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

July 5, 2024 updated by: Federation Francophone de Cancerologie Digestive

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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).

Study Type

Interventional

Enrollment (Actual)

117

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Aix En Provence, France
        • CH
      • Amiens CEDEX 1, France, 80054
        • CHU Amiens - Hôpital Nord
      • Angers, France, 49933
        • CHU d'Angers
      • Angers, France
        • ICO
      • Auxerre, France
        • CH
      • Bayonne, France
        • Centre d'oncologie et de radiothérapie
      • Bayonne, France, 64109
        • CH de la Côte Basque
      • Bobigny, France, 93000
        • Hopital Avicenne
      • Bobigny, France
        • CHU APHP Hôpital Avicenne
      • Bordeaux, France
        • Polyclinique Bordeaux Nord
      • Bordeaux, France
        • CHU- Hôpital Saint André
      • Boulogne Sur Mer, France
        • Ch - Hôpital Duchenne
      • Brive La Gaillarde, France
        • CH
      • Béziers, France
        • CH
      • Caen, France
        • CHU côte de Nacre
      • Chambery, France
        • CH
      • Cherbourg, France
        • CH Public du Cotentin
      • Clermont Ferrand, France
        • CHU Estaing
      • Contamine Sur Arve, France
        • CH Alpes Léman
      • Corbeil-Essonnes, France, 91106
        • Centre Hospitalier Sud Francilien
      • Dijon, France, 21000
        • Institut de Cancérologie de Bourgogne - GRReCC
      • Dijon, France
        • Chu Le Bocage
      • Elbeuf, France
        • CH
      • Gap, France
        • CHICAS
      • La Roche Sur Yon, France
        • CHD Vendée
      • Libourne, France
        • CH Robert Boulin
      • Limoges, France
        • CHU
      • Limoges, France, 87000
        • Clinique Francois Chenieux
      • Longjumeau, France, 91160
        • CH Longjumeau
      • Lorient, France
        • CH Hôpital du Surcoff
      • Lyon, France
        • CH Saint Joseph - Saint Luc
      • Marseille, France
        • Hopital Européen de Marseille
      • Marseille, France
        • CHU APHM Hôpital Nord
      • Marseille, France
        • CHU APHM La Timone
      • Meaux, France
        • CH
      • Montelimar, France
        • CH
      • Nantes, France
        • CHU - Hôtel Dieu
      • Narbonne, France
        • Polyclinique de Languedoc
      • Orleans, France, 45067
        • CHR La Source
      • Paris, France, 75010
        • Saint-Louis CHU AP-HP Paris
      • Perpignan, France
        • CH
      • Pessac CEDEX, France, 33604
        • Hopital Haut Leveque
      • Poitiers, France
        • CHU Hôpital de la Milétrie
      • Pringy, France
        • Centre Hospitalier Annecy Genevois
      • Rennes, France
        • Centre Eugene Marquis
      • Rouen, France
        • CHU
      • Saint Herblain, France
        • ICO
      • Saint Jean De Luz, France
        • Polyclinique Côte Basque Sud
      • Saint-Brieuc, France
        • CARIO - Hôpital Privé des Côte d'Armor
      • Saintes, France
        • Ch Saintonges
      • Sarcelles, France
        • Centre de Cancerologie Paris Nord
      • Tarbes, France
        • CH de Bigorre
      • Thonon Les Bains, France
        • Hopitaux du Leman
      • Toulouse, France
        • CHU Hôpital Rangueil
      • Tours, France
        • Hôpital TROUSSEAU
      • Vannes, France
        • CHBA
      • Villejuif, France
        • Institut Gustave Roussy
      • Villeneuve d'Ascq, France
        • Hopital Prive de Villeneuve d'Ascq

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

61 years and older (Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A
Aflibercept + LV5FU2
Drug: aflibercept
Other Names:
  • zaltrap
Drug: LV5FU2
Active Comparator: B
LV5FU2
Drug: LV5FU2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Primary Objective Was the Percentage of Patients Alive and Without Progression 6 Months After the Randomization.
Time Frame: At 6 months after randomization
Progression was assessed by the investigator according to RECIST 1.1 criteria based on imaging studies performed every 8 weeks, even in case of deferred treatments. Clinical progressions, not confirmed on imaging, were not be counted in the primary endpoint
At 6 months after randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS)
Time Frame: Up to 3 years after the treatment start
Overall survival was defined as the time from the date of randomization to the patient's death (all causes). For alive patients, the date of the latest news was taken into account
Up to 3 years after the treatment start
Progression-free Survival (PPFS)
Time Frame: up to 12 months after randomization
It was defined as the time between t randomization and the date of the first radiological progression (RECIST 1.1 criteria) according to the investigator or death; Patients alive without progression were censored at the date of last news
up to 12 months after randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Federation Francophone de Cancerologie Digestive

Investigators

  • Principal Investigator: Jean Louis LEGOUX, MD, ORLEANS - Centre Hospitalier La Source

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2015

Primary Completion (Actual)

June 1, 2021

Study Completion (Actual)

June 1, 2021

Study Registration Dates

First Submitted

January 28, 2015

First Submitted That Met QC Criteria

March 4, 2015

First Posted (Estimated)

March 10, 2015

Study Record Updates

Last Update Posted (Actual)

July 10, 2024

Last Update Submitted That Met QC Criteria

July 5, 2024

Last Verified

July 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PRODIGE25

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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