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”

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.

Study Type: Interventional

Study Design: Treatment, Open Label

Study Primary Completion Date: June 2009

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.

Intervention(s) in this Clinical Trial

• Drug: hydroxychloroquine
• Drug: temozolomide
• Procedure: 3-dimensional conformal radiation therapy
• Procedure: adjuvant therapy
• Procedure: immunologic technique
• Procedure: intensity-modulated radiation therapy
• Procedure: laboratory biomarker analysis
• Procedure: mutation analysis
• Procedure: pharmacological study
• Procedure: polymerase chain reaction

Primary Measures

• Maximum tolerated dose of hydroxychloroquine (Phase I)
  • Safety Issue?: Yes
• Safety
  • Safety Issue?: Yes
• Overall survival
  • Safety Issue?: No
• Death
  • Safety Issue?: No

Secondary Measures

• Toxicity and tolerability (Phase I)
  • Safety Issue?: Yes
• Frequency of toxicity (Phase II)
  • Safety Issue?: Yes
• Pharmacokinetics and pharmacodynamics of hydroxychloroquine
  • Safety Issue?: No
• Correlation of the presence of TP53 and PTEN genes and BECN1 with toxicity and clinical outcomes
  • Safety Issue?: Yes
• Correlation of the average change in autophagic vesicles from baseline with genotype, toxicity, and clinical outcomes
  • Safety Issue?: Yes

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

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• 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

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Cancer Institute (NCI)

Overall Clinical Trial Officials and Contacts

Myrna Rosenfeld, MD, PhD Study Chair University of Pennsylvania  

Information obtained from ClinicalTrials.gov on January 08, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00486603

Study ID Number: CDR0000549734

ClinicalTrials.gov Identifier: NCT00486603

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database