A phase II, open label, multicenter trial investigating Irinotecan plus cetuximab rechallenge compared with trifluridine/tipiracil plus bevacizumab as third line treatment in circulating tumor DNA molecularly selected metastatic colorectal cancer: the ROMANCE-GOIM trial

The primary objective is to demonstrate the superiority of irinotecan plus cetuximab compared with trifluridine/tipiracil plus bevacizumab in terms of objective response rate in patients with metastatic colorectal cancer selected by circulating tumor DNA molecular analysis receiving third-line treatment. This comparison addresses a critical clinical question regarding optimal rechallenge strategies in molecularly selected patients who have previously responded to anti-EGFR therapy.

The secondary objectives include:

• Evaluation of clinical activity through assessment of progression-free survival and overall survival of irinotecan plus cetuximab rechallenge therapy compared with trifluridine/tipiracil plus bevacizumab

• Assessment of safety and tolerance profiles of both treatment combinations

• Evaluation of the impact on quality of life for both therapeutic regimens

• Collection of efficacy data regarding subsequent lines of treatment following study therapy

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population includes both **male** and **female** participants aged **18 years and older**. Participants are diagnosed with histologically or cytologically confirmed **metastatic colorectal cancer** and must have an **Eastern Cooperative Oncology Group Performance Status (ECOG-PS)** of 1 or less. The trial population was selected based on specific molecular characteristics, requiring **KRAS/NRAS/BRAFV600E wild-type** status and additional molecular markers including **RAS/BRAF/EGFR/PIK3CAex20/MAP2K1/MET wild-type** and **HER2** not amplified as determined by circulating tumor DNA testing. Eligible participants must have previously received and progressed on first-line anti-EGFR-containing therapy with at least a partial response lasting 6 months or more, followed by progression on a second-line treatment that did not include anti-EGFR agents or **irinotecan**. Participants must be refractory to prior treatment with **5-fluorouracil/capecitabine**, irinotecan, **oxaliplatin**, and **bevacizumab**, and must have had an anti-EGFR-free interval of at least 4 months. Key health requirements include adequate **hematological function** with white blood cell count of at least 2.5 × 10⁹/L, absolute neutrophil count of at least 1.5 × 10⁹/L, **platelet** count of at least 100 × 10⁹/L, and **hemoglobin** of at least 9 g/dL. Adequate **hepatic function** is defined by total **bilirubin** level not exceeding 1.5 times the upper limit of normal and **AST** and **ALT** levels not exceeding 2.5 times the upper limit of normal, or 5 times for participants with documented liver metastases. Adequate **renal function** requires an estimated **creatinine clearance** greater than 30 mL/min. Participants must have a life expectancy of at least 3 months and at least one measurable lesion according to **RECIST 1.1** criteria. Women of childbearing potential must have a negative pregnancy test and both participants and their partners must use adequate contraception during the study and for at least 6 months following the last dose of study treatment.

This is a phase II, open-label, multicenter clinical trial evaluating treatment options for patients with metastatic colorectal cancer. The trial employs a randomized design comparing two treatment regimens: irinotecan plus cetuximab versus trifluridine/tipiracil (Lonsurf) plus bevacizumab as third-line therapy. The study is classified as a low-intervention trial utilizing authorized medicinal products in accordance with their approved indications and published evidence, thereby presenting minimal additional risk compared to standard clinical practice. Patient selection is based on circulating tumor DNA molecular profiling, specifically requiring RAS/BRAF/EGFR/PIK3CAex20/MAP2K1/MET wild-type status and absence of HER2 amplification at baseline using the FoundationOne CDx test.

The primary objective of the trial is to demonstrate the superiority of irinotecan plus cetuximab compared with trifluridine/tipiracil plus bevacizumab in terms of objective response rate. The primary endpoint is defined as the proportion of patients achieving a partial or complete response to therapy according to RECIST 1.1 criteria, with radiological assessments performed by a blinded external radiology department. Secondary endpoints include progression-free survival, defined as the time from randomization to disease progression or death from any cause; overall survival, measured as the interval from enrollment to death from any cause; safety profile of the investigational drugs assessed using NCI-CTCAE version 5.0, including adverse events, serious adverse events, clinical laboratory assessments, vital signs, physical examination, ECG parameters, and ECOG performance status; and quality of life evaluated using the EORTC QLQ-C30 questionnaire.

Eligible participants must be adults aged 18 years or older with histologically or cytologically confirmed colorectal cancer and at least one measurable lesion according to RECIST 1.1 criteria. Key inclusion criteria require an Eastern Cooperative Oncology Group Performance Status of 0 or 1, KRAS/NRAS/BRAFV600E wild-type status of the primary tumor or related metastasis, and progression following previous first-line anti-EGFR-containing therapy that produced at least a partial response lasting 6 months or longer. Patients must have received and progressed on an anti-EGFR and irinotecan-free second-line treatment, with an anti-EGFR free interval of at least 4 months, and must be refractory to previous treatment with 5-fluorouracil/capecitabine, irinotecan, oxaliplatin, and bevacizumab. No prior treatment with trifluridine/tipiracil is permitted. Additional requirements include adequate hematological function with white blood cell count ≥2.5 × 10⁹/L, absolute neutrophil count ≥1.5 × 10⁹/L, platelet count ≥100 × 10⁹/L, and hemoglobin ≥9 g/dL; adequate hepatic function with total bilirubin ≤1.5 × upper limit of normal and AST/ALT levels ≤2.5 × ULN or ≤5 × ULN for patients with documented hepatic metastases; adequate renal function with estimated creatinine clearance >30 mL/min; and a life expectancy of at least 3 months. Women of childbearing potential must have a negative pregnancy test at screening, and all participants and their partners must agree to use adequate contraception during the study and for at least 6 months following the last dose of study treatment.

The investigational medicinal products include bevacizumab administered as a concentrate for solution for infusion via the intravenous route at a maximum daily dose of 5 mg/kg and maximum total dose of 325 mg/kg over a treatment period of up to 30 weeks; irinotecan administered as a concentrate for solution for infusion via intraportal infusion at a maximum daily dose of 180 mg/m² and maximum total dose of 117,000 mg/m² over a treatment period of up to 30 months; trifluridine/tipiracil hydrochloride (Lonsurf 20 mg/8.19 mg film-coated tablets) administered orally at a maximum daily dose of 35 mg/m² and maximum total dose of 10,500 mg/m² over a treatment period of up to 30 weeks; and cetuximab administered as a solution for infusion via intravenous infusion at a maximum daily dose of 500 mg/m² and maximum total dose of 32,500 mg/m² over a treatment period of up to 30 weeks. Irinotecan and cetuximab serve as test products, while trifluridine/tipiracil and bevacizumab function as comparator products.

The estimated recruitment start date for the trial is January 30, 2026, with an estimated completion date of January 30, 2031, yielding an overall trial duration of approximately 5 years. Participant involvement begins with a screening visit to assess eligibility criteria, including molecular profiling of circulating tumor DNA, verification of prior treatment history, assessment of performance status, and evaluation of organ function through hematological, hepatic, and renal parameters. Following enrollment and randomization, participants undergo regular follow-up visits for administration of study treatments, monitoring of disease response through radiological assessments, evaluation of adverse events and safety parameters, collection of blood samples for laboratory assessments, and completion of quality of life questionnaires. The frequency and timing of study visits are determined by the treatment schedule and disease assessment intervals as specified in the trial protocol. The end-of-study visit occurs upon disease progression, completion of treatment, or study withdrawal, at which time final assessments of disease status, safety parameters, and quality of life are performed. Early termination from the study may occur under several conditions, including disease progression as defined by RECIST 1.1 criteria, unacceptable toxicity or adverse events requiring discontinuation of study treatment, withdrawal of informed consent by the participant, investigator decision based on safety concerns or protocol violations, pregnancy during the study period, or death of the participant.

The experimental treatment arm consists of **irinotecan** administered as a **concentrate for solution for infusion** via **intraportal infusion**. The maximum daily dose is 180 mg/m² with a maximum total dose of 117,000 mg/m² over a treatment period of up to 30 weeks. Irinotecan is classified as a chemotherapeutic and anti-EGFR agent in this study.

**Cetuximab** is administered as a **solution for infusion** via **intravenous infusion** as part of the experimental treatment regimen. The maximum daily dose is 500 mg/m² with a maximum total dose of 32,500 mg/m² over a treatment period of up to 30 months. Cetuximab is categorized as a chemotherapeutic agent for the purposes of this trial.

The comparator treatment arm includes **trifluridine/tipiracil hydrochloride**, marketed as Lonsurf 20 mg/8.19 mg **film-coated tablets**, administered via **oral use**. The active substances are trifluridine and tipiracil hydrochloride, both of chemical origin. The maximum daily dose is 35 mg/m² with a maximum total dose of 10,500 mg/m² over a treatment period of up to 30 months. This combination is classified as a chemotherapeutic agent.

**Bevacizumab** is administered as a **concentrate for solution for infusion** via **intravenous** route as part of the comparator treatment arm. The maximum daily dose is 5 mg/kg with a maximum total dose of 325 mg/kg over a treatment period of up to 30 months. Bevacizumab contains the active substance bevacizumab, which is a protein-based therapeutic agent.

The primary endpoint is overall response rate (ORR) assessed according to RECIST 1.1 criteria, defined as the proportion of patients who achieve a partial or complete response to therapy. An external radiology department will receive radiological re-evaluation images from the participating sites, and the imaging will be assessed by a blinded operator.

Secondary endpoints include progression-free survival (PFS), defined as the time from randomization to disease progression or death from any cause, and overall survival (OS), defined as the interval from enrollment to death from any cause. The safety profile of the trial drugs will be measured by the incidence of adverse events evaluated using the NCI-CTCAE version 5.0, serious adverse events, clinical laboratory assessments, vital signs, physical examination, ECG parameters, and ECOG performance status. Quality of life will be assessed using the EORTC QLQ-C30 questionnaire.