Phase III Trial of Single-Agent Pemetrexed (Alimta®) Versus the Combination of Carboplatin and Pemetrexed in Patients With Advanced Non-small-cell Lung Cancer and Performance Status of 2

Inclusion Criteria:

- Newly diagnosed NSCLC in stage IIIB (with a cytologically positive pleural or
pericardial effusion) or stage IV, according to the sixth edition of the American
Joint Committee on Cancer (AJCC) Cancer Staging Manual37;

- Age > 18 years;

- No prior chemotherapy, including adjuvant or neoadjuvant therapy, for the treatment
of NSCLC;

- Histological confirmation of any non-squamous histological type of NSCLC, given the
recent findings of treatment benefit in this population44;

- ECOG performance status of 2;

- At least 3 weeks must have elapsed since major surgery, and at least 1 week since
mediastinoscopy, pleuroscopy, or thoracostomy;

- Patients must have measurable disease, defined as lesions that can be accurately
measured in at least 1 dimension (longest diameter to be recorded) as ≥ 20 mm with
conventional techniques (computed tomography [CT] or magnetic resonance imaging [MRI]
scan) or as ≥ 10 mm with spiral CT scan;

- Adequate organ function as indicated by the following:

- White blood cell (WBC) count ≥ 3500/mm3

- Absolute neutrophil count (ANC) ≥1500/mm3

- Hemoglobin ≥ 9.0 g/dL

- Platelet count ≥ 100,000/ mm3

- Total bilirubin ≤ 2 times the upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times
the ULN, unless liver metastases present, in which case AST and ALT have to be ≤
5 times the ULN

- Estimated glomerular filtration rate (GFR) ≥ 45 mL/min

- Female patients of childbearing potential must have a negative serum pregnancy test
within 7 days prior to registration;

- Fertile patients (male or female) must agree to use an acceptable method of
contraception to avoid pregnancy for the duration of the study and for 3 months
thereafter;

- Patients must sign an Informed Consent Form;

- Have the ability to take folic acid, Vitamin B12, and dexamethasone according to
protocol requirements;

Exclusion Criteria:

- ECOG performance status other than 2;

- Prior chemotherapy for the treatment of NSCLC;

- Lesions that have been irradiated cannot be included as sites of measurable disease.
If the only measurable lesion was previously irradiated the patient cannot be
included;

- Symptomatic central nervous system (CNS) metastases. Prior CNS metastases are allowed
if the patient is neurologically stable and not receiving corticosteroids;

- Serious uncontrolled intercurrent medical or psychiatric illness;

- Active and ongoing systemic infection;

- Second primary malignancy (except in situ carcinoma of the cervix, in situ carcinoma
of the bladder, adequately treated basal-cell carcinoma of the skin, adequately
treated squamous-cell carcinoma of the skin, T1 vocal cord cancer in remission, or
prior malignancy treated more than 5 years prior to enrollment and without
recurrence);

- Known hypersensitivity to pemetrexed;

- known hypersensitivity to carboplatin;

- Pregnancy or lactation;

- Use of any investigational agent within 30 days prior to enrollment into the study;

- Unable to discontinue administration of non-steroidal anti-inflammatory (NSAIDSs)
agents for 2 days before, the day of and 2 days after the dose of pemetrexed, in the
case of NSAIDs with short half-life, such as ibuprofen (total of 5 days), in patients
with a GFR between 45 and 79 mL/min; and for 5 days before, the day of and 2 days
after the dose of pemetrexed, in the case of NSAIDs with long half-life (total of 8
days, see 7.4.2) in all patients; patients with a GFR ≥ 80 mL/min may receive
concomitant study treatment and ibuprofen or aspirin (≤ 1.3 g/day);

- Inability to comply with requirements and procedures of study.