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

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00312728
• Collaborator: (none)
• Enrollment: 115
• Arm: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer; Brain Neoplasms	Drug: bevacizumab; Drug: First-Line Chemotherapy Agents; Drug: Second-Line Chemotherapy Agents	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 115 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: Mar 1, 2006
• Actual Primary Completion Date: Jun 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: bevacizumab

Drug: bevacizumab; 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.; Other Names: Avastin ; Drug: First-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.; Drug: Second-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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: David Karlin, M.D., Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00312728
• Other Study ID Numbers: AVF3752g
• First Posted: Apr 11, 2006
• Last Update Posted: Aug 8, 2011
• Last Verified: Aug 1, 2011

• Keywords provided by , ,: Brain Cancer; Brain Metastases; Avastin; NSCLC; Lung Cancer; PASSPORT
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis; Brain Neoplasms; Bevacizumab

Study Results

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 Detail	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.

Arm/Group Title	Bevacizumab
Arm/Group Description	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
Period Title: Overall Study
STARTED	115
COMPLETED	5
NOT COMPLETED	110

Baseline Characteristics

Arm/Group Title	Bevacizumab
Arm/Group Description	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
Overall Participants	115
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (10.6)
Age, Customized (patients) [Number]
18-40 years	6
41-64 years	77
>=65 years	32
Sex: Female, Male (Count of Participants)
Female	53 46.1%
Male	62 53.9%

Outcome Measures

1. Primary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

The safety-evaluable population consisted of all patients who received at least one dose of bevacizumab.

Arm/Group Title	Bevacizumab
Arm/Group Description	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
Measure Participants	106
Number (90% Confidence Interval) [percentage of participants]	0 0%

2. Secondary Outcome

Title	Overall Survival (OS) in First-line Setting
Description	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)

Outcome Measure Data

Analysis Population Description

The first-line efficacy-evaluable population consisted of 70 patients who received at least one dose of bevacizumab.

Arm/Group Title	Bevacizumab
Arm/Group Description	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
Measure Participants	70
Median (95% Confidence Interval) [Months]	11.8

3. Secondary Outcome

Title	Number of Participants With Overall Survival (OS) in First-line Setting [1-Year or More Survival]
Description	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)

Outcome Measure Data

Analysis Population Description

The first-line efficacy-evaluable population consisted of 70 patients who received at least one dose of bevacizumab.

Arm/Group Title	Bevacizumab
Arm/Group Description	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
Measure Participants	70
Number [participants]	30 26.1%

4. Secondary Outcome

Title	OS in First-line and Second-line Settings
Description	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)

Outcome Measure Data

Analysis Population Description

The efficacy-evaluable population consisted of all patients who received at least one dose of bevacizumab.

Arm/Group Title	Bevacizumab
Arm/Group Description	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
Measure Participants	106
Median (95% Confidence Interval) [Months]	12.1

5. Secondary Outcome

Title	Number of Participants With OS in First-line and Second-line Settings [1-Year or More Survival]
Description	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)

Outcome Measure Data

Analysis Population Description

The efficacy-evaluable population consisted of all patients who received at least one dose of bevacizumab.

Arm/Group Title	Bevacizumab
Arm/Group Description	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
Measure Participants	106
Number [participants]	49 42.6%

6. Secondary Outcome

Title	Number of Participants With Selected Adverse Events
Description	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)

Outcome Measure Data

Analysis Population Description

The safety-evaluable population consisted of all patients who received at least one dose of bevacizumab.

Arm/Group Title	Bevacizumab
Arm/Group Description	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
Measure Participants	106
Any grade CNS hemorrhage	0 0%
Any grade pulmonary hemorrhage	4 3.5%
Grade ≥ 2 arterial thromboembolic event	1 0.9%
Grade ≥ 3 non-CNS non-pulmonary hemorrhage	2 1.7%
Grade ≥ 3 venous thromboembolic event	7 6.1%
Any grade gastrointestinal perforation	0 0%
Grade ≥ 3 hypertension	3 2.6%
Grade ≥ 3 proteinuria	0 0%
Grade ≥ 2 left ventricular systolic dysfunction	0 0%
Reversible Posterior Leukoencephalopathy Syndrome	1 0.9%
Any event leading to treatment discontinuation	30 26.1%

Adverse Events

Time Frame	From start of bevacizumab treatment to 60 days following discontinuation of bevacizumab (up to 2 years).
Arm/Group Title	Bevacizumab
Arm/Group Description	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
All Cause Mortality
	Bevacizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bevacizumab
	Affected / at Risk (%)	# Events
Total	45/106 (42.5%)
Blood and lymphatic system disorders
Anemia	2/106 (1.9%)
Febrile Neutropenia	1/106 (0.9%)
Thrombocytopenia	1/106 (0.9%)
Endocrine disorders
Hypoaldosteronism	1/106 (0.9%)
Gastrointestinal disorders
Gastrointestinal Hemorrhage	2/106 (1.9%)
Abdominal Pain	1/106 (0.9%)
Constipation	1/106 (0.9%)
Gastroesophageal Reflux Disease	1/106 (0.9%)
Nausea	1/106 (0.9%)
Pancreatitis	1/106 (0.9%)
Small Intestinal Obstruction	1/106 (0.9%)
Vomiting	1/106 (0.9%)
General disorders
Chest Pain	2/106 (1.9%)
Death	1/106 (0.9%)
Pyrexia	1/106 (0.9%)
Infections and infestations
Pneumonia	3/106 (2.8%)
Urinary Tract Infection	2/106 (1.9%)
Diverticulitis	1/106 (0.9%)
Lobar Pneumonia	1/106 (0.9%)
Perirectal Abscess	1/106 (0.9%)
Rectal Abscess	1/106 (0.9%)
Injury, poisoning and procedural complications
Hip Fracture	1/106 (0.9%)
Spinal Compression Fracture	1/106 (0.9%)
Metabolism and nutrition disorders
Dehydration	2/106 (1.9%)
Anorexia	1/106 (0.9%)
Failure to Thrive	1/106 (0.9%)
Musculoskeletal and connective tissue disorders
Muscular Weakness	1/106 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung Neoplasm Malignant	1/106 (0.9%)
Nervous system disorders
Convulsion	4/106 (3.8%)
Ataxia	1/106 (0.9%)
BRAIN OEDEMA	1/106 (0.9%)
Cerebral Arteriosclerosis	1/106 (0.9%)
Headache	1/106 (0.9%)
Leukoencephalopathy	1/106 (0.9%)
Syncope	1/106 (0.9%)
Transient Ischemic Attack	1/106 (0.9%)
Psychiatric disorders
Mental Status Changes	2/106 (1.9%)
Renal and urinary disorders
Renal Failure Acute	1/106 (0.9%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	6/106 (5.7%)
Pulmonary Hemorrhage	3/106 (2.8%)
Chronic Obstructive Pulmonary Disease	1/106 (0.9%)
Hemoptysis	1/106 (0.9%)
Respiratory Distress	1/106 (0.9%)
Respiratory Failure	1/106 (0.9%)
Vascular disorders
Hypotension	1/106 (0.9%)
Orthostatic Hypotension	1/106 (0.9%)
Venous Thrombosis Limb	1/106 (0.9%)
Other (Not Including Serious) Adverse Events
	Bevacizumab
	Affected / at Risk (%)	# Events
Total	7/106 (6.6%)
Blood and lymphatic system disorders
Thrombocytopenia	7/106 (6.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.