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

Study Overview
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Brief Summary
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This randomized phase III trial studies sunitinib malate to see how well it works when given as maintenance therapy (meaning it is approved for treatment after chemotherapy) in patients with stage IIIB-IV non-small cell lung cancer who have responded to prior treatment with combination chemotherapy. Sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether sunitinib malate is effective in helping tumors continue to shrink or stop growing.

Detailed Description
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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.

Official Title
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Randomized, Phase III, Double-Blind Placebo-Controlled Trial of Sunitinib (NSC #736511) as Maintenance Therapy in Non-progressing Patients Following an Initial Four Cycles of Platinum-Based Combination Chemotherapy in Advanced, Stage IIIB / IV Non-small Cell Lung Cancer

Conditions
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Stage IIIB Lung Non-Small Cell Cancer AJCC v7, Stage IV Non-Small Cell Lung Cancer AJCC v7

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Placebo
* Other: Quality-of-Life Assessment
* Drug: Sunitinib Malate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (sunitinib malate)<br>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. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Sunitinib Malate<br>* Given PO<br>* Other names: Sutent;|
| Placebo Comparator: Arm II (placebo)<br>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. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Progression Free Survival (PFS) was defined as the time from randomization until disease progression or death, whichever occurs first. The median PFS with 95% CI was estimated using the Kaplan-Meier method. Progression is defined as in the primary outcome measure. | Time from randomization to disease progression and death of any cause, whichever comes first (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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. | Time from randomization to death (up to 5 years) | 
| Response Rate (RR) | The percentage 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. | Duration of treatment (up to 5 years) | 
| Percentage of Deterioration in QOL at 3 Months Using the EORTC QLQ-C30 Global Health Subscale | The percentage of patients with at least a 10% drop in the EORTC-QLQ-C30 Global Health Subscale score from baseline to 3-months. The difference between groups will be tested using Fisher's exact test. | At 3 months | 
| Percentage of Deterioration in Symptom Progression at 3 Months Using the EORTC LC13 Dyspnea Subscale | The percentage of patients with at least a 10% drop in the EORTC LC13 Dyspnea Subscale score from baseline to 3-months. The difference between groups will be tested using Fisher's exact test. | At 3 months | 
| Grade and Type of Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Grade 3 or 4 adverse events which affected more than 5% of participants are summarized by arm. | Duration of study (up to 5 years) |