Trial Information

Phase I/II Study on Concomitant and Adjuvant Temozolomide and Radiotherapy With or Without PTK787/ZK222584 in Newly Diagnosed GBM

OBJECTIVES:

Primary

- Determine the maximum tolerated dose and recommended phase II dose of vatalanib when
given in combination with temozolomide and radiotherapy in patients with newly
diagnosed glioblastoma multiforme. (Phase I)

- Determine the safety and tolerability of this regimen in these patients. (Phase I)

- Determine the 6-month progression-free survival of patients treated with
chemoradiotherapy comprising temozolomide and radiotherapy with or without vatalanib
followed by adjuvant therapy comprising temozolomide and vatalanib or temozolomide
alone with or without maintenance therapy comprising vatalanib alone. (Phase II)

Secondary

- Determine 12-month overall survival of patients treated with these regimens. (Phase II)

- Determine the toxicity profile of these regimens in these patients. (Phase II)

- Correlate expression of angiogenesis and hypoxia markers and MGMT methylation status
with clinical outcome in patients treated with these regimens.

OUTLINE: This is a phase I, multicenter, open-label, non-randomized, dose-escalation study
of vatalanib followed by a phase II, randomized, controlled study. Patients enrolled in the
phase II portion of the study are stratified according to participating center, age (< 50
years vs ≥ 50 years), corticosteroid intake (yes vs no), and mini-mental status evaluation
score (< 27 vs 27-29 vs 30).

- Phase I:

- Chemoradiotherapy: Patients receive oral temozolomide once daily for 6-7 weeks and
oral vatalanib once daily for 6 weeks. Patients also undergo radiotherapy once
daily, 5 days a week, for 6 weeks. Four weeks after the completion of
chemoradiotherapy, patients proceed to adjuvant therapy. During the 4-week period
between chemoradiotherapy and adjuvant therapy, patients continue to receive oral
vatalanib twice daily.

Cohorts of 3-6 patients receive escalating doses of vatalanib during chemoradiotherapy until
the maximum tolerated dose is determined (MTD). The MTD is defined as the dose preceding
that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6
patients are treated at the MTD.

- Adjuvant therapy: Patients receive oral temozolomide once daily on days 1-5 and oral
vatalanib twice daily on days 1-28. Treatment repeats every 28 days for 6 courses in
the absence of disease progression or unacceptable toxicity. Patients then proceed to
maintenance therapy.

- Maintenance therapy: Patients continue to receive oral vatalanib twice daily in the
absence of disease progression or unacceptable toxicity.

- Phase II: Patients are randomized to 1 of 3 treatment arms.

- Arm I:

- Chemoradiotherapy: Patients receive oral temozolomide once daily for 6-7 weeks and
undergo radiotherapy once daily, 5 days a week, for 6 weeks. Four weeks after the
completion of chemoradiotherapy, patients proceed to adjuvant therapy.

- Adjuvant therapy: Patients receive oral temozolomide once daily on days 1-5.
Treatment repeats every 28 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity.

- Arm II:

- Chemoradiotherapy: Patients receive temozolomide and undergo radiotherapy as in
arm I. Patients also receive vatalanib twice daily for 6 weeks at the MTD
determined in phase I. Four weeks after the completion of chemoradiotherapy,
patients proceed to adjuvant therapy. During the 4-week period between
chemoradiotherapy and adjuvant therapy, patients continue to receive oral
vatalanib twice daily.

- Adjuvant therapy: Patients receive temozolomide and vatalanib as in phase I
adjuvant therapy. Patients then proceed to maintenance therapy.

- Maintenance therapy: Patients continue to receive vatalanib as in phase I
maintenance therapy.

- Arm III:

- Chemoradiotherapy: Patients receive temozolomide and undergo radiotherapy as in
arm I. Four weeks after the completion of chemoradiotherapy, patients proceed to
adjuvant therapy. During the 4-week period between chemoradiotherapy and adjuvant
therapy, patients receive oral vatalanib twice daily.

- Adjuvant therapy: Patients receive temozolomide and vatalanib as in phase I
adjuvant therapy. Patients then proceed to maintenance therapy.

- Maintenance therapy: Patients continue to receive vatalanib as in phase I
maintenance therapy.

After completion of study treatment, patients are followed every 3 months for survival.

PROJECTED ACCRUAL: Approximately 3-18 patients will be accrued for the phase I portion of
this study. A total of 201 patients (67 per treatment arm) will be accrued for the phase II
portion of this study.