A Study of Cetuximab and Bevacizumab in Combination With Paclitaxel and Carboplatin in Stage IIIb/IV NSCLC

Study Overview
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Brief Summary
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The primary objective of this study will be to determine the progression free survival of patients with stage IIIb/IV non-small cell lung cancer (NSCLC) treated with dual agent monoclonal antibody therapy consisting of cetuximab and bevacizumab in combination with two different regimens of paclitaxel and carboplatin chemotherapy.

Official Title
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Phase II Randomized, Open-Label Study of Cetuximab and Bevacizumab in Combination With Paclitaxel and Carboplatin in Patients With Stage IIIB/IV Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Biological: Cetuximab
* Biological: Bevacizumab
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient has histologically or cytologically confirmed non-small cell lung cancer (NSCLC), except squamous cell carcinoma. Mixed tumors will be categorized by the predominant cell type, but the presence of small cell lung cancer elements will make the patient ineligible. Cytologic or histologic elements can be established on metastatic tumor aspirates or biopsy. The patient has advanced NSCLC (Stage IIIB with malignant pleural effusion or Stage IV or recurrent disease). Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST). The patient's Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1. The patient has adequate hematologic function as defined by an Absolute Neutrophil Count greater than or equal to 1500/mm³,hemoglobin greater than or equal to 9 gm/dL, and a platelet count greater than or equal to 100,000/mm³ obtained within 2 weeks prior to the first dose of study medication. The patient has adequate hepatic function as defined by a total bilirubin greater than or equal to 1.5 mg/dL and transaminases and alkaline phosphatase less than or equal to 5 x the Upper Limit of Normal (ULN) obtained within 2 weeks prior to the first dose of study medication. The patient has adequate renal function as defined by serum creatinine less than or equal to 1.5 x ULN or calculated creatinine clearance (CrCl) >60 mL/minute, and urine dipstick for proteinuria <1+ (ie, either 0 or trace) obtained within 2 weeks prior to the first dose of study medication. If urine dipstick is greater than or equal to 1+, then a 24-hour urine for protein must demonstrate <500 mg of protein in 24 hours to allow participation in the study. The patient has adequate coagulation function as defined by International Normalized Ratio less than or equal to 1.5 and a Prothrombin time and partial thromboplastin time less than or equal to ULN obtained within 2 weeks prior to the first dose of study medication. The patient, if a woman of childbearing potential, agrees to use an accepted and effective method of contraception (hormonal or barrier methods, abstinence) prior to study entry and for the duration of the study. If a male and sexually active, the patient agrees to use effective contraception. Exclusion Criteria: The patient has known Central Nervous System metastases. A head computed tomography (CT) is required within 4 weeks prior to the first dose of study medication (magnetic resonance imagines [MRIs] are also acceptable). The patient has received prior cetuximab therapy. The patient has received prior bevacizumab therapy. The patient has received prior systemic chemotherapy or radiation therapy at any time for lung cancer. Any concurrent malignancy other than basal cell skin cancer, or carcinoma in situ of the cervix. Patients with adequately treated cancers of other histologies who have been disease-free for more than 3 years prior to the first treatment dose are eligible. Concurrent treatment with other anti-cancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, chemoembolization, or targeted therapy. The patient has an ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. The patient has a history of thrombotic or hemorrhagic disorders. The patient has uncontrolled hypertension (>150/100 mmHg) on a standard regimen of anti-hypertensive therapy. The patient is receiving chronic daily treatment with aspirin (>325 mg/day) or nonsteroidal anti-inflammatory agents known to inhibit platelet function. The patient is receiving treatment with dipyridamole (Persantine®), ticlopidine (Ticlid®), clopidogrel (Plavix®) and /or cilostazol (Pletal®). The patient is receiving anti-coagulation therapy. Prophylactic anti-coagulation of venous access devices is allowed. Caution should be taken on treating patients with low dose heparin or low molecular weight heparin for deep vein thrombosis (DVT) prophylaxis during treatment with bevacizumab as there may be an increased risk of bleeding. Patients with a history of gross hemoptysis (defined as bright red blood or greater than or equal to ½ teaspoon). The patient has a serious non-healing wound ulcer, bone fracture, or major surgical procedure within 30 days prior to first dose of study medication. Elective or planned major surgery to be performed during the course of the trial. The patient has a pre-existing neuropathy >grade 1. The patient, if a woman, is pregnant or lactating.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6)<br>Cycles 1-6: Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Paclitaxel 200 mg/m² on day 1 of every 3 week cycle Carboplatin area under curve (AUC=6 min*mg/mL) on day 1 of every 3 week cycle Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met | Biological: Cetuximab<br>* Administered intravenously<br>* Other names: Erbitux;Biological: Bevacizumab<br>* Administered intravenously<br>Drug: Paclitaxel<br>* Administered intravenously<br>Drug: Carboplatin<br>* Administered intravenously<br>|
| Active Comparator: Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3)<br>Cycles 1-6: Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Cycles 1-3: Paclitaxel 200 mg/m² on day 1 of each 3 week cycle for the first 3 cycles Carboplatin AUC=6 min*mg/mL on day 1 of each 3 week cycle for the first 3 cycles Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met | Biological: Cetuximab<br>* Administered intravenously<br>* Other names: Erbitux;Biological: Bevacizumab<br>* Administered intravenously<br>Drug: Paclitaxel<br>* Administered intravenously<br>Drug: Carboplatin<br>* Administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from randomization until the date of progression of disease (PD) or death from any cause. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. PD ≥20% increase in sum of longest diameter of target lesions. Participants who are alive and without PD will be censored at the date of their last tumor assessment. | Randomization to PD or date of death from any cause up to 33.1 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from randomization to death. Participants who are alive will be censored on the last known alive date. | Randomization to the date of death from any cause up to 42.7 months | 
| Percentage of Participants Achieving an Objective Overall Response (Overall Response Rate) | The best objective overall response rate (ORR) is the percentage of randomized participants with a best overall response of complete response (CR) or partial response (PR), as classified by the investigator according to the RECIST guidelines. CR=disappearance of all target lesions; PR≥30% decrease in sum of longest diameter of target lesions. ORR is calculated as a total number of participants with CR or PR divided by the total number of participants treated in that arm, multiplied by 100. Participants with no post-baseline evaluation will be considered as a non-responder. | Randomization to measured progressive disease up to 31.8 months | 
| Duration of Overall Response | The duration of response, in participants with best overall response of CR or PR, is measured from the date criteria are met for CR/PR (whichever is first recorded), until the first date that the criteria for PD is met or death. CR, PR, and PD, as classified by the investigator according to the RECIST guidelines. CR=disappearance of all target lesions; PR≥30% decrease in sum of longest diameter of target lesions; PD≥20% increase in sum of longest diameter of target lesions. Participants who are alive and without PD will be censored at the date of their last tumor assessment. | Time of first response to the first date of PD or death due to any cause up to 31.8 months | 
| Percentage of Participants With Symptomatic Response (Symptom Response Rate) | Functional Assessment of Cancer Therapy for Patients With Lung Cancer (FACT-L) measures domains of health-related quality of life (HR-QL): physical wellbeing (WB), social/family WB, emotional WB, functional WB, and additional lung cancer concerns. Symptom response (improvement) was defined as ≥2 point increase from baseline in the 7-item Lung cancer subscale (LCS) score maintained for 2 consecutive assessments. Scores range from 0-28 with higher scores indicating fewer symptoms. Patients with a score of >26 were not evaluable for symptom response, since a score of 28 is the maximum possible. | From date of partial response until progression of disease up to 31.8 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Small Cell Lung Cancer, Malignant pleural effusions