Aflibercept +/- LV5FU2 in First Line of Non-resectalbe Metastatic Colorectal Cancers

Colorectal Neoplasms Clinical Trial

— FOLFA  

Official title:

Phase II Randomized Trial Evaluting Aflibercept Associated With LV5FU2 Regimen as First Line Treatment of Non-resectalbe Metastatic Colorectal Cancers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02384759
• Other study ID #: PRODIGE25
• Status: Completed
• Phase: Phase 2
• Start date: May 2015
• Est. completion date: June 2021

Study information

• Verified date: March 2022
• Source: Federation Francophone de Cancerologie Digestive
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is what the FFCD 11-01 - PRODIGE 25 trial proposes to study, as a preliminary for strategic studies evaluating the usefulness of including targeted therapeutics from the first line with aflibercept +/- LV5FU2.

Description:

The aflibercept-5-FU combination has never been evaluated as yet. Aflibercept, at a dose of 4 mg/kg, has already been used in combination with 5-FU at the doses used in the simplified LV5FU2 regimen (folinic acid 400 mg/m2 IV in 90 min, then 5-FU 400 mg/m2 IV bolus on D1, followed by continuous perfusion of 5-FU 2,400 mg/m2 in 46h) (23) as part of the above-mentioned VELOUR trial, evaluating its combination with FOLFIRI (= simplified LV5FU2 + irinotecan). This trial was preceded by a phase I trial validating the doses used (24). It is therefore not necessary to perform a phase I trial if you use the same doses of 5-FU without irinotecan, within the context of a strategy for reducing toxicity in patients to be treated over a long period, and not search for the maximum tolerated dose of the combination.

The aflibercept-LV5FU2 combination can be useful for patients who will never be resectable or operable, and for whom 5-FU monotherapy can be suggested to delay the toxicities of combined chemotherapies. Within this context, it is possible for aflibercept to provide a survival benefit. The previous VELOUR trial (18) did not indicate that toxicity would have a major effect on quality of life and increase the hope of prolonged progression-free survival in the arm with aflibercept.

This is what the FFCD 11-01 - PRODIGE 25 trial proposes to study, as a preliminary for strategic studies evaluating the usefulness of including targeted therapeutics from the first line.

This trial will evaluate the efficacy of the combination and its tolerance by studying toxicities and quality of life. Quality of life will be studied via the EORTC questionnaire QLQ-C30.

The thymidylate synthase polymorphism type 2R2R-2R3R versus 3R3R seems to predict greater efficacy of 5-FU monotherapy. Stratification in this criterion will confirm or negate the prognostic or predictive nature of 5-FU efficacy linked to these polymorphisms.

The draft version of this trial has been studied and evaluated by the scientific council of the Fédération Francophone de Cancérologie Digestive (FFCD) then the Digestive Group of the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) within the framework of their Partnership for Research in Digestive Oncology (PRODIGE cooperation).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 117
• Est. completion date: June 2021
• Est. primary completion date: June 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

Inclusion Criteria:

• Age = 65 years

• General condition WHO = 2

• Metastatic rectal or colonic adenocarcinoma, histologically proved on the primary tumour or a metastasis

• Metastases non-resectable and/or patient inoperable

• patients where a single agent chemotherapy combined with an anti-angiogenic agent is an appropriate approach

• At least one measurable target according to RECIST v1.1 criteria, no previously irradiated

• No previous treatment of the metastatic disease. Previous chemotherapy in an adjuvant situation completed 6 months or more before diagnosis of the metastasis is authorized.

• Adequate biological examination: Hb > or = 9 g/dl, polynuclear neutrophils > or = 1,500/mm3, platelets > or =100,000/mm3, total bilirubin < or = 1.5 x UNL, creatinine clearance, calculated according to Cockroft-Gault formula, > 50 ml/min creatininemia < 1.5 x UNL, ALP < 5 x UNL, transaminases < 5 x ULN, GGT< 5 x UNL

• Proteinuria (strip) < 2+; if > or = 2+, test proteinuria over 24 hours which must be = 1 g.

• Central genotyping of thymidylate synthase (TS) in blood DNA

• Patients treated with anticoagulants (coumadin, warfarin) can be included if the INR can be closely monitored. A change in anticoagulant treatment for low molecular weight heparin is preferable in order to respect indications

• Signed written informed consent obtained prior to inclusion

Exclusion Criteria:

• Patients with a primary tumour in place and presenting clinical symptoms (occlusion, haemorrhage)

• History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis or new evidence of brain or leptomeningeal disease.

• Uncontrolled hypercalcemia

• Uncontrolled hypertension (SBP > 150 mmHg and DBP > 100 mmHg) or history of hypertensive attacks or hypertensive encephalopathy

• Any progressive pathology not balanced over the past 6 months: hepatic insufficiency, renal insufficiency, respiratory insufficiency,

• Any of the following within 6 months prior to inclusion: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA class III or IV congestive heart failure, stroke or transient ischemic attack.

• Any of the following within 3 months prior to inclusion: Grade 3-4 gastrointestinal bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event, wound or fractured bone

• Major surgery during the 28 days preceding the start of treatment

• Known acquired immunodeficiency syndrome (AIDS-related illnesses) or known HIV disease requiring antiretroviral treatment.

• Treatment with concomitant anticonvulsivant agents that are CYP3A4 inducers (phenytoin, phenobarbital, carbamazepine), unless discontinued >7 days.

• Anti-tumoral treatments other than the trial treatments (chemotherapy, targeted therapy, immunotherapy)

• Macronodular peritoneal carcinosis (risk of perforation)

• Known DPD deficit

• Prior history of malignant haemopathy or cancer except those treated more than 5 years ago and considered to be cured, in situ cervical carcinomas and treated skin cancers (excluding melanoma)

• Patients on new oral anticoagulant therapy (rivaroxaban XARELTOR, apixaban ELIQUIS, dagigatran PRADAXA except if relay by vitamine K antagonist therapy)

• Any contraindication to the treatments used in the trial

• Impossibility of undergoing medical monitoring during the trial for geographic, social or psychological reasons

Related Conditions & MeSH terms

• Colorectal Neoplasms

Intervention

Drug:
• aflibercept

• LV5FU2

Locations

Country	Name	City	State
France	CH	Aix En Provence
France	CHU Amiens - Hôpital Nord	Amiens CEDEX 1
France	Chu D'Angers	Angers
France	ICO	Angers
France	CH	Auxerre
France	Centre D'Oncologie Et de Radiothérapie	Bayonne
France	CH de la Côte Basque	Bayonne
France	CH	Béziers
France	CHU APHP Hôpital Avicenne	Bobigny
France	Hôpital Avicenne	Bobigny
France	CHU- Hôpital Saint André	Bordeaux
France	Polyclinique Bordeaux Nord	Bordeaux
France	CH - Hôpital Duchenne	Boulogne Sur Mer
France	CH	Brive La Gaillarde
France	CHU Côte de Nacre	Caen
France	Ch	Chambery
France	CH Public du Cotentin	Cherbourg
France	CHU Estaing	Clermont Ferrand
France	CH Alpes Leman	Contamine Sur Arve
France	Centre hospitalier Sud Francilien	Corbeil-Essonnes
France	CHU Le Bocage	Dijon
France	Institut de cancérologie de Bourgogne - GRRECC	Dijon
France	CH	Elbeuf
France	Chicas	Gap
France	CHD Vendée	La Roche Sur Yon
France	CH Robert Boulin	Libourne
France	CHU	Limoges
France	Clinique François Chénieux	Limoges
France	Ch Longjumeau	Longjumeau
France	CH Hôpital du Surcoff	Lorient
France	Ch Saint Joseph - Saint Luc	Lyon
France	CHU APHM Hôpital Nord	Marseille
France	CHU APHM La Timone	Marseille
France	Hôpital Européen de Marseille	Marseille
France	CH	Meaux
France	CH	Montelimar
France	CHU - Hôtel Dieu	Nantes
France	Polyclinique de Languedoc	Narbonne
France	CHR La Source	Orleans
France	Saint-Louis CHU AP-HP Paris	Paris
France	CH	Perpignan
France	Hôpital Haut Leveque	Pessac CEDEX
France	CHU Hôpital de la Milétrie	Poitiers
France	Centre Hospitalier Annecy Genevois	Pringy
France	Centre Eugène Marquis	Rennes
France	CHU	Rouen
France	ICO	Saint Herblain
France	Polyclinique Côte Basque Sud	Saint Jean De Luz
France	CARIO - Hôpital Privé des Côte d'Armor	Saint-Brieuc
France	Ch Saintonges	Saintes
France	Centre de cancérologie Paris Nord	Sarcelles
France	CH de Bigorre	Tarbes
France	Hôpitaux du Leman	Thonon Les Bains
France	CHU Hôpital Rangueil	Toulouse
France	Hôpital Trousseau	Tours
France	CHBA	Vannes
France	Institut Gustave Roussy	Villejuif
France	Hôpital Privé de Villeneuve d'Ascq	Villeneuve d'Ascq

Sponsors (1)

Lead Sponsor	Collaborator
Federation Francophone de Cancerologie Digestive

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Radiological progression-free survival according to the investigator		up to 6 months
Secondary	Overall survival		up to the end of the follow-up or death (whatever the cause)
Secondary	progression-free survival		up to the end of the follow-up or occurence of progression or death (whatever the cause)