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

Primary Purpose

Colorectal Cancer Metastatic

Status

Terminated

Phase

Phase 1

Locations

Italy

Study Type

Interventional

Intervention

Aflibercept AVE0005

Oxaliplatin

Capecitabine

About this trial

This is an interventional treatment trial for Colorectal Cancer Metastatic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Investigational Site Number 380-001
Investigational Site Number 380-002

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Aflibercept + XELOX (Oxaliplatin and Capecitabine)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT01955629

First Posted

September 13, 2013

Last Updated

March 18, 2016

Sponsor

Sanofi

Collaborators

Regeneron Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT01955629

Brief Title

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

Acronym

AMOR

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2016

Overall Recruitment Status

Terminated

Why Stopped

The study enrollment was prematurely halted due to safety reasons.

Study Start Date

December 2013 (undefined)

Primary Completion Date

March 2015 (Actual)

Study Completion Date

March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sanofi

Collaborators

Regeneron Pharmaceuticals

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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

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".

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colorectal Cancer Metastatic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

4 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Aflibercept + XELOX (Oxaliplatin and Capecitabine)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Aflibercept AVE0005

Other Intervention Name(s)

Zaltrap

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Oxaliplatin

Other Intervention Name(s)

Eloxatin, SR96669

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Capecitabine

Intervention Description

Pharmaceutical form: Tablets; Route of administration: Oral

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Cycle 1 (Up to 3 weeks)

Title

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

Description

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

Time Frame

6 months after the start of maintenance therapy.

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

Baseline and every 9 weeks up to DP (up to 15 months).

Title

Part 2: Progression Free Survival (PFS)

Description

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.

Time Frame

From the date of enrollment up to the date of DP or death, whichever occurred first (up to 15 months).

Title

Part 2: Overall Survival (OS)

Description

Time Frame

From the date of enrollment up to the date of death (up to 15 months).

Title

Part 2: Overall Rate of Resectability of Metastatic Lesions

Description

Time Frame

12 months after the last participant enrolled.

Title

Part 2: Number of Participants With CR or PR

Description

Time Frame

Baseline and every 9 weeks up to end of study completion (15 months).

Title

Part 2: Pharmacodynamic Parameters: Modulation of Circulating Analytes

Description

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.

Time Frame

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.

Title

Part 2: Aflibercept Biomarkers Evaluation

Description

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.

Time Frame

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.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Sciences & Operations

Organizational Affiliation

Sanofi

Official's Role

Study Director

Facility Information:

Facility Name

Investigational Site Number 380-001

City

Genova

ZIP/Postal Code

16132

Country

Italy

Facility Name

Investigational Site Number 380-002

City

Milano

Country

Italy

12. IPD Sharing Statement

Learn more about this trial

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

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