Brain Neoplasms, Non-Small Cell Lung Cancer
Conditions
Keywords
Brain Cancer, Brain Metastases, Avastin, NSCLC, Lung Cancer, PASSPORT
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.
Interventions
DRUGbevacizumab
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.
DRUGFirst-Line Chemotherapy Agents
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.
DRUGSecond-Line Chemotherapy Agents
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.
Sponsors
Genentech, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | From the first administration of bevacizumab until 60 days after discontinuation of bevacizumab treatment was reported (up to 2 years) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) in First-line Setting | Time from enrollment to death from any cause (up to 2 years) | 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. |
| Number of Participants With Overall Survival (OS) in First-line Setting [1-Year or More Survival] | Time from enrollment to death from any cause (up to 2 years) | 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. |
| OS in First-line and Second-line Settings | Time from enrollment to death from any cause (up to 2 years) | 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. |
| Number of Participants With OS in First-line and Second-line Settings [1-Year or More Survival] | Time from enrollment to death from any cause (up to 2 years) | 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. |
| Number of Participants With Selected Adverse Events | From start of bevacizumab treatment to 60 days following discontinuation of bevacizumab (up to 2 years) | 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. |
Participant flow
Recruitment details
Approximately 110 subjects were to be enrolled at approximately 40 sites to obtain 100 bevacizumab-treated evaluable subjects. Study started 28 NOV 2005 and completed 5 JUN 2009.
Pre-assignment details
This was an open-label, multicenter, single-arm, Phase II trial of bevacizumab combined with first- or second-line therapy in subjects with metastatic non-squamous non-small cell lung cancer (NSCLC) with previously treated CNS metastases.
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab 15 mg/kg IV on the first day of each 21- to 28-day cycle (+/-4 days) in combination with first or second-line therapy | 115 |
| Total | 115 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 32 |
| Overall Study | Other | 10 |
| Overall Study | Progressive disease | 53 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Required non-protocol cancer treatment | 2 |
| Overall Study | Withdrawal by Subject | 10 |
Baseline characteristics
| Characteristic | Bevacizumab |
|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 10.6 |
| Age, Customized 18-40 years | 6 patients |
| Age, Customized 41-64 years | 77 patients |
| Age, Customized >=65 years | 32 patients |
| Sex: Female, Male Female | 53 Participants |
| Sex: Female, Male Male | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 106 |
| serious Total, serious adverse events | 45 / 106 |
Outcome results
Primary
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
Time frame: From the first administration of bevacizumab until 60 days after discontinuation of bevacizumab treatment was reported (up to 2 years)
Population: The safety-evaluable population consisted of all patients who received at least one dose of bevacizumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab | 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 | 0 percentage of participants |
Secondary
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 frame: Time from enrollment to death from any cause (up to 2 years)
Population: The efficacy-evaluable population consisted of all patients who received at least one dose of bevacizumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab | Number of Participants With OS in First-line and Second-line Settings [1-Year or More Survival] | 49 participants |
Secondary
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 frame: Time from enrollment to death from any cause (up to 2 years)
Population: The first-line efficacy-evaluable population consisted of 70 patients who received at least one dose of bevacizumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab | Number of Participants With Overall Survival (OS) in First-line Setting [1-Year or More Survival] | 30 participants |
Secondary
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.
Time frame: From start of bevacizumab treatment to 60 days following discontinuation of bevacizumab (up to 2 years)
Population: The safety-evaluable population consisted of all patients who received at least one dose of bevacizumab.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab | Number of Participants With Selected Adverse Events | Any grade CNS hemorrhage | 0 participants |
| Bevacizumab | Number of Participants With Selected Adverse Events | Any grade pulmonary hemorrhage | 4 participants |
| Bevacizumab | Number of Participants With Selected Adverse Events | Grade ≥ 2 arterial thromboembolic event | 1 participants |
| Bevacizumab | Number of Participants With Selected Adverse Events | Grade ≥ 3 non-CNS non-pulmonary hemorrhage | 2 participants |
| Bevacizumab | Number of Participants With Selected Adverse Events | Grade ≥ 3 venous thromboembolic event | 7 participants |
| Bevacizumab | Number of Participants With Selected Adverse Events | Any grade gastrointestinal perforation | 0 participants |
| Bevacizumab | Number of Participants With Selected Adverse Events | Grade ≥ 3 hypertension | 3 participants |
| Bevacizumab | Number of Participants With Selected Adverse Events | Grade ≥ 3 proteinuria | 0 participants |
| Bevacizumab | Number of Participants With Selected Adverse Events | Grade ≥ 2 left ventricular systolic dysfunction | 0 participants |
| Bevacizumab | Number of Participants With Selected Adverse Events | Reversible Posterior Leukoencephalopathy Syndrome | 1 participants |
| Bevacizumab | Number of Participants With Selected Adverse Events | Any event leading to treatment discontinuation | 30 participants |
Secondary
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 frame: Time from enrollment to death from any cause (up to 2 years)
Population: The efficacy-evaluable population consisted of all patients who received at least one dose of bevacizumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab | OS in First-line and Second-line Settings | 12.1 Months |
Secondary
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 frame: Time from enrollment to death from any cause (up to 2 years)
Population: The first-line efficacy-evaluable population consisted of 70 patients who received at least one dose of bevacizumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab | Overall Survival (OS) in First-line Setting | 11.8 Months |