Study of AVE0005 (VEGF Trap) in Locally Advanced or Metastatic Platinum- and Erlotinib- Resistant Non-small-cell-lung Adenocarcinoma

Study Overview
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Brief Summary
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This study evaluated the efficacy and safety of aflibercept in the treatment of participants with advanced chemoresistant non-small cell lung adenocarcinoma (NSCLA). Primary objective: To determine the overall objective response rate (ORR) of AVE0005 (ziv-aflibercept, aflibercept, VEGF trap, ZALTRAP®) 4.0 mg/kg intravenously (IV) every 2 weeks in participants with platinum- and erlotinib-resistant, locally advanced or metastatic NSCLA. Secondary objective: To assess duration of response (DR), progression-free survival (PFS), and overall survival (OS) in this participant population To evaluate the safety profile of IV AVE0005 (ziv-aflibercept, aflibercept, VEGF trap, ZALTRAP®). This study employed an Independent Review Committee (IRC) for radiological tumor assessments. For all tumor assessment-related efficacy variables, two analyses were performed: the primary analysis was based on Independent Review Committee (IRC) reviewed data and the secondary analysis was based on Investigator evaluation. In addition, both Response Evaluation Criteria In Solid Tumors (RECIST) and Modified Response Evaluation Criteria In Solid Tumors (mRECIST) were used to assess tumors. Where as RECIST criteria only consider the longest diameter of the tumors for calculations pertaining to changes in tumor size, mRECIST assessments also account for the differences in the cavities of lesions observed in non-small-cell lung cancer (NSCLC). Responses based on RECIST and mRECIST are reported.

Detailed Description
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The study included : A screening phase up to 21 days followed by registration Treatment initiation within 5 working days of registration A treatment phase with 14-day study treatment cycles until a study withdrawal criterion was met or up to the clinical database cut-off date (18 July 2008) A follow-up phase - up to 60 days after end of treatment Withdrawal criteria that led to treatment discontinuation were: The participant or their legally authorized representative requested to withdraw In the investigator's opinion, continuation of the study would be detrimental to the participant's well being, due to reasons such as disease progression, unacceptable toxicity, noncompliance, or logistical considerations. A specific request by the Sponsor Participant had intercurrent illness that prevented further administration of study treatment Participant had more than 2 aflibercept dose reductions Participant had arterial thromboembolic events, including cerebrovascular accidents, myocardial infarctions, transient ischemic attacks, new onset or worsening of pre-existing angina Participant had radiographic evidence of intestinal obstruction (e.g., dilated loops of bowel accompanied by air-fluid levels) or gastrointestinal perforation (e.g., presence of extraluminal gas) requiring surgical intervention Participant was lost to follow-up After discontinuing treatment, participants remained on the study until the last post-treatment visit or until recovery of drug related toxicities, whichever was later.

Official Title
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A Multicenter, Open-label, Single-arm, Two-stage Study of the Efficacy and Safety of AVE0005 (VEGF Trap) Administered Intravenously Every 2 Weeks in Patients With Platinum- and Erlotinib-resistant Locally Advanced or Metastatic Non-small-cell Lung Adenocarcinoma

Conditions
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Pulmonary Diseases, Neoplasms, Lung

Intervention / Treatment
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* Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)


Participation Criteria
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Eligibility Criteria
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Participants who met the following criteria were eligible for the study. Inclusion Criteria: Histologically confirmed non-small-cell lung adenocarcinoma that is locally advanced or metastatic Prior treatment with at least 2 cancer drug regimens in the advanced disease setting Platinum- and erlotinib-resistant disease defined by relapse or progression during or after treatment Measurable disease by RECIST criteria ECOG Performance status less than or equal to 2 Resolution of any toxic effects of prior therapy Adequate organ and bone marrow function Female patients must be post-menopausal, surgically sterile or using effective contraception Willing and able to comply with study procedures and sign informed consent Exclusion Criteria: Diagnosis of squamous-cell lung cancer or any second malignancy within the last 5 years (except for adequately treated basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri) Prior treatment with a VEGF or VEGF receptor inhibitor with the exception of bevacizumab (Avastin-TM) Anticipation of a need for major surgical procedure Treatment with chemotherapy, radiotherapy, surgery, blood products, or an investigational agent within 3 weeks (6 weeks for nitrosoureas, mitomycin C, immunotherapy, or cytokine therapy) of study enrollment Uncontrolled hypertension Any severe or acute medical or psychiatric problem within the past 6 months requiring further investigation or that may cause undue risk for the patient's safety History of brain metastases, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease Active infection or on antiretroviral therapy for HIV disease Pregnant or breast-feeding The above information is not intended to contain all considerations relevant to potential participation in a clinical trial.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: aflibercept 4.0 mg/kg<br>Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept every 2 weeks until a study withdrawal criterion was met. | Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)<br>* Aflibercept 4.0 mg/kg administered intravenously (IV) over a period of at least 1 hour once every 2 weeks. Aflibercept could be reduced by 1 dose level (to 3.0 mg/kg) or 2 dose levels (to 2.0 mg/kg) in case of uncontrolled hypertension or urinary protein >3.5 g/24 hours. Intrapatient dose escalation was not to be permitted. Participants requiring more than 2 dose level reductions would be withdrawn from study treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response (OR) Based Upon Modified Response Evaluation Criteria in Solid Tumors (RECIST) Assessed by the Independent Review Committee (IRC). | OR was either complete response (CR) or partial response (PR) based on RECIST or modified RECIST. CR was the disappearance of all target/nor-target lesions; and PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, with reference to the baseline sum LD (According to modified RECIST, to calculate LD for cavitated lesions, the longest cavitation diameters were subtracted from the LD of cavitated target lesions). Assessments were made by the IRC, and confirmed by repeat tumor imaging 4-6 weeks after documentation of the initial response. | up to 2.5 years from initial treatment | 
| Confirmed Objective Response Based Upon Modified Response Evaluation Criteria in Solid Tumors (RECIST) Assessed by the Investigator. | OR was either complete response (CR) or partial response (PR) based on RECIST or modified RECIST. CR was the disappearance of all target/nor-target lesions; and PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, with reference to the baseline sum LD (According to modified RECIST, to calculate LD for cavitated lesions, the longest cavitation diameters were subtracted from the LD of cavitated target lesions). Assessments were made by the Investigator, and confirmed by repeat tumor imaging 4-6 weeks after documentation of the initial response. | up to 2.5 years from initial treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DR) | DR was the time interval from the first complete response (CR) or partial response (PR) to the date of tumor progression or death from any cause, whichever was earlier. The duration of response was calculated only for those participants who achieved CR or PR. | up to 2.5 years from initial treatment | 
| Progression-free Survival (PFS) Time Assessed by the Independent Review Committee (IRC) | PFS time was interval from the date of registration to the date of tumor progression (by RECIST or modified RECIST), or death from any cause, whichever was earlier. Median PFS time was estimated from Kaplan-Meier Plots. Progression was at least a 20% increase in the sum of the longest diameter (LD) of tumors, compared to smallest sum LD recorded since treatment started, or the appearance of one or more new tumors. If a participant did not progress or die, the date was censored to the date of last valid tumor assessment or the date of data cut-off, whichever was earlier. | up to 2.5 years from initial treatment | 
| Progression-free Survival (PFS) Time Assessed by the Investigator | PFS time was interval from the date of registration to the date of tumor progression (by RECIST or modified RECIST), or death from any cause, whichever was earlier. If a participant did not progress or die, the date was censored to the date of last valid tumor assessment or the date of data cut-off, whichever was earlier. Median PFS time was estimated from Kaplan-Meier Plots. Progression was at least a 20% increase in the sum of the longest diameter (LD) of tumors, compared to smallest sum LD recorded since treatment started, or the appearance of one or more new tumors. | up to 2.5 years from initial treatment | 
| Overall Survival (OS) | OS was the time interval between registration to the date of death from any cause. The median time for OS was estimated from Kaplan-Meier Plots. A participant was to be censored for the OS analysis if the participant was alive by the study cut-off date. The censoring date was either the date that the participant was last known to be alive or the date of study cut-off, whichever came earlier. | up to 2.5 years from initial treatment | 
| Heath-related Quality of Life (QOL) Measured Via the Lung Cancer Subscale | HRQL was assessed with the Functional Assessment of Cancer Therapy-Lung Cancer Subscale (FACT-LCS) questionnaire, which was completed by the participants on Day 1 of Cycle 1 only (for baseline value), then on Day 14 of each even-numbered cycle to evaluate the participants symptoms. The questionnaire scored 7 symptoms: shortness of breath, weight loss, clarity in thinking, coughing, appetite, chest tightness, ease of breathing, on a 0-4 scale. The total FACT-LCS score ranged from 0-28 (where 28 was related to the worst outcome). To calculate a change, the baseline score was subtracted from the score obtained after treatment. A negative value implied an improvement in HRQL. | Baseline to 2.5 years | 
| Overall Safety - Number of Participants With Adverse Events | All AEs regardless of seriousness or relationship to study treatment, spanning from the first administration of study treatment until 60 days after the last administration of study treatment, were recorded, and followed until resolution or stabilization. The number of participants with all treatment emergent adverse events (TEAE), serious adverse events (SAE), TEAE leading to death, and TEAE leading to permanent treatment discontinuation are reported. | up to 60+/-5 days after treatment discontinuation, or or until TEAE was resolved or stabilized (Collected till 18 July 2008) | 
| Number of Participants With Laboratory Abnormalities | Participants with abnormal laboratory results for Liver and renal function (Alkaline phosphatase, Alanine aminotransferase [ALT], aspartate aminotransferase [AST], Creatinine, Hyperbilirubinemia), Electrolytes (Hypercalcemia, Hypocalcemia, Hypokalemia, Hypernatremia, Hyponatremia, Hypophosphatemia) Metabolism (Hypoalbuminemia, Hyperglycemia, Hypoglycemia) Hematology (Partial thromboplastin time, Anemia, Lymphopenia, Neutropenia, Thrombocytopenia, Leukopenia) | Up to 2.5 years | 
| Peak of Free Aflibercept (VEGF Trap) | Plasma free aflibercept levels after the first aflibercept infusion were estimated by a validated direct measured by enzyme-linked immunosorbent assay (ELISA), with a limit of quantification (LOQ) of 15.6 ng/mL. | Day 1 of the first infusion of Aflibercept (cycle 1) | 
| Free and VEGF-bound Trough Aflibercept Concentrations (VEGF Trap) | Median free and VEGF-bound trough concentrations were determined at the end of each cycle beyond Cycle 2 (Steady-state) for each participant. Plasma free aflibercept levels were estimated by a validated direct ELISA, with an LOQ of 15.6 ng/mL. Plasma VEGF-bound aflibercept levels were also estimated by a separate validated direct ELISA with an LOQ of 43.9 ng/mL. Mean ± SD (coefficient of variation [CV%]) values were estimated from the median values calculated for each participant. | At the end of each treatment cycle (up to 2.5 years) | 
| Number of Participants With Anti-drug Antibodies | Anti-drug antibodies in a participant's serum sample were assayed with an anti-drug ELISA assay, with a lower limit of quantitation of 238.4 ng/mL for an undiluted human serum sample. Serum for anti-drug antibody analysis was collected pre-dose on every fourth cycle after Cycle 1 Day 1 (at 8 week intervals), at end of treatment (EOT), and during post-treatment follow-up 60 days after the last dose. | up to 2.5 years after initial treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung, cancer, non-small-cell lung cancer, metastatic, carcinoma, lung neoplasm, lung diseases, angiogenesis, anti-angiogenesis, anti-angiogenesis inhibitors, cancer and other neoplasms, respiratory tract, (lung and bronchial) diseases