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

NCT ID: NCT02173990

Last Updated: 2021-10-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-07-31
• Study Completion Date: 2019-10-22

Brief Summary

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

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.

Conditions

Metastatic Colorectal Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Aflibercept-FOLFIRI

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

Other Intervention Names

ZALTRAP-FOLFIRI

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sanofi

INDUSTRY

Sponsor Role: collaborator

Centre Oscar Lambret

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Antoine ADENIS, MD, PhD

Role: STUDY_DIRECTOR

Centre Oscar Lambret - France

Locations

Institut Bergonié

Bordeaux, , France

Centre Georges François Leclerc

Dijon, , France

Kremlin Bicetre

Le Kremlin-Bicêtre, , France

Centre Oscar Lambret

Lille, , France

CHRU

Lille, , France

Institut Paoli Calmettes

Marseille, , France

Hôpital Universitaire Paul Brousse

Villejuif, , France

Gustave Roussy

Villejuif, , France

Countries

France

Other Identifiers

2013-004540-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PULSAR-1303

Identifier Type: -

Identifier Source: org_study_id