Carboplatin, Pemetrexed Disodium, and Bevacizumab in Treating Patients With Stage IIIB, Stage IV, or Recurrent Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as carboplatin and pemetrexed disodium, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pemetrexed disodium may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving carboplatin and pemetrexed disodium together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving carboplatin and pemetrexed disodium together with bevacizumab works in treating patients with stage IIIB, stage IV, or recurrent non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary Determine the median time to disease progression in patients with stage IIIB or IV or recurrent non-squamous cell non-small cell lung cancer treated with carboplatin, pemetrexed disodium, and bevacizumab. Secondary Determine the response rate and duration of response in patients treated with this regimen. Determine the toxic effects of this regimen in these patients. Determine the overall survival of patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive pemetrexed disodium IV over 10 minutes, carboplatin IV over 30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients with complete response, partial response, or stable disease continue to receive pemetrexed disodium and bevacizumab in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Official Title
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Phase II Trial of Carboplatin and Pemetrexed Plus Bevacizumab in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: carboplatin
* Drug: pemetrexed


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically* or cytologically* confirmed non-small cell lung cancer Any histology, except squamous cell carcinoma, allowed Mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is ineligible No histology in close proximity to a major vessel or cavitation NOTE: *Histologic or cytologic elements may be established on metastatic tumor aspirates or biopsy Meets 1 of the following stage criteria: Stage IIIB disease (with malignant pleural effusion) Stage IV disease Recurrent disease Measurable or non-measurable disease No known CNS metastases by CT scan or MRI PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-1 Life expectancy Not specified Hematopoietic Absolute neutrophil count > 1,500/mm^3 Platelet count > 100,000/mm^3 No history of hemorrhagic disorders Hepatic Bilirubin < 1.5 mg/dL AST and ALT < 5 times upper limit of normal INR < 1.5 PTT normal Renal Creatinine clearance ≥ 45 mL/min Urine protein:creatinine ≤ 1.0 by spot urinalysis Cardiovascular No myocardial infarction within the past 6 months No New York Heart Association class II-IV congestive heart failure No unstable angina pectoris No serious cardiac arrhythmia requiring medication No stroke within the past 6 months No peripheral vascular disease ≥ grade 2 No uncontrolled hypertension (i.e., blood pressure ≥ 150/100 mm Hg) Patients with a history of hypertension allowed provided blood pressure is well controlled on a stable regimen of anti-hypertensive therapy No history of thrombotic disorders No other clinically significant cardiovascular disease Pulmonary No history of gross hemoptysis, defined as bright red blood of a ½ teaspoon or more Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Must be willing and able to take daily oral folic acid, intermittent vitamin B_12 injections, and corticosteroid premedication No ongoing or active infection No serious, non-healing wound, ulcer, or bone fracture No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months No psychiatric illness or social situation that would preclude study compliance PRIOR CONCURRENT THERAPY: Biologic therapy More than 3 weeks since prior immunotherapy Chemotherapy No prior systemic chemotherapy Endocrine therapy More than 3 weeks since prior hormonal therapy Radiotherapy See Disease Characteristics More than 3 weeks since prior radiotherapy Surgery More than 4 weeks since prior major surgery More than 1 week since prior minor surgery, fine needle aspiration, or core biopsy No concurrent major surgery Other Recovered from all prior therapy More than 4 weeks since prior and no concurrent participation in another experimental drug study No aspirin or other nonsteroidal anti-inflammatory drug (NSAID) 2 days before and 2 days after each pemetrexed disodium infusion (5 days before and 2 days after each pemetrexed disodium infusion for NSAIDs with a long half-life [e.g., naproxen, rofecoxib, or celecoxib]) No concurrent therapeutic anticoagulation Concurrent prophylactic anticoagulation for venous access devices allowed provided requirements for INR and PTT are met No concurrent administration of any of the following: Chronic daily treatment with aspirin (> 325 mg per day) NSAIDs known to inhibit platelet function, including any of the following: Dipyridamole Ticlopidine Clopidogrel Cilostazol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Carboplatin + pemetrexed + bevacizumab | Biological: bevacizumab<br>* 5 mg/kg administered intravenously over 90 minutes on day 1 of each cycle (cycle = 3 weeks)<br>* Other names: Avastin;Drug: carboplatin<br>* Administered intravenously at a dose of AUC=6 over 30 minutes on day 1 of each cycle (1 cycle = 3 weeks)<br>Drug: pemetrexed<br>* Administered intravenously at a dose of 500 mg/m2 over 10 minutes on day 1 of each cycle (1 cycle = 3 weeks)<br>* Other names: pemetrexed disodium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival | Progression Free Survival (PFS) in patients treated with the combination of carboplatin, pemetrexed and bevacizumab is defined as the time from registration to the time of documented disease progression or death from any cause. Patients that were lost to follow up or withdrew consent were censored at that point. | Approximately every 3 weeks until disease progression or death. Median follow up of 13 months (range 0.8 to 34.4 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall Response Rate (ORR) of patients treated with carboplatin, pemetrexed, and bevacizumab combination is defined as the number of patients who's best response is a Complete Response (CR) plus Partial Response (PR)as recorded from the start of treatment until disease progression as assessed by RECIST 1.0. CR=Disappearance of all target lesions for a minimum of 4 weeks. PR=At least a 30% decrease in the sum of the longest diameter (LD) of target lesions for a minimum of 4 weeks, taking as reference the baseline sum LD. No simultaneous increase in the size of any lesion or the appearance of a new lesion may occur. | Every two cycles until disease progression. Median follow up of 13 months (range 0.8 to 34.4 months) | 
| Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | To characterize the toxicity profile of carboplatin, pemetrexed and bevacizumab combination treatment. Toxicity data will be collected from initiation of treatment, every cycle, until 30 days post last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). Only toxicity determined to be a least possibility related to at least one study drug and grade 3 or 4 was collected for this outcome measure. In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE | From treatment initiation, at the beginning of each cycle where one cycle equals 21 days until 30 days post treatment (range of cycles 1-51) | 
| Overall Survival Rate | Overall Survival (OS) Rate of carboplatin, pemetrexed and bevacizumab combination treatment is defined from the time of registration to the study until death from any cause. Patients that are lost to follow up will be censored from last documentation of survival status. | During treatment and then every 3 months x 2 years, then every 6 months x 3 years or until death. | 
| Duration of Response | Duration of Response for patients treated with the combination of carboplatin, pemetrexed and bevacizumab is measured from the time measurement criteria are met for Complete Response or Partial Response (whichever is first recorded) until the first date of documented progressive disease. | From documentation of response, every two cycles (1 cycle = 21 days) until progressive disease with range of cycles completed 1-51. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer, adenocarcinoma of the lung, bronchoalveolar cell lung cancer, large cell lung cancer