A Study of Bevacizumab in Combination With First- or Second-Line Therapy in Subjects With Treated Brain Metastases Due to Non-Squamous NSCLC (PASSPORT)

Study Overview
=================
Brief Summary
-----------------
This was an open-label, multicenter, single-arm, Phase II trial of bevacizumab combined with first- or second-line therapy in patients with metastatic non-squamous non-small cell lung cancer (NSCLC) with previously treated central nervous system (CNS) metastases. A total of 115 patients enrolled in the study.

Official Title
-----------------
A Phase II Trial of Bevacizumab in Combination With First- or Second-Line Therapy in Subjects With Treated Brain Metastases Due to Non-Squamous Non-Small Cell Lung Cancer

Conditions
-----------------
Non-Small Cell Lung Cancer, Brain Neoplasms

Intervention / Treatment
-----------------
* Drug: bevacizumab
* Drug: First-Line Chemotherapy Agents
* Drug: Second-Line Chemotherapy Agents


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent Histologically or cytologically confirmed NSCLC except for squamous cell carcinoma Treated brain metastases without evidence of progression or hemorrhage after treatment, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period Appropriateness for first- or second-line systemic therapy for advanced NSCLC Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Age ≥ 18 years For women of childbearing potential and sexually active males, use of an accepted and effective method of contraception (e.g., hormonal or barrier methods, abstinence) prior to study entry and for the duration of the study Exclusion Criteria: Brain biopsy/neurosurgical procedure performed within 3 months prior to Day 1 Progressive neurologic symptoms Active malignancy other than lung cancer Current, recent, or planned participation in an experimental drug study Prior treatment with an investigational or marketed agent that acts by anti-angiogenesis mechanisms Gross hemoptysis within 3 months prior to Day 1 Inadequately controlled hypertension Unstable angina or New York Heart Association Grade II or greater congestive heart failure (CHF) Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1 Myocardial infarction within 6 months prior to Day 1 Stroke within 6 months prior to Day 1 Active symptomatic peripheral vascular disease within 6 months prior to Day 1 History of significant vascular disease Evidence of bleeding diathesis or coagulopathy Known hypersensitivity to any components of bevacizumab Inadequate organ function Serious non-healing wound, ulcer, or bone fracture Urine protein/creatinine (UPC) ratio of ≥ 1.0 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, or anticipation of need for major surgical procedure during the course of the study Pregnancy or lactation Known evidence of disseminated intravascular coagulation (DIC) Active infection or fever > 38.5°C within 3 days prior to Day 1 Any other medical condition (including mental illness or substance abuse) deemed by the clinician to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results

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 |
| --- | --- |
| Experimental: bevacizumab<br> | Drug: bevacizumab<br>* 15 mg/kg intravenously (IV) on the first day of each 21- to 28-day cycle (± 4 days); the interval between infusions could not be < 17 days, but could extend beyond 28 days if chemotherapy was delayed to allow recovery from toxicity.<br>* Other names: Avastin;Drug: First-Line Chemotherapy Agents<br>* Carboplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, vinorelbine, pemetrexed, or erlotinib administered on Day 1 of every 21-day cycle except gemcitabine, which was administered on Days 1 and 8 of every cycle. Agents were administered as a platinum doublet, or erlotinib alone, at the investigator's discretion. Chemotherapy was administered for a total of 6 planned cycles (up to 8 cycles with prior approval from the Medical Monitor), followed by single-agent bevacizumab therapy. The chemotherapy regimen was to be consistent throughout the study. Erlotinib was administered orally daily. All agents were dosed and administered per institutional standards using the respective package insert as a guideline.<br>Drug: Second-Line Chemotherapy Agents<br>* Erlotinib, pemetrexed, docetaxel, or chemotherapy at the investigator's discretion. Erlotinib was administered orally daily; pemetrexed and docetaxel were administered IV on Day 1 of every 21-day cycle. Single-agent bevacizumab therapy could be continued at the investigator's discretion if the second-line agent was discontinued. All agents were dosed and administered per institutional standards using the respective package insert as a guideline.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Symptomatic National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0 (NCI CTCAE) Grade ≥2 Central Nervous System (CNS) Hemorrhage | The percentage of participants with symptomatic NCI CTCAE Grade ≥ 2 CNS hemorrhage, defined as the presence of clinical symptoms determined by the investigator to be directly referable to a Grade ≥ 2 CNS hemorrhage. Grade 1: Asymptomatic, radiographic findings only Grade 2: Medical intervention indicated Grade 3: Ventriculostomy, intracranial pressure (ICP) monitoring, intraventricular thrombolysis, or operative intervention indicated Grade 4: Life-threatening consequences; neurologic deficit or disability Grade 5: Death | From the first administration of bevacizumab until 60 days after discontinuation of bevacizumab treatment was reported (up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in First-line Setting | To assess overall survival in the subset of subjects treated in the first-line setting with bevacizumab plus either chemotherapy or erlotinib for non-squamous NSCLC with previously treated brain metastases. | Time from enrollment to death from any cause (up to 2 years) | 
| Number of Participants With Overall Survival (OS) in First-line Setting [1-Year or More Survival] | Number of Participants with overall survival in the subset of subjects treated in the first-line setting with bevacizumab plus either chemotherapy or erlotinib for non-squamous NSCLC with previously treated brain metastases. | Time from enrollment to death from any cause (up to 2 years) | 
| OS in First-line and Second-line Settings | To assess overall survival in the subset of subjects treated in the first-line setting with bevacizumab plus either chemotherapy or erlotinib for non-squamous NSCLC with previously treated brain metastases. | Time from enrollment to death from any cause (up to 2 years) | 
| Number of Participants With OS in First-line and Second-line Settings [1-Year or More Survival] | To assess the number of participants with overall survival in the subset of subjects treated in the first-line setting with bevacizumab plus either chemotherapy or erlotinib for non-squamous NSCLC with previously treated brain metastases. | Time from enrollment to death from any cause (up to 2 years) | 
| Number of Participants With Selected Adverse Events | Number of participants with selected adverse events (all grades based on NCI CTCAE) included any grade CNS hemorrhage, any grade pulmonary hemorrhage, any grade gastrointestinal (GI) perforation, Grade ≥ 2 arterial thromboembolic event, Grade ≥ 2 left ventricular systolic dysfunction, Grade ≥ 3 non-CNS non-pulmonary hemorrhage, Grade ≥ 3 proteinuria, Grade ≥ 3 proteinuria, Grade ≥ 3 hypertension, any serious adverse event*, and any adverse event leading to study treatment discontinuation. *For serious adverse events, please see Adverse Event Reporting Section. | From start of bevacizumab treatment to 60 days following discontinuation of bevacizumab (up to 2 years) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Brain Cancer, Brain Metastases, Avastin, NSCLC, Lung Cancer, PASSPORT