A Double Blind Placebo Controlled Randomized Trial of PF-804 in Patients With Incurable Stage IIIB/IV Non-Small Cell Lung Cancer After Failure of Standard Therapy for Advanced or Metastatic Disease

Inclusion Criteria

Eligibility Criteria

- Histologically confirmed diagnosis of non-small cell carcinoma of the lung. Patients
must have an adequate histopathology or cytology specimen must consent to release of
all specimens for this protocol, and the centre/pathologist must have agreed to
submission of the specimens.

- Patients must have evidence of disease, but measurable disease is not mandatory. To
be considered evaluable for complete or partial response assessment, patients must
have at least one measurable lesion as follows:

X-ray ≥ 20 mm Spiral CT scan or physical exam ≥ 10 mm (lymph nodes must be ≥ 15 mm in the
short axis); Measurable lesions must be outside a previous radiotherapy field if they are
the sole site of disease, unless disease progression has been documented.

- Male or female, 18 years of age or older.

- ECOG performance status of 0, 1, 2 or 3. Patients with performance status of 3 are
eligible providing that the investigator attests that the patient has a reasonable
life expectancy (≥ 6 weeks).

- Adequate renal and hepatic functions as defined by the following required laboratory
values obtained within 14 days prior to randomization. If anemic, patients should be
asymptomatic and should not be decompensated.

Creatinine <1.5 upper limit of normal Total bilirubin < 1.5 upper limit of normal ALT
(SGPT) < 2.5 times the upper limit of normal. Note: If clearly attributable to liver
metastasis, ALT (SGPT) values < 5 times the upper limit of normal are permitted.

- Previous Therapy Failure of a treatment regimen is defined as the inability to continue
a regimen for any reason including, but not limited to, progressive disease, toxicity, or
patient request. Up to a maximum of three lines of chemotherapy for advanced/metastatic
disease (defined below) and at least one of erlotinib or gefitinib for advanced/
metastatic disease (defined below) should have failed.

Exchange of one chemotherapy agent for another within a combination chemotherapy regimen
is not considered a new regimen in the following circumstances

- carboplatin is substituted for cisplatin due to nephrotoxicity

- one agent in the combination regimen is changed due to hypersensitivity occurring in
the first cycle.

Chemotherapy for Advanced/Metastatic Disease:

Patients must have recovered from any reversible toxic effects and at least 21 days must
have elapsed from the last dose and prior to randomization (14 days from the last dose for
chemotherapy regimens administered on a weekly schedule). Further palliative cytotoxic
chemotherapy must not be planned.

Patients < 70 years:

• Must have received 1 and up to a maximum of 3prior chemotherapy regimens (at least one
of the three must have been a combination regimen and at least one must have contained
platinum).

Patients ≥ 70 years (generally accepted as being at the time of the administration of the
first regimen of chemotherapy for advanced disease):

• Must have received 1 and up to a maximum of 3 prior chemotherapy regimens for their
disease. These may have been single agent chemotherapy regimens and a platinum agent is
not required in keeping with current standards of practice.

Adjuvant Chemotherapy: Patients may ALSO have had prior adjuvant therapy for completely
resected disease, providing completed at least 12 months prior to randomization. Adjuvant
regimens < 12 months prior to randomization and combined chemotherapy/radiation regimens
for irresectable locally advanced stage III disease (irrespective of timing), are
considered to be for advanced/metastatic disease and constitute one of the 3 permissible
regimens. Patients must have recovered from any reversible treatment related toxicities
prior to randomization.

EGFR Inhibitor Therapy: Patients may only be enrolled after failure of prior gefitinib or
erlotinib for advanced or metastatic disease. Patients who have received adjuvant
gefitinib or erlotinib for completely resected NSCLC and who have recurred < 12 months
after discontinuing erlotinib or gefitinib are eligible. Patients who received gefitinib
or erlotinib for neoadjuvant therapy only are not eligible. EGFR inhibitor therapy must
have been discontinued at least 21 days prior to randomization. Patients who discontinued
prior gefitinib or erlotinib therapy for severe or life threatening organ toxicity are not
eligible. Patients may also have received other EGFR active agents (such as reversible
oral agents or monoclonal antibodies or vaccines) in addition to erlotinib or gefitinib
but may not have received ANY prior irreversible EGFR inhibitor such as BIBW2992, HKI-272
(neratinib).

Maintenance Therapy: The same chemotherapy or agent/s continued for longer than 4-6 cycles
for the purposes of 'maintenance' is considered one regimen; if another chemotherapy agent
is given with 'maintenance' intent, it is considered a second regimen providing that
'failure' is documented. Patients who received erlotinib or gefitinib with 'maintenance'
intent after completion of 1st line chemotherapy are eligible providing that 'failure' is
documented.

Radiation: Patients may have had prior radiation therapy provided that a minimum of 14
days has elapsed between the end of radiotherapy and randomization onto the study.
(Exceptions may be made however, for low dose, non-myelosuppressive radiotherapy. Patients
must have recovered from any acute toxic effects from radiation prior to randomization.

Previous Surgery: Previous surgery is permitted provided that wound healing has occurred
and at least 14 days have elapsed (major surgery).

- Patient able (i.e. sufficiently fluent) and willing to complete the quality of life
questionnaires. The baseline assessment must already have been completed. Inability
(illiteracy, loss of sight, or other equivalent reason) to complete the
questionnaires will not make the patient ineligible for the study. However, ability
but unwillingness to complete the questionnaires will make the patient ineligible.

- Patient consent must be appropriately obtained in accordance with applicable local
and regulatory requirements. Each patient must sign a consent form prior to
enrollment in the trial to document their willingness to participate.

- Patients must be accessible for treatment and follow-up. All randomized patients must
be followed and treated at participating centres. Investigators must assure
themselves the patients randomized on this trial will be available for complete
documentation of the treatment, adverse events, and follow-up.

- In accordance with NCIC CTG policy, protocol treatment is to begin within 2 working
days of patient randomization.

Ineligibility Criteria

Patients who fulfill any of the following criteria are not eligible for admission to the
study:

- Patients receiving concurrent treatment with other experimental drugs or anti-cancer
therapy.

- Patients who have experienced untreated and/or uncontrolled cardiovascular conditions
and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart
failure, myocardial infarction within the previous year or cardiac ventricular
arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular
conduction defects). Patients with a significant cardiac history, even if controlled,
should have a LVEF > 50%.

- Patients with untreated brain or meningeal metastases are not eligible (CT scans are
not required to rule this out unless there is a clinical suspicion of CNS disease).
Patients with treated CNS disease who have radiologic or clinical evidence of stable
brain metastases, with no evidence of cavitation or hemorrhage in the brain lesion,
are eligible providing that they are asymptomatic and do not require corticosteroids
(must have discontinued steroids at least 1 week prior to randomization).

- Patients with active or uncontrolled infections, or with serious illnesses or medical
conditions which would not permit the patient to be managed according to the
protocol, including

- Severe dry eye syndrome

- Keratoconjunctivitis sicca

- Sjogren's syndrome

- Severe exposure keratopathy

- Disorders that might increase the risk for epithelium-related complications
(e.g., bullous keratopathy, aniridia, severe chemical burns, neutrophilic
keratitis)

- Uncontrolled inflammatory gastrointestinal diseases (Crohn's, ulcerative colitis
etc.)

- Prior pneumonitis/ILD secondary to EGFR inhibitors

- Mean QTc with Bazetts correction > 470msec in screening ECG or history of familial
long QT syndrome.

- Drugs that are highly dependent on CYP2D6 for metabolism are prohibited, since PF-804
is a potent CYP2D6 inhibitor in in vitro assays. These inhibitors or inducers are
prohibited from 7 days prior to the first dose until the end of treatment with
PF-804. These include: S-metoprolol, propafenone, timolol, amitriptyline,
clomipramine, desipramine, imipramine, paroxetine, haloperidol, risperidone,
thioridazine, codeine, flecainide, mexilletine, tamoxifen, venlafaxine. Lidocaine may
be used with clinical monitoring (including telemetry). Opiates such as morphine,
oxycodone, dihydrocodeine, hydrocodone, and tramadol can be used as substitutes to
replace codeine. Use of these opiates should be monitored for altered analgesia
during treatment with PF-804 as they may be partly metabolized by CYP2D6. If PF-804
is administered with drugs which are P-glycoprotein (P-gp) substrates and have a
narrow therapeutic index, monitoring for exaggerated effect and/or toxicities is
recommended.

- Pregnancy or inadequate contraception. Women must be post-menopausal, surgically
sterile, or use two reliable forms of contraception. Women of child-bearing potential
must have a pregnancy test taken and proven negative within 7 days prior to
randomization. Men must be surgically sterile or use a barrier method of
contraception.