A Phase III Randomized Trial of Adjuvant Chemotherapy With or Without Bevacizumab for Patients With Completely Resected Stage IB (≥ 4 cm) - IIIA Non-small Cell Lung Cancer (NSCLC)
A Phase III Randomized Trial of Adjuvant Chemotherapy With or Without Bevacizumab for Patients With Completely Resected Stage IB (≥ 4 cm) - IIIA Non-small Cell Lung Cancer (NSCLC)
This randomized phase III trial studies chemotherapy and bevacizumab to see how well they work compared to chemotherapy alone in treating patients with stage IB, stage II, or stage IIIA non-small cell lung cancer that was removed by surgery. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab also may stop the growth of non-small cell lung cancer by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether chemotherapy is more effective with or without bevacizumab in treating non-small cell lung cancer.
PRIMARY OBJECTIVES:
I. To evaluate overall survival with chemotherapy with or without bevacizumab used in the adjuvant setting in patients with resected stage IB (>= 4 cm) - IIIA non-small cell lung cancer (NSCLC).
SECONDARY OBJECTIVES:
I. To evaluate disease-free survival and toxicity with chemotherapy with or without bevacizumab used in the adjuvant setting in patients with resected stage IB (>= 4 cm) - IIIA NSCLC.
CORRELATIVE OBJECTIVES:
I. To perform analyses of tissue and blood to establish factors that predict clinical outcome in patients receiving chemotherapy, with or without bevacizumab, for resected early stage NSCLC.
II. To determine whether smoking status is linked to outcome for patients with resected stage IB (>= 4 cm) - IIIA NSCLC treated with chemotherapy with or without bevacizumab in the adjuvant setting.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I (adjuvant chemotherapy without bevacizumab): Patients receive 1 of 4 chemotherapy regimens.
REGIMEN 1: Patients receive vinorelbine ditartrate intravenously (IV) over 10 minutes on days 1 and 8 and cisplatin IV over 60 minutes on day 1 immediately following vinorelbine ditartrate administration.
REGIMEN 2: Patients receive docetaxel IV over 1 hour on day 1 and cisplatin over 1 hour on day 1 immediately following docetaxel administration.
REGIMEN 3: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and cisplatin IV over 60 minutes on day 1 immediately following gemcitabine administration.
REGIMEN 4 (non-squamous histology only): Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 1 hour on day 1 immediately following pemetrexed disodium administration.
In all regimens, treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
ARM II (adjuvant chemotherapy with bevacizumab): Patients receive chemotherapy as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab repeats every 21 days for up to 1 year.
After completion of study treatment, patients are followed up periodically for 10 years.
Inclusion Criteria:
In order to be eligible for this trial, patients must have undergone complete resection of their non-small cell lung cancer (NSCLC) [stage IB (>= 4 cm)] - [IIIA (T2-3N0, T1-3N1, T1-3N2] prior to enrollment; accepted types of resection will consist of lobectomy, sleeve lobectomy, bi-lobectomy or pneumonectomy; resections by segmentectomy or wedge resection will not be accepted; mediastinal lymph node sampling at specified levels is required pre-operatively (mediastinoscopy) or intraoperatively (level 7 and 4 for right sided tumors or level 7 and 5 and/or 6 for left sided tumors)
Patients must be no less than 6 weeks (42 days) and no more than 12 weeks (84 days) post-thoracotomy at the time of randomization and must be adequately recovered from surgery
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Patients must not have received the following:
Patients must not have any history of cancer within 5 years from randomization, with the exception of in-situ carcinoma of the cervix or completely resected non-melanoma skin cancer
Absolute neutrophil count (ANC) >= 1500 mm^3
Platelets >= 100,000/mm^3
Prothrombin time/international normalized ratio (INR) =< 1.5
Partial thromboplastin time (PTT) =< institutional upper limit of normal (ULN) OR, if patient is on therapeutic anticoagulation, PTT must be =< 1.5 x ULN
Total bilirubin =< 1.5 mg/dL
Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 5 x upper limit of normal (ULN)
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x upper limit of normal (ULN)
Serum creatinine =< 1.5 x institutional upper limit of normal (ULN)
Urine protein should be screened by urine analysis for urine protein creatinine (UPC) ratio; for UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be < 1000 mg (1 g) for patient enrollment
Patients with a known history of myocardial infarction or other evidence of arterial thrombotic disease (angina) will be allowed on study only if they have had no evidence of active disease for at least 12 months prior to randomization
Patients with any history of cerebral vascular accident (CVA) or transient ischemic attack (TIA) will not be allowed on trial
Women must not be pregnant or breast-feeding
Both fertile men and women must agree to use adequate contraceptive measures during study treatment and for at least 6 months after completion of bevacizumab
Patients must not have any clinically significant ongoing, active or serious infection, symptomatic or uncontrolled congestive heart failure, symptomatic or uncontrolled cardiac arrhythmia or any other medical condition or psychiatric illness/social situations that would limit compliance with study requirements
Patients must have no history of bleeding diathesis or coagulopathy
All patients must have a documented blood pressure (BP) with systolic =< 150 and diastolic =< 90 within 28 days of registration; patients with known hypertension must be on a stable regimen of anti-hypertensive therapy
Patients receiving daily treatment with aspirin or non-steroidal anti-inflammatory agents (NSAIDS) are eligible; treatment with dipyridamole (Persantine), ticlopine (Ticlid), clopidogrel (Plavix) and/or cilostazol (Pletal) is not allowed; patients must have stopped taking any of these agents at least 7 days prior to randomization
Patients must not have serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization OR core biopsy within 7 days prior to randomization
Patients must not have a history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to randomization
Patients must not have any anticipated major surgical procedure(s) during the course of the study
Patients must not have known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
Patients may be on a stable regimen of therapeutic anticoagulation or may be receiving prophylactic anticoagulation of venous access devices, provided that coagulation studies meet entry criteria above; caution must be exercised for patients requiring anticoagulation, including treatment with low dose heparin or low molecular weight heparin for deep vein thrombosis (DVT) prophylaxis while on study
Patients with ongoing post-operative hemoptysis (defined as bright red blood of 1/2 teaspoon or more) are not eligible; patients with pre-operative hemoptysis that has resolved post-operatively are eligible
Patients who will receive pemetrexed (pemetrexed disodium)/cisplatin therapy must also meet the following criteria:
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