Aflibercept and Chemotherapy as First Line Treatment for Metastatic Colorectal Cancer Assessable With DCE-US (PULSAR). (PULSAR)
Primary Purpose
Metastatic Colorectal Cancer
Status
Terminated
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Aflibercept-FOLFIRI
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring adenocarcinoma, colon and/or rectum
Eligibility Criteria
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
Sites / Locations
- Institut Bergonié
- Centre Georges François Leclerc
- Kremlin Bicetre
- Centre Oscar Lambret
- CHRU
- Institut Paoli Calmettes
- Hôpital Universitaire Paul Brousse
- Gustave Roussy
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Aflibercept-FOLFIRI
Arm Description
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.
Outcomes
Primary Outcome Measures
Progression-Free Rate will be assessed according to RECIST 1.1 with central radiological review.
Secondary Outcome Measures
Overall Response Rate (ORR) will be determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Best Response Rate (BRR)
Progression-free survival (PFS)
Progression-free survival rate
Patterns of PFS according to DCE-US early assessment
Pharmacodynamic activity
Safety and tolerance
Full Information
NCT ID
NCT02173990
First Posted
February 17, 2014
Last Updated
October 19, 2021
Sponsor
Centre Oscar Lambret
Collaborators
Sanofi
1. Study Identification
Unique Protocol Identification Number
NCT02173990
Brief Title
Aflibercept and Chemotherapy as First Line Treatment for Metastatic Colorectal Cancer Assessable With DCE-US (PULSAR).
Acronym
PULSAR
Official Title
A Phase 2 Study of Aflibercept and Chemotherapy as First Line Treatment for Metastatic Colorectal Cancer Assessable With DCE-US.
Study Type
Interventional
2. Study Status
Record Verification Date
October 2021
Overall Recruitment Status
Terminated
Why Stopped
Lack of enrollment
Study Start Date
July 2014 (Actual)
Primary Completion Date
November 2, 2018 (Actual)
Study Completion Date
October 22, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre Oscar Lambret
Collaborators
Sanofi
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Colorectal Cancer
Keywords
adenocarcinoma, colon and/or rectum
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Aflibercept-FOLFIRI
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Aflibercept-FOLFIRI
Other Intervention Name(s)
ZALTRAP-FOLFIRI
Intervention Description
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
Primary Outcome Measure Information:
Title
Progression-Free Rate will be assessed according to RECIST 1.1 with central radiological review.
Time Frame
At 10-month
Secondary Outcome Measure Information:
Title
Overall Response Rate (ORR) will be determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Time Frame
through the end of study treatment, an average of 1 year
Title
Best Response Rate (BRR)
Time Frame
through the end of study treatment, an average of 1 year
Title
Progression-free survival (PFS)
Time Frame
through study completion, an average of 3 years
Title
Progression-free survival rate
Time Frame
through study completion, an average of 3 years
Title
Patterns of PFS according to DCE-US early assessment
Time Frame
at day 28 ± 2
Title
Pharmacodynamic activity
Time Frame
at day 7 ± 1, and day 28 ± 2
Title
Safety and tolerance
Time Frame
up to 30 days after the end of the study treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Antoine ADENIS, MD, PhD
Organizational Affiliation
Centre Oscar Lambret - France
Official's Role
Study Director
Facility Information:
Facility Name
Institut Bergonié
City
Bordeaux
ZIP/Postal Code
33076
Country
France
Facility Name
Centre Georges François Leclerc
City
Dijon
ZIP/Postal Code
21079
Country
France
Facility Name
Kremlin Bicetre
City
Le Kremlin Bicetre
ZIP/Postal Code
94275
Country
France
Facility Name
Centre Oscar Lambret
City
Lille
ZIP/Postal Code
59020
Country
France
Facility Name
CHRU
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
Institut Paoli Calmettes
City
Marseille
ZIP/Postal Code
13273
Country
France
Facility Name
Hôpital Universitaire Paul Brousse
City
Villejuif
ZIP/Postal Code
94804
Country
France
Facility Name
Gustave Roussy
City
Villejuif
ZIP/Postal Code
94805
Country
France
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Aflibercept and Chemotherapy as First Line Treatment for Metastatic Colorectal Cancer Assessable With DCE-US (PULSAR).
We'll reach out to this number within 24 hrs