A Study of Cisplatin + Pemetrexed + Avastin as First-Line Therapy in Patients With Advanced Non-Small Cell Lung Carcinoma (NSCLC)

The majority of patients with NSCLC present with inoperable locally advanced or metastatic
disease for which no curative therapy is available. For these patients, platinum based
doublet combination regimens have become standard of care due to increased survival rates
over platinum therapy alone.

In order to try to improve on the overall survival, clinicians have attempted to add a third
cytotoxic agent to their standard regimen(s). Although this approach demonstrated an
improved objective response, no additional benefit was noted in overall survival.

Recent development and approval of new targeted chemotherapies during the past 10 years has
prompted clinical trials to test the efficacy of newly FDA approved agents such as
gefitinib, erlotinib, and bevacizumab in advanced NSCLC.

Although gefitinib and erlotinib have both demonstrated clinical activity in refractory
NSCLC, neither agent improved clinical outcome when added to standard 1st line platinum
based chemotherapy. In contrast, a recently completed randomized Phase 3 trial investigating
the addition of bevacizumab to 1st line paclitaxel plus carboplatin chemotherapy reported a
23% improvement in the median overall survival for the paclitaxel/carboplatin plus
bevacizumab treatment arm (12.5m vs. 10.2m; p=0.007). It is therefore appealing to study a
cisplatin combination with bevacizumab to determine if there is any additive benefit.
Pemetrexed is an ideal agent to use in combination with cisplatin since it is well tolerated
and efficacy is comparable to other cisplatin combinations. Patients will receive a maximum
of 6 cycles. Those who complete 1 cycle will be evaluated for toxicity; more than 1 cycle,
response.

Inclusion Criteria:

- Have stage IIIB (malignant pleural or pericardial effusion) or stage IV disease.

- Be chemotherapy naïve.

- Have measurable disease by RECIST, defined as at least 1 lesion that can be
accurately measured in at least 1 dimension as >20 mm with conventional techniques or
>10 mm with spiral CT scan; the longest diameter is to be recorded.

- Are 18 years of age or older.

- Have a life expectancy greater than 3 months.

- Have an ECOG performance status of 0 or 1.

- Are able to provide written informed consent in accordance with all applicable
regulations and follow the study procedures. Patients must be capable of
understanding the investigational nature, potential risks and benefits of the study.

- The ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the
day of, and 2 days following administration of Alimta and the ability to take folic
acid, Vitamin B12 and dexamethasone according to protocol.

Exclusion Criteria:

- Have had prior chemotherapy (or an EGFR TKI) for treatment of advanced disease

- Intrathoracic lung carcinoma of squamous cell histology

• Mixed tumors will be categorized by the predominant cell type unless small cell
elements are present, in which case the patient is ineligible; sputum cytology alone
is not acceptable. Patients with extrathoracic-only squamous cell NSCLC are eligible.
Patients with only peripheral lung lesions (of any NSCLC histology) will also be
eligible (a peripheral lesion is defined as a lesion in which the epicenter of the
tumor is ≤ 2 cm from the costal or diaphragmatic pleura in a three-dimensional
orientation based on each lobe of the lung and is > 2 cm from the trachea, main, and
lobar bronchi).

- History of hemoptysis (bright red blood of 1/2 teaspoon or more per episode) within 1
month prior to study enrollment.

- Current, ongoing treatment with full-dose warfarin or its equivalent (i.e.,
unfractionated and/or low molecular weight heparin).

- Current or recent (within 10 days of enrollment) use of aspirin (>325 mg/day) or
chronic use of other NSAIDs.

- Cardiovascular concerns:

- Blood pressure of >150/100 mmHg

- Unstable angina within 6 months prior to Day 1

- New York Heart Association (NYHA) Grade II or greater congestive heart failure
(see Appendix E)

- History of myocardial infarction within 6 months

- History of stroke within 6 months

- Clinically significant peripheral vascular disease

- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair
or recent peripheral arterial thrombosis) within 6 months prior to Day 1.

- Have had radiation therapy within 2 weeks prior to enrollment.

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 0, anticipation of need for major surgical procedure during the course
of the study.

- Minor surgical procedures such as fine needle aspirations or core biopsies within 7
days prior to Day 0.

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to Day 1.

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

- Have inadequate organ function at the Screening visit as defined by the following
laboratory values:

- Platelet count <100 x 109/L

- Hemoglobin <9.0 g/dL

- Absolute neutrophil count (ANC) <1.5 x109/L

- INR ≥1.5 within 1 week prior to randomization

- Creatinine clearance (Cockroft-Gault) < 50ml/min

- Urine protein:creatinine ratio ≥1.0 at screening

- Aspartate transaminase (AST) >2.5 times the upper limit of the normal range
(ULN)

- Alanine transaminase (ALT) >2.5 times ULN

- Total bilirubin >1.5 times ULN or ≥5 times ULN in patients with liver metastases

- Known CNS disease, except for treated brain metastasis

• Treated brain metastases are defined as having no evidence of progression or
hemorrhage after treatment and no ongoing requirement for dexamethasone, as
ascertained by clinical examination and brain imaging (MRI or CT) during the
screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain
metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma
Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating
physician. Patients with CNS metastases treated by neurosurgical resection or brain
biopsy performed within 3 months prior to Day 1 will be excluded.

- Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic
anticoagulation).

- Have uncontrolled active systemic infection requiring treatment.

- Have had treatment for a cancer other than NSCLC within 5 years prior to enrollment,
with the exception of basal cell carcinoma or cervical cancer in situ.

- Have known human immunodeficiency virus (HIV) positive or hepatitis B surface
antigen-positive status or known active hepatitis C infection. Patients assessed by
the investigator to be at risk for HIV, hepatitis B or C infection should be tested
in accordance with local regulations.

- Are a pregnant or breast-feeding female. Confirmation that the patient is not
pregnant must be established by a negative serum Beta-human chorionic gonadotropin
(β-hCG) pregnancy test result obtained during the Screening Period. Pregnancy testing
is not required for post-menopausal or surgically sterilized women.

- Are unwilling to employ adequate means of contraception (condoms, diaphragm, birth
control pills, injections, intrauterine device, or abstinence).

- Are currently receiving or have previously received an investigational agent for any
reason within 4 weeks of enrollment.

- Presence of third space fluid which cannot be controlled by drainage.

- Inability to comply with study and/or follow-up procedures.

- Prior history of hypertensive crisis or hypertensive encephalopathy.

- History of stroke or transient ischemic attack within 6 months prior to Day 1.