Aflibercept and Chemotherapy as First Line Treatment for Metastatic Colorectal Cancer Assessable With DCE-US (PULSAR).

Study Overview
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Brief Summary
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The PULSAR trial is an international, investigator-initiated, single arm open-label phase II study. The aim of this study is to measure the clinical activity of the combination FOLFIRI-aflibercept in an homogeneous group of patients with metastatic colorectal cancer, and treated with a FOLFIRI-aflibercept regimen as first line treatment.

Detailed Description
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Patients with an unresectable metastatic colorectal carcinoma (mCRC) histologically proven will be treated with a combination of Irinotecan/bolus-infusion-5-Fluorouracil/Leucovorin (FOLFIRI regimen) and aflibercept. On day 1 of each cycle patients will receive aflibercept followed by irinotecan, 5-Fluorouracil (FU) and leucovorin (FOLFIRI regimen). This treatment will be repeated every 2 weeks until RECIST progression or unacceptable toxicities, investigator's decision or patient's refusal of further treatment or death, whichever comes first. All patients will be assessed during their FOLFIRI-aflibercept with Dynamic Contrast Enhanced Ultrasound (DCE-US) at baseline, D7 (± 1 day), D28 (± 2 days). The recruitment period is 24 months. The average duration of the study per patient will be approximately 12 months, i.e. 3 weeks for screening, 10 months for the combination of FOLFIRI plus aflibercept and 30 days for follow-up of adverse events after the last dose of study treatment.

Official Title
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A Phase 2 Study of Aflibercept and Chemotherapy as First Line Treatment for Metastatic Colorectal Cancer Assessable With DCE-US.

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Aflibercept-FOLFIRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent, and willing and able to comply with protocol requirements Histologically proven adenocarcinoma of the colon and/or rectum Metastatic disease confirmed clinically/radiologically, and evaluable by dynamic contrast ultrasound No prior therapy for metastatic disease Duly documented inoperable metastatic disease, i.e. not suitable for complete curative surgical resection At least one measurable or evaluable lesion as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1 Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 0-2 Adequate hematological status: neutrophils (ANC) ≥ 1.5 x109/L; platelets ≥ 100x109/L; haemoglobin ≥ 9g/ dL Adequate renal function: serum creatinine level < 1.5 mg/dl and Glomerular Filtration Rate > 50 ml/min by cockroft/ Gault formula Adequate liver function: serum bilirubin ≤ 1.5 x upper normal limit (ULN), alkaline phosphatase, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) < 5 x ULN Proteinuria < 2+ (dipstick urinalysis) or ≤ 1g/24 hour Female patients must commit to using reliable and appropriate methods of contraception until at least 6 months after the end of Aflibercept and 3 months after the end of Irinotecan (when applicable). Male patients with a partner of childbearing potential must agree to use contraception in addition to having their partner use another contraceptive method until at least 6 months after the end of Aflibercept and 3 months after the end of Irinotecan. Exclusion Criteria: Uncontrolled hypercalcemia Uncontrolled systemic hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg despite medical therapy), or history of hypertensive crisis, or hypertensive encephalopathy Right-left shunt or severe pulmonary arterial hypertension (pulmonary artery pressure > 90 mmHg) Respiratory distress syndrome Concomitant antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy) Treatment with any other investigational medicinal product within 28 days prior to study entry History or presence of Central Nervous System (CNS) metastasis unless adequately treated (e.g. non irradiated CNS metastasis, seizures not controlled with standard medical therapy) Gilbert's syndrome Intolerance to atropine sulfate or loperamide Known dihydropyrimidine dehydrogenase deficiency Treatment with Cytochrome P450 3A4 (CYP3A4) inducers unless discontinued > 7 days prior to registration Any of the following in 3 months prior to inclusion: grade 3-4 gastrointestinal bleeding (unless due to resected tumor), treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or chronic inflammatory bowel disease, or diverticulitis Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for > 5 years, Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days Pregnant or breastfeeding women Patients with known allergy to any excipients to study drugs (including hypersensitivity to sulphur hexafluoride or to any of the components of SonoVue) History of myocardial infarction and/or stroke or other arterial thrombotic events or pulmonary embolism or unstable angina pectoris within 6 months prior to registration Poorly controlled cardiac arrhythmias Typical Angina Pectoris at rest within the previous 7 days, or significant worsening of cardiac symptoms in the previous 7 days, or recent intervention on the coronary arteries or other factors suggesting clinical instability (eg recent deterioration of ECG changes in clinical parameters or biological), or acute heart failure, or heart failure stage III or IV, or severe arrhythmias Bowel obstruction History of severe tumour bleeding or bleeding disorders Poorly controlled anti-coagulation therapy (INR > 3.0 on coumadin or heparin compounds) Palliative radiation therapy within 4 weeks prior to registration St John's Wort medication

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-FOLFIRI<br>On day 1 of each cycle patients will receive aflibercept followed by irinotecan, 5-FU and leucovorin (FOLFIRI regimen). This treatment will be repeated every 2 weeks until RECIST progression or intolerance. | Drug: Aflibercept-FOLFIRI<br>* Aflibercept : 4 mg/kg, IV over 1 h on Day 1 FOLFIRI : Irinotecan 180 mg/m² IV infusion in 500 mL D5W (5% Dextrose in Water solution) over 90 minutes and dl leucovorin* 400 mg/m² IV infusion over 2 hours, at the same time, in bags using a Y-line, followed by : 5-FU 400 mg/m² IV bolus given over 2-4 minutes, followed by : 5-FU 2400 mg/m² continuous IV infusion in 500 mL over 46-hours. *400 mg/m² of leucovorin expressed in dl racemic. When the l-isomer form is used the dose should be divided by 2, i.e. 200 mg/m²<br>* Other names: ZALTRAP-FOLFIRI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Rate will be assessed according to RECIST 1.1 with central radiological review. |  | At 10-month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) will be determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. |  | through the end of study treatment, an average of 1 year | 
| Best Response Rate (BRR) |  | through the end of study treatment, an average of 1 year | 
| Progression-free survival (PFS) |  | through study completion, an average of 3 years | 
| Progression-free survival rate |  | through study completion, an average of 3 years | 
| Patterns of PFS according to DCE-US early assessment |  | at day 28 ± 2 | 
| Pharmacodynamic activity |  | at day 7 ± 1, and day 28 ± 2 | 
| Safety and tolerance |  | up to 30 days after the end of the study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma, colon and/or rectum