Cisplatin or Carboplatin, and Etoposide With or Without Sunitinib Malate in Treating Patients With Extensive-Stage Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine the phase II dose for sunitinib (sunitinib malate) combined with cisplatin
and etoposide. (Phase IB) II. To compare the progression-free survival of patients with
extensive stage small cell lung cancer treated with cisplatin or carboplatin and etoposide
followed by maintenance sunitinib to patients receiving the same chemotherapy followed by
placebo. (Phase II)

SECONDARY OBJECTIVES:

I. To assess the single agent response rate for sunitinib given as monotherapy after
chemotherapy. (Phase II) II. To assess the overall survival of patients treated with
cisplatin or carboplatin and etoposide followed by sunitinib. (Phase II) III. To evaluate the
toxicity and tolerability of maintenance sunitinib after cisplatin or carboplatin and
etoposide. (Phase II) IV. To determine the association between vascular endothelial growth
factor (VEGF) plasma levels and tumor response. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of sunitinib malate followed by a
randomized phase II study.

PHASE I (close to accrual 5/17/08):

COMBINATION THERAPY: Patients receive cisplatin or carboplatin intravenously (IV) on day 1,
etoposide IV on days 1-3, and sunitinib malate orally (PO) once daily (QD) on days 1-14.
Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive sunitinib malate PO alone QD. Treatment continues in
the absence of disease progression or unacceptable toxicity.

PHASE II:

COMBINATION THERAPY: Patients receive cisplatin or carboplatin and etoposide as in Phase I.
Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE THERAPY: Beginning 3-8 weeks after completion of combination chemotherapy or >= 4
courses of combination therapy, patients with a responding or stable disease are randomized
to 1 of 2 treatment arms. All patients must be euthyroid before starting on maintenance
therapy.

ARM I: Patients receive sunitinib malate PO QD. Courses repeat every 3 weeks in the absence
of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO QD. Courses repeat every 3 weeks in the absence of
disease progression or unacceptable toxicity. Patients with disease progression may cross
over to Arm I.

After completion of study treatment, patients are followed up every 3 months for 1 year and
then every 6 months for 2 years.

Inclusion Criteria:

- All patients must have histologically or cytologically documented small cell lung
cancer

- Eligible disease stages: the extensive disease classification for this protocol
includes all patients with disease sites not defined as limited stage; limited
stage disease category includes patients with disease restricted to one
hemithorax with regional lymph node metastases, including hilar, ipsilateral and
contralateral mediastinal, and/or ipsilateral supraclavicular nodes; extensive
stage patients are defined as those patients with extrathoracic metastatic,
malignant pleural effusion, bilateral or contralateral supraclavicular adenopathy
or contralateral hilar adenopathy

- All patients must have measurable disease:

- Measurable disease is defined as 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 computed tomography (CT)
scan

- Lesions that are considered non-measurable, which would make the patient not
eligible, 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

- No prior chemotherapy for small cell lung cancer (SCLC)

- Radiation therapy must have been completed at least one week before initiation of
protocol therapy

- Common Toxicity Criteria (CTC) performance status:

- Phase IB: 0-1

- Phase II: 0-2

- No "currently active" second malignancy other than non-melanoma skin cancers

- No history of brain metastases, spinal cord compression, or carcinomatous meningitis

- No ongoing cardiac dysrhythmias, atrial fibrillation, or QTc interval >= 500 msec; the
use of agents with proarrhythmic potential (e.g., quinidine, procainamide,
disopyramide, sotalol, probucol, pedridel, haloperidol, risperidone, indapamide,
flecainide) is not recommended while on protocol therapy

- Patients with class I New York Heart Association (NYHA) are eligible; patients with a
history of class II NYHA are eligible, provided they meet 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 class III or IV NYHA heart failure within 12 months prior
to registration are not eligible

- Additionally, no myocardial infarction, severe/unstable angina, coronary/peripheral
artery bypass graft or stenting, cerebrovascular accident including transient ischemic
attack, or pulmonary embolism 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 doses of coumarin-derivative anticoagulants
such as warfarin are excluded, although doses of up to 2 mg daily are permitted for
prophylaxis of thrombosis; Note: Low molecular weight heparin is permitted provided
the patient's prothrombin time (PT) international normalized ratio (INR) is =< 1.5

- No evidence of hemoptysis within 4 weeks prior to starting study treatment; 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

- None of the following within 28 days of 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 there use
is discouraged

- Non-pregnant and non-nursing

- Granulocytes >= 1,500/ul

- Platelets >= 100,000/ul

- Creatinine clearance >= 70 ml/min

- Total bilirubin =< 1.5 mg/dl

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN) (patients w/ liver metastases may have AST/ALT =< 5 x ULN)

- Partial thromboplastin time (PTT) =< 1.5 x ULN