Randomized, Double-Blind Trial of Erlotinib/Pazopanib or Erlotinib/Placebo in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer

Erlotinib is the current treatment standard for second- or third-line therapy of advanced
NSCLC. Since angiogenesis inhibitors have also shown activity in NSCLC, the simultaneous
inhibition of the EGFR and VEGF pathway may improve the efficacy of therapy. In a recently
reported Phase III trial (Hainsworth et al. 2008), the combination of bevacizumab and
erlotinib improved the Progression- Free-Survival (PFS) vs. erlotinib alone when given as
second-line therapy in NSCLC (3.4 months vs. 1.7 months, respectively; HR 0.63). Pazopanib
also inhibits the angiogenesis pathway, and may have advantages over bevacizumab including:
(1) inhibition of other potentially important targets, including PDGFR; and (2) more
convenient oral administration.

Inclusion Criteria:

1. Pathologic confirmation of stage IIIB/IV NSCLC (squamous carcinoma, adenocarcinoma,
or large cell carcinoma) per the American Joint Committee on Cancer Cancer Staging
Manual, 6th edition. Patients with mixed tumors with small- cell elements are
ineligible.

2. At least one lesion that can be accurately measured in at least one dimension
(longest diameter to be recorded) as >20 mm with conventional techniques, or as >10
mm with spiral computerized tomography scan according to the Response Evaluation
Criteria in Solid Tumors version 1.1 (Eisenhauer et al. 2009)

3. Failure of at least 1, and no more than 2, prior chemotherapy regimens for advanced
disease (either due to progressive disease or toxicity).

4. Recovery from any toxic effects of prior therapy to ≤ grade 1 per the National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

5. Completion of radiation therapy at least 28 days prior to the start of study
treatment (not including palliative local radiation). Previously irradiated lesions
in the advanced setting cannot be included as target lesions unless clear tumor
progression has been observed since the end of radiation.

6. ECOG Performance Status of 0-2.

7. Adequate hematologic, hepatic and renal function.

8. A female is eligible to enter and participate in this study if she is of:

- non-childbearing potential (i.e., physiologically incapable of becoming
pregnant), including any female who has had hysterectomy, bilateral oophorectomy
(ovariectomy), bilateral tubal ligation, is post-menopausal

- childbearing potential, including any female who has had a negative serum
pregnancy test within 1 week prior to the first dose of study treatment,
preferably as close to the first dose as possible, and agrees to use adequate
contraception.

9. Patients entering the study must be willing to provide a serum sample at baseline and
at off-study for disease progression for correlative serum proteomic testing.

10. Willingness to provide a plasma sample at baseline, and at off-study for disease
progression for correlative testing of circulating plasma biomarkers.

11. Patients entering this study must be willing to provide tissue from a previous tumor
biopsy (if available) for correlative tissue testing.

12. Patients must be able to understand the nature of this study, give written informed
consent, and comply with study requirements.

Exclusion Criteria:

1. Past or current history of neoplasm (other than the entry diagnosis), with the
exception of treated non-melanoma skin cancer or carcinoma in-situ of the cervix, or
other cancers cured by local therapy alone, and a disease-free survival ≥3 years.

2. Prior treatment with EGFR tyrosine kinase inhibitors or vascular endothelial factor
receptor tyrosine kinase inhibitors for NSCLC. [Note: prior bevacizumab (Avastin®)
use is permitted].

3. Prior use of an investigational agent within 28 days or 5 half-lives, whichever is
longer, prior to the first dose of study drug.

4. History of any one or more of the following cardiovascular conditions within the past
6 months:

- Cardiac angioplasty or stenting

- Myocardial infarction

- Unstable angina

- Coronary artery bypass graft surgery

- Symptomatic peripheral vascular disease

- Class III or IV congestive heart failure, as defined by New York Heart
Association classification

5. History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
metastases, are asymptomatic, and have had no requirement for steroids or
anti-seizure medication for 1 week prior to first dose of study drug. Screening with
CNS imaging (CT or magnetic resonance imaging) is required only if clinically
indicated or if the subject has a history of CNS metastases.

6. Women who are pregnant or lactating. All females of childbearing potential must have
negative serum or urine pregnancy tests within 7 days prior to study treatment.

7. Poorly controlled hypertension [defined as systolic blood pressure of ≥150 mmHg or
diastolic blood pressure of ≥90mmHg].

8. Presence of uncontrolled infection.

9. Prolongation of heart rate-corrected QT interval (QTc) ≥480 msec (using Bazett's
formula).

10. Use of any of the medications on the prohibited medication list within 14 days of
study treatment (with the exception of Amiodarone, which is prohibited from 6 months
prior to screening through discontinuation from the study).

11. A serious underlying medical condition that would impair the ability of the patient
to receive protocol treatment.

12. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
placement not considered to be major).

13. Minor surgical procedures (with the exception of the placement of portacath or other
central venous access) performed less than 7 days prior to beginning protocol
treatment.

14. History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism (PE), or untreated DVT within the past 6 months.

15. Previous treatment with cetuximab.

16. Patients with hemoptysis or tumor cavitation at baseline.

17. Any prior history of hypertensive crisis or hypertensive encephalopathy.

18. Pulmonary hemorrhage/bleeding event within 6 weeks prior to beginning study
treatment.

19. Any other non-pulmonary hemorrhage/bleeding event ≥ grade 3 within 28 days of study
treatment.

20. Evidence or history of bleeding diathesis.

21. Serious non-healing wound, ulcer, or bone fracture.

22. Known or suspected allergy/hypersensitivity to any agent given in the course of this
trial.

23. Clinically significant gastrointestinal (GI) abnormalities.