Safety and Quality of Life Study of Aflibercept in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen

A Multicenter, Single Arm, Open Label Clinical Trial to Evaluate the Safety and Health-Related Quality of Life of Aflibercept in Patients With Metastatic Colorectal Cancer (mCRC) Previously Treated With an Oxaliplatin-Containing Regimen

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01571284

Enrollment

781

Registered

2012-04-05

Start date

2012-05-30

Completion date

2017-01-31

Last updated

2018-04-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Colorectal Cancer Metastatic

Brief summary

Primary Objective: To provide metastatic colorectal cancer participants with access to aflibercept and to document the overall safety in these participants Secondary Objective: To document the Health-Related Quality of Life of aflibercept in this participants population

Detailed description

Each participants will be treated until disease progression, unacceptable toxicity, death, Investigator's decision or participant's refusal for further treatment (whichever comes first). Participants were followed-up during study treatment and for at least 30 days after last administration.

Interventions

DRUGAFLIBERCEPT AVE0005

Pharmaceutical form:Concentrate for solution for infusion Route of administration: Intravenous

DRUGFOLFIRI

irinotecan, 5-FU and leucovorin

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

: * Histologically or cytologically proven adenocarcinoma of the colon or rectum. * Metastatic disease. * Eastern Cooperative Oncology Group performance status 0-1. * One and only one prior chemotherapeutic regimen for metastatic disease. This prior chemotherapy was an oxaliplatin containing regimen. Participants must had progressed during or after the oxaliplatin based chemotherapy. Participants relapsed within 6 months of completion of oxaliplatin adjuvant chemotherapy were eligible. * Signed written informed consent obtained prior to inclusion.

Exclusion criteria

* Prior therapy with irinotecan. * Inadequate bone marrow, liver and renal function: neutrophils \< 1.5x109/L, platelets \< 100x109/L, hemoglobin \< 9.0 g/dL, total bilirubin \>1.5 x upper normal limit (ULN), transaminases \>3 x ULN (unless liver metastasis are present), alkaline phosphatase \>3 x ULN (unless liver metastasis are present), serum creatinine \> 1.5 x ULN. * Less than 4 weeks from prior radiotherapy, prior chemotherapy, prior major surgery (or until the surgical wound were fully healed). * Treatment with any investigational drug within the prior 30 days. * Treatment with concomitant anticonvulsivant agents that were CYP3A4 inducers (phenytoin, phenobarbital, carbamazepine), unless discontinued \>7 days. * History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis or new evidence of brain or leptomeningeal disease. * Prior malignancy (other than colorectal) including prior malignancy from which the participants had been disease free for \< 5 years (except adequately treated basal or squamous cell skin cancer or carcinoma in situ of the cervix). * Any of the following within 6 months prior to study inclusion: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, severe congestive heart failure, stroke or transient ischemic attack. * Any of the following within 3 months prior study inclusion: severe gastrointestinal bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event. * Occurrence of deep vein thrombosis within 4 weeks, prior to study inclusion. * Known acquired immunodeficiency syndrome (AIDS-related illnesses) or known HIV disease requiring antiretroviral treatment. * Known dihydropyrimidine dehydrogenase deficiency. * Predisposing colonic or small bowel disorders in which the symptoms were uncontrolled. * Prior history of chronic enteropathy, inflammatory enteropathy, chronic diarrhea, unresolved bowel obstruction/sub-obstruction, more than hemicolectomy, extensive small intestine resection with chronic diarrhea. * Known Gilbert's syndrome. * Unresolved or unstable toxicity from any prior anti cancer therapy at the time of inclusion. * History of anaphylaxis or known intolerance to atropine sulphate or loperamide or appropriate antiemetics to be administered in conjunction with FOLFIRI (irinotecan, 5-Fluorouracil, leucovorin). * Severe acute or chronic medical condition, which could impair the ability of the participants to participate to the study. * Urine protein-creatinine ratio (UPCR) \>1 on morning spot urinalysis or proteinuria \> 500 mg/24-h. * Uncontrolled hypertension within 3 months prior to study inclusion. * Participants on anticoagulant therapy with unstable dose of warfarin and/or had an out-of-therapeutic range INR within the 4 weeks prior to study inclusion. * Evidence of clinically significant bleeding predisposition or underlying coagulopathy, non-healing wound. * Pregnant or breast-feeding women. * Participants with reproductive potential who were not agree to use an accepted effective method of contraception. The above information wass not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Cycle Delay and/or Dose Modification	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	A theoretical cycle is a 2 week period i.e. 14 days. A cycle is delayed if duration of previous cycle is greater than 14+2 days ; dose modification includes dose reduction and dose omission.
Number of Participants With Abnormal Non-Gradable Biochemistry Parameters	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	Non-gradeable biochemistry parameters included; chloride, urea, total protein, blood urea nitrogen (BUN) and lactate dehydrogenase (LDH). Number of participants with \<lower limit of normal ranges (LLN) and \>upper limit of normal ranges (ULN) for each of these parameters were reported.
Number of Participants With Proteinuria Events	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	Proteinuria is defined as the ratio of protein to creatinine. Number of participants with proteinuria were analyzed by grades (Grades 1, 2, 3 ,4) as per NCI CTCAE Version 4.03 where Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling.
Number of Participants With Proteinuria Grade >=2	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	Proteinuria is defined as the ratio of protein to creatinine. Number of participants with proteinuria grade \>=2 (graded as per NCI CTCAE Version 4.03), where Grade\>=2 represents moderate to life-threatening/disabling event.
Number of Participants With Urinary Protein-Creatinine Ratio (UPCR)	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	Urinary protein creatinine ratio (UPCR) corresponds to the ratio of the urinary protein and urinary creatinine concentration (expressed in mg/dL). This ratio provides an accurate quantification of 24-hours urinary protein excretion. There is a high correlation between morning UPCR and 24-hour proteinuria in participants with normal or reduced renal functions. Normal ratio is \< or = 1.
Number of Participants With Proteinuria (Grade>=2) Concomitant With Hematuria and /or Hypertension	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	Proteinuria is defined as the presence of excess proteins in the urine (assessed either by spot sample, dipstick/ urine protein or 24 hour urine collection). Hematuria is defined as the presence of blood in urine (positive dipstick for RBC or reported AE). Number of participants with proteinuria grade \>=2 (graded as per NCI CTCAE Version 4.03), where Grade\>=2 represents moderate to life-threatening/disabling event. Hypertension (high blood pressure) is defined as having a blood pressure reading of more than 140/90 mmHg over a number of weeks.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	Any untoward medical occurrence in a participant who received investigational medicinal product (IMP) was considered an adverse event (AE) without regard to possibility of causal relationship with this treatment. A serious AE (SAE): Any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs. National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Version 4.03 was used to assess severity (Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling) of AEs.
Number of Participants With Abnormal Hematological Parameters	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	Abnormal hematological parameters included: anaemia, thrombocytopenia, leukopenia and neutropenia. Number of participants with each of these parameters were analyzed by grades (All Grades and Grades 3-4 as per NCI CTCAE (Version 4.03), where Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4.
Number of Participants With International Normalized Ratio (INR)	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	The INR is a derived measure of the prothrombin time. The INR is the ratio of a participant's prothrombin time to a normal control sample. Normal range (without anti coagulation therapy): 0.8-1.2; Targeted range (with anti coagulation therapy) 2.0-3.0.
Number of Participants With Abnormal Electrolytes Parameters	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	Abnormal electrolytes parameters included: hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, hypokalemia, and hyperkalemia. Number of participants with each of these parameters were analyzed by grades ( All Grades and Grades 3-4 as per NCI CTCAE Version 4.03, where Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4.
Number of Participants With Abnormal Renal and Liver Function Parameters	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	Renal and liver function parameters included: creatinine, hyperbilirubinemia, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase. Number of participants with each of these parameters were analyzed by grades (All Grades and Grades 3-4) as per NCI CTCAE version 4.03, where Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4.
Creatinine Clearance of Aflibercept Plus FOLFIRI	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	Creatinine clearance is a measure of kidney function. Creatinine clearance rate is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Creatinine clearance can be measured directly or estimated using established formulas. For this study, the creatinine clearance was calculated using the Cockroft-Gault or Modification of Diet in Renal Disease (MDRD).
Number of Participants With Other Abnormal Biochemistry Parameters	Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)	Other abnormal biochemistry parameters included: hypoglycemia, hyperglycemia and hypoalbuminemia. Number of participants with each of these parameters were analyzed by grades (All Grades and Grades 3-4) as per NCI CTCAE Version 4.03, where Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4.

Secondary

Measure	Time frame	Description
Mean Change From Baseline in HRQL EORTC QLQ-C30 Score: Functional Scales	Pre-dose at Baseline, Day 1 of every odd cycle (from Cycle 3 to 35); at EOT (within 30 days of last treatment) (maximum exposure: 214 weeks)	EORTC-QLQ-C30 is a cancer-specific instrument with 30 questions for evaluation of new chemotherapy and provides an assessment of participant reported outcome dimensions. First 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical,role,emotional,cognitive,social), 3 symptom scales (fatigue,nausea/vomiting,pain) & other single items. For each item,high score represented high level of symptomatology/problem. Last 2 questions represented participant's assessment of overall health & quality of life, coded on 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 observed values and change from baseline for global health status (scoring of questions 29 & 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28).Answers were converted into grading scale, with values between 0 and 100. A high score represented a favourable outcome with a best quality of life for participant.
Change From Baseline in HRQL EORTC QLQ-C30 Score: Symptom Scales	Pre-dose at Baseline, Day 1 of every odd cycle (from Cycle 3 to 35); at EOT (within 30 days of last treatment) (maximum exposure: 214 weeks)	EORTC-QLQ-C30 is a cancer-specific instrument with 30 questions for evaluation of new chemotherapy and provides an assessment of participant reported outcome dimensions. First 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical,role,emotional,cognitive,social), 3 symptom scales (fatigue,nausea/vomiting,pain) & other single items. For each item,high score represented high level of symptomatology/problem. Last 2 questions represented participant's assessment of overall health & quality of life, coded on 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 observed values and change from baseline for global health status (scoring of questions 29 & 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28). Answers were converted into grading scale, with values between 0 and 100. A high score represented a favorable outcome with a best quality of life for participant.
Change From Baseline in HRQL EQ-5D-3L Quality of Life: Single Index Utility Score	Pre-dose at Baseline, Day 1 of every odd cycle (from Cycle 3 to 35); at EOT (within 30 days of last treatment) (maximum exposure: 214 weeks)	EQ-5D was a standardized HRQL questionnaire consisting of EQ-5D descriptive system and Visual Analogue Scale (VAS). EQ-5D descriptive system comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression measured on 3 levels (no problem, some problems & severe problems) within a particular EQ-5D dimension. 5 dimensional 3-level system was converted into single index utility score. Possible values for single index utility score ranged from -0.594 (severe problems in all dimensions) to 1.0 (no problem in all dimensions) on scale where 1 represented best possible health state.
Change From Baseline in HRQL EQ-5D-3L VAS Score	Pre-dose at Baseline, Day 1 of every odd cycle (from Cycle 3 to 35); at EOT (within 30 days of last treatment) (maximum exposure: 214 weeks)	EQ-5D was a standardized HRQL questionnaire consisting of EQ-5D descriptive system and VAS. EQ-5D descriptive system comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression measured on 3 levels (no problem, some problems & severe problems) within a particular EQ-5D dimension. 5 dimensional 3-level system was converted into single index utility score. The VAS recorded the respondent's self-rated health on a vertical visual analogue scale. The VAS 'thermometer' has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst imaginable health state) at the bottom. This information can be used as a quantitative measure of health outcome as judged by the individual respondents.
Mean Change From Baseline in Health Related Quality of Life (HRQL) European Organization for Research and Treatment for Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30 Score): Global Health Status	Pre-dose at Baseline, Day 1 of every odd cycle (from Cycle 3 to 35); at the end of treatment (EOT) (within 30 days of last treatment) (maximum exposure: 214 weeks)	EORTC-QLQ-C30 is a cancer-specific instrument with 30 questions for evaluation of new chemotherapy and provides an assessment of participant reported outcome dimensions. First 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical,role,emotional,cognitive,social), 3 symptom scales (fatigue,nausea/vomiting,pain) & other single items. For each item,high score represented high level of symptomatology/problem. Last 2 questions represented participant's assessment of overall health & quality of life, coded on 7-point scale (1=very poor to 7=excellent).EORTC QLQ-C30 observed values and change from baseline for global health status (scoring of questions 29 & 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28). Answers were converted into grading scale, with values between 0 and 100. A high score represented a favourable outcome with a best quality of life for participant.

Countries

Belgium, Brazil, Canada, Chile, Czechia, Denmark, Finland, Germany, Ireland, Israel, Italy, Lebanon, Mexico, Netherlands, Norway, Puerto Rico, Russia, Spain, Sweden, Thailand, Turkey (Türkiye), United Kingdom, United States

Participant flow

Recruitment details

The study was conducted at 151 sites in 23 countries. A total of 798 participants were screened between 30 May 2012 and 03 January 2015, out of which 781 participants were enrolled and 779 participants were treated.

Pre-assignment details

Participants enrolled in the study to assess the safety of Aflibercept in participants treated with a combination of Aflibercept with FOLFIRI regimen (Irinotecan, Leucovorin and 5-Fluorouracil \[5-FU\]).

Participants by arm

Arm	Count
Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin) Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m\^2 IV infusion over 90 minutes and Leucovorin 400 mg/m\^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m\^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m\^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment.	779
Total	779

Arm

Count

Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)

Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m\^2 IV infusion over 90 minutes and Leucovorin 400 mg/m\^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m\^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m\^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment.

779

Total

779

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Enrolled but not treated	2
Overall Study	Lost to Follow-up	3
Overall Study	Other than specified above	80
Overall Study	Participant's decision	84

Baseline characteristics

Characteristic	Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
Age, Continuous	60.3 years STANDARD_DEVIATION 11
Any Relevant Medical/Surgical History	640 Participants
Body Surface Area (BSA)	1.80 m^2 STANDARD_DEVIATION 0.23
Diastolic Blood Pressure	76.4 mmHg STANDARD_DEVIATION 9
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0	484 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1	292 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG PS) Missing	3 Participants
Histology Adenocarcinoma	778 Participants
Histology Other	1 Participants
History of Thrombovascular Event and/or Presence of Cardiovascular Risk Factor	424 Participants
Location of Primary Tumor Colon	406 Participants
Location of Primary Tumor Other	2 Participants
Location of Primary Tumor Recto sigmoid	171 Participants
Location of Primary Tumor Rectum	200 Participants
Organs with Metastases at Baseline 1	358 Participants
Organs with Metastases at Baseline >1	421 Participants
Race/Ethnicity, Customized American Asian	121 Participants
Race/Ethnicity, Customized Black or African	8 Participants
Race/Ethnicity, Customized Other	19 Participants
Race/Ethnicity, Customized White	631 Participants
Sex: Female, Male Female	314 Participants
Sex: Female, Male Male	465 Participants
Systolic Blood Pressure	126.4 mmHg STANDARD_DEVIATION 13.4
Time From Initial Histological Diagnosis till Baseline Visit	19.1 Months STANDARD_DEVIATION 17.2

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	48 / 779
other Total, other adverse events	744 / 779
serious Total, serious adverse events	272 / 779

Outcome results

Primary

Creatinine Clearance of Aflibercept Plus FOLFIRI

Creatinine clearance is a measure of kidney function. Creatinine clearance rate is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Creatinine clearance can be measured directly or estimated using established formulas. For this study, the creatinine clearance was calculated using the Cockroft-Gault or Modification of Diet in Renal Disease (MDRD).