Phase 2 Trial of Bevacizumab in Combination With Pemetrexed

Phase 2

Completed

Conditions: Lung Cancer
Neoplasm Metastasis
Non-small Cell Lung Cancer (NSCLC)

Interventions: Drug: Bevacizumab
Drug: Pemetrexed
Drug: Vitamin B12
Drug: Folate
Drug: Dexamethasone

Registration Number: NCT00227019

Lead Sponsor: Heather Wakelee

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).

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 16

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
bevacizumab+ pemetrexed	Folate	pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV). In addition to Vitamin B12 + Folate + Dexamethasone
bevacizumab+ pemetrexed	Dexamethasone	pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV). In addition to Vitamin B12 + Folate + Dexamethasone
bevacizumab+ pemetrexed	Pemetrexed	pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV). In addition to Vitamin B12 + Folate + Dexamethasone
bevacizumab+ pemetrexed	Bevacizumab	pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV). In addition to Vitamin B12 + Folate + Dexamethasone
bevacizumab+ pemetrexed	Vitamin B12	pemetrexed (500 mg/m² IV) + bevacizumab (15 mg/kg IV). In addition to Vitamin B12 + Folate + Dexamethasone

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
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).
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).

Trial Locations

Locations (4): Stanford University School of Medicine
🇺🇸
Stanford, California, United States
Norris Cotton Cancer Center
🇺🇸
Lebanon, New Hampshire, United States
Cooper Cancer Institute
🇺🇸
Voorhees, New Jersey, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States