To determine the MTD toxicity of standard dose cetuximab together with concurrent individualized, isotoxic accelerated radiotherapy and cisplatin-vinorelbine

Phase I trial with escalating doses of vinorelbine and standard doses of radiotherapy, cisplatin and cetuximab.

Eligible patients receive 2 cycles of carboplatin (AUC 5) day 1 and gemcitabine (1250 mg/m2) days 1,8. One cycle duration is 21 days.

Patients without progressive disease (PD) according to the RECIST criteria (appendix 1) will be entered in the phase I dose-escalation part of the study. Chest radiation is given concurrently with cetuximab, cisplatin and vinorelbine. The latter drug will be escalated in three steps until dose-limiting toxicity occurs.

On day 43, i.e. 14 days after the last gemcitabine delivery, radiotherapy is started.

Radiotherapy: In all patients in every dose-step, the radiation will be given as follows: first 3 weeks: 1.5 Gy BID to a dose of 45 Gy in 30 fractions, then 2 Gy QD to a mean lung dose (MLD, this is related to radiation-induced lung damage) of 19 Gy. Maximum dose: 69 Gy given in 5.5 weeks. Maximum dose to the spinal cord: 50 Gy.

Cetuximab: All patients will receive a starting dose 400 mg/ m2 7 days before the beginning of radiotherapy (i.e. day 36), thereafter a weekly dose 250 mg/ m2 during the course of radiotherapy for 5 consecutive weeks. Cetuximab will be delivered at the same days as chemotherapy.

Cisplatin: In all patients in every dose-step, cisplatin will be given as follows: Step 1, 2 and 3: 50 mg/ m2 days 43, 50; 40 mg/m2 day 64.

Vinorelbine will be escalated in three steps:

Step 1: 10 mg/ m2 days 43, 50; 8 mg/m2 days 66 and 73. Step 2: 20 mg/ m2 days 43, 50; 8 mg/m2 days 66 and 73. Step 3: 20 mg/ m2 days 43, 50; 15 mg/m2 days 66 and 73.

Inclusion Criteria:

• Histologically confirmed non-small cell lung cancer
• Inoperable stage III (UICC 2002; sixth edition) (no pleural effusion)
• WHO performance status 0 or 1
• Less than 10% weight loss in the last 6 months
• Lung function: FEV1 at least 50% and DLCO at least 50% of the predicted value
• No recent severe cardiac disease
• Adequate bone marrow function
• Adequate renal function
• Adequate hepatic function
• Life expectancy more than 6 months
• Measurable cancer
• Willing and able to comply with study prescriptions
• 18 years or older
• Not pregnant or breast feeding
• Written informed consent
• No previous radiotherapy to the chest

Exclusion Criteria:

• Not non-small cell lung cancer histology
• Mixed pathology
• History of prior chest radiotherapy
• Recent (<3 months) myocardial infarction
• Uncontrolled infectious disease
• Less than 18 years old
• Inadequate pulmonary function
• Other active malignancy