Second-line Doublet Chemotherapy (FOLFOX or FOLFIRI) Plus Fruquintinib Versus Doublet Chemotherapy (FOLFOX or FOLFIRI) Plus Bevacizumab in Metastatic Colorectal Cancer

NCT ID: NCT07150403

Last Updated: 2025-09-08

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 74 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-12-31
• Study Completion Date: 2028-10-31

Brief Summary

The standard second-line treatment for metastatic colorectal cancer (mCRC) involves chemotherapy (FOLFOX or FOLFIRI) combined with an antiangiogenic agent, such as bevacizumab or aflibercept. Maintaining VEGF inhibition between first and second-line treatments has shown modest clinical benefits, with exploratory analyses suggesting that bevacizumab is more effective in smaller tumors. The ULYSSE trial aims to evaluate the efficacy and safety of Fruquintinib, a potent antiangiogenic agent, combined with a doublet chemotherapy (FOLFOX or FOLFIRI) in second-line treatment for BRAF wild-type, MSS mCRC patients who have failed prior treatment.

Conditions

Metastatic Colorectal Carcinoma (mCRC)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Experimental arm A FOLFOX/FOLFIRI + Fruquintinib

FOLFOX (if FOLFIRI in first line) OR FOLFIRI (if FOLFOX in first line); D1 = D15 + FRUQUINTINIB

Group Type: EXPERIMENTAL

Oxaliplatin intravenous

Intervention Type: DRUG

85 mg/m² IV over 2 hours ; 1 cycle each 15 days

5 FU bolus

Intervention Type: DRUG

5 fluorouracil : 400 mg/m² in bolus of 10 minutes (intravenous)

Folinic acid

Intervention Type: DRUG

400 mg/m² in intravenous

5 FU continuous

Intervention Type: DRUG

2400 mg/m² intravenously over 46 hours

Irinotecan

Intervention Type: DRUG

180 mg/m² IV over 1h30

FRUQUINTINIB

Intervention Type: DRUG

5 mg capsule, taken orally, once daily for 3 weeks, followed by a 7-day break, then resumed (Day 1= Day 29).

Control arm B FOLFOX/FOLFIRI + Bevacizumab

FOLFOX (if FOLFIRI in first line) OR FOLFIRI (if FOLFOX in first line); D1 = D15 + BEVACIZUMAB (D1 = D15)

Group Type: ACTIVE_COMPARATOR

Oxaliplatin intravenous

Intervention Type: DRUG

85 mg/m² IV over 2 hours ; 1 cycle each 15 days

5 FU bolus

Intervention Type: DRUG

5 fluorouracil : 400 mg/m² in bolus of 10 minutes (intravenous)

Folinic acid

Intervention Type: DRUG

400 mg/m² in intravenous

5 FU continuous

Intervention Type: DRUG

2400 mg/m² intravenously over 46 hours

Irinotecan

Intervention Type: DRUG

180 mg/m² IV over 1h30

BEVACIZUMAB

Intervention Type: DRUG

5 mg/kg over 90 minutes for the 1st course and in case of good tolerance the 2nd course should be administered over 60 minutes. The next courses should be administered in 30 minutes in case of good tolerance during the 2nd course

Interventions

Oxaliplatin intravenous

85 mg/m² IV over 2 hours ; 1 cycle each 15 days

Intervention Type: DRUG

5 FU bolus

5 fluorouracil : 400 mg/m² in bolus of 10 minutes (intravenous)

Intervention Type: DRUG

Folinic acid

400 mg/m² in intravenous

Intervention Type: DRUG

5 FU continuous

2400 mg/m² intravenously over 46 hours

Intervention Type: DRUG

Irinotecan

180 mg/m² IV over 1h30

Intervention Type: DRUG

FRUQUINTINIB

5 mg capsule, taken orally, once daily for 3 weeks, followed by a 7-day break, then resumed (Day 1= Day 29).

Intervention Type: DRUG

BEVACIZUMAB

5 mg/kg over 90 minutes for the 1st course and in case of good tolerance the 2nd course should be administered over 60 minutes. The next courses should be administered in 30 minutes in case of good tolerance during the 2nd course

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• - Age ≥ 18 years and ≤ 80 years; provided the score of the G8 geriatric questionnaire is >14 for patients 75 years or older
• Patients with a histologically confirmed diagnosis of metastatic colorectal cancer (mCRC), with a documented disease progression (as per RECIST v1.1, assessed by the investigator and confirmed through CT or MRI).
• Patients must have previously received first-line therapy with Bevacizumab or an EGFRi, in combination with either FOLFOX or FOLFIRI, for non-resectable mCRC. Patients who progressed during the adjuvant chemotherapy (FOLFOX) or within the 6 months following its completion are eligible for inclusion
• Patients must have an unresectable tumor at the time of enrollment.
• Patients must have at least one measurable/evaluable metastatic lesion according to RECIST v1.1 criteria; images have to be available for collection
• Metastases not amenable to surgery and/or thermo-ablation and/or stereotaxic radiotherapy
• WHO performance status 0 or 1
• Available parameters to compute the SPOD score: WHO PS, hemoglobin, platelet count, WBC/absolute neutrophil count ratio, lactate dehydrogenase (LDH), alkaline phosphatase, and the number of metastatic sites.
• Adequate liver functions: Total Bilirubinemia < 2,5 ULN, AST and ALT ≤ 5 ULN
• Adequate hematological (Hemoglobin ≥10g/dL, platelets ≥100G/L, neutrophils ≥1.5G/L) and renal (creatinine clearance ≥ 50 mL/min according to CKD-EPI) functions
• Proteinuria < 2+ (dipstick urinalysis) (if 2+ or more, proteinuria must be ≤1g/24hour)
• Life expectancy ≥ 3 months
• Women of childbearing potential must agree to use a highly effective method of contraception during the trial and for at least 15 months after discontinuation of the experimental treatments. Men who have sexual relations with women of childbearing potential must agree to use contraception during treatment and for at least 12 months after discontinuation of the experimental treatments
• Ability of the patient to understand, sign and date the information note and informed consent form before any study specific procedures
• Patient affiliated to a social security scheme
• Available tumor sample and pathology report for collection

Exclusion Criteria

• - Patients who have received more than one prior systemic therapy
• FOLFIRINOX Regimen +/- targeted therapy in the first line setting
• Unknown RAS status
• BRAF V600E mutated tumor
• MSI/dMMR tumor
• Known brain metastasis
• Known peritoneal carcinomatosis if there are signs of clinical occlusion or sub-occlusion
• History of gastric ulceration, or myocardial infarction, or severe coronaropathy or severe cardiac dysfunction, within the past 6 months prior to treatment start
• Patients with dihydropyrimidine dehydrogenase deficiency (uracilemia ≥ 16 ng/mL)
• Hypersensitivity to one of the study drugs or one of its excipients
• Inability to swallow capsules
• Live attenuated vaccines 30 days prior to treatment start
• Untreated bone fracture
• Significant haemorrhagic diathesis or coagulopathy (in the absence of anti-coagulant treatment)
• Major surgery, open biopsy or major traumatic lesion in the prior 30 days or the need for major surgery during the trial
• Pregnant or breastfeeding woman or patients with no adequate contraception
• Known Uridine Diphosphate Glucuronyltransferase (UGT1A1) deficiency or known Gilbert disease
• Strong inducers of CYP3A4 (treatment with St John's Wort (Hypericum perforatum), fampicin, phenobarbital, primidone, phenytoin and carbamazepine)

-- Strong inhibitors of CYP3A4, continuous use of azole antifungals (posaconazole, voriconazole, itraconazole, isavuconazole), ritonavir, verapamil, diltiazem, grapefruit juice (equivalent to half a fresh grapefruit/day)

• Concomitant or recent treatment with sorivudine or its analogs (including brivudine) within 4 weeks prior to the administration of protocol treatment (related to Fluorouracil)
• Concomitant treatment with phenytoin or its analogs
• QT/QTc interval > 450 ms for men and > 470 ms for women
• Uncontrolled hypertension (defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg) or history of hypertensive crisis (TA systolic> 20 mmHg) or hypertensive encephalopathy
• History of veinous thromboembolic events, including deep vein thrombosis and pulmonary embolism, within the past month prior to study enrollment
• History of stroke and/or transient ischemic attack (TIA) within the past 12 months
• Residual Oxaliplatin neuropathy (grade ≥ 2) counter indicates FOLFOX administration
• Persistence of clinically significant symptoms after a thromboembolic event despite anticoagulant treatment
• Arterial thromboembolism (myocardial infarction, stroke, transient ischemic attack) occurring under antiangiogenic therapy
• Other active cancers or history of cancer treated within the last 5 years except for carcinoma in situ of the cervix or basal cell or squamous cell skin carcinoma or any other carcinoma in situ, considered cured
• Persons deprived of liberty or under guardianship or unable of giving consent
• Inability to undergo the medical follow-up of the trial for geographical, social or psychological reasons

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Federation Francophone de Cancerologie Digestive

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

ICO Site Paul Papin

Angers, , France

Les Bonnettes

Arras, , France

Ght Unyon Auxerre

Auxerre, , France

Bayeux Ch

Bayeux, , France

Cote Basque

Bayonne, , France

Beauvais Ch

Beauvais, , France

Jean Minjoz

Besançon, , France

Centre Pierre Curie

Beuvry, , France

BERGONIÉ

Bordeaux, , France

TIVOLI

Bordeaux, , France

Chauny Ch

Chauny, , France

Cholet Ch

Cholet, , France

Saint Côme

Compiègne, , France

Clinique de Flandre

Coudekerque-Branche, , France

GHPSO Site de Creil

Creil, , France

Centre Leonard de Vinci

Dechy, , France

Dijon Bourgogne

Dijon, , France

Institut de cancérologie de Bourgogne GRReCC

Dijon, , France

CHD Vendée

La Roche-sur-Yon, , France

Docteur Schaffner

Lens, , France

Franco Britannique

Levallois-Perret, , France

Jean Mermoz

Lyon, , France

La Timone

Marseille, , France

LAYNÉ CH

Mont-de-Marsan, , France

Centre de Cancérologie du Grand Montpellier

Montpellier, , France

Confluent Sas

Nantes, , France

Groupe Hospitalier Diaconesses Croix Saint Simon

Paris, , France

Hôpital Européen G Pompidou

Paris, , France

La Pitié Salpêtrière

Paris, , France

Saint Louis

Paris, , France

La Miletrie

Poitiers, , France

Jean Godinot

Reims, , France

Robert Debré

Reims, , France

Saint Gregoire Chp

Saint-Grégoire, , France

ICO Site René Gauducheau

Saint-Herblain, , France

Clinique Mutualiste de L'Estuaire

Saint-Nazaire, , France

Hopital Nord Chu Saint Etienne

Saint-Priest-en-Jarez, , France

Saint Malo Ch

St-Malo, , France

ICAN Institut de Cancérologie de Strasbourg Europe

Strasbourg, , France

Sainte Anne

Strasbourg, , France

LEMAN

Thonon-les-Bains, , France

Valence Ch

Valence, , France

BRABOIS

Vandœuvre-lès-Nancy, , France

Ch Nord Ouest

Villefranche-sur-Saône, , France

Gustave Roussy

Villejuif, , France

Countries

France

Central Contacts

Sofia BOUHLAL JOURDAN, PhD

Role: CONTACT

prodige115.ulysse@ffcd.fr

+33(0)7 55 67 67 95

Facility Contacts

Victor SIMMET, MD

Role: primary

victor.simmet@ch-cholet.fr

Bruno HUGUENIN, MD

Role: primary

drbhuguenin@orange.fr

Anne-Laure VILLING, MD

Role: primary

alvilling@ch-auxerre.fr

Annie PEYTIER, MD

Role: primary

a.peytier@ch-ab.fr

Franck AUDEMAR, MD

Role: primary

faudemar@ch-cotebasque.fr

Hanifa AMMARGUELLAT, MD

Role: primary

h.ammarguellat@ch-beauvais.fr

Antoine EL KADDISSI, MD

Role: primary

aelkaddissi@chu-besancon.fr

Laurent BASSON, MD

Role: primary

laurent.basson@ichf.fr

Simon PERNOT, MD

Role: primary

s.pernot@bordeaux.unicancer.fr

Valérie COCHIN, MD

Role: primary

v.cochin@tivoli-oncologie.fr

Marc KANAAN, MD

Role: primary

marc.kanaan@ch-chauny.fr

Thomas DAVIEAU, MD

Role: primary

thomas.davieau@ch-cholet.fr

Kaïs ALDABBAGH, MD

Role: primary

kais.aldabbagh@stcome.com

Jean Baptiste AISENFARB, MD

Role: primary

jbaisenfarb@iadonco.org

Candice CAROLA DELVALLEZ, MD

Role: primary

Candice.CarolaDelvallez@ghpso.fr

Claire GIRAUD, MD

Role: primary

cgiraud@clinique-psv.fr

Jean-Louis JOUVE, MD

Role: primary

jean-louis.jouve@chu-dijon.fr

Antoine DROUILLARD, MD

Role: primary

adrouillard@icb-cancer.fr

Margot LALY, MD

Role: primary

margot.laly@ght85.fr

Fabienne WATELLE, MD

Role: primary

fwatelle@ch-lens.fr

Benoist CHIBAUDEL, MD

Role: primary

benoist.chibaudel@ihfb.org

Léa CLAVEL, MD

Role: primary

leaclavel1@gmail.com

Laétitia DAHAN, MD

Role: primary

laetitia.dahan@ap-hm.fr

Morgan ANDRE, MD

Role: primary

morgan.andre@ch-mdm.fr

Emmanuel GUARDIOLA, MD

Role: primary

guardiola@ccgm.fr

Benjamin LINOT, MD

Role: primary

benjamin.linot@groupeconfluent.fr

Olivier DUBREUIL, MD

Role: primary

odubreuil@hopital-dcss.org

Julien TAIEB, MD

Role: primary

julien.taieb@aphp.fr

Jean-Baptiste BACHET, MD

Role: primary

jean-baptiste.bachet@aphp.fr

Thomas APARICIO, MD

Role: primary

thomas.aparicio@aphp.fr

David TOUGERON, MD

Role: primary

david.tougeron@chu-poitiers.fr

Damien BOTSEN, MD

Role: primary

dbotsen@chu-reims.fr

Olivier BOUCHÉ, MD

Role: primary

obouche@chu-reims.fr

Caroline CHENEAU, MD

Role: primary

caroline.cheneau@icrb.fr

Sandrine HIRET, MD

Role: primary

sandrine.hiret@ico.unicancer.fr

Catherine LIGEZA POISSON, MD

Role: primary

catherine.ligeza@hospigrandouest.fr

Jean-Marc PHELIP, MD

Role: primary

j.marc.phelip@chu-st-etienne.fr

Anaïs BODERE, MD

Role: primary

a.bodere@ch-stmalo.fr

Meher BEN ABDELGHANI, MD

Role: primary

m.ben-abdelghani@icans.eu

Louis-Marie DOURTHE, MD

Role: primary

lm.dourthe@solcrr.org

Fanny POMMERET, MD

Role: primary

f-pommeret@ch-hopitauxduleman.fr

Nicolas ETCHEPARE, MD

Role: primary

netchepare@ch-valence.fr

Marie MULLER, MD

Role: primary

m.muller7@chru-nancy.fr

Boris MOREL, MD

Role: primary

bomorel@hno.fr

Valérie BOIGE, MD

Role: primary

valerie.boige@gustaveroussy.fr

Other Identifiers

2025-522108-26-00

Identifier Type: CTIS

Identifier Source: secondary_id

PRODIGE 115 - FFCD 2406-ULYSSE

Identifier Type: -

Identifier Source: org_study_id