Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

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.

Further Study Information

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.

Eligibility 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

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

Trial Contact Information

Trial Lead Organizations/Sponsors

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Myrna Rosenfeld

Study Chair

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00486603
Information obtained from ClinicalTrials.gov on December 14, 2011

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