ROMANCE: "Irinotecan Plus Cetuximab Rechallenge Versus Trifluridine/Tipiracil Plus Bevacizumab in Molecularly Selected Metastatic Colorectal Cancer"

NCT07381764 | Not Yet Recruiting Phase 2

• 2 other identifiers: ROMANCE - GOIM2025-521319-38-00
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 26

Brief Summary

This study is a phase II, open-label, multicenter clinical trial designed to evaluate two different treatment options for patients with metastatic colorectal cancer whose disease has progressed after standard therapies. The study compares a rechallenge treatment using irinotecan plus cetuximab with the current standard of care, trifluridine/tipiracil plus bevacizumab, as third-line therapy. Patients enrolled in the study are selected based on specific molecular characteristics of their cancer, identified through circulating tumor DNA analysis from a blood sample. The main purpose of the study is to determine whether the rechallenge with irinotecan and cetuximab leads to a higher tumor response rate compared with trifluridine/tipiracil plus bevacizumab. Secondary objectives include evaluating progression-free survival, overall survival, safety, and quality of life. Patients will be randomly assigned to one of the two treatment groups and will receive treatment until disease progression, unacceptable side effects, or withdrawal of consent. Tumor response will be assessed using standard imaging techniques according to RECIST criteria.

Conditions

Metastatic Colorectal Cancer (CRC)

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  Objective Response Rate (ORR) is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR) according to RECIST version 1.1 criteria. Tumor assessments are based on radiological imaging reviewed centrally by an independent blinded radiology reviewe

  From Week 8 through disease progression or end of treatment, up to approximately 24 months.

Secondary Outcomes (5)

• Progressio-Free Survival (PFS)

  From date of randomization until the date of first documented disease progression per RECIST v1.1 or death from any cause, whichever occurs first, assessed up to 36 months.

• Overall Survival (OS)

  From date of enrollment until death from any cause, assessed up to 36 months.

• Incidence of Adverse Events and Serious Adverse Events

  From first dose of study treatment until 30 days after the last dose of study treatment.

• Treatment Exposure as a Measure of Tolerability

  Through study completion, an average of approximately 24 months

• The impact of treatment with irinotecan plus cetuximab and trifluridine/tipiracil plus bevacizumab on quality of life

  From baseline through study completion, an average of approximately 12 months

Other Outcomes (1)

• Progression-Free Survival (PFS) of the Subsequent Line of Treatment

  From initiation of subsequent line of treatment until documented disease progression per RECIST v1.1 or death from any cause, whichever occurs first, assessed up to approximately 36 months.

Study Arms (2)

Experimental: Arm A - Irinotecan + Cetuximab

EXPERIMENTAL

This arm is for participants with molecularly selected metastatic colorectal cancer who have progressed after standard first- and second-line therapies and previously achieved clinical benefit from an anti-EGFR-based regimen. Participants randomized to this arm will receive irinotecan in combination with cetuximab as a rechallenge strategy. The objective of this arm is to evaluate the antitumor activity and safety of irinotecan plus cetuximab compared with the control treatment in the third-line setting.

Drug: Erbitux (Cetuximab); Drug: Irinotecan

Active Comparator: Arm B - Trifluridine/Tipiracil + Bevacizumab

ACTIVE COMPARATOR

This arm is for participants with molecularly selected metastatic colorectal cancer who have progressed after standard first- and second-line therapies. Participants randomized to this arm will receive trifluridine/tipiracil in combination with bevacizumab, which represents the current standard of care in the third-line treatment setting. This arm serves as the control group for comparison with the experimental rechallenge strategy.

Drug: Bevacizumab; Drug: Trifluridine/tipiracil

Interventions

Erbitux (Cetuximab) DRUG

This is an anti-EGFR monoclonal antibody administered in combination with chemotherapy. The dose is 500 mg/m2 over 120 minutes

Experimental: Arm A - Irinotecan + Cetuximab

Bevacizumab DRUG

This is an anti-VEGF monoclonal antibody used as an active comparator in the control arm of the study. The dose is 5 mg/Kg of body weight given once every 2 weeks.

Active Comparator: Arm B - Trifluridine/Tipiracil + Bevacizumab

Irinotecan DRUG

Irinotecan is a cytotoxic chemotherapy agent administered intravenously in combination with cetuximab the dose is 180 mg/m2 over 90 minutes, once every 2 weeks.

Experimental: Arm A - Irinotecan + Cetuximab

Trifluridine/tipiracil DRUG

Trifluridine/tipiracil is an oral antineoplastic combination administered in combination with bevacizumab as part of the control treatment arm. The dose is 5 mg/ m² twice daily on Days 1 to 5 and Days 8 to 12 on a cycle of 28 days.

Active Comparator: Arm B - Trifluridine/Tipiracil + Bevacizumab

Eligibility Criteria

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

You may qualify if:

• Male or female aged ≥18 years
• Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤1
• Diagnosis of histologically or cytologically confirmed colorectal cancer.
• At least one measurable lesion according to RECIST1.1
• KRAS/NRAS/BRAFV600E wt status of primary CRC or related metastasis (local laboratory assessment).
• Progression to previous first-line anti-EGFR-containing therapy producing at least a partial response ≥ 6 months.
• Received and progressed to an anti-EGFR and irinotecan free second-line treatment.
• Have an anti-EGFR free interval of at least 4 months.
• Refractory to previous 5-fluorouracil/capecitabine, irinotecan, oxaliplatin, bevacizumab.
• RAS/BRAF/EGFR/PIK3CAex20/MAP2K1/MET WT and HER2 not amplified ctDNA at FoundationOne CDx test at baseline.
• Life expectancy of at least 3 months.
• Adequate hematological function defined by white blood cell (WBC) count ≥ 2.5 × 109/L with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused).
• Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and alanine aminotransferase (ALT) levels ≤ 2.5 × ULN for all subjects or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver).
• Adequate renal function defined by an estimated creatinine clearance \> 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).
• No contraindication to the study drugs.

You may not qualify if:

• ECOG PS ≥2
• Received more than 2 lines of treatment for metastatic disease.
• Previous treatment with trifluridine/tipiracil
• RAS/BRAF/EGFR/PIK3CAex20/MAP2K1/MET WT HER2 not amplified status at liquid biopsy analysis during screening.
• Previous history of malignancy within the last 2 years will be excluded with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ
• Evidence of bleeding diathesis or coagulopathy.
• Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.
• Known severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v 5 Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
• Clinically significant cardiovascular disease, active inflammatory bowel disease, active autoimmune disease.
• Diagnosis of interstitial pneumonitis or pulmonary fibrosis.
• History of abdominal fistula, GI perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to the first study treatment.
• Pregnant or lactating women.
• Psychiatric or addictive disorders would preclude study participation.
• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating study treatments.
• Withdrawal of the consent to take part to the study.

Sponsors & Collaborators

• Gruppo Oncologico Italia Meridionale: lead

Study Sites (26)

Azienda Ospedaliero Universitaria "SS Antonio e Biagio e Cesare Arrigo"

Alessandria, Italy

Location

A.O.U. Ospedali Riuniti

Ancona, Italy

Location

Centro di Riferimento Oncologico (CRO), IRCCS

Aviano, Italy

Location

A.O.R.N. "Sant'anna e San Sebastiano"

Caserta, Italy

Location

Ospedale IRCCS 'Saverio de Bellis'

Castellana Grotte, Italy

Location

A.R.N.A.S. Garibaldi - P.O. Garibaldi-Nesima

Catania, Italy

Location

Azienda Ospedaliero-Universitaria Renato Dulbecco

Catanzaro, Italy

Location

A.O.U. Careggi

Florence, Italy

Location

Istituto Romagnolo per lo Studio dei Tumori 'Dino Amadori'

Meldola, Italy

Location

ASST Grande Ospedale Metropolitano Niguarda

Milan, Italy

Location

Fondazione IRCCS Istituto Nazionale Tumori

Milan, Italy

Location

Istituto Europeo di Oncologia

Milan, Italy

Location

Casa di Cura Villa Maria

Mirabella Eclano, Italy

Location

AOU Policlinico di Modena

Modena, Italy

Location

A.O.U. dell'Università degli studi della Campania "Luigi Vanvitelli"

Naples, Italy

Location

Istituto Nazionale Tumori 'Fondazione G. Pascale'

Naples, Italy

Location

Istituto Oncologico Veneto IRCCS

Padua, Italy

Location

ARNAS Civico - Di Cristina-Benfratelli - P. O. 'Civico e Benfratelli'

Palermo, Italy

Location

Casa di cura Macchiarella

Palermo, Italy

Location

A.O.U. Pisana

Pisa, Italy

Location

Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS

Roma, Italy

Location

Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza

San Giovanni Rotondo, Italy

Location

A.O.U. Sassari

Sassari, Italy

Location

Ospedale San Giuseppe Moscati

Statte, Italy

Location

A.O. 'Pia Fondazione Cardinale G. Panico'

Tricase, Italy

Location

ASST Sette Laghi-Ospedale di Circolo Fondazione Macchi

Varese, Italy

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Cetuximab; Bevacizumab; Irinotecan; trifluridine tipiracil drug combination

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)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Camptothecin; Alkaloids; Heterocyclic Compounds

Central Study Contacts

Davide Ciardiello DC Principal Investigator

CONTACT

02/94372686; davide.ciardiello@ieo.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: ARM A: Cetuximab + irinotecan (75 patients) ARM B: Trifluridine/tipiracil + bevacizumab (75 patients)

Study Record Dates

• First Submitted: January 16, 2026
• First Posted: February 2, 2026
• Study Start: March 30, 2026
• Primary Completion (Estimated): March 30, 2031
• Study Completion (Estimated): March 30, 2031
• Last Updated: February 2, 2026

Record last verified: 2026-01

Locations

IT (26)