A Study of Cisplatin + Pemetrexed + Avastin as First-Line Therapy in Patients With Advanced Non-Small Cell Lung Carcinoma (NSCLC)

Study Overview
=================
Brief Summary
-----------------
In the past, patients with advanced lung cancer who were inoperable underwent chemotherapy with one or more chemotherapeutic agents. More recently, novel new agents targeting specific enzymes or pathways responsible for cell division have been developed and clinicians have begun to utilize various combinations of these drugs with standard chemotherapeutic agents for the treatment of NSCLC. Some of these approaches have demonstrated a small but significant increase in survival among patients with advanced disease. Because a recently completed Phase 3 study of bevacizumab + Taxol/Carboplatin in first line NSCLC therapy demonstrated a 23% improvement in median survival, it would be appealing to see if a regimen of bevacizumab/ cisplatin/Alimta would also demonstrate a similar, or perhaps better, response rate.

Detailed Description
-----------------
The majority of patients with NSCLC present with inoperable locally advanced or metastatic disease for which no curative therapy is available. For these patients, platinum based doublet combination regimens have become standard of care due to increased survival rates over platinum therapy alone. In order to try to improve on the overall survival, clinicians have attempted to add a third cytotoxic agent to their standard regimen(s). Although this approach demonstrated an improved objective response, no additional benefit was noted in overall survival. Recent development and approval of new targeted chemotherapies during the past 10 years has prompted clinical trials to test the efficacy of newly FDA approved agents such as gefitinib, erlotinib, and bevacizumab in advanced NSCLC. Although gefitinib and erlotinib have both demonstrated clinical activity in refractory NSCLC, neither agent improved clinical outcome when added to standard 1st line platinum based chemotherapy. In contrast, a recently completed randomized Phase 3 trial investigating the addition of bevacizumab to 1st line paclitaxel plus carboplatin chemotherapy reported a 23% improvement in the median overall survival for the paclitaxel/carboplatin plus bevacizumab treatment arm (12.5m vs. 10.2m; p=0.007). It is therefore appealing to study a cisplatin combination with bevacizumab to determine if there is any additive benefit. Pemetrexed is an ideal agent to use in combination with cisplatin since it is well tolerated and efficacy is comparable to other cisplatin combinations. Patients will receive a maximum of 6 cycles. Those who complete 1 cycle will be evaluated for toxicity; more than 1 cycle, response.

Official Title
-----------------
A Phase 2 Study of Cisplatin + Pemetrexed + Avastin as First-Line Therapy in Patients With Advanced Non-Squamous, Non-Small Cell Lung Carcinoma

Conditions
-----------------
Non-Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: Pemetrexed, Cisplatin, Bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have stage IIIB (malignant pleural or pericardial effusion) or stage IV disease. Be chemotherapy naïve. Have measurable disease by RECIST, defined as at least 1 lesion that can be accurately measured in at least 1 dimension as >20 mm with conventional techniques or >10 mm with spiral CT scan; the longest diameter is to be recorded. Are 18 years of age or older. Have a life expectancy greater than 3 months. Have an ECOG performance status of 0 or 1. Are able to provide written informed consent in accordance with all applicable regulations and follow the study procedures. Patients must be capable of understanding the investigational nature, potential risks and benefits of the study. The ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Alimta and the ability to take folic acid, Vitamin B12 and dexamethasone according to protocol. Exclusion Criteria: Have had prior chemotherapy (or an EGFR TKI) for treatment of advanced disease 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 not acceptable. Patients with extrathoracic-only squamous cell NSCLC are eligible. Patients with only peripheral lung lesions (of any NSCLC histology) will also be eligible (a peripheral lesion is defined as a lesion in which the epicenter of the tumor is ≤ 2 cm from the costal or diaphragmatic pleura in a three-dimensional orientation based on each lobe of the lung and is > 2 cm from the trachea, main, and lobar bronchi). History of hemoptysis (bright red blood of 1/2 teaspoon or more per episode) within 1 month prior to study enrollment. Current, ongoing treatment with full-dose warfarin or its equivalent (i.e., unfractionated and/or low molecular weight heparin). Current or recent (within 10 days of enrollment) use of aspirin (>325 mg/day) or chronic use of other NSAIDs. Cardiovascular concerns: Blood pressure of >150/100 mmHg Unstable angina within 6 months prior to Day 1 New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E) History of myocardial infarction within 6 months History of stroke within 6 months Clinically significant peripheral vascular disease Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1. Have had radiation therapy within 2 weeks prior to enrollment. 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. 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. Have inadequate organ function at the Screening visit as defined by the following laboratory values: Platelet count <100 x 109/L Hemoglobin <9.0 g/dL Absolute neutrophil count (ANC) <1.5 x109/L INR ≥1.5 within 1 week prior to randomization Creatinine clearance (Cockroft-Gault) < 50ml/min Urine protein:creatinine ratio ≥1.0 at screening Aspartate transaminase (AST) >2.5 times the upper limit of the normal range (ULN) Alanine transaminase (ALT) >2.5 times ULN Total bilirubin >1.5 times ULN or ≥5 times ULN in patients with liver metastases 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. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation). Have uncontrolled active systemic infection requiring treatment. Have had treatment for a cancer other than NSCLC within 5 years prior to enrollment, with the exception of basal cell carcinoma or cervical cancer in situ. Have known human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status or known active hepatitis C infection. Patients assessed by the investigator to be at risk for HIV, hepatitis B or C infection should be tested in accordance with local regulations. Are a pregnant or breast-feeding female. Confirmation that the patient is not pregnant must be established by a negative serum Beta-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during the Screening Period. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Are unwilling to employ adequate means of contraception (condoms, diaphragm, birth control pills, injections, intrauterine device, or abstinence). Are currently receiving or have previously received an investigational agent for any reason within 4 weeks of enrollment. Presence of third space fluid which cannot be controlled by drainage. Inability to comply with study and/or follow-up procedures. Prior history of hypertensive crisis or hypertensive encephalopathy. History of stroke or transient ischemic attack within 6 months prior to Day 1.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pemetrexed, Cisplatin, Bevacizumab<br>Chemotherapy infusion on Day 1 of a 3-week cycle | Drug: Pemetrexed, Cisplatin, Bevacizumab<br>* Pre-hydration for 1-1/2 hours at 250 ml/hour Pemetrexed 500 mg/m2 IV over 10 minutes Return to hydration for 30 minutes at 250 ml/hour Cisplatin 75mg/m2 IV over 60-120 minutes Bevacizumab 15mg/kg IV over 90 minutes<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival |  | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate |  | 6 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NSCLC