Trial Information

A Phase I Study Of ZD 1839 In Combination With Radiation And Chemotherapy In Locally Advanced Squamous Cell Carcinoma Of The Head And Neck

PRIMARY OBJECTIVES:

I. To establish the safety profile of daily oral administration of ZD1839 ("Iressa",
AstraZeneca, Inc.) that can be given with concurrent irradiation alone or combined
concurrently with weekly cisplatin in previously untreated patients with locally advanced
HNSCC, AJCC clinical stage III-IVB, deemed not suitable for surgery. Hence, the
maximum-tolerated dose of ZD1839 will be determined.

II. To delineate and quantitate any dose-dependent local and or systemic toxicities of
ZD1839 given concurrently with irradiation or combined concurrently with weekly cisplatin to
patients with locally advanced, HNSCC, AJCC stage III-IVB, deemed not suitable for surgery.

III. To determine the feasibility and toxicity profile of protracted continuous daily dosing
of ZD1839 beginning 8 weeks after the completion of the head and neck radiation therapy for
a period not to exceed 2 years.

SECONDARY OBJECTIVES:

I. Secondary endpoints will include determination of the response rates, relapse-free
survival rates and overall survival rates for this group of patients.

II. To perform correlative studies assessing the biological effects of ZD1839 within the
primary tumor.

OUTLINE: This is a multicenter, dose-escalation study of gefitinib.

All patients receive oral gefitinib once daily beginning at least 7 days before and
continuing throughout radiotherapy or chemoradiotherapy in the absence of disease
progression or unacceptable toxicity. Patients are entered into 1 of 5 levels.

Level I: Patients undergo concurrent boost radiotherapy 5 days per week comprising once
daily radiotherapy for 3.5 weeks followed by twice daily radiotherapy for 2.5 weeks.

Level II: Patients receive escalated dose of gefitinib and undergo radiotherapy as in level
I.

Level III: Patients receive original dose of gefitinib, undergo standard fractionation
radiotherapy comprising once daily radiotherapy 5 days per week for 7 weeks, and receive
cisplatin IV over 30-60 minutes at the beginning of each week of radiotherapy.

Level IV: Patients receive escalated dose of gefitinib as in level II and undergo
radiotherapy and chemotherapy as in level III.

Level V: Patients receive the maximum tolerated dose (MTD) of gefitinib, radiotherapy 5 days
a week for 6 weeks, and chemotherapy as in level III.

Patients with clinical or radiologic evidence of residual disease are required to undergo
neck dissection approximately 8 weeks after completion of radiotherapy or chemoradiotherapy.

Patients resume oral gefitinib daily beginning 8 weeks after the completion of radiotherapy
or chemoradiotherapy (12 weeks for patients who undergo neck dissection) and continuing for
2 years in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients are enrolled sequentially beginning at level I until the MTD of
gefitinib is determined. The MTD is the dose preceding that at which at least 2 of 6
patients experience dose-limiting toxicity.

Twelve additional patients receive the MTD of gefitinib in combination with radiotherapy
with or without cisplatin.

Patients are followed every 6 months for at least 5 years.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.