Combination Chemotherapy and Bevacizumab With or Without Bevacizumab Maintenance Therapy in Treating Patients With Metastatic Colorectal Cancer
Primary Purpose
Colorectal Cancer
Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
bevacizumab
FOLFIRI regimen
fluorouracil
irinotecan hydrochloride
leucovorin calcium
Sponsored by
About this trial
This is an interventional treatment trial for Colorectal Cancer focused on measuring stage IV colon cancer, stage IV rectal cancer
Eligibility Criteria
DISEASE CHARACTERISTICS:
Histologically confirmed colorectal cancer
- Metastatic disease
- Not a candidate for curative surgery
- At least 1 tumor target measurable by RECIST criteria
- No metastasis potentially resectable after receiving chemotherapy
- No occlusive tumors
- No macronodular peritoneal carcinomatosis
- No known or suspected CNS metastases
PATIENT CHARACTERISTICS:
- OMS status 0-2
- Life expectancy ≥ 3 months
- ANC ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- Hemoglobin ≥ 9 g/dL
- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
- Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in the presence of hepatic metastases)
- Creatinine ≤ 1.5 times ULN
- Proteinuria ≤1 g
- Not pregnant or nursing
- No gastroduodenal ulcer, wound, or fractured bone
- No acute or subacute intestinal occlusion or history of inflammatory bowel disease or large resection of small bowel
- No clinically relevant coronary artery disease or a history of a myocardial infarction within the last 6 months
- No uncontrolled hypertension while receiving chronic medication
- No other malignancy within the past 5 years except for basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix
- No medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study
PRIOR CONCURRENT THERAPY:
- See Patient Characteristics
No prior chemotherapy for metastatic disease
- Adjuvant chemotherapy allowed provided it was completed > 6 months ago
- No prior irinotecan or other antiangiogenic therapy
- At least 4 weeks since surgery (except for diagnostic biopsy) or irradiation
- No other drugs not allowed for medical reasons
Concurrent oral anticoagulants (e.g., coumadin, warfarin) allowed provided the INR is closely monitored
- A change of anticoagulants to low-molecular weight heparin is preferred
Sites / Locations
- CH
- Centre Radiothérapie et Oncologie de Moyenne Garonne
- CHU
- Centre Paul Papin
- CHU
- Pringny
- CH
- CH
- Polyclinique Sainte Marguerite
- CH
- Ch
- CH
- CHU
- Centre Pierre Curie
- Ch
- Hôpital Avicenne
- Clinique Tivoli
- Institut Bergonié
- CH
- CH
- CH
- CH
- CHIC
- Hôpital Privé Sainte Marie
- CH
- Clinique des Cèdres
- CH
- CH
- Centre Léonard de Vinci
- Centre Leclerc
- CHU
- Parc
- CH
- CH
- CH
- Hôpital Chicas
- CH
- CH
- CH
- CH
- Centre Bourgogne
- Clinique F. Chenieux
- CH
- CHBS
- Centre Léon Bérard
- CHU Edouard Herriot
- Clinique de la Sauvegarde
- Clinique Mutualiste
- Croix Rousse
- Hôpital Saint Joseph
- CH
- CHU La Timone
- Hôpital A. Paré
- Hôpital Nord
- Hôpital Saint Joseph
- CH
- CHG
- CH
- CH
- CH Le Raincy
- Centre Cancérologique
- Centre Azuréen
- Hôpital Saint Herblain
- Polyclinique
- CH
- Centre Antoine Lacassagne
- L'Archet II
- CHU
- Clinique Valdegour, Centre ONCOGARD - Institut de Cancérologie du Gard
- CHR (Oncologie Médicale)
- CHR
- Clinique Les Murlins
- Bichat
- CHU - Kremlin Bicêtre
- HEGP
- Hôpital Saint Louis
- Pitié Salpetière
- CH
- CH
- CH
- CH
- CH
- CH
- CH
- CH
- CHU
- CH
- HIA Begin
- Clinique Mutualiste
- CHU Saint Etienne
- Clinique Armoricaine
- Centre Joliot Curie
- Centre Paul Strauss
- CHU Trousseau
- CH
- Clinique Générale
- CH
- CAC
- CH Bretagne Atlantique
- Clinique
- CH
- Hôpital Intercommunal
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Maintenance with bevacizumab
No maintenance with bevacizumab
Arm Description
FOLFIRI + Avastin and during the chemotherapy-free interval maintenance with bevacizumab
FOLFIRI + Avastin and during the chemotherapy-free interval NO maintenance
Outcomes
Primary Outcome Measures
Disease-control duration
Secondary Outcome Measures
Objective response rate
Rate of non-hematologic grade 3-4 toxicities (except alopecia)
Overall toxicity rate
Duration of chemotherapy-free interval
Progression-free survival
Overall survival
Time-to-treatment failure
Quality of life as assessed by EORTC QLQ-C30
Geriatric evaluation
Full Information
NCT ID
NCT00952029
First Posted
August 1, 2009
Last Updated
March 27, 2020
Sponsor
Federation Francophone de Cancerologie Digestive
1. Study Identification
Unique Protocol Identification Number
NCT00952029
Brief Title
Combination Chemotherapy and Bevacizumab With or Without Bevacizumab Maintenance Therapy in Treating Patients With Metastatic Colorectal Cancer
Official Title
Multicenter Phase III Randomized Study of FOLFIRI Plus Bevacizumab Following or Not by a Maintenance Therapy With Bevacizumab in Patients With Non-Pretreated Metastatic Colorectal Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
March 2010 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
January 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Federation Francophone de Cancerologie Digestive
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
RATIONALE: Drugs used in chemotherapy, such as irinotecan hydrochloride, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bevacizumab may stop the growth of colorectal cancer by blocking blood flow to the tumor. It is not yet known whether giving more than one drug (combination chemotherapy) is more effective when given with or without bevacizumab in treating patients with metastatic colorectal cancer.
PURPOSE: This randomized phase III trial is studying giving combination chemotherapy with or without bevacizumab to see how well it works in treating patients with metastatic colorectal cancer.
Detailed Description
OBJECTIVES:
Primary
Compare disease-control duration in patients with metastatic colorectal cancer receiving FOLFIRI chemotherapy in combination with bevacizumab with or without bevacizumab maintenance therapy.
Secondary
Determine objective response rate.
Determine non-hematologic grade 3-4 (except alopecia) toxicity rate.
Determine overall toxicity rate.
Determine duration of chemotherapy-free interval.
Determine progression-free survival.
Determine overall survival.
Determine time-to-treatment failure.
Determine quality of life (EORTC QLQ-C30).
Complete geriatric evaluation.
OUTLINE: This is a multicenter study. Patients are stratified according to cancer center, primary tumor (resected vs unresected), and Köhne criteria (low vs intermediate vs high). Patients are randomized to 1 of 2 treatment arms.
Arm A: Patients receive FOLFIRI chemotherapy comprising irinotecan hydrochloride IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours on days 1-2. Chemotherapy treatment repeats every 2 weeks for 12 courses. Patients also receive bevacizumab IV over 30-90 minutes once every 2 weeks during chemotherapy. Patients then receive bevacizumab maintenance therapy once every 2 weeks during the chemotherapy-free interval.
Arm B: Patients receive FOLFIRI chemotherapy and bevacizumab as in arm A. Patients receive no treatment during the chemotherapy-free interval.
In all arms, the chemotherapy treatment and the chemotherapy-free interval treatment repeats in the absence of disease progression during the chemotherapy portion or unacceptable toxicity. Patients who progress during the chemotherapy-free interval will receive 12 more courses of chemotherapy.
All patients complete quality of life questionnaires (QLQ-30) and patients ≥ 75 also complete the geriatric questionnaire at baseline and every 8 weeks during study treatment.
After completion of study treatment, patients are followed up every 8 weeks.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer
Keywords
stage IV colon cancer, stage IV rectal cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
492 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Maintenance with bevacizumab
Arm Type
Experimental
Arm Description
FOLFIRI + Avastin and during the chemotherapy-free interval maintenance with bevacizumab
Arm Title
No maintenance with bevacizumab
Arm Type
Active Comparator
Arm Description
FOLFIRI + Avastin and during the chemotherapy-free interval NO maintenance
Intervention Type
Biological
Intervention Name(s)
bevacizumab
Intervention Type
Drug
Intervention Name(s)
FOLFIRI regimen
Intervention Type
Drug
Intervention Name(s)
fluorouracil
Intervention Type
Drug
Intervention Name(s)
irinotecan hydrochloride
Intervention Type
Drug
Intervention Name(s)
leucovorin calcium
Primary Outcome Measure Information:
Title
Disease-control duration
Time Frame
one year after last patient included
Secondary Outcome Measure Information:
Title
Objective response rate
Time Frame
one year after last patient is included
Title
Rate of non-hematologic grade 3-4 toxicities (except alopecia)
Time Frame
one year after last patient is included
Title
Overall toxicity rate
Time Frame
one year after last patient is included
Title
Duration of chemotherapy-free interval
Time Frame
one year after last patient is included
Title
Progression-free survival
Time Frame
one year after last patient is included
Title
Overall survival
Time Frame
one and 2 year after last patient is included
Title
Time-to-treatment failure
Time Frame
one year after last patient is included
Title
Quality of life as assessed by EORTC QLQ-C30
Time Frame
one year after last patient is included
Title
Geriatric evaluation
Time Frame
one year after last patient is included
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
120 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS:
Histologically confirmed colorectal cancer
Metastatic disease
Not a candidate for curative surgery
At least 1 tumor target measurable by RECIST criteria
No metastasis potentially resectable after receiving chemotherapy
No occlusive tumors
No macronodular peritoneal carcinomatosis
No known or suspected CNS metastases
PATIENT CHARACTERISTICS:
OMS status 0-2
Life expectancy ≥ 3 months
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 9 g/dL
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in the presence of hepatic metastases)
Creatinine ≤ 1.5 times ULN
Proteinuria ≤1 g
Not pregnant or nursing
No gastroduodenal ulcer, wound, or fractured bone
No acute or subacute intestinal occlusion or history of inflammatory bowel disease or large resection of small bowel
No clinically relevant coronary artery disease or a history of a myocardial infarction within the last 6 months
No uncontrolled hypertension while receiving chronic medication
No other malignancy within the past 5 years except for basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix
No medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study
PRIOR CONCURRENT THERAPY:
See Patient Characteristics
No prior chemotherapy for metastatic disease
Adjuvant chemotherapy allowed provided it was completed > 6 months ago
No prior irinotecan or other antiangiogenic therapy
At least 4 weeks since surgery (except for diagnostic biopsy) or irradiation
No other drugs not allowed for medical reasons
Concurrent oral anticoagulants (e.g., coumadin, warfarin) allowed provided the INR is closely monitored
A change of anticoagulants to low-molecular weight heparin is preferred
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas Aparicio, Pr
Organizational Affiliation
Hopital Avicenne BOBIGNY
Official's Role
Principal Investigator
Facility Information:
Facility Name
CH
City
Abbeville
Country
France
Facility Name
Centre Radiothérapie et Oncologie de Moyenne Garonne
City
Agen
Country
France
Facility Name
CHU
City
Amiens
Country
France
Facility Name
Centre Paul Papin
City
Angers
Country
France
Facility Name
CHU
City
Angers
Country
France
Facility Name
Pringny
City
Annecy
Country
France
Facility Name
CH
City
Aubenas
Country
France
Facility Name
CH
City
Auxerre
Country
France
Facility Name
Polyclinique Sainte Marguerite
City
Auxerre
Country
France
Facility Name
CH
City
Avignon
Country
France
Facility Name
Ch
City
Bayonne
Country
France
Facility Name
CH
City
Beauvais
Country
France
Facility Name
CHU
City
Besançon
Country
France
Facility Name
Centre Pierre Curie
City
Beuvry
Country
France
Facility Name
Ch
City
Blois
Country
France
Facility Name
Hôpital Avicenne
City
Bobigny
Country
France
Facility Name
Clinique Tivoli
City
Bordeaux
Country
France
Facility Name
Institut Bergonié
City
Bordeaux
Country
France
Facility Name
CH
City
Bourg en Bresse
Country
France
Facility Name
CH
City
Bourges
Country
France
Facility Name
CH
City
Béziers
Country
France
Facility Name
CH
City
Cahors
Country
France
Facility Name
CHIC
City
Castres
Country
France
Facility Name
Hôpital Privé Sainte Marie
City
Chalon sur Saone
Country
France
Facility Name
CH
City
Cholet
Country
France
Facility Name
Clinique des Cèdres
City
Cornebarrieu
Country
France
Facility Name
CH
City
Creteil
Country
France
Facility Name
CH
City
Dax
Country
France
Facility Name
Centre Léonard de Vinci
City
Dechy
Country
France
Facility Name
Centre Leclerc
City
Dijon
Country
France
Facility Name
CHU
City
Dijon
Country
France
Facility Name
Parc
City
Dijon
Country
France
Facility Name
CH
City
Dunkerque
Country
France
Facility Name
CH
City
Elbeuf
Country
France
Facility Name
CH
City
Frejus
Country
France
Facility Name
Hôpital Chicas
City
Gap
Country
France
Facility Name
CH
City
La Roche sur Yon
Country
France
Facility Name
CH
City
Langres
Country
France
Facility Name
CH
City
Le Mans
Country
France
Facility Name
CH
City
Libourne
Country
France
Facility Name
Centre Bourgogne
City
Lille
Country
France
Facility Name
Clinique F. Chenieux
City
Limoges
Country
France
Facility Name
CH
City
Longjumeau
Country
France
Facility Name
CHBS
City
Lorient
Country
France
Facility Name
Centre Léon Bérard
City
Lyon
Country
France
Facility Name
CHU Edouard Herriot
City
Lyon
Country
France
Facility Name
Clinique de la Sauvegarde
City
Lyon
Country
France
Facility Name
Clinique Mutualiste
City
Lyon
Country
France
Facility Name
Croix Rousse
City
Lyon
Country
France
Facility Name
Hôpital Saint Joseph
City
Lyon
Country
France
Facility Name
CH
City
Macon
Country
France
Facility Name
CHU La Timone
City
Marseille
Country
France
Facility Name
Hôpital A. Paré
City
Marseille
Country
France
Facility Name
Hôpital Nord
City
Marseille
Country
France
Facility Name
Hôpital Saint Joseph
City
Marseille
Country
France
Facility Name
CH
City
Meaux
Country
France
Facility Name
CHG
City
Mont de Marsan
Country
France
Facility Name
CH
City
Montauban
Country
France
Facility Name
CH
City
Montelimar
Country
France
Facility Name
CH Le Raincy
City
Montfermeil
Country
France
Facility Name
Centre Cancérologique
City
Montpellier
Country
France
Facility Name
Centre Azuréen
City
Mougins
Country
France
Facility Name
Hôpital Saint Herblain
City
Nantes
Country
France
Facility Name
Polyclinique
City
Narbonne
Country
France
Facility Name
CH
City
Neuilly sur Seine
Country
France
Facility Name
Centre Antoine Lacassagne
City
Nice
Country
France
Facility Name
L'Archet II
City
Nice
Country
France
Facility Name
CHU
City
Nimes
Country
France
Facility Name
Clinique Valdegour, Centre ONCOGARD - Institut de Cancérologie du Gard
City
Nimes
Country
France
Facility Name
CHR (Oncologie Médicale)
City
Orléans
Country
France
Facility Name
CHR
City
Orléans
Country
France
Facility Name
Clinique Les Murlins
City
Orléans
Country
France
Facility Name
Bichat
City
Paris
Country
France
Facility Name
CHU - Kremlin Bicêtre
City
Paris
Country
France
Facility Name
HEGP
City
Paris
Country
France
Facility Name
Hôpital Saint Louis
City
Paris
Country
France
Facility Name
Pitié Salpetière
City
Paris
Country
France
Facility Name
CH
City
Pau
Country
France
Facility Name
CH
City
Perigueux
Country
France
Facility Name
CH
City
Perpignan
Country
France
Facility Name
CH
City
Pessac
Country
France
Facility Name
CH
City
Rang Du Fliers
Country
France
Facility Name
CH
City
Reims
Country
France
Facility Name
CH
City
Romans sur Isere
Country
France
Facility Name
CH
City
Roubaix
Country
France
Facility Name
CHU
City
Rouen
Country
France
Facility Name
CH
City
Saint Brieuc
Country
France
Facility Name
HIA Begin
City
Saint Mande
Country
France
Facility Name
Clinique Mutualiste
City
Saint Nazaire
Country
France
Facility Name
CHU Saint Etienne
City
Saint Priest en Jarez
Country
France
Facility Name
Clinique Armoricaine
City
Saint-Brieuc
Country
France
Facility Name
Centre Joliot Curie
City
Saint-Martin-Boulogne
Country
France
Facility Name
Centre Paul Strauss
City
Strasbourg
Country
France
Facility Name
CHU Trousseau
City
Tours
Country
France
Facility Name
CH
City
Valence
Country
France
Facility Name
Clinique Générale
City
Valence
Country
France
Facility Name
CH
City
Valenciennes
Country
France
Facility Name
CAC
City
Vandoeuvre Les Nancy
Country
France
Facility Name
CH Bretagne Atlantique
City
Vannes
Country
France
Facility Name
Clinique
City
Vienne
Country
France
Facility Name
CH
City
Villejuif
Country
France
Facility Name
Hôpital Intercommunal
City
Villeneuve Saint Georges
Country
France
12. IPD Sharing Statement
Citations:
PubMed Identifier
25677925
Citation
Aparicio T, Linot B, Le Malicot K, Bouche O, Boige V, Francois E, Ghiringhelli F, Legoux JL, Ben Abdelghani M, Phelip JM, Faroux R, Dahan L, Taieb J, Bedenne L. FOLFIRI+bevacizumab induction chemotherapy followed by bevacizumab or observation in metastatic colorectal cancer, a phase III trial (PRODIGE 9--FFCD 0802). Dig Liver Dis. 2015 Apr;47(4):271-2. doi: 10.1016/j.dld.2015.01.146. Epub 2015 Jan 20. No abstract available.
Results Reference
background
PubMed Identifier
29346040
Citation
Aparicio T, Ghiringhelli F, Boige V, Le Malicot K, Taieb J, Bouche O, Phelip JM, Francois E, Borel C, Faroux R, Dahan L, Jacquot S, Genet D, Khemissa F, Suc E, Desseigne F, Texereau P, Lepage C, Bennouna J; PRODIGE 9 Investigators. Bevacizumab Maintenance Versus No Maintenance During Chemotherapy-Free Intervals in Metastatic Colorectal Cancer: A Randomized Phase III Trial (PRODIGE 9). J Clin Oncol. 2018 Mar 1;36(7):674-681. doi: 10.1200/JCO.2017.75.2931. Epub 2018 Jan 18.
Results Reference
result
PubMed Identifier
32015513
Citation
Aparicio T, Bennouna J, Le Malicot K, Boige V, Taieb J, Bouche O, Phelip JM, Francois E, Borel C, Faroux R, Dahan L, Bachet JB, Egreteau J, Kaminsky MC, Gornet JM, Cojocarasu O, Gasmi M, Guerin-Meyer V, Lepage C, Ghiringhelli F; for PRODIGE investigators/collaborators. Predictive factors for early progression during induction chemotherapy and chemotherapy-free interval: analysis from PRODIGE 9 trial. Br J Cancer. 2020 Mar;122(7):957-962. doi: 10.1038/s41416-020-0735-8. Epub 2020 Feb 4.
Results Reference
result
PubMed Identifier
33422006
Citation
Guilloteau A, Abrahamowicz M, Boussari O, Jooste V, Aparicio T, Quantin C, Le Malicot K, Binquet C. Impact of time-varying cumulative bevacizumab exposures on survival: re-analysis of data from randomized clinical trial in patients with metastatic colo-rectal cancer. BMC Med Res Methodol. 2021 Jan 9;21(1):14. doi: 10.1186/s12874-020-01202-9.
Results Reference
derived
PubMed Identifier
31101691
Citation
Dohan A, Gallix B, Guiu B, Le Malicot K, Reinhold C, Soyer P, Bennouna J, Ghiringhelli F, Barbier E, Boige V, Taieb J, Bouche O, Francois E, Phelip JM, Borel C, Faroux R, Seitz JF, Jacquot S, Ben Abdelghani M, Khemissa-Akouz F, Genet D, Jouve JL, Rinaldi Y, Desseigne F, Texereau P, Suc E, Lepage C, Aparicio T, Hoeffel C; PRODIGE 9 Investigators and PRODIGE 20 Investigators. Early evaluation using a radiomic signature of unresectable hepatic metastases to predict outcome in patients with colorectal cancer treated with FOLFIRI and bevacizumab. Gut. 2020 Mar;69(3):531-539. doi: 10.1136/gutjnl-2018-316407. Epub 2019 May 17.
Results Reference
derived
Learn more about this trial
Combination Chemotherapy and Bevacizumab With or Without Bevacizumab Maintenance Therapy in Treating Patients With Metastatic Colorectal Cancer
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