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Pharmaceutical Solutions

Capecitabine

Aflibercept

Oxaliplatin

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Angiogenesis Inhibitors

Growth Inhibitors

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.

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

Aflibercept AVE0005

Pharmaceutical form: Tablets; Route of administration: Oral

Clinical Sciences & Operations

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".

Study of Aflibercept as Maintenance Therapy Following Induction With Aflibercept in Combination With XELOX, as First-Line Treatment for Metastatic Colorectal Cancer Patient

A Single-Arm, Open Label Study of Aflibercept as Maintenance Therapy Following Induction With Aflibercept in Combination With XELOX, as First-Line Treatment for Metastatic Colorectal Cancer Patient

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.

It describes the number of participants alive without progression at 6 months after the start of Aflibercept maintenance therapy.

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.

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.

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.

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.

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.

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.

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.

Regeneron Pharmaceuticals

Sanofi

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).

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.

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.

Age, Categorical

Sex: Female, Male

The study enrollment was prematurely halted due to safety reasons.

Trial Transparency Team

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.

Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)

Due to premature recruitment discontinuation, none of the planned efficacy analyses was performed.

Part 2: Number of Participants With Progression Free Survival (PFS) at 6 Months After the Start of Maintenance Therapy

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.

Part 1: Number of Participants With Tumor Responses (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Progressive Disease [PD])

Part 2: Progression Free Survival (PFS)

Part 2: Overall Survival (OS)

Part 2: Overall Rate of Resectability of Metastatic Lesions

Part 2: Number of Participants With CR or PR

Due to premature recruitment discontinuation, no samples had been collected and none of the planned efficacy/pharmacodynamic analyses was performed.

Part 2: Pharmacodynamic Parameters: Modulation of Circulating Analytes

Due to premature recruitment discontinuation, no samples had been collected and none of the planned biomarker analyses was performed.

Part 2: Aflibercept Biomarkers Evaluation

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.

Overall Study

Micronutrients

Hematinics

Vitamins

Leucovorin

Fluorouracil

Irinotecan

Immunosuppressive Agents

Immunologic Factors

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antidotes

Protective Agents

Folic Acid

Vitamin B Complex

Trace Elements

Folate

Vitamin B9

aflibercept IV infusion for 1 hour followed by FOLFIRI IV infusion every 2 weeks

Pharmaceutical form:Solution for infusion Route of administration: Intravenous

5-Fluorouracil

Primary Objective:

To assess the safety and pharmacokinetics preliminarily of the dose of intravenous (IV) aflibercept used in western studies in combination with FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) given intravenously every 2 weeks in Chinese patients with solid tumors.

Secondary Objectives:

* To make a preliminary assessment of antitumor effects of the combination of FOLFIRI plus aflibercept in patients with measurable disease (RECIST 1.1).
* To evaluate the immunogenicity of IV aflibercept.

Total duration of the study per patient is in the range of 17 to 29 weeks.

This trial is being conducted in China, 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".

A Phase I Study of Aflibercept Plus FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) in Chinese Patients With Advanced Solid Malignancies

A Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Aflibercept in Combination With FOLFIRI Administrated Every 2 Weeks in Chinese Patients With Advanced Solid Malignancies

Intravenous (IV) infusion on Day 1 every 3 weeks, followed by CAPOX (capecitabine by oral administration on Day 1 to Day 14 and oxaliplatin intravenous (IV) infusion on Day 1 every 3 weeks) for the induction treatment period (6 cycles) after which the patient may enter the maintenance period during which the treatment is Aflibercept + Capecitabine

Pharmaceutical form:tablet Route of administration: oral

Pharmaceutical form:concentrate for infusion Route of administration: intravenous

Pharmaceutical form:solution for infusion Route of administration: intravenous

Oxaliplatin SR96669

Primary Objective:

Efficacy: To assess the progression-free survival rate at 10 months in patients on maintenance therapy with capecitabine plus aflibercept.

Secondary Objectives:

To evaluate:

* Efficacy: Progression Free Survival (PFS)
* Efficacy: Overall Survival (OS)
* Efficacy: Objective Response Rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST version 1.1) criteria
* Health related Quality of Life (HRQL): EORTC QLQ-C30 scores and EQ5D-3L
* Safety

Exploratory Objective:

To collect blood and tumor samples to perform investigations for potential biomarker testing.

Total study duration for a participant can be up to 28 months.

This trial is being conducted in countries 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".

Capecitabine Plus Aflibercept as Maintenance Therapy Following Capecitabine Plus Oxaliplatin Plus Aflibercept in Patients With Metastatic Colorectal Cancer

Phase II Study of First-line Capecitabine Plus Oxaliplatin Plus Aflibercept for 6 Cycles Followed by Capecitabine Plus Aflibercept as Maintenance Therapy in Patients With Metastatic Colorectal Cancer: DROP and GO Trial

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Aflibercept as Maintenance Therapy Following Induction With Aflibercept in Combination With XELOX, as First-Line Treatment for Metastatic Colorectal Cancer Patient	NCT01955629	Colorectal Canc...	Aflibercept AVE... Oxaliplatin Capecitabine	18 Years -	Sanofi
A Phase I Study of Aflibercept Plus FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) in Chinese Patients With Advanced Solid Malignancies	NCT01930552	Neoplasm Malign...	Aflibercept AVE... Leucovorin Irinotecan 5-Fluorouracil	18 Years -	Sanofi
Capecitabine Plus Aflibercept as Maintenance Therapy Following Capecitabine Plus Oxaliplatin Plus Aflibercept in Patients With Metastatic Colorectal Cancer	NCT02085005	Colorectal Canc...	Capecitabine Aflibercept AVE... Oxaliplatin SR9...	18 Years -	Sanofi
Study of Aflibercept as Maintenance Therapy Following Induction With Aflibercept in Combination With XELOX, as First-Line Treatment for Metastatic Colorectal Cancer Patient	NCT01955629	Colorectal Canc...	Aflibercept AVE... Oxaliplatin Capecitabine	18 Years -	Sanofi

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