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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Drug: Aflibercept AVE0005
* Drug: Oxaliplatin
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically or cytologically-proven adenocarcinoma of the colon or rectum. Metastatic disease not amenable to potentially curative treatment (i.e. unresectable). Measurable lesion as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. No prior systemic anti-cancer treatment for metastatic disease. No prior adjuvant treatment after resection of distant metastases. No prior treatment with angiogenesis inhibitors. Exclusion criteria: Age <18 years. Eastern Cooperative Oncology Group Performance status >/= 2. Less than 4 weeks from prior radiotherapy or prior surgery (or until the surgical wound is fully healed). Treatment with any other investigational product within the prior 28 days. Other prior neoplasm. History of brain metastases, active seizure disorder, uncontrolled spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Any of the following within the prior 6 months: 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 the prior 3 months: moderate/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. Deep vein thrombosis within the prior 4 weeks. Any severe acute or chronic medical condition, which could impair the ability of the participant to participate in the study. Inadequate bone marrow, liver and renal function: neutrophils < 1.5x10^9/L, platelets < 100x10^9/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. Participants on anticoagulant therapy with warfarin. Symptomatic peripheral sensory neuropathy. Inability to take oral medications. Prior history of chronic enteropathy, inflammatory enteropathy, chronic diarrhea, malabsorption syndrome, unresolved bowel obstruction/sub-obstruction, surgery more extensive than hemicolectomy, extensive small intestine resection with chronic diarrhea. Known dihydropyrimidine dehydrogenase deficiency. known history of hypersensitivity to aflibercept. Any contraindication to administer oxaliplatin or capecitabine as per package insert of each drug. Urine protein-creatinine ratio (UPCR) >1 on morning spot urinalysis or proteinuria > 500 mg/24-h. Uncontrolled hypertension within the prior 3 months. Evidence of clinically significant bleeding predisposition or underlying coagulopathy, non-healing wound. Pregnant or breast-feeding women. Participants with reproductive potential who do not agree to use an accepted effective method of contraception. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aflibercept + XELOX (Oxaliplatin and Capecitabine)<br>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. | Drug: Aflibercept AVE0005<br>* Pharmaceutical form: Concentrate for solution for infusion; Route of administration: Intravenous<br>* Other names: Zaltrap;Drug: Oxaliplatin<br>* Pharmaceutical form: Concentrate for solution for infusion; Route of administration: Intravenous<br>* Other names: SR96669;Drug: Capecitabine<br>* Pharmaceutical form: Tablets; Route of administration: Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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. | 

Secondary Outcome Measures

| Outcome Measure | 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. | 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. |