Clinical trial NCT00227019: Phase 2 Trial of Bevacizumab in Combination With Pemetrexed
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer (NSCLC)
Lung Cancer
Neoplasm Metastasis
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: Eli Lilly and Company
name: Genentech, Inc.
First posted: 2005-09-27
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of Central Nervous System (CNS) Hemorrhagic Events
timeFrame: 18 months
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: 18 months
measure: Overall Survival (OS)
timeFrame: 18 months
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center
state: New Hampshire
city: Voorhees
country: United States
facility: Cooper Cancer Institute
state: New Jersey
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
Study officials:
affiliation: Stanford University
name: Heather A. Wakelee
role: PRINCIPAL_INVESTIGATOR
References: