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

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00284141
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 98
• Locations: 3
• Arm: 1
• Duration (Months): 30
• Patients Per Site: 32.7
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Diseases; Neoplasms, Lung	Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 98 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm

Intervention/Treatment

Experimental: aflibercept 4.0 mg/kg 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®); 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.

Outcome Measures

Primary Outcome Measures

1. Confirmed Objective Response (OR) Based Upon Modified Response Evaluation Criteria in Solid Tumors (RECIST) Assessed by the Independent Review Committee (IRC). [up to 2.5 years from initial treatment]

   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.

2. Confirmed Objective Response Based Upon Modified Response Evaluation Criteria in Solid Tumors (RECIST) Assessed by the Investigator. [up to 2.5 years from initial treatment]

   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.

Secondary Outcome Measures

1. Duration of Response (DR) [up to 2.5 years from initial treatment]

   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.

2. Progression-free Survival (PFS) Time Assessed by the Independent Review Committee (IRC) [up to 2.5 years from initial treatment]

   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.

3. Progression-free Survival (PFS) Time Assessed by the Investigator [up to 2.5 years from initial treatment]

   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.

4. Overall Survival (OS) [up to 2.5 years from initial treatment]

   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.

5. Heath-related Quality of Life (QOL) Measured Via the Lung Cancer Subscale [Baseline to 2.5 years]

   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.

6. Overall Safety - Number of Participants With Adverse Events [up to 60+/-5 days after treatment discontinuation, or or until TEAE was resolved or stabilized (Collected till 18 July 2008)]

   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.

7. Number of Participants With Laboratory Abnormalities [Up to 2.5 years]

   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)

8. Peak of Free Aflibercept (VEGF Trap) [Day 1 of the first infusion of Aflibercept (cycle 1)]

   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.

9. Free and VEGF-bound Trough Aflibercept Concentrations (VEGF Trap) [At the end of each treatment cycle (up to 2.5 years)]

   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.

10. Number of Participants With Anti-drug Antibodies [up to 2.5 years after initial treatment]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sanofi-Aventis Administrative Office	Bridgewater	New Jersey	United States	08807
2	Sanofi-Aventis Administrative Office	Laval		Canada
3	Sanofi-Aventis Administrative Office	Paris		France

Sponsors and Collaborators

• Sanofi
• Regeneron Pharmaceuticals

Investigators

• Study Director: ICD CSD, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT00284141
• Other Study ID Numbers: ARD6123; AVE0005B/2001
• First Posted: Jan 31, 2006
• Last Update Posted: Dec 10, 2012
• Last Verified: Jul 1, 2011

• Keywords provided by Sanofi: 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
• Additional relevant MeSH terms: Neoplasms; Adenocarcinoma; Adenocarcinoma of Lung; Lung Neoplasms; Aflibercept

Study Results

Participant Flow

Recruitment Details	98 participants were registered into the study, of whom, 96 were exposed to study treatment.

Arm/Group Title	Aflibercept 4.0 mg/kg
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks until a study withdrawal criterion was met.
Period Title: Overall Study
STARTED	98
TREATED	96
ONGOING TREATMENT	2
COMPLETED	0
NOT COMPLETED	98

Baseline Characteristics

Arm/Group Title	Aflibercept 4.0 mg/kg
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks until a study withdrawal criterion was met.
Overall Participants	98
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.2 (11.0)
Sex: Female, Male (Count of Participants)
Female	58 59.2%
Male	40 40.8%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	79 80.6%
Black	3 3.1%
Asian, Oriental	5 5.1%
Unknown or Not Reported	11 11.2%

Outcome Measures

1. Primary Outcome

Title	Confirmed Objective Response (OR) Based Upon Modified Response Evaluation Criteria in Solid Tumors (RECIST) Assessed by the Independent Review Committee (IRC).
Description	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.
Time Frame	up to 2.5 years from initial treatment

Outcome Measure Data

Analysis Population Description

Simon's cohort: The first 84 evaluable participants, based on Simon's two-stage study design that required 84 evaluable participants to maintain a targeted 90% power.

Arm/Group Title	Aflibercept 4.0 mg/kg Arm Assessed by Modified RECIST	Aflibercept 4.0 mg/kg Arm Assessed by RECIST
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks assessed by RECIST criteria.	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks assessed by modified RECIST criteria.
Measure Participants	84	84
Number [Participants]	0 0%	0 NaN

2. Secondary Outcome

Title	Duration of Response (DR)
Description	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.
Time Frame	up to 2.5 years from initial treatment

Outcome Measure Data

Analysis Population Description

No modified RECIST responses, as confirmed by the IRC review, were observed. Only 2 responders were reported by the Investigators. Therefore, the analyses for duration of response was not performed.

Arm/Group Title	Aflibercept 4.0 mg/kg
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks until a study withdrawal criterion was met.
Measure Participants	0

3. Secondary Outcome

Title	Progression-free Survival (PFS) Time Assessed by the Independent Review Committee (IRC)
Description	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.
Time Frame	up to 2.5 years from initial treatment

Outcome Measure Data

Analysis Population Description

All registered participants. 18 participants were censored.

Arm/Group Title	Aflibercept 4.0 mg/kg Arm Assessed by Modified RECIST	Aflibercept 4.0 mg/kg Arm Assessed by RECIST
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks assessed by RECIST criteria.	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks assessed by modified RECIST criteria.
Measure Participants	98	98
Measure Participants with PFS Events	80	80
Median (95% Confidence Interval) [weeks]	11.3	11.3

4. Secondary Outcome

Title	Progression-free Survival (PFS) Time Assessed by the Investigator
Description	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.
Time Frame	up to 2.5 years from initial treatment

Outcome Measure Data

Analysis Population Description

All registered participants. 17 participants were censored.

Arm/Group Title	Aflibercept 4.0 mg/kg Arm Assessed by Modified RECIST	Aflibercept 4.0 mg/kg Arm Assessed by RECIST
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks assessed by RECIST criteria.	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks assessed by modified RECIST criteria.
Measure Participants	98	98
Measure Participants with PFS Events	81	81
Median (95% Confidence Interval) [weeks]	12.0	11.9

5. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	up to 2.5 years from initial treatment

Outcome Measure Data

Analysis Population Description

All registered participants. 38 participants were censored for OS.

Arm/Group Title	Aflibercept 4.0 mg/kg
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks until a study withdrawal criterion was met.
Measure Participants	98
Measure Participant with OS Event (death)	60
Median (95% Confidence Interval) [months]	26.9

6. Secondary Outcome

Title	Heath-related Quality of Life (QOL) Measured Via the Lung Cancer Subscale
Description	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.
Time Frame	Baseline to 2.5 years

Outcome Measure Data

Analysis Population Description

All registered participants with available questionnaires at the timepoint assessed.

Arm/Group Title	Aflibercept 4.0 mg/kg
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks until a study withdrawal criterion was met.
Measure Participants	83
Baseline FACT-LCS Score (N=83)	19.9 (3.9)
Change from baseline at Cycle 2 (N=58)	-1.5 (3.6)
Change from baseline at Cycle 4 (N=41)	-1.9 (4.7)
Change from baseline at Cycle 6 (N=25)	-1.0 (5.0)
Change from baseline at Cycle 8 (N=13)	-1.4 (4.7)
Change from baseline at Cycle 10 (N=10)	-1.7 (6.9)
Change from baseline to last assessment (N=70)	-3.3 (5.2)

7. Secondary Outcome

Title	Overall Safety - Number of Participants With Adverse Events
Description	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.
Time Frame	up to 60+/-5 days after treatment discontinuation, or or until TEAE was resolved or stabilized (Collected till 18 July 2008)

Outcome Measure Data

Analysis Population Description

All participants who received at least part of 1 dose of study treatment.

Arm/Group Title	Aflibercept 4.0 mg/kg
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks until a study withdrawal criterion was met.
Measure Participants	96
With any TEAE	96 98%
With any Serious TEAE	47 48%
With any TEAE leading to Death	16 16.3%
with any TEAE leading to Treatment discontinuation	19 19.4%

8. Secondary Outcome

Title	Number of Participants With Laboratory Abnormalities
Description	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)
Time Frame	Up to 2.5 years

Outcome Measure Data

Analysis Population Description

All participants who received at least part of 1 dose of study treatment.

Arm/Group Title	Aflibercept 4.0 mg/kg
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks until a study withdrawal criterion was met.
Measure Participants	96
LIVER AND RENAL FUNCTION- Alkaline Phosphatase	39 39.8%
LIVER AND RENAL FUNCTION - ALT	35 35.7%
LIVER AND RENAL FUNCTION - AST	37 37.8%
LIVER AND RENAL FUNCTION - Creatinine	15 15.3%
LIVER AND RENAL FUNCTION - Hyperbilirubinemia	4 4.1%
ELECTROLYTES - Hypercalcemia	6 6.1%
ELECTROLYTES - Hypocalcemia	15 15.3%
ELECTROLYTES - Hyperkalemia	24 24.5%
ELECTROLYTES - Hypokalemia	10 10.2%
ELECTROLYTES - Hypernatremia	5 5.1%
ELECTROLYTES - Hyponatremia	41 41.8%
ELECTROLYTES - Hypophosphatemia (N=91)	14 14.3%
METABOLISM - Hypoalbuminemia (N=91)	44 44.9%
METABOLISM - Hyperglycemia	81 82.7%
METABOLISM - Hypoglycemia	10 10.2%
HEMATOLOGY - Partial thromboplastin time (N=81)	30 30.6%
HEMATOLOGY - Anemia	34 34.7%
HEMATOLOGY - Lymphopenia (N=84)	60 61.2%
HEMATOLOGY - Neutropenia (N=78)	4 4.1%
HEMATOLOGY - Thrombocytopenia	11 11.2%
HEMATOLOGY - Leukopenia	11 11.2%

9. Secondary Outcome

Title	Peak of Free Aflibercept (VEGF Trap)
Description	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.
Time Frame	Day 1 of the first infusion of Aflibercept (cycle 1)

Outcome Measure Data

Analysis Population Description

All participants who received at least part of 1 dose of study treatment and had evaluable blood samples.

Arm/Group Title	Aflibercept 4.0 mg/kg
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks until a study withdrawal criterion was met.
Measure Participants	47
Mean (Standard Deviation) [micrograms/mL]	71.4 (31.8)

10. Secondary Outcome

Title	Free and VEGF-bound Trough Aflibercept Concentrations (VEGF Trap)
Description	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.
Time Frame	At the end of each treatment cycle (up to 2.5 years)

Outcome Measure Data

Analysis Population Description

All participants who received at least part of 1 dose of study treatment and had evaluable blood samples on Day 1 of Cycle 3 for measurement of VEGF-bound aflibercept.

Arm/Group Title	Aflibercept 4.0 mg/kg
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks until a study withdrawal criterion was met.
Measure Participants	61
Trough free aflibercept concentration	9.53 (6.28)
Trough VEGF-bound aflibercept concentration	3.48 (1.04)

11. Primary Outcome

Title	Confirmed Objective Response Based Upon Modified Response Evaluation Criteria in Solid Tumors (RECIST) Assessed by the Investigator.
Description	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.
Time Frame	up to 2.5 years from initial treatment

Outcome Measure Data

Analysis Population Description

Simon's cohort: The first 84 evaluable participants, based on Simon's two-stage study design that required 84 evaluable participants to maintain a targeted 90% power.

Arm/Group Title	Aflibercept 4.0 mg/kg Arm Assessed by Modified RECIST	Aflibercept 4.0 mg/kg Arm Assessed by RECIST
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks assessed by RECIST criteria.	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks assessed by modified RECIST criteria.
Measure Participants	84	84
Objective response (OR)	2 2%	2 NaN
Complete response (CR)	0 0%	0 NaN
Partial response (PR)	2 2%	2 NaN

12. Secondary Outcome

Title	Number of Participants With Anti-drug Antibodies
Description	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.
Time Frame	up to 2.5 years after initial treatment

Outcome Measure Data

Analysis Population Description

All participants who received at least part of 1 dose of study treatment and had evaluable blood samples.

Arm/Group Title	Aflibercept 4.0 mg/kg
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks until a study withdrawal criterion was met.
Measure Participants	80
Number [participants]	0 0%

Adverse Events

Time Frame	From treatment initiation to February 24, 2009.
Arm/Group Title	4 mg/kg
Arm/Group Description	Participants with metastatic non-small-cell lung adenocarcinoma administered 4.0 mg/kg Aflibercept intravenously every 2 weeks until a study withdrawal criterion was met.
All Cause Mortality
	4 mg/kg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	4 mg/kg
	Affected / at Risk (%)	# Events
Total	48/96 (50%)
Blood and lymphatic system disorders
Febrile neutropenia	1/96 (1%)
Cardiac disorders
Atrial flutter	1/96 (1%)
Cardiac failure congestive	2/96 (2.1%)
Cardio-respiratory arrest	1/96 (1%)
Cardiomyopathy	1/96 (1%)
Gastrointestinal disorders
Abdominal discomfort	1/96 (1%)
Abdominal pain	1/96 (1%)
Dysphagia	1/96 (1%)
Nausea	1/96 (1%)
Obstruction gastric	1/96 (1%)
Pancreatitis acute	1/96 (1%)
General disorders
Asthenia	1/96 (1%)
Disease progression	7/96 (7.3%)
Fatigue	2/96 (2.1%)
Non-cardiac chest pain	2/96 (2.1%)
Infections and infestations
Cellulitis	1/96 (1%)
Pneumonia	6/96 (6.3%)
Sepsis	2/96 (2.1%)
Injury, poisoning and procedural complications
Facial bones fracture	1/96 (1%)
Fall	1/96 (1%)
Radiation injury	1/96 (1%)
Investigations
Blood creatinine increased	1/96 (1%)
Metabolism and nutrition disorders
Dehydration	2/96 (2.1%)
Diabetic ketoacidosis	1/96 (1%)
Failure to thrive	1/96 (1%)
Hyponatraemia	1/96 (1%)
Musculoskeletal and connective tissue disorders
Bone pain	1/96 (1%)
Musculoskeletal pain	1/96 (1%)
Pathological fracture	1/96 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukaemia	1/96 (1%)
Metastatic pain	1/96 (1%)
Nervous system disorders
Cerebral ischaemia	1/96 (1%)
Cerebrovascular accident	1/96 (1%)
Reversible posterior leukoencephalopathy syndrome	1/96 (1%)
Psychiatric disorders
Anxiety	1/96 (1%)
Mental status changes	1/96 (1%)
Renal and urinary disorders
Bladder stenosis	1/96 (1%)
Hydronephrosis	1/96 (1%)
Urinary retention	1/96 (1%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	2/96 (2.1%)
Dyspnoea	8/96 (8.3%)
Epistaxis	2/96 (2.1%)
Haemoptysis	2/96 (2.1%)
Pleural effusion	2/96 (2.1%)
Pneumothorax	1/96 (1%)
Pulmonary embolism	4/96 (4.2%)
Respiratory failure	2/96 (2.1%)
Vascular disorders
Axillary vein thrombosis	1/96 (1%)
Deep vein thrombosis	2/96 (2.1%)
Hypertension	2/96 (2.1%)
Superior vena caval occlusion	1/96 (1%)
Other (Not Including Serious) Adverse Events
	4 mg/kg
	Affected / at Risk (%)	# Events
Total	93/96 (96.9%)
Gastrointestinal disorders
Abdominal pain	6/96 (6.3%)
Constipation	27/96 (28.1%)
Diarrhoea	12/96 (12.5%)
Dry mouth	6/96 (6.3%)
Dysphagia	6/96 (6.3%)
Nausea	23/96 (24%)
Oral pain	5/96 (5.2%)
Vomiting	16/96 (16.7%)
General disorders
Asthenia	16/96 (16.7%)
Chest pain	5/96 (5.2%)
Disease progression	6/96 (6.3%)
Fatigue	39/96 (40.6%)
Mucosal inflammation	5/96 (5.2%)
Oedema peripheral	20/96 (20.8%)
Pain	6/96 (6.3%)
Pyrexia	11/96 (11.5%)
Infections and infestations
Pneumonia	5/96 (5.2%)
Upper respiratory tract infection	6/96 (6.3%)
Urinary tract infection	11/96 (11.5%)
Investigations
Weight decreased	9/96 (9.4%)
Metabolism and nutrition disorders
Anorexia	24/96 (25%)
Decreased appetite	9/96 (9.4%)
Dehydration	5/96 (5.2%)
Hyponatraemia	7/96 (7.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	14/96 (14.6%)
Back pain	8/96 (8.3%)
Bone pain	7/96 (7.3%)
Flank pain	5/96 (5.2%)
Musculoskeletal chest pain	7/96 (7.3%)
Musculoskeletal pain	10/96 (10.4%)
Myalgia	8/96 (8.3%)
Pain in extremity	7/96 (7.3%)
Nervous system disorders
Dizziness	8/96 (8.3%)
Headache	38/96 (39.6%)
Psychiatric disorders
Anxiety	7/96 (7.3%)
Depression	8/96 (8.3%)
Insomnia	10/96 (10.4%)
Renal and urinary disorders
Proteinuria	15/96 (15.6%)
Respiratory, thoracic and mediastinal disorders
Cough	22/96 (22.9%)
Dysphonia	27/96 (28.1%)
Dyspnoea	37/96 (38.5%)
Epistaxis	19/96 (19.8%)
Haemoptysis	11/96 (11.5%)
Oropharyngeal pain	6/96 (6.3%)
Pleural effusion	5/96 (5.2%)
Productive cough	6/96 (6.3%)
Skin and subcutaneous tissue disorders
Rash	8/96 (8.3%)
Vascular disorders
Hypertension	38/96 (39.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The investigator shall have the right to independently publish study results from his site after a multicenter publication, or 12 months after the completion of the study by all sites. He must provide the sponsor a copy of any such publication derived from the study for review and comment at least 45 days (20 days for abstracts) in advance of any submission, and delay publication till the approval of the publication is given in writing by the Sponsor (not to exceed ninety days).