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| ID | Type | Description | Link |
|---|---|---|---|
| 2013-000858-22 | |||
| U1111-1143-3015 | Other Identifier | UTN |
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The study enrollment was prematurely halted due to safety reasons.
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| Name | Class |
|---|---|
| Regeneron Pharmaceuticals | INDUSTRY |
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Primary Objectives:
Study Part 1: To determine the recommended dose for the aflibercept, oxaliplatin and capecitabine (XELOX) combination to be used in the Part 2 of the study.
Study Part 2: To assess the percentage of participants without progression of the disease at 6 months after the start of maintenance therapy with aflibercept single-agent, following the first-line induction therapy with XELOX and aflibercept combination in participants with previously untreated metastatic colorectal cancer.
Secondary Objective:
Study Part 2: Include the evaluation of progression free survival, overall survival, response to treatment, the overall safety (during induction and maintenance therapy) and the assessment of aflibercept pharmacodynamics and biomarkers parameters.
The duration of the study for each participant includes a period for screening of up to 3 weeks, study drug administrations every 3 weeks up to disease progression, unacceptable toxicity or participant's refusal of further study treatment, followed by a minimum of 30-day follow-up after the last study treatment administration.
After study treatment discontinuation each participant will be followed-up until death, participant's refusal or end of study (whichever comes first).
This trial is being conducted in Europe, where the INN designation for the study molecule is "aflibercept" and this term is therefore used throughout the synopsis. In the US, the US proper name is "ziv-aflibercept".
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Aflibercept + XELOX (Oxaliplatin and Capecitabine) | Experimental | Aflibercept 6 mg/kg every 3 weeks (q3w) in combination with Oxaliplatin 100 mg/m^2 q3w and Capecitabine 850 mg/m^2 twice daily orally (from Day 1 to Day 14 of each cycle), up to 6 cycles as induction therapy, followed by aflibercept 6 mg/kg q3w as maintenance therapy up to disease progression or unacceptable toxicity or participant's refusal of further treatment. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Aflibercept AVE0005 | Drug | Pharmaceutical form: Concentrate for solution for infusion; Route of administration: Intravenous |
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| Measure | Description | Time Frame |
|---|---|---|
| Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) | DLTs were assessed using the national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) version 4.03. DLTs were defined as any of following AEs: grade 4 neutropenia lasting >7 consecutive days; febrile neutropenia or neutropenic infection; grade 4 thrombocytopenia; grade 3 thrombocytopenia associated with bleeding requiring transfusion; grade 4 non-hematological treatment related event; grade 3 nausea/vomiting or diarrhea lasting >/= 4 days despite corrective measures; grade 3 other non-hematological toxicities: anorexia, fatigue, hypertension only if G4 or not medically controlled and G3 peripheral sensory neuropathy that did not improve to G<2 at time of retreatment; urinary protein excretion of >3.5 gram per 24 hours that did not recover to <2.0 gram per 24 hours within 2 weeks; symptomatic arterial thromboembolic events including cerebrovascular accidents, myocardial infarction, transient ischemic attacks, new onset or worsening of pre-existing angina. | Cycle 1 (Up to 3 weeks) |
| Part 2: Number of Participants With Progression Free Survival (PFS) at 6 Months After the Start of Maintenance Therapy | It describes the number of participants alive without progression at 6 months after the start of Aflibercept maintenance therapy. | 6 months after the start of maintenance therapy. |
| Measure | Description | Time Frame |
|---|---|---|
| Part 1: Number of Participants With Tumor Responses (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Progressive Disease [PD]) | Tumor assessment was performed by abdomino-pelvic computed tomography scan or magnetic resonance imaging (MRI) and chest X-ray or chest CT-scan to assess the disease status at baseline and then every 9 weeks during study treatment up to DP. Target lesions were evaluated using response evaluation criteria in solid tumors (RECIST) version 1.1, wherein CR = disappearance of all target lesions; PR = 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD; PD =20% increase in the sum of the LD of target lesions taking as reference the smallest sum in the study and SD = small changes that did not meet above criteria. |
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Inclusion criteria:
Exclusion criteria:
The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Sciences & Operations | Sanofi | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Investigational Site Number 380-001 | Genova | 16132 | Italy | |||
| Investigational Site Number 380-002 |
Participants enrolled in Part-1 of study to assess recommended phase 2 dose (RP2D) of combination of aflibercept with oxaliplatin and capecitabine. 3 participants discontinued due to adverse events (AE) and 1 participant due to disease progression (DP) at dose level 1 of treatment. Part-2 of study (efficacy and safety evaluation) was not performed.
The study was conducted at 2 sites in Italy. A total of 6 participants were screened between 17 Dec 2013 and 24 Feb 2014, out of which 4 participants were enrolled and treated.
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| ID | Title | Description |
|---|---|---|
| FG000 | Aflibercept + XELOX (Oxaliplatin and Capecitabine) | Aflibercept 6 mg/kg intravenous (IV) infusion every 3 weeks (q3w) in combination with Oxaliplatin 100 mg/m^2 IV infusion q3w and Capecitabine 850 mg/m^2 twice daily orally (from Day 1 to Day 14 of each cycle), up to 6 cycles as induction therapy, followed by aflibercept 6 mg/kg IV infusion q3w as maintenance therapy up to DP or unacceptable toxicity or participant's refusal of further treatment. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Oxaliplatin | Drug | Pharmaceutical form: Concentrate for solution for infusion; Route of administration: Intravenous |
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| Capecitabine | Drug | Pharmaceutical form: Tablets; Route of administration: Oral |
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| Baseline and every 9 weeks up to DP (up to 15 months). |
| Part 2: Progression Free Survival (PFS) | PFS was defined as the time interval from the date of registration into the study to the date of first observation of DP or death (due to any cause), whichever was first. | From the date of enrollment up to the date of DP or death, whichever occurred first (up to 15 months). |
| Part 2: Overall Survival (OS) | OS was defined as the time interval from the date of registration into the study to the date of death due to any cause. In the absence of confirmation of death, survival time was to be censored at the earliest between the last date the participant was known to be alive and the end of study date. | From the date of enrollment up to the date of death (up to 15 months). |
| Part 2: Overall Rate of Resectability of Metastatic Lesions | Overall metastases resection rate was defined as the percentage of participants reaching an R0 metastases resection, defined as the complete absence of invasive carcinoma on histological examination at the time of definitive surgery. | 12 months after the last participant enrolled. |
| Part 2: Number of Participants With CR or PR | Tumor assessment was performed by abdomino-pelvic computed tomography scan or MRI and chest X-ray or chest CT-scan to assess the disease status at baseline and then every 9 weeks during study treatment up to DP. Target lesions were evaluated using RECIST version 1.1, wherein CR = disappearance of all target lesions; PR = 30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD. | Baseline and every 9 weeks up to end of study completion (15 months). |
| Part 2: Pharmacodynamic Parameters: Modulation of Circulating Analytes | Blood and tumor samples were to be collected to evaluate the pharmacodynamic parameters including the assessment of the modulation of circulating analytes such as cytokines and angiogenic factors. | Baseline (within 21 days before registration); Day 1/pre-dose of Cycle 1, 2 and 3 of induction phase and maintenance phase; 30 ± 3 days after the last aflibercept administration. |
| Part 2: Aflibercept Biomarkers Evaluation | Blood and tumor samples were to be collected to evaluate proteomic biomarkers such as factors and receptors related to angiogenesis process, inflammation, and tumor progression. | Baseline (within 21 days before registration); Day 1/pre-dose of Cycle 1, 2 and 3 of induction phase and maintenance phase; 30 ± 3 days after the last aflibercept administration. |
| Milan |
| Italy |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Aflibercept + XELOX (Oxaliplatin and Capecitabine) | Aflibercept 6 mg/kg IV infusion q3w in combination with Oxaliplatin 100 mg/m^2 IV infusion q3w and Capecitabine 850 mg/m^2 twice daily orally (from Day 1 to Day 14 of each cycle), up to 6 cycles as induction therapy, followed by aflibercept 6 mg/kg IV infusion q3w as maintenance therapy up to DP or unacceptable toxicity or participant's refusal of further treatment. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) | DLTs were assessed using the national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) version 4.03. DLTs were defined as any of following AEs: grade 4 neutropenia lasting >7 consecutive days; febrile neutropenia or neutropenic infection; grade 4 thrombocytopenia; grade 3 thrombocytopenia associated with bleeding requiring transfusion; grade 4 non-hematological treatment related event; grade 3 nausea/vomiting or diarrhea lasting >/= 4 days despite corrective measures; grade 3 other non-hematological toxicities: anorexia, fatigue, hypertension only if G4 or not medically controlled and G3 peripheral sensory neuropathy that did not improve to G<2 at time of retreatment; urinary protein excretion of >3.5 gram per 24 hours that did not recover to <2.0 gram per 24 hours within 2 weeks; symptomatic arterial thromboembolic events including cerebrovascular accidents, myocardial infarction, transient ischemic attacks, new onset or worsening of pre-existing angina. | Evaluable DLT population defined as the subset of the whole part 1 participants that were exposed to at least 1 dose (even incomplete) of the study treatment and had a DLT assessment at Cycle 1. | Posted | Number | Participants | Cycle 1 (Up to 3 weeks) |
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| Primary | Part 2: Number of Participants With Progression Free Survival (PFS) at 6 Months After the Start of Maintenance Therapy | It describes the number of participants alive without progression at 6 months after the start of Aflibercept maintenance therapy. | Due to premature recruitment discontinuation, none of the planned efficacy analyses was performed. | Posted | 6 months after the start of maintenance therapy. |
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| Secondary | Part 1: Number of Participants With Tumor Responses (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Progressive Disease [PD]) | Tumor assessment was performed by abdomino-pelvic computed tomography scan or magnetic resonance imaging (MRI) and chest X-ray or chest CT-scan to assess the disease status at baseline and then every 9 weeks during study treatment up to DP. Target lesions were evaluated using response evaluation criteria in solid tumors (RECIST) version 1.1, wherein CR = disappearance of all target lesions; PR = 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD; PD =20% increase in the sum of the LD of target lesions taking as reference the smallest sum in the study and SD = small changes that did not meet above criteria. | Evaluable Population (EP) for tumor response was defined as a subset of ITT population (all participants who gave their informed consent and successfully registered into study) with measurable disease at study entry, who received at least 1 cycle of study treatment, with at least 1 post baseline tumor evaluation, except for early DP or death. | Posted | Number | Participants | Baseline and every 9 weeks up to DP (up to 15 months). |
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| Secondary | Part 2: Progression Free Survival (PFS) | PFS was defined as the time interval from the date of registration into the study to the date of first observation of DP or death (due to any cause), whichever was first. | Due to premature recruitment discontinuation, none of the planned efficacy analyses was performed. | Posted | From the date of enrollment up to the date of DP or death, whichever occurred first (up to 15 months). |
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| Secondary | Part 2: Overall Survival (OS) | OS was defined as the time interval from the date of registration into the study to the date of death due to any cause. In the absence of confirmation of death, survival time was to be censored at the earliest between the last date the participant was known to be alive and the end of study date. | Due to premature recruitment discontinuation, none of the planned efficacy analyses was performed. | Posted | From the date of enrollment up to the date of death (up to 15 months). |
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| Secondary | Part 2: Overall Rate of Resectability of Metastatic Lesions | Overall metastases resection rate was defined as the percentage of participants reaching an R0 metastases resection, defined as the complete absence of invasive carcinoma on histological examination at the time of definitive surgery. | Due to premature recruitment discontinuation, none of the planned efficacy analyses was performed. | Posted | 12 months after the last participant enrolled. |
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| Secondary | Part 2: Number of Participants With CR or PR | Tumor assessment was performed by abdomino-pelvic computed tomography scan or MRI and chest X-ray or chest CT-scan to assess the disease status at baseline and then every 9 weeks during study treatment up to DP. Target lesions were evaluated using RECIST version 1.1, wherein CR = disappearance of all target lesions; PR = 30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD. | Due to premature recruitment discontinuation, none of the planned efficacy analyses was performed. | Posted | Baseline and every 9 weeks up to end of study completion (15 months). |
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| Secondary | Part 2: Pharmacodynamic Parameters: Modulation of Circulating Analytes | Blood and tumor samples were to be collected to evaluate the pharmacodynamic parameters including the assessment of the modulation of circulating analytes such as cytokines and angiogenic factors. | Due to premature recruitment discontinuation, no samples had been collected and none of the planned efficacy/pharmacodynamic analyses was performed. | Posted | Baseline (within 21 days before registration); Day 1/pre-dose of Cycle 1, 2 and 3 of induction phase and maintenance phase; 30 ± 3 days after the last aflibercept administration. |
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| Secondary | Part 2: Aflibercept Biomarkers Evaluation | Blood and tumor samples were to be collected to evaluate proteomic biomarkers such as factors and receptors related to angiogenesis process, inflammation, and tumor progression. | Due to premature recruitment discontinuation, no samples had been collected and none of the planned biomarker analyses was performed. | Posted | Baseline (within 21 days before registration); Day 1/pre-dose of Cycle 1, 2 and 3 of induction phase and maintenance phase; 30 ± 3 days after the last aflibercept administration. |
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All AEs were collected from signature of the informed consent form up to 30 days after the last administration of treatment regardless of seriousness or relationship to study treatment.
Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (from the first study treatment administration to 30 days after the last study treatment administration).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Aflibercept + XELOX (Oxaliplatin and Capecitabine) | Aflibercept 6 mg/kg intravenous(IV) infusion every 3 weeks (q3w) in combination with Oxaliplatin 100 mg/m^2 IV infusion q3w and Capecitabine 850 mg/m^2 twice daily orally (from Day 1 to Day 14 of each cycle), up to 6 cycles as induction therapy, followed by aflibercept 6 mg/kg IV infusion q3w as maintenance therapy up to DP or unacceptable toxicity or participant's refusal of further treatment. | 3 | 4 | 4 | 4 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute coronary syndrome | Cardiac disorders | MedDRA 18.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 18.0 | Systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA 18.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bradycardia | Cardiac disorders | MedDRA 18.0 | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA 18.0 | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA 18.0 | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 18.0 | Systematic Assessment |
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| Haemorrhoids | Gastrointestinal disorders | MedDRA 18.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 18.0 | Systematic Assessment |
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| Stomatitis | Gastrointestinal disorders | MedDRA 18.0 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 18.0 | Systematic Assessment |
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| Asthenia | General disorders | MedDRA 18.0 | Systematic Assessment |
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| Chest pain | General disorders | MedDRA 18.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 18.0 | Systematic Assessment |
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| Localised oedema | General disorders | MedDRA 18.0 | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA 18.0 | Systematic Assessment |
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| Device related infection | Infections and infestations | MedDRA 18.0 | Systematic Assessment |
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| Pharyngitis | Infections and infestations | MedDRA 18.0 | Systematic Assessment |
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| Incisional hernia | Injury, poisoning and procedural complications | MedDRA 18.0 | Systematic Assessment |
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| Weight decreased | Investigations | MedDRA 18.0 | Systematic Assessment |
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| Weight increased | Investigations | MedDRA 18.0 | Systematic Assessment |
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| Decreased appetite | Metabolism and nutrition disorders | MedDRA 18.0 | Systematic Assessment |
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| Dehydration | Metabolism and nutrition disorders | MedDRA 18.0 | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 18.0 | Systematic Assessment |
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| Flank pain | Musculoskeletal and connective tissue disorders | MedDRA 18.0 | Systematic Assessment |
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| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA 18.0 | Systematic Assessment |
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| Dysgeusia | Nervous system disorders | MedDRA 18.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 18.0 | Systematic Assessment |
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| Paraesthesia | Nervous system disorders | MedDRA 18.0 | Systematic Assessment |
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| Depression | Psychiatric disorders | MedDRA 18.0 | Systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA 18.0 | Systematic Assessment |
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| Haematuria | Renal and urinary disorders | MedDRA 18.0 | Systematic Assessment |
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| Hydronephrosis | Renal and urinary disorders | MedDRA 18.0 | Systematic Assessment |
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| Proteinuria | Renal and urinary disorders | MedDRA 18.0 | Systematic Assessment |
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| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA 18.0 | Systematic Assessment |
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| Hiccups | Respiratory, thoracic and mediastinal disorders | MedDRA 18.0 | Systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA 18.0 | Systematic Assessment |
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| Hypotension | Vascular disorders | MedDRA 18.0 | Systematic Assessment |
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The study enrollment was prematurely halted due to safety reasons.
If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Trial Transparency Team | Sanofi | Contact-US@sanofi.com |
| ID | Term |
|---|---|
| C533178 | aflibercept |
| D000077150 | Oxaliplatin |
| D000069287 | Capecitabine |
| ID | Term |
|---|---|
| D056831 | Coordination Complexes |
| D009930 | Organic Chemicals |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D005472 | Fluorouracil |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
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