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

NCT07150403 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: PRODIGE 115 - FFCD 2406-ULYSSE2025-522108-26-00
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 45

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)

Outcome Measures

Primary Outcomes (1)

• Disease Control Rate (DCR)

  the percentage of patients with a complete response, a partial response or a stable disease at 4 months after the start of treatment.

  at 4 months after the start of treatment

Study Arms (2)

Experimental arm A FOLFOX/FOLFIRI + Fruquintinib

EXPERIMENTAL

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

Drug: Oxaliplatin intravenous; Drug: 5 FU bolus; Drug: Folinic acid; Drug: 5 FU continuous; Drug: Irinotecan; Drug: FRUQUINTINIB

Control arm B FOLFOX/FOLFIRI + Bevacizumab

ACTIVE COMPARATOR

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

Drug: Oxaliplatin intravenous; Drug: 5 FU bolus; Drug: Folinic acid; Drug: 5 FU continuous; Drug: Irinotecan; Drug: BEVACIZUMAB

Interventions

Oxaliplatin intravenous DRUG

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

Control arm B FOLFOX/FOLFIRI + Bevacizumab; Experimental arm A FOLFOX/FOLFIRI + Fruquintinib

5 FU bolus DRUG

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

Control arm B FOLFOX/FOLFIRI + Bevacizumab; Experimental arm A FOLFOX/FOLFIRI + Fruquintinib

Folinic acid DRUG

400 mg/m² in intravenous

Control arm B FOLFOX/FOLFIRI + Bevacizumab; Experimental arm A FOLFOX/FOLFIRI + Fruquintinib

5 FU continuous DRUG

2400 mg/m² intravenously over 46 hours

Control arm B FOLFOX/FOLFIRI + Bevacizumab; Experimental arm A FOLFOX/FOLFIRI + Fruquintinib

Irinotecan DRUG

180 mg/m² IV over 1h30

Control arm B FOLFOX/FOLFIRI + Bevacizumab; Experimental arm A FOLFOX/FOLFIRI + Fruquintinib

FRUQUINTINIB DRUG

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

Experimental arm A FOLFOX/FOLFIRI + Fruquintinib

BEVACIZUMAB 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

Control arm B FOLFOX/FOLFIRI + Bevacizumab

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- 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 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

You may not qualify if:

• \- 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

Sponsors & Collaborators

• Federation Francophone de Cancerologie Digestive: lead

Study Sites (45)

ICO Site Paul Papin

Angers, France

Location

Les Bonnettes

Arras, France

Location

Ght Unyon Auxerre

Auxerre, France

Location

Bayeux Ch

Bayeux, France

Location

Cote Basque

Bayonne, France

Location

Beauvais Ch

Beauvais, France

Location

Jean Minjoz

Besançon, France

Location

Centre Pierre Curie

Beuvry, France

Location

BERGONIÉ

Bordeaux, France

Location

TIVOLI

Bordeaux, France

Location

Chauny Ch

Chauny, France

Location

Cholet Ch

Cholet, France

Location

Saint Côme

Compiègne, France

Location

Clinique de Flandre

Coudekerque-Branche, France

Location

GHPSO Site de Creil

Creil, France

Location

Centre Leonard de Vinci

Dechy, France

Location

Dijon Bourgogne

Dijon, France

Location

Institut de cancérologie de Bourgogne GRReCC

Dijon, France

Location

CHD Vendée

La Roche-sur-Yon, France

Location

Docteur Schaffner

Lens, France

Location

Franco Britannique

Levallois-Perret, France

Location

Jean Mermoz

Lyon, France

Location

La Timone

Marseille, France

Location

LAYNÉ CH

Mont-de-Marsan, France

Location

Centre de Cancérologie du Grand Montpellier

Montpellier, France

Location

Confluent Sas

Nantes, France

Location

Groupe Hospitalier Diaconesses Croix Saint Simon

Paris, France

Location

Hôpital Européen G Pompidou

Paris, France

Location

La Pitié Salpêtrière

Paris, France

Location

Saint Louis

Paris, France

Location

La Miletrie

Poitiers, France

Location

Jean Godinot

Reims, France

Location

Robert Debré

Reims, France

Location

Saint Gregoire Chp

Saint-Grégoire, France

Location

ICO Site René Gauducheau

Saint-Herblain, France

Location

Clinique Mutualiste de L'Estuaire

Saint-Nazaire, France

Location

Hopital Nord Chu Saint Etienne

Saint-Priest-en-Jarez, France

Location

Saint Malo Ch

St-Malo, France

Location

ICAN Institut de Cancérologie de Strasbourg Europe

Strasbourg, France

Location

Sainte Anne

Strasbourg, France

Location

LEMAN

Thonon-les-Bains, France

Location

Valence Ch

Valence, France

Location

BRABOIS

Vandœuvre-lès-Nancy, France

Location

Ch Nord Ouest

Villefranche-sur-Saône, France

Location

Gustave Roussy

Villejuif, France

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Leucovorin; Irinotecan; HMPL-013; Bevacizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Camptothecin; Alkaloids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

Sofia BOUHLAL JOURDAN, PhD

CONTACT

+33(0)7 55 67 67 95; prodige115.ulysse@ffcd.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2025
• First Posted: September 2, 2025
• Study Start: December 31, 2025
• Primary Completion (Estimated): February 28, 2028
• Study Completion (Estimated): October 31, 2028
• Last Updated: September 8, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (45)