Pemetrexed or Docetaxel With or Without Erlotinib in Stage IIIB or Stage IV Non-Small Cell Lung Cancer

OBJECTIVES:

Primary

- To evaluate whether maintenance erlotinib hydrochloride added to standard of care
(pemetrexed disodium or docetaxel) chemotherapy in patients with erlotinib
hydrochloride-responsive advanced non-small cell lung cancer leads to an improved
progression-free survival as compared to standard of care pemetrexed disodium or
docetaxel alone.

Secondary

- To evaluate the effect of maintenance erlotinib hydrochloride on the response rate to
standard of care (pemetrexed disodium or docetaxel) therapy in patients with erlotinib
hydrochloride-responsive advanced non-small cell lung cancer as compared to standard of
care (pemetrexed disodium or docetaxel) alone.

- To evaluate whether maintenance erlotinib hydrochloride added to standard of care
(pemetrexed disodium or docetaxel) chemotherapy in patients with erlotinib
hydrochloride-responsive advanced non-small cell lung cancer leads to an improved
overall survival as compared to standard of care (pemetrexed disodium or docetaxel)
alone.

- To evaluate the effect of maintenance erlotinib hydrochloride on the disease
stabilization (complete response [CR] + partial response [PR] + stable disease [SD])
rate to standard of care (pemetrexed disodium or docetaxel) therapy in patients with
erlotinib hydrochloride-responsive advanced non-small cell lung cancer as compared to
standard of care (pemetrexed disodium or docetaxel) alone.

- To evaluate the utility of early positron emission tomography (PET) scanning (baseline
versus 1 cycle of protocol therapy) on overall disease assessment and prediction of
treatment responsiveness.

OUTLINE: This is a multicenter, randomized study. Patients are stratified according to
lifetime smoking status (never vs ever) and ECOG performance status (0-1 vs ≥ 2). Patients
are randomized to 1 of 2 treatment arms.

- Arm I: (standard of care alone): Patients receive pemetrexed disodium intravenously
(IV) over 10 minutes OR docetaxel IV over 60 minutes on day 1. Treatment repeats every
21 days for up to 8 courses in the absence of disease progression or unacceptable
toxicity.

- Arm II: (standard of care plus erlotinib): Patients receive pemetrexed disodium IV over
10 minutes OR docetaxel IV over 60 minutes on day 1 and erlotinib hydrochloride orally
(PO) once daily on days 2-19. Treatment repeats every 21 days for up to 8 courses in
the absence of disease progression or unacceptable toxicity.

Patients may continue to receive standard chemotherapy with or without erlotinib
hydrochloride in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 8 weeks.

INCLUSION CRITERIA

- Pathologic diagnosis of stage IIIB (with pleural effusion) or IV non-small cell lung
cancer

- Progression following at least twelve weeks of treatment with single-agent erlotinib
(or in combination with other experimental agents) during which time the patients
experienced a clinical benefit as assessed by his/her treating physician and
corroborated by radiographic assessment (at least one CT scan following at least 4
weeks of erlotinib monotherapy demonstrating stable disease or response on erlotinib
therapy).

- At least one measurable lesion as defined by modified Response Evaluation Criteria In
Solid Tumors (RECIST) criteria

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Life expectancy of at least 12 weeks

- Absolute neutrophil count (ANC) >= 1.5x10(9)/L

- Platelet count >= 100x 10(9)

- Hemoglobin >= 8.0 g/dl

- Serum creatinine =< 1.5 upper limit of normal OR calculated creatinine clearance >=
45 mL/min

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

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN

- Available baseline diagnostic tumor specimen for correlative studies, any diagnostic
material will be acceptable- paraffin block, cell block, fine needle aspirate etc.

- Patients must provide verbal and written informed consent to participate in the study

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures

- Patient must be able to take folic acid, vitamin B12 as well as dexamethasone therapy
as per protocol guidelines

- Patient must be able to interrupt nonsteroidal anti-inflammatory drugs (NSAIDs) 2
days before (5 days for long-acting NSAIDs), the day of, and 2 days following
administration of pemetrexed (this exclusion criteria applies only to patients who
have not received pemetrexed chemotherapy prior)

EXCLUSION CRITERIA

- Active central nervous system disease (CNS) metastases, as indicated by clinical
symptoms, cerebral edema or progressive growth (subjects with a clinical history of
CNS metastases or cord compression are allowable if they have been definitively
treated and are clinically stable for at least 4 weeks before first dose of study
treatment for prior whole brain radiation and 2 weeks for prior gamma knife therapy)

- More than 1 prior cytotoxic chemotherapy regimen for relapsed or metastatic disease
(not including erlotinib)

- Any prior epidermal growth factor receptor (EGFR) inhibitor therapy except for
erlotinib

- Major surgery, chemotherapy, or investigational agents within 3 weeks of treatment
day 1 (except for erlotinib). Radiation therapy within 2 weeks of treatment day 1
(except for erlotinib).

- Prior treatment with both pemetrexed and docetaxel chemotherapy

- Pregnancy or breastfeeding or not receiving adequate contraception (including the
patients spouse)

- Other severe acute or chronic medical or psychiatric conditions or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or may interfere with the interpretation of study results, and in
the judgment of the investigator would make the patient inappropriate for entry into
this study

- Patients who must receive pemetrexed and have the presence of third space fluid which
cannot be controlled by drainage

- Patients who must receive docetaxel and who have peripheral neuropathy > grade 2

- Patients who must receive docetaxel and who have had a hypersensitivity reaction to
medications formulated with polysorbate 80