A Comparative Study Of PF-06439535 Plus Paclitaxel-Carboplatin And Bevacizumab Plus Paclitaxel-Carboplatin Patients With Advanced Non-Squamous NSCLC

Study Overview
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Brief Summary
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This is a multinational, double-blind, randomized, parallel-group Phase 3 clinical trial evaluating the efficacy and safety of bevacizumab-Pfizer plus paclitaxel and carboplatin versus bevacizumab-EU plus paclitaxel and carboplatin in first-line treatment for patients with advanced (unresectable, locally advanced, recurrent or metastatic) non-squamous NSCLC.

Official Title
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A PHASE 3 RANDOMIZED, DOUBLE-BLIND STUDY OF PF- 06439535 PLUS PACLITAXEL-CARBOPLATIN AND BEVACIZUMAB PLUS PACLITAXEL -CARBOPLATIN FOR THE FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED NON-SQUAMOUS NON-SMALL CELL LUNG CANCER.

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Bevacizumab-Pfizer
* Drug: Bevacizumab-EU
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients age at least 18 years of age, or age of consent in the region. Newly diagnosed Stage IIIB or IV non-small cell lung cancer (according to Revised International System for Staging Lung Cancer criteria of 2010) or recurrent non-small cell lung cancer (NSCLC). Histologically or cytologically confirmed diagnosis of predominately non-squamous NSCLC. Be eligible to receive study treatment of bevacizumab, paclitaxel, and carboplatin based on local standard of care, for the treatment of advanced or metastatic non-squamous NSCLC. Exclusion Criteria: Small cell lung cancer (SCLC) or combination SCLC and NSCLC. Squamous-cell tumors and mixed adenosquamous carcinomas of predominantly squamous nature. Evidence of a tumor that compresses or invades major blood vessels or tumor cavitation that is likely to bleed. Known sensitizing EGFR mutations (for example, deletion 19 or L858R) or EML4-ALK translocation positive mutations. Prior systemic therapy for NSCLC; prior neoadjuvant or adjuvant therapy is allowed if surgical resection for primary disease was performed.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab-Pfizer<br>Bevacizumab-Pfizer plus paclitaxel and carboplatin | Drug: Bevacizumab-Pfizer<br>* Bevacizumab-Pfizer: 15 mg/kg IV on Day 1 of a 21-day cycle for each of at least 4 and no more than six (6) 21-day cycles, followed by the assigned blinded bevacizumab monotherapy.<br>Drug: Paclitaxel<br>* Paclitaxel 200 mg/m2 via IV infusions on Day 1 of a 21-day cycle for each of at least 4 and no more than six (6) 21-day cycles.<br>Drug: Carboplatin<br>* carboplatin AUC =6.0 via IV infusions on Day 1 of a 21-day cyclefor each of at least 4 and no more than six (6) 21-day cycles.<br>|
| Active Comparator: Bevacizumab-EU<br>Bevacizumab-EU plus paclitaxel and carboplatin | Drug: Bevacizumab-EU<br>* bevacizumab-EU: 15 mg/kg IV on Day 1 of a 21-day cycle for each of at least 4 and no more than six (6) 21-day cycles followed by the assigned blinded bevacizumab monotherapy.<br>Drug: Paclitaxel<br>* Paclitaxel 200 mg/m2 via IV infusions on Day 1 of a 21-day cycle for each of at least 4 and no more than six (6) 21-day cycles.<br>Drug: Carboplatin<br>* carboplatin AUC =6.0 via IV infusions on Day 1 of a 21-day cyclefor each of at least 4 and no more than six (6) 21-day cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) by Week 19 | ORR refers to percentage of participants who achieved complete response (CR) or partial response (PR) by Week 19 of the study in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 which was subsequently confirmed by Week 25. A participant achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved PR if target lesions achieved CR or PR, non-target lesions were assessed as non-CR/non-PD (progressive disease), indeterminate or missing, and no new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes must decrease to normal size); PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target lesions, CR: disappearance of all non-target lesions and normalization of tumor marker levels and all lymph nodes must be normal in size; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits. | 25 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events | AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causal relationship to study treatment. Treatment-emergent AEs (TEAEs) were defined as AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. | 55 weeks | 
| Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality) | Laboratory evaluation included hematology (hemoglobin, white blood cells, platelets and absolute neutrophil count), blood chemistry (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, serum or plasma creatinine, sodium, potassium, total calcium, magnesium, blood urea nitrogen or urea, and albumin ), coagulation (international normalized ratio for prothrombin time and activated partial thromboplastin time) and urinalysis (dipstick followed by a quantitative urine protein analysis for results of 2+ or greater). | 55 weeks | 
| Duration of Response (DOR) | DOR was defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause in the absence of documented PD. DOR was based on the Brookmeyer and Crowley method. | 55 weeks | 
| Progression Free Survival Rate at 55 Weeks | This outcome measure refers to the possibility of being progression free at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method. | 55 weeks | 
| Survival Rate at 55 Weeks | This outcome measure refers to the possibility of being alive at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method. | 55 weeks | 
| Serum Concentration of Bevacizumab up to 1 Year |  | Pre-dose from Cycle 1 to Cycle 17, 2.5 hours post-dose in Cycle 1, and 1.5 hours post-dose in Cycle 5 | 
| Number of Participants With Anti-Drug Antibody (ADA) | ADA assay was performed using a sensitive, specific, and semi-quantitative electrochemiluminescent (ECL) method, which used biotinylated- and ruthenium-labeled PF-06439535 as reagents. Samples with ADA titer greater than or equal to (>=) 2.29 were considered positive. | 55 weeks | 
| Number of Participants With Neutralizing Antibody (NAb) | Only samples that were confirmed positive for ADA were further tested for NAb. The NAb analysis was conducted using a single validated quasi-quantitative enzyme-linked immunosorbent assay (ELISA) that utilized PF-06439535 as a reagent. Samples with NAb titer >=1.70 were considered positive. | 55 weeks |