Both pemetrexed and cetuximab have single agent activity in NSCLC and non-overlapping toxicity profiles. While 2-drug combination therapy has proven superior to single agent therapy in the first-line setting of NSCLC, no such phase III trials have been reported in the second-line setting. Therefore, the purpose of this study is to determine the feasibility of combining these drugs, assessing the toxicity profile, determining the MTD and evaluating the activity of the combination in an expanded phase II setting. If the combination appears to have promising activity, further evaluation of this regimen may be warranted comparing it to single agent pemetrexed or cetuximab alone.

OUTLINE: This is a multi-center study.

Week 1 (day 1):

• Cetuximab 400mg/m2

Week 2 (Cycle 1, Day 1):

• Cetuximab 250mg/m2 plus premetrexed at the assigned dose level.

Patients will be treated with cetuximab on day 1, 8, 15 of each 21 day cycle.

Patients will be treated with pemetrexed on day 1 of each 21 day cycle for a maximum of 6 cycles.

Acceptable toxicity and SD, PR or CR: treat up to 6 cycles then continue cetuximab weekly until PD or excess toxicity

Performance status: ECOG 0-2

Life expectancy: At least 12 weeks

Hematopoietic:

• ANC > 1,500/mm3
• Platelets > 100,000/mm3

Hepatic:

• Bilirubin less than or equal to the upper limit of normal (ULN)
• Aspartate aminotransferase (AST) < 1.5 X ULN. AST may be < 5 X ULN for patients with liver metastases
• Alkaline phosphatase < 5 X ULN

Renal:

• Calculated creatinine clearance > 45 mL/min (by Cockcroft-Gault)

Cardiovascular:

• No significant history of uncontrolled cardiac disease (i.e., uncontrolled hypertension, unstable angina, and congestive heart failure)

Pulmonary:

• Not specified

Inclusion Criteria:

• Histologic or cytologic diagnosis of NSCLC
• Recurrent or metastatic disease that is not amenable to curative therapyMeasurable disease according to RECIST
• At least one prior platinum containing regimen for either locally advanced or metastatic disease
• Prior chemotherapy must be completed at least 21 days prior to being registered for protocol therapy and the subject must have recovered from the acute toxicity effects of the regimen
• Ability and willingness to interrupt aspirin or other nonsteroidal anti-inflammatory agents for a 5-day period
• Prior radiation therapy allowed to < 25% of the bone marrow
• Negative pregnancy test

Exclusion Criteria:

• No active infection that in the opinion of the investigator would compromise the subject's ability to tolerate therapy.
• No serious concomitant systemic disorders that would compromise the safety of the subject or compromise the subject's ability to complete the study, at the discretion of the investigator.
• No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the subject has been disease-free for at least 2 years.
• No major thoracic or abdominal surgery within 30 days prior to being registered for protocol therapy.
• No current breastfeeding