics and pharmacodynamics of this regimen in these patients.
3. Correlate the average change in autophagic vesicles from baseline with genotype, toxicity, and clinical outcomes.
4. Correlate the presence of TP53 and PTEN genes and BECN1 with toxicity and clinical outcomes.

Entry Criteria

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

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

Patient Characteristics:

• Karnofsky performance status 60-100%
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin ≤ 1.5 mg/dL
• Creatinine ≤ 2 times upper limit of normal (ULN)
• ALT and AST ≤ 4 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Mini Mental State Exam score ≥ 15
• No concurrent psoriasis unless the disease is well controlled and patient is under the care of a specialist for the disorder who agrees to monitor for exacerbations
• No prior macular degeneration or diabetic retinopathy
• No concurrent serious infection or medical illness that would preclude study therapy
• No other malignancy within the past 5 years except for curatively treated carcinoma in situ or basal cell carcinoma of the skin
• No porphyria

Expected Enrollment

Outcomes

Maximum tolerated dose of hydroxychloroquine (Phase I)
Safety
Overall survival
Death

Toxicity and tolerability (Phase I)
Frequency of toxicity (Phase II)
Pharmacokinetics and pharmacodynamics of hydroxychloroquine
Correlation of the presence of TP53 and PTEN genes and BECN1 with toxicity and clinical outcomes
Correlation of the average change in autophagic vesicles from baseline with genotype, 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.

Trial Contact Information

Trial Lead Organizations

Adult Brain Tumor Consortium

Myrna Rosenfeld, MD, PhD, Protocol chair		Ph: 215-746-4707 Email: myrna@mail.med.upenn.edu

U.S.A.
Alabama
	Birmingham
	UAB Comprehensive Cancer Center
		Clinical Trials Office - UAB Comprehensive Cancer Center	Ph:  205-934-0309
Florida
	Tampa
	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
		Clinical Trials Office - H. Lee Moffitt Cancer Center and Reseach Institute	Ph:  800-456-7121
			Email: canceranswers@moffitt.org
Georgia
	Atlanta
	Winship Cancer Institute of Emory University
		Jeffrey Olson, MD	Ph:  404-778-5770 888-946-7447
Maryland
	Baltimore
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Ph:  410-955-8804
			Email: jhcccro@jhmi.edu
Massachusetts
	Boston
	Massachusetts General Hospital
		Clinical Trials Office - Massachusetts General Hospital	Ph:  877-726-5130
Michigan
	Detroit
	Josephine Ford Cancer Center at Henry Ford Hospital
		Tom Mikkelsen, MD	Ph:  313-916-8641 888-734-5322
			Email: nstom@neuro.hfh.edu
North Carolina
	Winston-Salem
	Wake Forest University Comprehensive Cancer Center
		Clinical Trials Office - Wake Forest University Comprehensive Cancer Center	Ph:  336-713-6771
Ohio
	Cleveland
	Case Comprehensive Cancer Center
		Clinical Trials Office - Case Comprehensive Cancer Center	Ph:  800-641-2422
Pennsylvania
	Philadelphia
	Abramson Cancer Center of the University of Pennsylvania
		Clinical Trials Office - Abramson Cancer Center of the University of Pennsylvania	Ph:  800-474-9892

Registry Information
Official Title		A Phase I/II Trial of Hydroxychloroquine in Conjunction with Radiation Therapy and Concurrent and Adjuvant Temozolomide in Patients with Newly Diagnosed Glioblastoma Multiforme
Trial Start Date		2007-10-11
Trial Completion Date		2009-06-24 (estimated)
Registered in ClinicalTrials.gov		NCT00486603
Date Submitted to PDQ		2007-05-08
Information Last Verified		2009-06-07
NCI Grant/Contract Number		CA62475

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