Phase II Bevacizumab, Gemcitabine and Carboplatin in Newly Diagnosed Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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A multi-center study of bevacizumab in combination with gemcitabine and carboplatin as treatment for newly-diagnosed advanced non-small cell lung cancer (NSCLC).

Detailed Description
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This is a open-label, phase 2, single-arm, multi-center study of bevacizumab combined with gemcitabine and carboplatin. This treatment is for newly-diagnosed advanced non-small cell lung cancer (NSCLC), excluding squamous cell carcinoma. All subjects will receive 15 mg/kg bevacizumab every 3 weeks cycle, 1000 mg/m² of gemcitabine on day 1 and 8 every 3 weeks cycle and carboplatin (AUC= 5 ) every 3 weeks. Carboplasm will be administered 1 hour prior to the gemcitabine infusion, bevacizumab will be administered 1 hour following chemotherapy infusion. Subjects will receive a maximum of 6 cycles of chemotherapy, but treatment with bevacizumab may continue as long as patients have no evidence of progressive disease and no significant treatment-related toxicities.

Official Title
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Phase II Trial of Bevacizumab in Combination With Gemcitabine and Carboplatin in Patients With Newly Diagnosed Non-Small Cell Lung Cancer (Excluding Squamous Cell Carcinoma)

Conditions
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Lung Cancer, Non-small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Gemcitabine
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria : Age 18 or higher Life expectancy of at least 3 months ECOG Performance status 0 to 1 Advanced stage non-small cell lung cancer, NSCLC, Stage IIIB with malignant pleural effusion or Stage 4, excluding squamous cell histology, with measurable or evaluable disease No prior systemic therapy for advanced NSCLC (prior therapy for early stage disease with one regimen is acceptable if it was completed at least 6 months prior to study entry) Palliative radiotherapy to painful bony metastases is permitted prior to study entry if completed prior to initiation of study treatment, and there are no residual sequelae of therapy such as bone marrow suppression Willingness to use appropriate contraception to avoid pregnancy during the study Leukocytes ≥ 3,000/µL Absolute neutrophil count ≥ 1,500/ µL Platelets ≥ 100,000/ µL Total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) ≤ 2.5 x institutional upper limit of normal Creatinine: Within normal institutional limits Creatinine clearance ≥ 60 mL/min/1.73 m² for patients with creatinine levels above institutional normal Ability to sign informed consent Exclusion Criteria: Prior systemic treatment for advanced NSCLC (one prior regimen of up to 4 cycles of neoadjuvant or adjuvant therapy for early stage disease will be allowed, if completed at least 6 months prior to study entry) Known brain metastases Prior treatment with bevacizumab History of allergic reactions Sensitivity attributed to compounds of similar chemical or biologic composition to bevacizumab 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 Evidence of bleeding diathesis Coagulopathy Use of anti-coagulant agents including warfarin, heparin, aspirin, NSAIDs Pregnant Lactating 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 within 7 days prior to day 0 Fine needle aspirations within 7 days prior to day 0 Core biopsies within 7 days prior to day 0 Urine protein: creatinine ratio ≥ 1.0 at screening History of abdominal fistula within 6 months prior to Day 0 Gastrointestinal perforation within 6 months prior to Day 0 Intra-abdominal abscess within 6 months prior to Day 0 Serious, non-healing wound Ulcer Bone fracture Lung carcinoma of squamous cell histology Any histology in close proximity to a major vessel 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) Blood pressure of > 150/100 mmHg Unstable angina New York Heart Association (NYHA) Grade 2 or greater congestive heart failure History of myocardial infarction within 6 months History of stroke within 6 months Clinically significant peripheral vascular disease Psychiatric illness/social situations that would limit compliance with study requirements Another active malignancy except for non-melanoma skin cancers Inability to comply with study and/or follow-up procedures

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab + carboplatin + gemcitabine<br>Bevacizumab in combination with carboplatin and gemcitabine: •Carboplatin, administered IV at area under the curve (AUC) of 5, every 3 weeks on day 1 of each 3-week cycle (once per cycle) for up to 6 cycles. Carboplatin was administered before the gemcitabine infusion: •Gemcitabine, administered 1000 mg/m² IV on days 1 and 8 of each 3-week cycle (twice per cycle) for up to 6 cycles Bevacizumab was administered 1 hour after end of all chemotherapy infusions: •Bevacizumab was administered 15 mg/kg IV on day 1 of each 3-week cycle (once per cycle) for up to 6 cycles in combination with chemotherapy, then continuing until evidence of progressive disease or significant treatment-related toxicity | Drug: Bevacizumab<br>* Murine humanized anti-vascular endothelial growth factor A (VEGF-A) monoclonal antibody<br>* Other names: rhuMAb-VEGF;Drug: Gemcitabine<br>* Nucleoside analog<br>* Other names: Gemzar;Drug: Carboplatin<br>* Alkylating agent<br>* Other names: CBDCA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Median progression-free survival (PFS) was assessed as the time to disease progression; toxicity requiring treatment discontinuation; or death. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (CR + PR + SD) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions, by computed tomography (CT); bone scan; positron emission tomography (PET) scan; and/or magnetic resonance imaging (MRI) as necessary to assess diseasE Response determined as the number of subjects with any clinical response (CR + PR + SD) per RECIST criteria. Complete Response (CR) = disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, or appearance of new cancer lesions Stable Disease (SD): No significant effect, does not meet criteria for PR or PD. | 6 weeks | 
| Overall Survival (OS) | To evaluate the safety of the combination regimen. | 36 months | 
| Partial Response (PR) | Number of subjects with PR per RECIST criteria | 6 weeks | 
| Complete Response (CR) | Number of subjects with CR per RECIST criteria | 6 weeks | 
| Stable Disease (SD) | Number of subjects with SD per RECIST criteria | 6 weeks | 
| Time-to-First Event | Median time-to-first event, with events defined as disease progression, death, or toxicity requiring drug discontinuation | 18 months | 
| Overall Survival (OS) at 12 Months | Number of subjects surviving 1 year after treatment initiation | 12 months | 
| Overall Survival (OS) at 24 Months | Number of subjects surviving 2 years after treatment initiation | 24 months |