Bevacizumab (Avastin®) + Erlotinib as First-line Therapy for Stage IIIB/IV or Recurrent, Non-squamous Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
In an attempt to improve the therapeutic index for initial therapy of metastatic NSCLC, the combination of bevacizumab and erlotinib is being proposed as first-line treatment in place of conventional chemotherapy. This trial is intended to provide pilot data for a future randomized trial of this combination of targeted agents versus conventional chemotherapy for advanced NSCLC.

Detailed Description
-----------------
The combination of Bevacizumab and Erlotinib show encouraging activity for patients with previously treated, non-small-cell lung cancer. In a phase I/II study of erlotinib and bevacizumab in patients with nonsquamous stage IIIB/IV NSCLC with one or more prior chemotherapy exposures, a recommended phase II dose was established at erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days (13) Forty patients were treated at the recommended Phase II dose. The median age was 59 years (range, 36 to 72 years), 21 were female, 30 had adenocarcinoma histology, nine were never-smokers, and 22 had > or = two prior regimens (three patients had > or = four prior regimens). The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. No pharmacokinetic interactions were identified. Eight patients (20.0%; 95% CI, 7.6% to 32.4%) had partial responses and 26 (65.0%; 95% CI, 50.2% to 79.8%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. These data compare favorably with conventional chemotherapy in the salvage setting for NCSLC where the response rates are < 10% and median survivals are 6-8 months (14-16). In an attempt to improve the therapeutic index for initial therapy of metastatic NSCLC, the combination of bevacizumab and erlotinib is being proposed as first-line treatment in place of conventional chemotherapy. The regimen will be beneficial if toxicity is reduced and efficacy is unchanged or if efficacy is improved. Since this regimen causes no hair loss, minimal nausea and no cytopenia, which nearly eliminated the risks of infections and bleeding, the combination of targeted agents appears to be better tolerated than conventional chemotherapy. Efficacy may also be improved since its activity in the salvage setting when patients are less likely to respond to any treatment rivals that of conventional chemotherapy in the untreated setting. In addition, erlotinib alone in the untreated setting can yield results that are not dissimilar from chemotherapy under similar conditions. Hence, it is hypothesized that the combination of erlotinib plus bevacizumab can produce superior results with less toxicity. This trial is intended to provide pilot data for a future randomized trial of this combination of targeted agents versus conventional chemotherapy for advanced NSCLC.

Official Title
-----------------
AVF4236s: Bevacizumab (Avastin®) + Erlotinib as First-line Therapy for Stage IIIB/IV or Recurrent, Non-squamous Cell Lung Cancer

Conditions
-----------------
Cancer

Intervention / Treatment
-----------------
* Drug: Bevacizumab and Erlotinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Histological or cytological diagnosis of non-squamous, non-small cell lung cancer. Mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is ineligible. Stage wet IIIB-IV or recurrent disease No significant hemoptysis (bright red blood< 1/2 teaspoon or more per episode within 3 months) Performance status of 0-1 Prior radiation allowed if > 15 days. No prior treatment for metastatic disease. Adjuvant treatment allowed if greater than 6 months has passed. Exclusion Criteria Disease-Specific Exclusions History of hemoptysis (bright red blood of 1/2 teaspoon or more per episode) within 3 months prior to study enrollment. Current, ongoing treatment with full-dose warfarin Current or recent (within 10 days of enrollment) use of aspirin (>325 mg/day) or chronic use of other NSAIDs. Performance status =2-4 Known HIV-related disease General Medical Exclusions Subjects meeting any of the following criteria are ineligible for study entry: Inability to comply with study and/or follow-up procedures 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 Bevacizumab (Avastin®)-Specific Exclusions Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications) Any prior history of hypertensive crisis or hypertensive encephalopathy New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E) History of myocardial infarction or unstable angina within 6 months prior to study enrollment History of stroke or transient ischemic attack within 6 months prior to study enrollment Significant vascular disease (e.g., aortic aneurysm, aortic dissection) Symptomatic peripheral vascular disease Evidence of bleeding diathesis or coagulopathy Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment Serious, non-healing wound, ulcer, or bone fracture Proteinuria at screening as demonstrated by either Urine protein:creatinine (UPC) ratio > 1.0 at screening OR Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible). Known hypersensitivity to any component of bevacizumab Pregnant (positive pregnancy test) or lactating. Use of effective means of contraception (men and women) in subjects of child-bearing potential

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 1<br> | Drug: Bevacizumab and Erlotinib<br>* Erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days<br>* Other names: Erlotinib: Tarceva®;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Overall Survival | The length of time from the start of treatment for a disease that patients are still alive. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Progression-free Survival | The length of time during and after bevacizumab-erlotinib that a patient lives with the disease but does not progress according to RECIST 1.0 Criteria. Per Response Evaluation Criteria In Solid Tumors (RECIST v1.0) for target lesions and assessed by CT: Progressive Disease (PD), >=20% increase in the sum of the longest diameter of target lesions | 2 years | 
| Evaluation of Response Rate | The percentage of patients in which response (CR + PR) was observed: Per Response Evaluation Criteria In Solid Tumors (RECIST v1.0) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions | 2 years |