Pemetrexed and/or Sunitinib as Second-Line Therapy in Treating Patients With Stage IIIB or Stage IV Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To estimate the 18 week progression-free survival rate of pemetrexed (pemetrexed disodium)
alone (Arm I), sunitinib (sunitinib malate) alone (Arm II) and pemetrexed plus sunitinib (Arm
III) in the second-line setting of advanced non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To compare the progression-free survival of the three arms. II. To estimate the response
rate, duration of response, rate of stable disease, overall survival and to characterize the
toxicity profiles of the three arms.

III. To estimate the response rate, duration of response, rate of stable disease, overall
survival and toxicity of sunitinib in those patients on Arm I that receive this regimen in
the third line setting.

IV. To assess vascular endothelial growth factor (VEGF) haplotypes in advanced non-small cell
lung cancer.

V. To test change in tumor size at 6 weeks (after 2 cycles of therapy, typically the first
evaluation point in this type of study) as an early predictor of therapeutic activity in
second-line treatment of non-small cell lung cancer.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: 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.
Patients with documented disease progression may then receive sunitinib malate as in Arm II
as third-line therapy.

ARM II: Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-21. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients
with documented disease progression may then receive pemetrexed disodium as in Arm I as
third-line therapy.

ARM III: Patients receive pemetrexed disodium IV over 10 minutes on day 1 and sunitinib
malate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression
or unacceptable toxicity. Patients with documented disease progression may then receive
third-line therapy at the discretion of the treating physician.

After completion of study treatment, patients are followed up every 6 weeks until disease
progression and then every 6 months for 2 years.

Inclusion Criteria:

- Histologic documentation: histologic or cytologic documentation of NSCLC

- Stage: IIIB/IV with evidence of disease progression following first-line therapy

- Tumor site: lung (non-small cell)

- No cavitary lesions

- Only one prior chemotherapy regimen in the first-line stage IIIB/IV setting is
allowed; this could have been either a platinum- or non-platinum-based regimen

- First-line therapy must be completed >= 28 days before registration

- Prior adjuvant therapy is allowed provided the patient had one previous regimen in the
advanced stage IIIB/IV setting

- At least 28 days from prior major surgery and at least 14 days from any prior
radiotherapy before registration

- No prior inhibitors of VEGF receptor (VEGFR) (e.g., SU5416, SU6668, AZ6474, SU11248,
PTK787, AZD2171, AEE-788, sorafenib); prior treatment with epidermal growth factor
receptor (EGFR) inhibitors and bevacizumab is allowed, provided at least 4 weeks has
elapsed

- No prior pemetrexed

- Patients must have measurable or non-measurable disease

- Measurable disease

- Lesions that can be accurately measured in at least one dimension (longest
diameter to be recorded) as >= 2 cm with conventional techniques or as >= 1
cm with spiral computed tomography (CT) scan

- Non-measurable disease

- All other lesions, including small lesions (longest diameter < 20 mm with
conventional techniques or < 10 mm with spiral CT scan) and truly
nonmeasurable lesions

- Lesions that are considered non-measurable include the following:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Lymphangitis cutis/pulmonis

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

- Cystic lesions

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Pregnant or nursing mothers are not eligible for this study; patients in their child
bearing years must have a baseline negative pregnancy test (in the case of females);
males and females must practice appropriate contraceptive measures during the period
of protocol therapy and for 6 months after completion of protocol therapy; appropriate
methods of birth control include abstinence, oral contraceptives, implantable hormonal
contraceptives (Norplant), or double barrier method (diaphragm plus condom)

- No ongoing cardiac dysrhythmias, atrial fibrillation, or history of corrected QT
interval (QTc interval) > 500 msec (within 2 years prior to registration); the use of
agents with proarrhythmic potential (e.g., quinidine, procainamide, disopyramide,
sotalol, probucol, bepridil, haloperidol, risperidone, indapamide, flecainide) is not
recommended while on protocol therapy

- Patients with class I New York Heart Association (NYHA) heart failure are eligible;
patients with a history of class II NYHA heart failure are eligible, provided they
meet at least one of the following criteria:

- Patients with a history of class II heart failure who are asymptomatic on
treatment

- Patients with prior anthracycline exposure

- Patients who have received central thoracic radiation that included the heart in
the radiotherapy port

- Patients with a history of symptomatic congestive heart failure within 12 months prior
to entry are not eligible

- No myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft or stenting, cerebrovascular accident or transient ischemic attack within the
last year

- Patients with hypertension that cannot be controlled by medications (> 150/100 mmHg
despite optimal medical therapy) are not eligible

- Patients who require use of therapeutic anticoagulation for thromboembolic disease are
not eligible; Note: low doses of Coumadin (up to 2 mg daily) are permitted for
prophylaxis of thrombosis

- No history of venous thrombosis, pulmonary embolism, or hypercoagulopathy syndrome

- No history of pulmonary hemorrhage, bleeding diathesis, or evidence of hemoptysis;
patients with blood-tinged or blood-streaked sputum will be permitted on study if the
hemoptysis amounts to less than 5 mL of blood per episode and less than 10 mL of blood
per 24-hour period in the best estimate of the investigator

- Patients with a history of hypothyroidism or hyperthyroidism are eligible, provided
they are currently euthyroid

- None of the following within 28 days of beginning treatment: abdominal fistula,
gastrointestinal perforation, intra-abdominal abscess, serious or non-healing wound,
ulcer, or bone fracture

- The use of the following specific inhibitors and inducers of cytochrome P450, family
3, subfamily A, polypeptide 4 (CYP3A4) is not permitted; the following inhibitors of
CYP3A4 are prohibited within 7 days before and during treatment with sunitinib: azole
antifungals (ketoconazole, itraconazole), diltiazem, clarithromycin, erythromycin,
verapamil, delavirdine, and human immunodeficiency virus (HIV) protease inhibitors
(indinavir, saquinavir, ritonavir, atazanavir, nelfinavir); the following inducers of
CYP3A4 are prohibited within 12 days before beginning and during treatment with
sunitinib: rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John's
Wort, efavirenz, tipranavir

- Other inhibitors and inducers of CYP3A4 may be used if necessary, but their use
is discouraged

- No symptomatic or untreated central nervous system (CNS) metastases; patients with CNS
metastases must be asymptomatic, must have received definitive therapy (>= 6 weeks
since resection or >= 2 weeks since radiotherapy) for brain metastases, and be off
steroids or on a stable dose for 2 weeks prior to registration

- No chronic daily treatment with aspirin (> 325 mg/day) or non-steroidal
antiinflammatory agents known to inhibit platelet function; treatment with
dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and/or
cilostazol (Pletal) is not allowed

- No pleural effusions or ascites that are detectable on physical exam