Inclusion Criteria

INCLUSION CRITERIA

1. Histological confirmation of predominantly squamous/non-squamous NSCLC

2. Have a tissue biopsy available for sending to the central laboratory to determine
ERCC1 status

3. Presentation with stage IIIb (not amenable to curative treatment) or IV disease -
staging scans must be no more than 28 days prior to registration. Patients with
relapsed NSCLC must not have received prior chemotherapy or biological therapy
(previous surgery or radical radiotherapy allowed)

4. At least one measurable lesion according to Response Evaluation Criteria in Solid
Tumours

5. Either sex, at least 18 years of age

6. ECOG performance status 0-1

7. Estimated life expectancy of at least 8 weeks

8. Adequate bone marrow function as evidenced by the following (assessed within 14 days
of registration):

- Absolute neutrophil count (ANC) ≥1.5 × 109/L

- Platelet count ≥100 × 109/L

- Haemoglobin ≥9 g/dL

9. Adequate liver function as evidenced by the following (assessed within 14 days of
registration):

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

- Aspartate transaminase (AST) ≤3 × ULN or ≤5 × ULN is acceptable with liver
metastases

- Alanine transaminase (ALT) ≤3 × ULN

10. Adequate renal function as evidenced by the following (assessed within 14 days of
registration):

- GFR > 60ml/min as measured by creatinine clearance through EDTA or 24 hour urine
collection. Alternatively, the Cockcroft and Gault formula may be used to estimate
GFR, but if < 60 ml/min then EDTA should be performed.

11. Previous palliative radiotherapy to non-target metastatic lesions is allowed for pain
relief prior to starting chemotherapy

12. Patients with stable brain metastases will be allowed to enrol. Stable brain
metastases being defined as no progression of brain metastases 28 days after
treatment as documented by a CT scan/MRI of the brain. Patients with incidentally
discovered asymptomatic brain metastases may be enrolled and treated with trial
chemotherapy without prior brain irradiation if deemed feasible by the treating
physician

13. Signed informed consent form

14. Use of effective contraception during, and for 6 months after trial treatment by
patients of reproductive potential and partners of reproductive potential. Patients
who receive aprepitant (anti-emetic) must be willing to use an alternative or back-up
method to hormonal contraceptives as aprepitant may reduce their efficacy. Female
patients with childbearing potential must have a negative serum pregnancy test prior
to registration.

EXCLUSION CRITERIA

1. Cytologically or clinically diagnosed NSCLC

2. Evidence of significant medical condition or laboratory finding which, in the opinion
of the treating physician or chief investigator, makes it undesirable for the patient
to participate in the trial

3. Presence of uncontrolled brain or leptomeningeal metastases thought to require
immediate radiotherapy

4. Presence of clinically significant third-space fluid collections (for example,
ascites or pleural effusions) that cannot be controlled by drainage or other
procedures prior to trial entry

5. Yellow fever vaccination received within the 30 days previous to study entry

6. Unable to interrupt aspirin or other NSAIDs (for pemetrexed arms of the trial)

7. Unable or unwilling to take vitamin B12 and folic acid (for pemetrexed arms of the
trial)

8. A history of prior malignant tumour, unless the patient has been without evidence of
disease for at least 3 years or the tumour was a non-melanoma skin tumour or early
cervical cancer

9. Pregnant or lactating women

10. Inability to comply with protocol or trial procedures