Phase I/II Trial of Bevacizumab, Pemetrexed and Erlotinib in Elderly Patients With Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a Phase I/II trial of elderly patients (> 70 years of age). Patients in this age group with previously un-treated Advanced Stage Non-Squamous Non-Small Cell Lung Cancer (NSCLC) with Stage IIIB (with malignant pleural effusion) and stage IV disease will be enrolled. Therapy consists of three drugs (Premetrexed[Alimta™], Bevacizumab and Erlotinib[Tarceva™]) which are given every 28 days.

Detailed Description
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This is a Phase I/II trial of elderly patients (> 70 years of age) with previously un-treated Advanced Stage Non-Squamous NSCLC with Stage IIIB (with malignant pleural effusion) and stage IV disease will be enrolled. Treatment Regimen: Premetrexed (Alimta™) 500 milligrams(mg)/Meter squared(m20 Intravenous(I.V.) Day 1 and Day 15; Bevacizumab 10mg/Kilogram(Kg) I. V. Day 1 and Day 15; Erlotinib (Tarceva™) 150mg Per Orally(PO) Once Daily(QD) for 7 days starting day 2 and day 15; Repeat cycles every 28 days. All three drugs will be continued for two cycles after maximal response. After which patient will be maintained only on the Bevacizumab and Erlotinib until progression. If patient has stable disease after the first two cycles then patient will be given another two cycles with all three drugs before maintenance treatment with Bevacizumab and Erlotinib is initiated.

Official Title
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Phase I/II Trial of Bevacizumab, Pemetrexed and Erlotinib in the First-Line Treatment of Elderly Patients With Advanced (Stage IIIB(With Malignant Pleural Effusion) or IV) Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Erlotinib
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have histologically proven diagnosis of Non-Squamous NSCLC. NSCLC histologies that will be included in this trial will be adenocarcinoma, large cell carcinoma and adeno-squamous carcinoma. Patients with bronchioloalveolar carcinoma (BAC) will be also included in this trial. Patients must be 70 years of age or older. Patient must have either stage IIIB disease with malignant pleural effusion or stage IV disease. All patients must have measurable disease. Evaluable disease will be separately outlined and elucidated. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1. Patient must have adequate renal function with a serum creatinine level of less than 1.5mg/dl and patient should have a calculated creatinine clearance of more than 45ml/min. Patient must have adequate hepatic function with a serum bilirubin level of less that 3mg/dl, and an alkaline phosphatase, Alanine Amino Transferase (ALT) and Aspartate Amino Transferase (AST) of less than three times the upper limit of normal Patient must also have evidence of adequate bone marrow function with an absolute neutrophil count of more than 1, 500 cells per deciliter and a platelet count of more than 100,000 per deciliter. Patients must be more than 28 days since prior open biopsy; more than 7 days since prior fine-needle aspiration; more than 7 days since prior core biopsy; more than 28 days since prior surgery. Patients must be able to take dexamethasone, folic acid and vitamin B-12 supplementation. All patients must sign informed consent that will detail the investigational nature of the study in accordance with the institutional and federal guidelines. Exclusion Criteria: Lung carcinoma of squamous cell histology or any histology in close proximity to a major vessel, with or without cavitation. Patients with hypercalcemia (corrected calcium of more than 11 mg/dl) will be excluded. Patients with history of hemoptysis, hematemesis, coagulopathy or thrombosis will be excluded. Patients requiring anticoagulation for any reason will be excluded. Patients who recently have an acute infection. History of palliative radiation therapy within 2 weeks. Blood pressure of >150/100 Millimeter Mercury(mmHg). Currently ongoing 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. Presence of central nervous system or brain metastases. 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. Pregnant (positive pregnancy test) or lactating. Urine calculated creatinine clearance of less than 45ml/minute and a urinary protein. Creatinine ratio of more than 1. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1. Serious, non-healing wound, ulcer, or bone fracture. Inability to comply with study and/or follow-up procedures.

Ages Eligible for Study
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Minimum Age: 70 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, Erlotinib, Pemetrexed<br>Single Arm Phase II trial in elderly patients with advanced stage Non-Squamous Non-Small Cell Lung Cancer | Drug: Bevacizumab<br>* Treatment Regimen Item 1: Bevacizumab 10 mg/Kg I. V. Day 1 and Day 15. Repeat cycles every 28 days.<br>* Other names: Avastin;Drug: Erlotinib<br>* Treatment Regimen Item 2: Erlotinib 150mg Per Orally (PO) Once Daily (QD) for 7 days starting day 2 and day 15. Repeat cycles every 28 days.<br>* Other names: Tarceva;Drug: Pemetrexed<br>* Treatment Regimen Item 3: Premetrexed 500mg/m2 I.V. Day 1 and Day 15. Repeat cycles every 28 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) | The primary objective was to determine the progression free survival (PFS), in newly diagnosed patients with advanced Non Small Cell Lung Cancer (NSCLC) who are treated with a regimen consisting of Bevacizumab(B), pemetrexed(A), and erlotnib(T). This was a Phase I/II study. This trial was halted after the Phase I component was completed. The Phase II component was never initiated. | 26 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year Survival(1-year S) | Secondary Objective: One-year survival(1-year S) in patients with advanced NSCLC treated with this regimen. | 26 Months | 
| Number of Patients Who Responded to Treatment | Phase I: Response Evaluation Criteria In Solid Tumors (RECIST)Criteria was used for Response. Partial Response (PR) is defined as at least a 30% decrease in the sum of Longest Dimention (LD) of target lesions taking as reference the baseline sum LD. | 26 Months | 
| Quality of Life (QOL) | The Scales we were intending to use were: Instrumental Activities of Daily Living (IADL): Range of Scale 0 (Best) to 8 (Worst). Cumulative Illness Rating Scale-Geriatric (CIRS-G): Range of Scores 1(Best) to 18 (Worst). Functional Assessment of Cancer Therapy-Lung (FACT-L): Range of Scores 0 (Best) to 48 (Worst). Fatigue Symptom Inventory (FSI): Range of Scores 0(Best) to 121 (Worst). Each scale would have been evaluated independently. Since the study was not completed and closed early due to poor accrual, none of the QOL parameters were analyzed. | 26 Months | 
| Number of Participants With Grade 3 and Grade 4 Adverse Events | By Safety, the intent was to capture, tabulate, list all of the grade 3 and 4 adverse effects seen by this protocol. For each toxicity, we followed the Common Toxicity Criteria(NCI CTC)Version 2.0 Toxicity scale guidelines. | 26 Months | 
| Overall Survival (Median Survival [MS]) | Secondary Objective: Determine the Overall Survival (median survival[MS]) in patients with advanced NSCLC treated with this regimen. Patients were to be followed until death and survival curves were to be generated. | 26 Months |