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.