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

Phase 3

Completed

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

Interventions: Other: Laboratory Biomarker Analysis
Other: Placebo
Other: Quality-of-Life Assessment
Drug: Sunitinib Malate

Registration Number: NCT00693992

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 210

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (placebo)	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.
Arm II (placebo)	Quality-of-Life Assessment	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.
Arm II (placebo)	Laboratory Biomarker Analysis	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.
Arm I (sunitinib malate)	Laboratory Biomarker Analysis	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.
Arm I (sunitinib malate)	Quality-of-Life Assessment	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.
Arm I (sunitinib malate)	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.

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Time from randomization to disease progression and death of any cause, whichever comes first (up to 5 years)	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	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.
Percentage of Deterioration in Symptom Progression at 3 Months Using the EORTC LC13 Dyspnea Subscale	At 3 months	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.
Grade and Type of Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0	Duration of study (up to 5 years)	Grade 3 or 4 adverse events which affected more than 5% of participants are summarized by arm.
Percentage of Deterioration in QOL at 3 Months Using the EORTC QLQ-C30 Global Health Subscale	At 3 months	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.
Response Rate (RR)	Duration of treatment (up to 5 years)	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.

Trial Locations

Locations (480): Northeast Alabama Regional Medical Center
🇺🇸
Anniston, Alabama, United States
Providence Hospital
🇺🇸
Mobile, Alabama, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
Veteran's Administration Medical Center
🇺🇸
Little Rock, Arkansas, United States
Kaiser Permanente-Anaheim
🇺🇸
Anaheim, California, United States
PCR Oncology
🇺🇸
Arroyo Grande, California, United States
Kaiser Permanente-Baldwin Park
🇺🇸
Baldwin Park, California, United States
Kaiser Permanente-Bellflower
🇺🇸
Bellflower, California, United States
East Bay Radiation Oncology Center
🇺🇸
Castro Valley, California, United States
Eden Hospital Medical Center
🇺🇸
Castro Valley, California, United States
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Northeast Alabama Regional Medical Center
🇺🇸Anniston, Alabama, United States