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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified May 2012 by Sidney Kimmel Comprehensive Cancer Center.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00486603
First received: June 13, 2007
Last updated: May 1, 2012
Last verified: May 2012
  Purpose

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.


Condition Intervention Phase
Brain and Central Nervous System Tumors
Drug: hydroxychloroquine
Drug: temozolomide
Genetic: mutation analysis
Genetic: polymerase chain reaction
Other: immunologic technique
Other: laboratory biomarker analysis
Other: pharmacological study
Procedure: adjuvant therapy
Radiation: 3-dimensional conformal radiation therapy
Radiation: intensity-modulated radiation therapy
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • Maximum tolerated dose of hydroxychloroquine (Phase I) [ Time Frame: continous ] [ Designated as safety issue: Yes ]
  • Safety [ Time Frame: continous ] [ Designated as safety issue: Yes ]
  • Overall survival [ Time Frame: continous ] [ Designated as safety issue: No ]
  • Death [ Time Frame: continous ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Toxicity and tolerability (Phase I) [ Time Frame: continous ] [ Designated as safety issue: Yes ]
  • Frequency of toxicity (Phase II) [ Time Frame: continous ] [ Designated as safety issue: Yes ]
  • Pharmacokinetics and pharmacodynamics of hydroxychloroquine [ Time Frame: continous ] [ Designated as safety issue: No ]
  • Correlation of the presence of TP53 and PTEN genes and BECN1 with toxicity and clinical outcomes [ Time Frame: continous ] [ Designated as safety issue: Yes ]
  • Correlation of the average change in autophagic vesicles from baseline with genotype, toxicity, and clinical outcomes [ Time Frame: continous ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 94
Study Start Date: October 2007
Estimated Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00486603

Locations
United States, Alabama
UAB Comprehensive Cancer Center
Birmingham, Alabama, United States, 35294
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
Tampa, Florida, United States, 33612-9497
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231-2410
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, Michigan
Josephine Ford Cancer Center at Henry Ford Hospital
Detroit, Michigan, United States, 48202
United States, North Carolina
Wake Forest University Comprehensive Cancer Center
Winston-Salem, North Carolina, United States, 27157-1096
United States, Ohio
Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106-5065
United States, Pennsylvania
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104-4283
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Investigators
Study Chair: Myrna Rosenfeld, MD, PhD Abramson Cancer Center of the University of Pennsylvania
  More Information

Additional Information:
No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00486603     History of Changes
Other Study ID Numbers: NABTT-0603 CDR0000549734, U01CA062475, ABTC-0603, NABTT-0603
Study First Received: June 13, 2007
Last Updated: May 1, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
adult glioblastoma
adult gliosarcoma
adult giant cell glioblastoma

Additional relevant MeSH terms:
Nervous System Neoplasms
Central Nervous System Neoplasms
Glioblastoma
Neoplasms by Site
Neoplasms
Nervous System Diseases
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Hydroxychloroquine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Antirheumatic Agents

ClinicalTrials.gov processed this record on September 16, 2014