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

Study Overview
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Brief Summary
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RATIONALE: Pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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 pemetrexed disodium and gemcitabine together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving pemetrexed disodium and gemcitabine together with bevacizumab works in treating patients with stage IIIB or stage IV non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary Determine the efficacy of pemetrexed disodium, gemcitabine hydrochloride, and bevacizumab in chemotherapy-naïve patients with stage IIIB or IV nonsquamous cell non-small cell lung cancer. Secondary Determine the response rate in patients treated with this regimen. Determine the time to treatment failure in patients treated with this regimen. Determine the overall survival of patients treated with this regimen. Determine the toxicity of this regimen in these patients. OUTLINE: Patients receive pemetrexed disodium IV over 10 minutes, gemcitabine hydrochloride IV over 30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 14 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients may then receive bevacizumab alone in the absence of disease progression or unacceptable toxicity. After the completion of study treatment, patients are followed periodically for 6 months. PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

Official Title
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A Phase II Trial of Pemetrexed, Gemcitabine, and Bevacizumab Every Two Weeks in Chemotherapy-Naive Patients With Stages IIIB/IV Non- Squamous, Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Lung Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: gemcitabine hydrochloride
* Drug: pemetrexed disodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Histologic or cytologic proof of non-squamous non-small cell lung cancer (NSCLC) (adenocarcinoma, bronchioloalveolar, large cell carcinoma). Must have Stage IV or IIIB NSCLC. Patients with Stage IIIB must have a pleural effusion or not be candidates for treatment for locally advanced disease with chemoradiotherapy. Cannot have a tumor with cavitation.. Have uni-dimensional measurable or evaluable disease. If disease is within a previous radiation port there must be documented progression. 18 years of age and have a life expectancy of greater than 12 weeks. Must not have had prior chemotherapy for advanced disease. Must have an ECOG performance status of 0-1. With treated brain metastases are eligble. for details. Adequate organ function: Absolute neutrophil count of > 1.5 x 109/L Platelet count > 100,000/109/L Hemoglobin > 8g/dl Calculated creatinine clearance > 45mL/min using the standard Cockroft and Gault formula Hepatic: bilirubin < 1.5 times the upper limit of normal,alkaline phosphatase, aspartate transaminase (AST) and alanine transaminase (ALT) < 3 times upper limit of normal. Alkaline phosphatase, AST, ALT < 5 times upper limit of normal is acceptable if liver has tumor involvement. Urine protein:creatinine ratio ≤1.0 at screening Patients of reproductive potential must use an approved contraceptive method during and for 3 months after study. Must sign an informed consent that details the investigational nature of the study according to the institutional and federal guidelines. Registered with the clinical trials office of the institution. Exclusion Criteria Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study Prior chemotherapy except for erlotinib for advanced disease. Uncontrolled hypertension (Blood pressure of >150/100 mmHg ) Unstable angina New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E) History of myocardial infarction within 6 months prior to day 1 History of hemorrhagic or thrombotic stroke or other CNS bleed within 6 months prior to day 1 Clinically significant peripheral vascular disease of 61 Evidence of bleeding diathesis or coagulopathy. Patients must not require full dose anticoagulants for any reason. Known CNS disease, except for treated brain metastasis Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study Minor surgical procedures such as fine needle aspirations or core biopsies within 7 days prior to Day 0 Urine protein:creatinine ratio > or = 1.0 at screening History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 6 months prior to Day 0 Serious, non-healing wound, ulcer, or bone fracture Evidence of cavitation in the tumor. Intrathoracic lung carcinoma of squamous cell histology Mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is ineligible; sputum cytology alone is unacceptable. Extrathoracic-only squamous cell NSCLC are eligible. Patients with only peripheral lung lesions (of any NSCLC histology) will also be eligible. History of hemoptysis (bright red blood of 1/2 teaspoon or more within 28 days of registration or clinical history of > Grade 2 Clinically significant effusions that cannot be drained Inability to comply with study and/or follow-up procedures Previous or concurrent malignancies with the exception of adequately treated squamous cell or basal cell carcinoma of the skin, in situ carcinoma of the cervix, or any other malignancy treated and in clinical remission for more than 3 years. Prior radiation therapy to the target lesion, unless the lesion is clearly progressing and the interval between the most recent radiation therapy and enrollment is at least 4 weeks. Pregnancy or lactating females. All pre-menopausal women should have a negative urine pregnancy test prior to enrollment. All patients of reproductive potential should agree to use an effective contraceptive method. Serious concomitant systemic disorders (including oncologic emergencies) incompatible with the study (at the discretion of the investigator). Inability to interrupt non-steroidal anti-inflammatory agents 2 days before, the day of, and 2 days after the dose of pemetrexed. Disease which cannot be radiologically imaged. Inability to take dexamethasone, folic acid or vitamin B12 administration.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab, gemcitabine hydrochloride<br>Bevacizumab 10mg/kg IV over 90 ± 15 minutes every 14 days Gemcitabine 1200 mg/m2 intravenously over 30 minutes following the pemetrexed disodium every 14 days Pemetrexed 400 mg/m2 intravenously over 10 minutes every 14 days. | Biological: bevacizumab<br>* Bevacizumab 10mg/kg IV over 90 ± 15 minutes every 14 days<br>* Other names: Avastin ®;Drug: gemcitabine hydrochloride<br>* Gemcitabine 1200 mg/m2 intravenously over 30 minutes following the pemetrexed every 14 days<br>* Other names: Gemzar ®;Drug: pemetrexed disodium<br>* Pemetrexed disodium 400 mg/m2 intravenously over 10 minutes every 14 days.<br>* Other names: Alimta®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | RECIST criteria for tumor progression of at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Response | The rate of response per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Every 8 weeks, for up to 54 months | 
| Number of Participants With Grade 3 or Grade 4 Toxicity | Grade 3/4 toxicity according to the NCI Common Toxicity Criteria v3.0 . | Every two weeks, for up to 54 months | 
| Time to Treatment Failure | Time to treatment failure using the Kaplan-Meier method. | Every 8 weeks, for up to 54 months | 
| Overall Survival | Overall survival using the Kaplan-Meier method. | Every 8 weeks, for up to 54 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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, recurrent non-small cell lung cancer