Clinical trial NCT02384759: Aflibercept +/- LV5FU2 in First Line of Non-resectalbe Metastatic Colorectal Cancers
Official title: Phase II Randomized Trial Evaluting Aflibercept Associated With LV5FU2 Regimen as First Line Treatment of Non-resectalbe Metastatic Colorectal Cancers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Neoplasms
Keywords: cancer, colorectal,
Lead sponsor: Federation Francophone de Cancerologie Digestive
Sponsor class: OTHER
First posted: 2015-03-10
Enrollment: 117
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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).

Eligibility criteria: 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

Primary outcomes:
measure: The Primary Objective Was the Percentage of Patients Alive and Without Progression 6 Months After the Randomization.
timeFrame: At 6 months after randomization
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to 3 years after the treatment start
measure: Progression-free Survival (PPFS)
timeFrame: up to 12 months after randomization
Other outcomes:
Locations:
city: Aix En Provence
country: France
facility: CH
city: Amiens CEDEX 1
country: France
facility: CHU Amiens - Hôpital Nord
city: Angers
country: France
facility: Chu D'Angers
city: Angers
country: France
facility: ICO
city: Auxerre
country: France
facility: CH
city: Bayonne
country: France
facility: CH de la Côte Basque
city: Bayonne
country: France
facility: Centre D'Oncologie Et de Radiothérapie
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Bobigny
country: France
facility: CHU APHP Hôpital Avicenne
city: Bordeaux
country: France
facility: CHU- Hôpital Saint André
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord
city: Boulogne Sur Mer
country: France
facility: CH - Hôpital Duchenne
city: Brive La Gaillarde
country: France
facility: CH
city: Béziers
country: France
facility: CH
city: Caen
country: France
facility: CHU Côte de Nacre
city: Chambery
country: France
facility: Ch
city: Cherbourg
country: France
facility: CH Public du Cotentin
city: Clermont Ferrand
country: France
facility: CHU Estaing
city: Contamine Sur Arve
country: France
facility: CH Alpes Leman
city: Corbeil-Essonnes
country: France
facility: Centre hospitalier Sud Francilien
city: Dijon
country: France
facility: Institut de cancérologie de Bourgogne - GRRECC
city: Dijon
country: France
facility: CHU Le Bocage
city: Elbeuf
country: France
facility: CH
city: Gap
country: France
facility: Chicas
city: La Roche Sur Yon
country: France
facility: CHD Vendée
city: Libourne
country: France
facility: CH Robert Boulin
city: Limoges
country: France
facility: Clinique François Chénieux
city: Limoges
country: France
facility: CHU
city: Longjumeau
country: France
facility: Ch Longjumeau
city: Lorient
country: France
facility: CH Hôpital du Surcoff
city: Lyon
country: France
facility: Ch Saint Joseph - Saint Luc
city: Marseille
country: France
facility: CHU APHM Hôpital Nord
city: Marseille
country: France
facility: CHU APHM La Timone
city: Marseille
country: France
facility: Hôpital Européen de Marseille
city: Meaux
country: France
facility: CH
city: Montelimar
country: France
facility: CH
city: Nantes
country: France
facility: CHU - Hôtel Dieu
city: Narbonne
country: France
facility: Polyclinique de Languedoc
city: Orleans
country: France
facility: CHR La Source
city: Paris
country: France
facility: Saint-Louis CHU AP-HP Paris
city: Perpignan
country: France
facility: CH
city: Pessac CEDEX
country: France
facility: Hôpital Haut Leveque
city: Poitiers
country: France
facility: CHU Hôpital de la Milétrie
city: Pringy
country: France
facility: Centre Hospitalier Annecy Genevois
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rouen
country: France
facility: CHU
city: Saint Herblain
country: France
facility: ICO
city: Saint Jean De Luz
country: France
facility: Polyclinique Côte Basque Sud
city: Saint-Brieuc
country: France
facility: CARIO - Hôpital Privé des Côte d'Armor
city: Saintes
country: France
facility: Ch Saintonges
city: Sarcelles
country: France
facility: Centre de cancérologie Paris Nord
city: Tarbes
country: France
facility: CH de Bigorre
city: Thonon Les Bains
country: France
facility: Hôpitaux du Leman
city: Toulouse
country: France
facility: CHU Hôpital Rangueil
city: Tours
country: France
facility: Hôpital Trousseau
city: Vannes
country: France
facility: CHBA
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Villeneuve d'Ascq
country: France
facility: Hôpital Privé de Villeneuve d'Ascq
Study officials:
affiliation: ORLEANS - Centre Hospitalier La Source
name: Jean Louis LEGOUX, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Legoux JL, Faroux R, Barriere N, Le Malicot K, Tougeron D, Lorgis V, Guerin-Meyer V, Bourgeois V, Malka D, Aparicio T, Baconnier M, Lebrun-Ly V, Egreteau J, Khemissa Akouz F, Terme M, Lepage C, Boige V. First-Line LV5FU2 with or without Aflibercept in Patients with Non-Resectable Metastatic Colorectal Cancer: A Randomized Phase II Trial (PRODIGE 25-FFCD-FOLFA). Cancers (Basel). 2024 Apr 16;16(8):1515. doi: 10.3390/cancers16081515.