Sunitinib Malate as Maintenance Therapy in Treating Patients With Stage III or Stage IV Non-Small Cell Lung Cancer Previously Treated With Combination Chemotherapy

• Overall Survival (OS) [ Time Frame: Time from randomization to death (up to 5 years) ]
  Overall survival (OS) is defined as the time from patient randomization to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.
• Response Rate (RR) [ Time Frame: Duration of treatment (up to 5 years) ]

  The proportion of patients who respond (completely or partially) to each combination regimen will be estimated. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria:

  Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions.

• Time to Deterioration in QOL and Symptom Progression Using the EORTC QLQ-C30 and LC13 [ Time Frame: Up to 5 years ]
  The time of symptom progression will be computed for each patient. Similar to PFS and OS, the univariate analysis with log rank test will be used to evaluate the effect of the experimental arm and the multivariate analysis with Cox's proportional hazard model will be used to evaluate the effect of the experimental arm while adjusting for other baseline prognostic factors. The rate of symptom progression at 3 and 6 months will be estimated for each arm and their difference will be tested using Fisher's exact test.
• Time to Quality of Life or Symptom Deterioration as Assessed by Continuous Quality of Life (QOL) Scores, Including QLQ-C30 and LC13 Subscales [ Time Frame: Up to 5 years ]
  The time of symptom progression will be computed for each patient. Similar to PFS and OS, the univariate analysis with log rank test will be used to evaluate the effect of the experimental arm and the multivariate analysis with Cox's proportional hazard model will be used to evaluate the effect of the experimental arm while adjusting for other baseline prognostic factors. The rate of symptom progression at 3 and 6 months will be estimated for each arm and their difference will be tested using Fisher's exact test.
• VEGF Levels and Correlation With Clinical Outcomes, Including RR, PFS, and OS [ Time Frame: Up to 6 weeks ]
• Grade and Type of Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [ Time Frame: Duration of study (up to 5 years) ]
  Grade 3 or 4 adverse events which affected more than 5% of participants are summarized by arm.

• Grade and type of toxicity
• Response rate
• Overall survival

PRIMARY OBJECTIVES:

I. To evaluate the effect of sunitinib (sunitinib malate) compared to placebo on progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) patients who have had either stable or responding disease over the course of their initial 4 cycles of platinum-based therapy.

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of sunitinib compared to placebo in the maintenance setting.

II. To evaluate the additional response rate as a result of sunitinib in this setting.

III. To assess the impact of sunitinib on overall survival compared to the placebo arm.

IV. To assess the impact of sunitinib on delaying the time to deterioration in quality of life and symptom progression compared to placebo using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and Lung Cancer Module (LC13).

V. To assess vascular endothelial growth factor (VEGF) haplotypes in advanced non-small cell lung cancer and sunitinib maintenance.

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

ARM I: 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.

ARM II: Patients receive placebo PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

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

• Stage IIIB Non-Small Cell Lung Cancer
• Stage IV Non-Small Cell Lung Cancer

• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Placebo
  Given PO
  Other Names:

  • placebo therapy
  • PLCB
  • sham therapy
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Drug: Sunitinib Malate
  Given PO
  Other Names:

  • SU011248
  • SU11248
  • sunitinib
  • Sutent

• Experimental: Arm I (sunitinib malate)
  Patients receive sunitinib malate 37.5 mg PO once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Other: Quality-of-Life Assessment
  • Drug: Sunitinib Malate
• Placebo Comparator: Arm II (placebo)
  Patients receive placebo 37.5 mg PO once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Other: Placebo
  • Other: Quality-of-Life Assessment

Inclusion Criteria:

• Histologic or cytologic documentation of primary non-small cell lung cancer
• Stage IIIB or IV disease patients who are not candidates for combined modality therapy (chemoradiotherapy)
• No evidence of symptomatic or untreated brain metastases, spinal cord compression, or carcinomatous meningitis; patients with central nervous system (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 cavitary lesions
• Patients must have received one chemotherapy regimen for stage IIIB or IV NSCLC; the regimen must include four cycles of platinum-based doublet chemotherapy with or without bevacizumab (bevacizumab may not be given beyond the fourth cycle of chemotherapy); patients must have achieved a complete response, partial response, or stable disease to first-line chemotherapy and have no evidence of disease progression; patients will be registered 3-5 weeks following day 1 of cycle 4 of prior therapy
• No prior adjuvant chemotherapy for stage I-III resected NSCLC or combined modality therapy for stage III NSCLC
• No other primary therapy (including experimental therapy) for NSCLC; palliative radiation therapy must have been completed at least one week before planned start of protocol therapy

• 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 non-measurable 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 or 1
• Non-pregnant and non-nursing
• No ongoing cardiac dysrhythmias, atrial fibrillation, or history of corrected QT (QTc) interval >= 500 msec (within 2 years prior to registration); the use of agents with proarrhythmic potential (e.g., quinidine, procainamide, disopyramide, sotalol, probucol, 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 class III or IV NYHA heart failure within 12 months prior to registration 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 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 following inhibitors of cytochrome P450 3A4 (CYP3A4) are prohibited within 7 days before beginning 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
• Patients unable to take oral medication are not eligible
• Granulocytes >= 1,500/mcl
• Platelet count >= 100,000/mcl
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)=< 2.5 x ULN; patients with liver metastases may have AST and ALT =< 5 x ULN; all other patients will have AST and ALT =< 2.5 x ULN
• Creatinine =< 1.5 mg/dl