Phase 2 Trial of Bevacizumab in Combination With Pemetrexed

• Sponsor: Heather Wakelee (Other)
• Overall Status: Completed
• CT.gov ID: NCT00227019
• Collaborator: Eli Lilly and Company (Industry), Genentech, Inc. (Industry)
• Enrollment: 16
• Locations: 4
• Arm: 1
• Duration (Months): 129.1
• Patients Per Site: 4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This trial evaluated the safety of combining bevacizumab and pemetrexed in non-small cell lung cancer (NSCLC) patients with stable brain metastases as second-line chemotherapy, while evaluating progression-free survival (PFS) and overall survival (OS).

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer (NSCLC); Lung Cancer; Neoplasm Metastasis	Drug: Bevacizumab; Drug: Pemetrexed; Drug: Vitamin B12; Drug: Folate; Drug: Dexamethasone	Phase 2

Detailed Description

Brain metastases are a common complication of advanced non-small-cell lung cancer (NSCLC) both at initial presentation and at the time of disease progression. Patients with brain metastases have often been excluded from large randomized phase III trials due to concerns of poorer survival and impaired ability of drugs to cross the blood-brain barrier. However, as survival has improved, some trials have included such patients, often finding similar benefit to patients with metastatic disease elsewhere.

Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor, has emerged as an important adjunct to platinum-based chemotherapy doublets for use in advanced NSCLC. This drug is normally used as a first line chemotherapy. Pemetrexed is a multi-targeted anti-folate agent,which is approved for use in first-line (with platinum), maintenance, and second-line treatment of advanced nonsquamous NSCLC. Based on the efficacy of pemetrexed as a second line agent and the safety questions surrounding bevacizumab in those with treated brain metastases, a trial was designed to look at the combination of both agents as a second line therapy in NSCLC patients with treated stable brain metastases

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Bevacizumab in Combination With Pemetrexed as Second Line Therapy in Patients With Stable Brain Metastases From Non-small Cell Lung Cancer (NSCLC) (Excluding Squamous Cell Carcinoma)
• Study Start Date: Mar 1, 2006
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: bevacizumab+ pemetrexed pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV). In addition to Vitamin B12 + Folate + Dexamethasone

Drug: Bevacizumab; 15 mg/kg, IV over 10 minutes every 3 weeks; Other Names: Avastin ; Drug: Pemetrexed; 500 mg/m²; IV over 10 minutes every 3 weeks; Other Names: Alimta ; Drug: Vitamin B12; 1000 micrograms, IM injection 1-2 weeks prior to treatment and repeated every 9 weeks until last dose of pemetrexed; Other Names: cobalamin Vit B12 ; Drug: Folate; 350 to 1000 micrograms 1 week prior to treatment and 3 weeks after last pemetrexed dose; Other Names: folacin Folic acid pteroyl-L-glutamic acid pteroyl-L-glutamate pteroylmonoglutamic acid vitamin B9 vitamin Bc ; Drug: Dexamethasone; 4 mg; oral, twice a day at the following times: the day before, of and after each dose of pemetrexed; Other Names: Decadron

Outcome Measures

Primary Outcome Measures

1. Incidence of Central Nervous System (CNS) Hemorrhagic Events [18 months]

   Number of events of brain or central nervous system (CNS) bleeding

Secondary Outcome Measures

1. Progression-free Survival (PFS) [18 months]

   Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of documented disease progression or death. Kaplan-Meier survival curves for PFS were generated with IBM SPSS Statistics version 19.0 (SPSS, Inc, Chicago, IL).

2. Overall Survival (OS) [18 months]

   Overall Survival (OS) is defined as the duration of time from start of treatment to deat. Kaplan-Meier survival curves for OS were generated with IBM SPSS Statistics version 19.0 (SPSS, Inc, Chicago, IL).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Advanced stage NSCLC excluding squamous cell histology with measurable or evaluable disease.

• Stable brain metastases required, no longer requiring active therapy such as steroid medications, which have been previously treated with radiation or surgery or both and have been documented to be stable on repeat imaging done at least one month after completion of therapy.

• Prior therapy with one standard doublet front-line regimen for NSCLC (platinum containing)

• Life expectancy of at least 3 months

• ECOG Performance status 0-1

• Age 18 or higher

• Use of effective means of contraception (men and women) in subjects of child-bearing potential

• Ability/willingness to comply with vitamin supplementation including vitamin B 12 and folic acid started at least 1 week before first dose of pemetrexed and continued for at least 3 weeks after last dose

• Ability/willingness to take dexamethasone the day before, of and after pemetrexed administration

• Drainage of any clinically significant effusion

• Ability to sign informed consent

Exclusion Criteria:

• Treatment with more than one prior chemotherapy regimen (unless one regimen was stopped for toxicity reasons with a different regimen replacement regimen started immediately and patient completed only 4-6 total cycles of first-line treatment. One prior regimen (up to 4 cycles) of neoadjuvant or adjuvant therapy for early stage disease will also be allowed.

• Prior treatment with pemetrexed or bevacizumab

• Prior chemotherapy within 28 days (6 weeks for BCNU, CCNU or mitomycin-C)

• Current, recent (within 4 weeks of the first infusion of this study), or planned participation in any other experimental drug study

• Concomitant chemotherapy, radiotherapy or investigational agents

• Uncontrolled effusion (large pleural or peritoneal effusion or small/moderate effusion which requires drainage for symptom management)

• Evidence of bleeding diathesis or coagulopathy

• Use of anti-coagulant agents including warfarin, heparin, aspirin, NSAIDs

• Pregnant (positive pregnancy test) or lactating women

• 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, fine needle aspirations or core biopsies within 7 days prior to day 0

• Urine protein:creatinine ratio greater than or equal to 1.0 at screening

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0

• Serious, non-healing wound, ulcer, or bone fracture

• Lung carcinoma of squamous cell histology or any histology in close proximity to a major vessel, or with significant cavitation as assessed by treating investigator in consultation with an attending radiologist

• History of hemoptysis (bright red blood of 1/2 teaspoon or more)

• Neutrophils < 1.5 x 10^9/ L

• Hemoglobin <10.0 g/dl

• Platelets <100 x 10^9/ L

• Serum glutamic oxaloacetic transaminase (SGOT/ AST) or serum glutamic pyruvic transaminase (SGPT/ ALT) > 2.5 times upper limits of normal

• Creatinine > 1.5 times upper limits of normal

• Significant co-morbidities including:

• Blood pressure of greater than 150/100 mmHg

• Unstable angina

• New York Heart Association (NYHA) Grade II or greater congestive heart failure

• History of myocardial infarction within 6 months

• History of stroke within 6 months

• Clinically significant peripheral vascular disease

• Inability to comply with study and/or follow-up procedures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305
2	Norris Cotton Cancer Center	Lebanon	New Hampshire	United States	03756
3	Cooper Cancer Institute	Voorhees	New Jersey	United States	08043
4	University of North Carolina	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• Heather Wakelee
• Eli Lilly and Company
• Genentech, Inc.

Investigators

• Principal Investigator: Heather A. Wakelee, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Heather Wakelee, Assistant Professor of Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT00227019
• Other Study ID Numbers: IRB-00892; 95913; LUN0014
• First Posted: Sep 27, 2005
• Last Update Posted: Mar 6, 2017
• Last Verified: Jan 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis; Vitamins; Folic Acid; Vitamin B 12; Hydroxocobalamin; Vitamin B Complex; Dexamethasone; Bevacizumab; Pemetrexed

Study Results

Participant Flow

Arm/Group Title	Bevacizumab Plus Pemetrexed
Arm/Group Description	Treatment group is adult patients with metastatic nonsquamous, non-small cell lung cancer (NSCLC) and stable brain metastases after progression on a platinum doublet regimen for advanced disease. All patients received pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV) every 3 weeks.
Period Title: Overall Study
STARTED	16
COMPLETED	16
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Bevacizumab Plus Pemetrexed
Arm/Group Description	Treatment group is adult patients with metastatic nonsquamous, non-small cell lung cancer (NSCLC) and stable brain metastases after progression on a platinum doublet regimen for advanced disease. All patients received pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV) every 3 weeks.
Overall Participants	16
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Gender (Count of Participants)
Female	9 56.3%
Male	7 43.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	6 37.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	10 62.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Eastern Cooperative Oncology Group (ECOG) performance status (participants) [Number]
0-1	15 93.8%
2	1 6.3%
Histology (participants) [Number]
Adeno-carcinoma	12 75%
Large cell carinoma	0 0%
Not otherwise specified (NOS)	4 25%

Outcome Measures

1. Primary Outcome

Title	Incidence of Central Nervous System (CNS) Hemorrhagic Events
Description	Number of events of brain or central nervous system (CNS) bleeding
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

All participants in this study are included in the analysis population

Arm/Group Title	Bevacizumab + Pemetrexed
Arm/Group Description	Treatment group is adult patients with metastatic non squamous, non-small cell lung cancer (NSCLC) and stable brain metastases after progression on a platinum doublet regimen for advanced disease. All patients received pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV) every 3 weeks.
Measure Participants	16
Number [CNS hemorrhagic events]	0

2. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of documented disease progression or death. Kaplan-Meier survival curves for PFS were generated with IBM SPSS Statistics version 19.0 (SPSS, Inc, Chicago, IL).
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab + Pemetrexed
Arm/Group Description	Treatment group is adult patients with metastatic non squamous, non-small cell lung cancer (NSCLC) and stable brain metastases after progression on a platinum doublet regimen for advanced disease. All patients received pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV) every 3 weeks.
Measure Participants	16
Median (95% Confidence Interval) [months]	7.2

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival (OS) is defined as the duration of time from start of treatment to deat. Kaplan-Meier survival curves for OS were generated with IBM SPSS Statistics version 19.0 (SPSS, Inc, Chicago, IL).
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab + Pemetrexed
Arm/Group Description	Treatment group is adult patients with metastatic nonsquamous, non-small cell lung cancer (NSCLC) and stable brain metastases after progression on a platinum doublet regimen for advanced disease. All patients received pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV) every 3 weeks.
Measure Participants	16
Median (95% Confidence Interval) [months]	14.8

Adverse Events

Time Frame	18 Months
Arm/Group Title	Bevacizumab Plus Pemetrexed
Arm/Group Description	Treatment group is adult patients with metastatic non squamous, non-small cell lung cancer (NSCLC) and stable brain metastases after progression on a platinum doublet regimen for advanced disease. All patients received pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV) every 3 weeks.
All Cause Mortality
	Bevacizumab Plus Pemetrexed
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bevacizumab Plus Pemetrexed
	Affected / at Risk (%)	# Events
Total	8/16 (50%)
Blood and lymphatic system disorders
Neutropenia +/- fever	3/16 (18.8%)
Elevated creatinine/ Actue Renal failure (ARF)	1/16 (6.3%)
Thrombosis/ deep vein thrombosis (DVT)	2/16 (12.5%)
Hyperglycemia	1/16 (6.3%)
Hyponatremia	1/16 (6.3%)
Leukopenia	1/16 (6.3%)
Syncope	1/16 (6.3%)
General disorders
Infection	6/16 (37.5%)
Fatigue	3/16 (18.8%)
Confusion	1/16 (6.3%)
Pain	1/16 (6.3%)
Weight gain	1/16 (6.3%)
Musculoskeletal and connective tissue disorders
Seizure-like activity	1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea/ respiratory distress	2/16 (12.5%)
cough	1/16 (6.3%)
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, specify	1/16 (6.3%)
Other (Not Including Serious) Adverse Events
	Bevacizumab Plus Pemetrexed
	Affected / at Risk (%)	# Events
Total	15/16 (93.8%)
Blood and lymphatic system disorders
Anemia	2/16 (12.5%)
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, specify	2/16 (12.5%)
Hearing impaired	1/16 (6.3%)
Endocrine disorders
Adrenal insufficiency	1/16 (6.3%)
Eye disorders
Blurred vision	3/16 (18.8%)
Eye disorders - Other, specify	1/16 (6.3%)
Gastrointestinal disorders
Constipation	5/16 (31.3%)
Dental caries	1/16 (6.3%)
Diarrhea	1/16 (6.3%)
Dyspepsia	2/16 (12.5%)
Periodontal disease	1/16 (6.3%)
Mucositis oral	1/16 (6.3%)
Nausea	7/16 (43.8%)
Pancreatitis	1/16 (6.3%)
Vomiting	3/16 (18.8%)
General disorders
Chills	1/16 (6.3%)
Localized edema	2/16 (12.5%)
Edema limbs	2/16 (12.5%)
Fatigue	11/16 (68.8%)
Fever	2/16 (12.5%)
Gait disturbance	1/16 (6.3%)
Injection site reaction	1/16 (6.3%)
Fever	3/16 (18.8%)
Pain	12/16 (75%)
Hepatobiliary disorders
Hepatobiliary disorders - Other, transiminitis	1/16 (6.3%)
Immune system disorders
Allergic reaction	1/16 (6.3%)
Infections and infestations
Catheter related infection	1/16 (6.3%)
Skin infection	1/16 (6.3%)
Urinary tract infection	1/16 (6.3%)
Upper respiratory infection	2/16 (12.5%)
Infections and infestations - Other, specify	1/16 (6.3%)
Sinusitis	1/16 (6.3%)
Injury, poisoning and procedural complications
Bruising	1/16 (6.3%)
Investigations
Alanine aminotransferase increased	1/16 (6.3%)
Aspartate aminotransferase increased	1/16 (6.3%)
Creatinine increased	2/16 (12.5%)
Neutrophil count decreased	1/16 (6.3%)
Weight loss	4/16 (25%)
Metabolism and nutrition disorders
Creatinine increased	8/16 (50%)
Anorexia	8/16 (50%)
Dehydration	1/16 (6.3%)
Nervous system disorders
Dizziness	2/16 (12.5%)
Dizziness	1/16 (6.3%)
Amnesia	1/16 (6.3%)
Depressed level of consciousness	1/16 (6.3%)
Tremor	1/16 (6.3%)
Psychiatric disorders
Insomnia	3/16 (18.8%)
Agitation	2/16 (12.5%)
Renal and urinary disorders
Proteinuria	1/16 (6.3%)
Urinary frequency	1/16 (6.3%)
Reproductive system and breast disorders
Erectile dysfunction	1/16 (6.3%)
Vaginal hemorrhage	1/16 (6.3%)
Vaginal dryness	1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Laryngeal mucositis	1/16 (6.3%)
Cough	5/16 (31.3%)
Dyspnea	8/16 (50%)
Epistaxis	6/16 (37.5%)
Sinus disorder	3/16 (18.8%)
Laryngeal hemorrhage	1/16 (6.3%)
Pharyngolaryngeal pain	1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders - Other, specify	1/16 (6.3%)
Voice alteration	1/16 (6.3%)
Skin and subcutaneous tissue disorders
Alopecia	1/16 (6.3%)
Palmar-plantar erythrodysesthesia syndrome	1/16 (6.3%)
Dry skin	1/16 (6.3%)
Hyperhidrosis	1/16 (6.3%)
Erythema multiforme	3/16 (18.8%)
Vascular disorders
Vascular disorders - Other, specify	1/16 (6.3%)
Hot flashes	2/16 (12.5%)
Hypertension	1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.