Clinical trial NCT00952029: 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
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Colorectal Cancer
Keywords: stage IV colon cancer
stage IV rectal cancer
Lead sponsor: Federation Francophone de Cancerologie Digestive
Sponsor class: OTHER
First posted: 2009-08-04
Enrollment: 492
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Disease-control duration
timeFrame: one year after last patient included
Secondary outcomes:
measure: Objective response rate
timeFrame: one year after last patient is included
measure: Rate of non-hematologic grade 3-4 toxicities (except alopecia)
timeFrame: one year after last patient is included
measure: Overall toxicity rate
timeFrame: one year after last patient is included
measure: Duration of chemotherapy-free interval
timeFrame: one year after last patient is included
measure: Progression-free survival
timeFrame: one year after last patient is included
measure: Overall survival
timeFrame: one and 2 year after last patient is included
measure: Time-to-treatment failure
timeFrame: one year after last patient is included
measure: Quality of life as assessed by EORTC QLQ-C30
timeFrame: one year after last patient is included
measure: Geriatric evaluation
timeFrame: one year after last patient is included
Other outcomes:
Locations:
city: Abbeville
country: France
facility: CH
city: Agen
country: France
facility: Centre Radiothérapie et Oncologie de Moyenne Garonne
city: Amiens
country: France
facility: CHU
city: Angers
country: France
facility: Centre Paul Papin
city: Angers
country: France
facility: CHU
city: Annecy
country: France
facility: Pringny
city: Aubenas
country: France
facility: CH
city: Auxerre
country: France
facility: CH
city: Auxerre
country: France
facility: Polyclinique Sainte Marguerite
city: Avignon
country: France
facility: CH
city: Bayonne
country: France
facility: Ch
city: Beauvais
country: France
facility: CH
city: Besançon
country: France
facility: CHU
city: Beuvry
country: France
facility: Centre Pierre Curie
city: Blois
country: France
facility: Ch
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Bordeaux
country: France
facility: Clinique Tivoli
city: Bordeaux
country: France
facility: Institut Bergonié
city: Bourg en Bresse
country: France
facility: CH
city: Bourges
country: France
facility: CH
city: Béziers
country: France
facility: CH
city: Cahors
country: France
facility: CH
city: Castres
country: France
facility: CHIC
city: Chalon sur Saone
country: France
facility: Hôpital Privé Sainte Marie
city: Cholet
country: France
facility: CH
city: Cornebarrieu
country: France
facility: Clinique des Cèdres
city: Creteil
country: France
facility: CH
city: Dax
country: France
facility: CH
city: Dechy
country: France
facility: Centre Léonard de Vinci
city: Dijon
country: France
facility: Centre Leclerc
city: Dijon
country: France
facility: CHU
city: Dijon
country: France
facility: Parc
city: Dunkerque
country: France
facility: CH
city: Elbeuf
country: France
facility: CH
city: Frejus
country: France
facility: CH
city: Gap
country: France
facility: Hôpital Chicas
city: La Roche sur Yon
country: France
facility: CH
city: Langres
country: France
facility: CH
city: Le Mans
country: France
facility: CH
city: Libourne
country: France
facility: CH
city: Lille
country: France
facility: Centre Bourgogne
city: Limoges
country: France
facility: Clinique F. Chenieux
city: Longjumeau
country: France
facility: CH
city: Lorient
country: France
facility: CHBS
city: Lyon
country: France
facility: Centre Léon Bérard
city: Lyon
country: France
facility: CHU Edouard Herriot
city: Lyon
country: France
facility: Clinique de la Sauvegarde
city: Lyon
country: France
facility: Clinique Mutualiste
city: Lyon
country: France
facility: Croix Rousse
city: Lyon
country: France
facility: Hôpital Saint Joseph
city: Macon
country: France
facility: CH
city: Marseille
country: France
facility: CHU La Timone
city: Marseille
country: France
facility: Hôpital A. Paré
city: Marseille
country: France
facility: Hôpital Nord
city: Marseille
country: France
facility: Hôpital Saint Joseph
city: Meaux
country: France
facility: CH
city: Mont de Marsan
country: France
facility: CHG
city: Montauban
country: France
facility: CH
city: Montelimar
country: France
facility: CH
city: Montfermeil
country: France
facility: CH Le Raincy
city: Montpellier
country: France
facility: Centre Cancérologique
city: Mougins
country: France
facility: Centre Azuréen
city: Nantes
country: France
facility: Hôpital Saint Herblain
city: Narbonne
country: France
facility: Polyclinique
city: Neuilly sur Seine
country: France
facility: CH
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nice
country: France
facility: L'Archet II
city: Nimes
country: France
facility: CHU
city: Nimes
country: France
facility: Clinique Valdegour, Centre ONCOGARD - Institut de Cancérologie du Gard
city: Orléans
country: France
facility: CHR (Oncologie Médicale)
city: Orléans
country: France
facility: CHR
city: Orléans
country: France
facility: Clinique Les Murlins
city: Paris
country: France
facility: Bichat
city: Paris
country: France
facility: CHU - Kremlin Bicêtre
city: Paris
country: France
facility: HEGP
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Pitié Salpetière
city: Pau
country: France
facility: CH
city: Perigueux
country: France
facility: CH
city: Perpignan
country: France
facility: CH
city: Pessac
country: France
facility: CH
city: Rang Du Fliers
country: France
facility: CH
city: Reims
country: France
facility: CH
city: Romans sur Isere
country: France
facility: CH
city: Roubaix
country: France
facility: CH
city: Rouen
country: France
facility: CHU
city: Saint Brieuc
country: France
facility: CH
city: Saint Mande
country: France
facility: HIA Begin
city: Saint Nazaire
country: France
facility: Clinique Mutualiste
city: Saint Priest en Jarez
country: France
facility: CHU Saint Etienne
city: Saint-Brieuc
country: France
facility: Clinique Armoricaine
city: Saint-Martin-Boulogne
country: France
facility: Centre Joliot Curie
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Tours
country: France
facility: CHU Trousseau
city: Valence
country: France
facility: CH
city: Valence
country: France
facility: Clinique Générale
city: Valenciennes
country: France
facility: CH
city: Vandoeuvre Les Nancy
country: France
facility: CAC
city: Vannes
country: France
facility: CH Bretagne Atlantique
city: Vienne
country: France
facility: Clinique
city: Villejuif
country: France
facility: CH
city: Villeneuve Saint Georges
country: France
facility: Hôpital Intercommunal
Study officials:
affiliation: Hopital Avicenne BOBIGNY
name: Thomas Aparicio, Pr
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.