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A Phase I/II Trial of Hydroxychloroquine in Conjunction With Radiation Therapy and Concurrent and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Brain and Central Nervous System Tumors

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Trial Information

A Phase I/II Trial of Hydroxychloroquine in Conjunction With Radiation Therapy and Concurrent and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of hydroxychloroquine (Phase I)

Outcome Time Frame:

continous

Safety Issue:

Yes

Principal Investigator

Myrna Rosenfeld, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Abramson Cancer Center of the University of Pennsylvania

Authority:

United States: Food and Drug Administration

Study ID:

NABTT-0603 CDR0000549734

NCT ID:

NCT00486603

Start Date:

October 2007

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • adult glioblastoma
  • adult gliosarcoma
  • adult giant cell glioblastoma
  • Glioblastoma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms

Name

Location

Case Comprehensive Cancer CenterCleveland, Ohio  44106-5065
Abramson Cancer Center of the University of PennsylvaniaPhiladelphia, Pennsylvania  19104-4283
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
Josephine Ford Cancer Center at Henry Ford HospitalDetroit, Michigan  48202
Winship Cancer Institute of Emory UniversityAtlanta, Georgia  30322
Wake Forest University Comprehensive Cancer CenterWinston-Salem, North Carolina  27157-1096
Massachusetts General HospitalBoston, Massachusetts  02114-2617
H. Lee Moffitt Cancer Center and Research Institute at University of South FloridaTampa, Florida  33612
UAB Comprehensive Cancer CenterBirmingham, Alabama  35294