Phase 2 Trial of Bevacizumab in Combination With Pemetrexed

Study Overview
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Brief Summary
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This trial evaluated the safety of combining bevacizumab and pemetrexed in non-small cell lung cancer (NSCLC) patients with stable brain metastases as second-line chemotherapy, while evaluating progression-free survival (PFS) and overall survival (OS).

Detailed Description
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Brain metastases are a common complication of advanced non-small-cell lung cancer (NSCLC) both at initial presentation and at the time of disease progression. Patients with brain metastases have often been excluded from large randomized phase III trials due to concerns of poorer survival and impaired ability of drugs to cross the blood-brain barrier. However, as survival has improved, some trials have included such patients, often finding similar benefit to patients with metastatic disease elsewhere. Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor, has emerged as an important adjunct to platinum-based chemotherapy doublets for use in advanced NSCLC. This drug is normally used as a first line chemotherapy. Pemetrexed is a multi-targeted anti-folate agent,which is approved for use in first-line (with platinum), maintenance, and second-line treatment of advanced nonsquamous NSCLC. Based on the efficacy of pemetrexed as a second line agent and the safety questions surrounding bevacizumab in those with treated brain metastases, a trial was designed to look at the combination of both agents as a second line therapy in NSCLC patients with treated stable brain metastases

Official Title
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Phase II Trial of Bevacizumab in Combination With Pemetrexed as Second Line Therapy in Patients With Stable Brain Metastases From Non-small Cell Lung Cancer (NSCLC) (Excluding Squamous Cell Carcinoma)

Conditions
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Lung Cancer, Non-small Cell Lung Cancer (NSCLC), Neoplasm Metastasis

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Pemetrexed
* Drug: Vitamin B12
* Drug: Folate
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced stage NSCLC excluding squamous cell histology with measurable or evaluable disease. Stable brain metastases required, no longer requiring active therapy such as steroid medications, which have been previously treated with radiation or surgery or both and have been documented to be stable on repeat imaging done at least one month after completion of therapy. Prior therapy with one standard doublet front-line regimen for NSCLC (platinum containing) Life expectancy of at least 3 months ECOG Performance status 0-1 Age 18 or higher Use of effective means of contraception (men and women) in subjects of child-bearing potential Ability/willingness to comply with vitamin supplementation including vitamin B 12 and folic acid started at least 1 week before first dose of pemetrexed and continued for at least 3 weeks after last dose Ability/willingness to take dexamethasone the day before, of and after pemetrexed administration Drainage of any clinically significant effusion Ability to sign informed consent Exclusion Criteria: Treatment with more than one prior chemotherapy regimen (unless one regimen was stopped for toxicity reasons with a different regimen replacement regimen started immediately and patient completed only 4-6 total cycles of first-line treatment. One prior regimen (up to 4 cycles) of neoadjuvant or adjuvant therapy for early stage disease will also be allowed. Prior treatment with pemetrexed or bevacizumab Prior chemotherapy within 28 days (6 weeks for BCNU, CCNU or mitomycin-C) Current, recent (within 4 weeks of the first infusion of this study), or planned participation in any other experimental drug study Concomitant chemotherapy, radiotherapy or investigational agents Uncontrolled effusion (large pleural or peritoneal effusion or small/moderate effusion which requires drainage for symptom management) Evidence of bleeding diathesis or coagulopathy Use of anti-coagulant agents including warfarin, heparin, aspirin, NSAIDs Pregnant (positive pregnancy test) or lactating women 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, fine needle aspirations or core biopsies within 7 days prior to day 0 Urine protein:creatinine ratio greater than or equal to 1.0 at screening History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0 Serious, non-healing wound, ulcer, or bone fracture Lung carcinoma of squamous cell histology or any histology in close proximity to a major vessel, or with significant cavitation as assessed by treating investigator in consultation with an attending radiologist History of hemoptysis (bright red blood of 1/2 teaspoon or more) Neutrophils < 1.5 x 10^9/ L Hemoglobin <10.0 g/dl Platelets <100 x 10^9/ L Serum glutamic oxaloacetic transaminase (SGOT/ AST) or serum glutamic pyruvic transaminase (SGPT/ ALT) > 2.5 times upper limits of normal Creatinine > 1.5 times upper limits of normal Significant co-morbidities including: Blood pressure of greater than 150/100 mmHg Unstable angina New York Heart Association (NYHA) Grade II or greater congestive heart failure History of myocardial infarction within 6 months History of stroke within 6 months Clinically significant peripheral vascular disease Inability to comply with study and/or follow-up procedures

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+ pemetrexed<br>pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV). In addition to Vitamin B12 + Folate + Dexamethasone | Drug: Bevacizumab<br>* 15 mg/kg, IV over 10 minutes every 3 weeks<br>* Other names: Avastin;Drug: Pemetrexed<br>* 500 mg/m²; IV over 10 minutes every 3 weeks<br>* Other names: Alimta;Drug: Vitamin B12<br>* 1000 micrograms, IM injection 1-2 weeks prior to treatment and repeated every 9 weeks until last dose of pemetrexed<br>* Other names: Vit B12;Drug: Folate<br>* 350 to 1000 micrograms 1 week prior to treatment and 3 weeks after last pemetrexed dose<br>* Other names: vitamin Bc;Drug: Dexamethasone<br>* 4 mg; oral, twice a day at the following times: the day before, of and after each dose of pemetrexed<br>* Other names: Decadron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Central Nervous System (CNS) Hemorrhagic Events | Number of events of brain or central nervous system (CNS) bleeding | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of documented disease progression or death. Kaplan-Meier survival curves for PFS were generated with IBM SPSS Statistics version 19.0 (SPSS, Inc, Chicago, IL). | 18 months | 
| Overall Survival (OS) | Overall Survival (OS) is defined as the duration of time from start of treatment to deat. Kaplan-Meier survival curves for OS were generated with IBM SPSS Statistics version 19.0 (SPSS, Inc, Chicago, IL). | 18 months |