Randomized Phase 3 Study of Precemtabart Tocentecan With or Without Bevacizumab Versus Trifluridine/Tipiracil + Bevacizumab in Treated Metastatic Colorectal Cancer

The primary objective of the trial in patients with metastatic colorectal cancer is to determine whether treatment with precemtabart tocentecan, administered as monotherapy or in combination with bevacizumab, improves overall survival relative to trifluridine/tipiracil plus bevacizumab.

Secondary objectives include:

• Evaluation of overall survival for precemtabart tocentecan monotherapy and the combination regimen.
• Demonstration of improvement in progression-free survival for both the monotherapy and combination arms compared with the comparator, and assessment of progression‑free survival for each regimen.
• Assessment of improvement in overall response rates for the investigational arms versus the comparator, and determination of overall response for each treatment.
• Determination of duration of response for precemtabart tocentecan monotherapy, the combination regimen, and the comparator.
• Evaluation of safety and tolerability of precemtabart tocentecan monotherapy versus the comparator, of the combination versus the comparator, and of monotherapy versus combination.
• Characterization of the pharmacokinetic profile of precemtabart tocentecan (both conjugated antibody and unconjugated payload) as monotherapy or in combination with bevacizumab.
• Characterization of the immunogenicity of precemtabart tocentecan.
• Assessment of quality of life using the EORTC QLQ‑C30 questionnaire during the investigational treatment phase for all treatment arms.

The trial enrolled 697 participants diagnosed with metastatic colorectal cancer. Both male and female adults were included, encompassing the age categories designated by codes 3 and 4. Eligible individuals had experienced disease progression or intolerance after no more than two prior systemic treatment regimens in the metastatic setting and demonstrated an ECOG Performance Status of 0 or 1. Participants were required to be capable of swallowing oral tablets and to comply with scheduled study evaluations. Selection was based on documented histopathological confirmation of the disease and the specified treatment history. No specific dietary, physical activity, or habit restrictions were stipulated in the available information.

The study is a randomized, open‑label, three‑arm Phase 3 trial evaluating metastatic colorectal cancer patients who have progressed after up to two prior systemic regimens. Participants are allocated to one of the following arms: (1) precemtabart tocentecan 2.8 mg/kg intravenously, (2) precemtabart tocentecan 2.8 mg/kg + bevacizumab 7.5 mg/kg intravenously, or (3) trifluridine/tipiracil 70 mg/m² orally + bevacizumab 7.5 mg/kg intravenously. The primary endpoint for all arms is overall survival. The trial recruitment period is from July 1 2026 to October 31 2029, with each participant remaining in the study until death, withdrawal, loss to follow‑up, or study termination. Key study visits include: • Screening visit to confirm eligibility, obtain baseline assessments, and collect informed consent. • Baseline visit (Day 1) for randomization and first drug administration. • Regular treatment cycles with safety and efficacy assessments every 2 weeks for intravenous drugs and every 4 weeks for oral therapy. • Follow‑up visits for disease assessment (RECIST v1.1) and quality‑of‑life questionnaires at defined intervals. • End‑of‑study visit conducted at death, withdrawal, or study close‑out to collect final outcome data. Participants are expected to be involved for up to 24 months, depending on survival and treatment duration. Early termination may occur if a participant experiences disease progression, unacceptable toxicity, withdraws consent, or fails to comply with protocol requirements.

Precemtabart Tocentecan is supplied as a powder for concentrate for solution for infusion. It is administered intravenously at a dose of 2.8 mg/kg, calculated based on the participant’s body weight and given according to the protocol‑specified schedule.

Bevacizumab is provided as a 25 mg/mL concentrate for solution for infusion. The drug is given intravenously at a dose of 7.5 mg/kg, weight‑based, and administered at intervals defined by the study protocol.

Trifluridine/Tipiracil is available as film‑coated tablets (15 mg/6.14 mg or 20 mg/8.19 mg). The tablets are taken orally at a dose of 70 mg/m², with the appropriate tablet strength selected based on the dosing calculation and administered per the protocol‑defined schedule.

All study medications are delivered in accordance with the defined treatment cycles. Dose modifications and treatment interruptions are permitted based on safety evaluations. Oral drug compliance is assessed by pill count and patient diary, while intravenous administrations are documented in the drug accountability log.

Efficacy will be assessed primarily by overall survival across all three treatment arms. Secondary efficacy endpoints include progression free survival, objective response and duration of response evaluated according to RECIST v1.1 by the Investigator, and changes from baseline in global health status, physical and role functioning subscale scores of the EORTC QLQ-C30 questionnaire. Additional pharmacokinetic and immunogenicity measures comprise observed concentration at end of infusion, trough concentration prior to the next dosing interval, and the presence of anti‑drug antibody as determined by an ADA assay.

Time‑to‑event outcomes (overall survival, progression free survival) will be analysed using survival analysis methods, while response rates and quality‑of‑life scores will be evaluated with appropriate categorical and continuous statistical techniques.