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

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

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.

Study Overview

• Status: Terminated
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Aflibercept-FOLFIRI

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Dijon, France, 21079
    • Centre Georges Francois Leclerc
  • Le Kremlin Bicetre, France, 94275
    • Kremlin bicêtre
  • Lille, France, 59020
    • Centre Oscar Lambret
  • Lille, France, 59037
    • CHRU
  • Marseille, France, 13273
    • Institut Paoli Calmettes
  • Villejuif, France, 94805
    • Gustave Roussy
  • Villejuif, France, 94804
    • Hôpital Universitaire Paul Brousse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed and dated informed consent, and willing and able to comply with protocol requirements
2. Histologically proven adenocarcinoma of the colon and/or rectum
3. Metastatic disease confirmed clinically/radiologically, and evaluable by dynamic contrast ultrasound
4. No prior therapy for metastatic disease
5. Duly documented inoperable metastatic disease, i.e. not suitable for complete curative surgical resection
6. At least one measurable or evaluable lesion as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1
7. Age ≥ 18 years
8. Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 0-2
9. Adequate hematological status: neutrophils (ANC) ≥ 1.5 x109/L; platelets ≥ 100x109/L; haemoglobin ≥ 9g/ dL
10. Adequate renal function: serum creatinine level < 1.5 mg/dl and Glomerular Filtration Rate > 50 ml/min by cockroft/ Gault formula
11. Adequate liver function: serum bilirubin ≤ 1.5 x upper normal limit (ULN), alkaline phosphatase, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) < 5 x ULN
12. Proteinuria < 2+ (dipstick urinalysis) or ≤ 1g/24 hour
13. 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:

1. Uncontrolled hypercalcemia
2. 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
3. Right-left shunt or severe pulmonary arterial hypertension (pulmonary artery pressure > 90 mmHg)
4. Respiratory distress syndrome
5. Concomitant antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy)
6. Treatment with any other investigational medicinal product within 28 days prior to study entry
7. 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)
8. Gilbert's syndrome
9. Intolerance to atropine sulfate or loperamide
10. Known dihydropyrimidine dehydrogenase deficiency
11. Treatment with Cytochrome P450 3A4 (CYP3A4) inducers unless discontinued > 7 days prior to registration
12. 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
13. 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,
14. Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days
15. Pregnant or breastfeeding women
16. Patients with known allergy to any excipients to study drugs (including hypersensitivity to sulphur hexafluoride or to any of the components of SonoVue)
17. 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
18. Poorly controlled cardiac arrhythmias
19. 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
20. Bowel obstruction
21. History of severe tumour bleeding or bleeding disorders
22. Poorly controlled anti-coagulation therapy (INR > 3.0 on coumadin or heparin compounds)
23. Palliative radiation therapy within 4 weeks prior to registration
24. St John's Wort medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Aflibercept-FOLFIRI; 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; 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; Other Names: ZALTRAP-FOLFIRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Centre Oscar Lambret
• Collaborators: Sanofi
• Investigators: Study Director: Antoine ADENIS, MD, PhD, Centre Oscar Lambret - France

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2014
• Primary Completion (Actual): November 2, 2018
• Study Completion (Actual): October 22, 2019

Study Registration Dates

• First Submitted: February 17, 2014
• First Submitted That Met QC Criteria: June 24, 2014
• First Posted (Estimate): June 25, 2014

Study Record Updates

• Last Update Posted (Actual): October 20, 2021
• Last Update Submitted That Met QC Criteria: October 19, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: adenocarcinoma; colon and/or rectum
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept
• Other Study ID Numbers: PULSAR-1303; 2013-004540-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No