Pemetrexed Disodium or Erlotinib Hydrochloride as Second-Line Therapy in Treating Patients With Advanced Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To evaluate whether there are differences in progression-free survival due to treatment
with erlotinib (erlotinib hydrochloride) compared to pemetrexed (pemetrexed disodium) for
subsets of previously treated non-small cell lung cancer (NSCLC) patients defined by
epidermal growth factor receptor (EGFR)-fluorescent in situ hybridization (FISH) positive
versus negativity.

SECONDARY OBJECTIVES:

I. Ascertain the presence or absence of true differences due to treatment in the objective
clinical endpoints of overall survival, confirmed response rate, and adverse event profile
for subsets of patients defined on the basis of the epidermal growth factor receptor
(EGFR)-FISH positivity versus negativity.

II. Ascertain the presence or absence of true differences due to treatment in objective
clinical endpoints (i.e., progression free survival, overall survival, confirmed response
rate, and adverse event profile) for subsets of patients defined on the basis of the
epidermal growth factor receptor (EGFR) expression as measured by immunohistochemistry
(IHC).

III. Ascertain the presence or absence of true differences due to treatment in objective
clinical endpoints (i.e., progression free survival, overall survival, confirmed response
rate, and adverse event profile) for subsets of patients defined on the basis of the
epidermal growth factor receptor (EGFR) gene mutation status (MUT).

IV. To evaluate the prognostic effect of EGFR copy number as measured by FISH separately by
treatment arm, i.e., is there a difference in outcome for FISH(+) patients receiving
erlotinib compared to FISH (-) patients receiving erlotinib, and similarly is there a
difference in outcome for FISH(+) patients receiving pemetrexed compared to FISH (-)
patients receiving pemetrexed.

V. To evaluate the prognostic effect of EGFR expression as measured by IHC separately by
treatment arm, i.e., is there a difference in outcome for IHC(+) patients receiving
erlotinib compared to IHC (-) patients receiving erlotinib, and similarly is there a
difference in outcome for IHC(+) patients receiving pemetrexed compared to IHC (-)patients
receiving pemetrexed.

VI. To evaluate the prognostic effect of EGFR mutation status separately by treatment arm,
i.e., is there a difference in outcome for MUT(+) patients receiving erlotinib compared to
MUT(-) patients receiving erlotinib, and similarly is there a difference in outcome for
MUT(+) patients receiving pemetrexed compared to MUT(-) patients receiving pemetrexed.

VII. To prospectively test the hypothesis that functionally relevant polymorphisms in the
genes encoding for pemetrexed targets, as well as genes encoding for one or more of the key
enzymes involved in the transport, activation, and inactivation of pemetrexed, either singly
or in combination, play a role in the efficacy and/or toxicity of pemetrexed.

VIII. To prospectively test the hypothesis that functionally relevant polymorphisms in the
EGFR gene as well as genes encoding for one or more of the key enzymes involved in the
metabolism of erlotinib, either singly or in combination, play a role in the efficacy and/or
toxicity of erlotinib.

IX. Evaluate proteomic signatures in blood samples as predictors of survival and response to
treatment with erlotinib.

X. To evaluate expression of thymidylate synthase, dihydrofolate reductase,
phosphoribosylglycineamide (GAR) formyltransferase, and methylthioadenosine phosphorylase
gene expression in tumor samples, as measured by IHC or quantitative polymerase chain
reaction, as predictors of survival and response to treatment with pemetrexed.

XI. To evaluate proteomic signatures in blood samples of patients as predictors of response
and survival to treatment with erlotinib.

XII. To evaluate the following variables measured in tumor samples, as predictors of
response and survival to treatment with pemetrexed: Expression of thymidylate synthase,
dihydrofolate reductase and GAR formyltransferase genes methylthioadenosine phosphorylase
expression by IHC or quantitative polymerase chain reaction (PCR).

XIII. To evaluate the following variables measured in tumor samples, as predictors of
response and survival to treatment with erlotinib: Rat sarcoma (Ras) mutational status, EGFR
mutational status and, epithelial to mesenchymal transition (EMT) status (measured by
E-cadherin expression and vimentin expression) by IHC.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive pemetrexed disodium intravenously (IV) over 10 minutes on day 1.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed every 3 months until disease
progression and then every 6 months for up to 5 years.

Inclusion Criteria:

- Documented recurrence or disease progression of NSCLC

- NSCLC must be confirmed by pathologic examination, either on initial diagnosis
or disease recurrence/progression; mixed histology allowed if all components
consistent with NSCLC

- Measurable disease, defined as at least one lesion whose longest diameter can be
accurately measured as >= 2.0 cm by conventional techniques or as >= 1.0 cm by spiral
computed tomography (CT); if spiral CT is used, it must be used for both pre- and
post- treatment tumor assessments

- Prior radiation therapy is permitted as long as:

- Recovered from the toxic effects of radiation treatment before study entry,
except for alopecia

- =< 25% of bone marrow radiated

- Presence of measurable disease whether in-field disease progression/recurrence
or disease outside the treatment fields of radiation port

- Absolute neutrophil count (ANC) >= 1,500 uL

- Platelet (PLT) >= 100,000 uL

- Hemoglobin (Hgb) >= 10 g/dL

- Total bilirubin: within normal institutional limits (WNL) OR direct bilirubin =<
upper limit of normal (ULN)

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

- International normalized ratio (INR) =< 1.5

- Calculated creatinine clearance >= 45 mL/min using the Cockcroft-Gault formula

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

- Negative pregnancy test done =< 7 days prior to pre-registration, for women of
childbearing potential only

- Ability to provide informed consent

- Life expectancy >= 12 weeks

- Tissue available and willing to submit tissue for central pathology review and EGFR
evaluation; performed on original diagnostic/recurrent tissue (preferably
paraffin-embedded tissue blocks); if institution unable to release tissue blocks,
willing to submit 25 unstained slides (15 sections cut at 5 microns mounted on
charged slides and 10 sections cut at 10 microns mounted on uncharged slides)

- Must be previously treated for advanced disease with only 1 chemotherapy regimen
which must contain cytotoxic agent(s); adjuvant/neoadjuvant treatment with cytotoxic
agent(s) administered < 12 months (from date chemotherapy was started) prior to
pre-registration will be considered as one prior treatment; NOTE:
adjuvant/neoadjuvant treatment administered >= 12 months, use of targeted agents such
as monoclonal antibodies prior to pre-registration will NOT be counted as one prior
treatment; patient could have had adjuvant/neoadjuvant chemotherapy >= 12 months and
1 systemic chemotherapy regimen for metastatic or recurrent disease

- Able to take folic acid, vitamin B12 supplementation, and dexamethasone

- Able to permanently discontinue aspirin dose of >= 1.3 grams/day >= 10 days before
and after pemetrexed treatment

- Fertile patients must use effective contraception

- Able to take folic acid, vitamin B_12 supplementation, and dexamethasone

- Stable brain metastasis that have been treated with either whole brain radiation
therapy or gamma knife surgery and are off steroid treatment for > 14 days prior to
pre-registration, if applicable

- Willingness to return to enrolling institution for treatment and follow-up

Exclusion Criteria:

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Any clinically significant infection, at the treating physician's discretion

- Known human immunodeficiency virus (HIV) positive patients

- Impairment of gastrointestinal (GI) function, inability to swallow pills in the
absence of a feeding tube, or GI disease that may significantly alter absorption of
oral medications (e.g. ulcerative disease, uncontrolled nausea and vomiting,
malabsorption syndromes, bowel obstruction, etc)

- Serious condition that, in the opinion of the investigator, would compromise the
patient's ability to complete the study or increase the risk for serious adverse
events

- Any of the following prior therapies:

- Prior radiation to > 25% of bone marrow

- EGFR tyrosine kinase inhibitors

- Pemetrexed

- Chemotherapy =< 3 weeks prior to pre-registration

- Mitomycin C/nitrosoureas =< 6 weeks prior to pre-registration

- Immunotherapy =< 2 weeks prior to pre-registration

- Biologic therapy =< 2 weeks prior to pre-registration

- Gene therapy =< 2 weeks prior to pre-registration

- Full field radiation therapy =< 4 weeks prior to pre-registration

- Limited field radiation therapy =< 2 weeks prior to pre-registration

- Major surgery (i.e., laparotomy), open biopsy, or significant traumatic injury
=< 4 weeks prior to pre-registration or anticipation of need for major surgical
procedure during the course of the study; minor surgery =< 2 weeks prior to
pre-registration; insertion of a vascular access device is not considered major
or minor surgery in this regard

- Other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, or any ancillary
therapy considered investigational (utilized for a non-Food and Drug Administration
[FDA]-approved indication and in the context of a research investigation) =< 4 weeks
prior to pre-registration

- Steroid therapy for brain metastasis =< 14 days prior to pre-registration

- Symptomatic serosal effusion (>= Common Terminology Criteria for Adverse Events
[CTCAE] v3.0 grade 2 dyspnea) that is not amenable to drainage prior to
pre-registration

- Other invasive solid or hematologic malignancy; exceptions: prior malignancy was
diagnosed and definitively treated >= 5 years previously with no subsequent evidence
of recurrence; patients with a history of low-grade (Gleason score =< 6) localized
prostate cancer will be eligible even if diagnosed < 3 years prior to
pre-registration; these patients may continue on medications concomitantly to
maintain their disease remission as necessary; patients with carcinoma in situ,
regardless of organ involvement, or non-melanoma cutaneous carcinomas are eligible if
these were definitively treated >= 3 years previously with no subsequent evidence of
recurrence; Note: patients with breast cancer that was definitively treated > 5 years
earlier but continue to receive aromatase inhibitors are NOT eligible

- Only non-measurable disease, defined as all other lesions, including small lesions
whose longest diameter measures < 2 cm with conventional techniques or < 1.0 cm with
spiral CT, and truly non-measurable lesions, which include the following as per
Response Evaluation Criteria In Solid Tumors (RECIST) criteria dated June 1999:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Inflammatory breast disease

- Lymphangitis cutis/pulmonis

- Abdominal masses that are not confirmed and followed by imaging techniques

- Cystic lesions

- Single disease site in prior radiation field

- Any of the following concurrent severe and/or uncontrolled medical conditions:

- Angina pectoris

- History of congestive heart failure =< 3 months prior to pre-registration,
unless ejection fraction > 40%

- Myocardial infarction =< 6 months prior to pre-registration

- Cardiac arrhythmia

- Diabetes mellitus

- Hypertension

- Any other severe underlying diseases which are, in the judgment of the
investigator, inappropriate for entry into this study

- Respiratory symptoms > CTCAE grade 1