Trial Information

A Phase I Study of CCI-779, and Temozolomide in Combination With Radiation Therapy in Glioblastoma Multiforme

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of temsirolimus when administered with temozolomide
in combination with radiotherapy followed by adjuvant temozolomide in patients with newly
diagnosed glioblastoma multiforme.

II. Assess and describe the adverse events associated with this regimen in these patients.

III. Evaluate the early response to therapy in these patients using an automated
morphological MRI change detector and physiological MRI techniques, including
diffusion-weighted imaging, perfusion-weighted imaging, and chemical shift imaging.

SECONDARY OBJECTIVES:

I. Determine the inhibition status of mTOR signaling pathways in peripheral blood
mononuclear cells in patients treated with this regimen.

II. Identify potential pharmacokinetic interactions between temozolomide and temsirolimus.

III. Correlate, preliminarily, survival, progression-free survival, and response with
pre-treatment tumor tissue molecular markers in these patients.

OUTLINE: This is a multicenter, dose-escalation study of temsirolimus. Patients are assigned
to 1 of 2 treatment groups.

GROUP 1: (temsirolimus with radiation and temozolomide) Patients receive temsirolimus IV
over 30 minutes once weekly. Beginning 7-10 days later, patients also receive oral
temozolomide daily and undergo concurrent 3-D conformal radiotherapy or intensity-modulated
radiotherapy once daily, 5 days a week, for 6 weeks. Patients are evaluated 4-6 weeks after
completion of chemoradiotherapy. Patients with stable or responding disease proceed to
adjuvant therapy. Cohorts of 3-6 patients receive escalating doses of temsirolimus 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 a dose-limiting toxicity. At least 6 patients are
treated at the MTD.

GROUP 2: (radiation and temozolomide) Patients receive oral temozolomide daily and undergo
concurrent 3-D conformal radiotherapy or intensity-modulated radiotherapy once daily, 5 days
a week, for 6 weeks. Patients are evaluated 4-6 weeks after completion of chemoradiotherapy.
Patients with stable or responding disease proceed to adjuvant therapy.

ADJUVANT THERAPY: Beginning 4-6 weeks after the completion of chemoradiotherapy patients
receive oral temozolomide on days 1-5. Treatment repeats every 28 days for up to 6 courses
in the absence of disease progression or unacceptable toxicity.

Some patients undergo blood collection for immune monitoring and translational/pharmacologic
studies. After completion of study treatment, patients are followed periodically for 5
years.