Phase 2 Randomized Open‑Label Study of Denikitug Monotherapy and Denikitug‑Based Combination Therapy in Adults with Advanced Microsatellite Stable Colorectal Cancer

Primary objective: to evaluate the effect of denikitug given as monotherapy or in combination with nivolumab or with trifluridine‑tipiracil plus bevacizumab on objective response rate as assessed by investigators according to RECIST 1.1 in patients with advanced microsatellite stable colorectal cancer. Secondary objectives: – assess duration of response and progression‑free survival under the same treatment regimens; – assess overall survival; – evaluate safety and tolerability of denikitug alone or in combination; – characterize pharmacokinetics and immunogenicity (antidrug antibodies) of denikitug administered alone or with the combination therapies.

Seventy‑six participants (both male and female) meeting the protocol‑defined adult age categories (codes 3 and 4) were enrolled. Eligible individuals had histologically or cytologically confirmed unresectable, recurrent, locally advanced or metastatic Advanced Microsatellite Stable (MSS) Colorectal Cancer with documented microsatellite stability or proficient mismatch repair, and had experienced disease progression following up to two prior systemic therapy regimens for advanced disease. Inclusion required an Eastern Cooperative Oncology Group performance status of 0–1, adequate hematologic, hepatic, renal and coagulation parameters, and measurable disease per RECIST 1.1. Key exclusion criteria encompassed prior exposure to HER2‑targeted therapy and recent peri‑operative or adjuvant chemotherapy not associated with progressive disease. No specific dietary, exercise or habit‑related requirements were stipulated for enrollment.

The study is a phase 2, open‑label, multicenter, randomized trial evaluating denikitug monotherapy and denikitug‑based combination regimens in participants with Advanced Microsatellite Stable (MSS) Colorectal Cancer. Eligible adults are randomized to receive either denikitug 30 mg intravenous infusion alone, denikitug plus nivolumab 480 mg intravenous infusion, or denikitug together with oral trifluridine‑tipiracil (70 mg/m²) and bevacizumab 5 mg/kg intravenous infusion; all treatments follow the dosing schedule defined in the protocol. The trial enrolment period begins on 1 June 2026 and is planned to conclude on 30 September 2028, with each participant remaining in the study for the duration of treatment and subsequent follow‑up until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. The visit schedule includes a screening visit to confirm eligibility, a baseline visit for randomization and initiation of therapy, regular treatment‑cycle visits for drug administration, safety monitoring, and efficacy assessments (including imaging per RECIST 1.1), and a final end‑of‑study visit after discontinuation of therapy or at the study’s closure. Early termination of a participant’s involvement may occur if progressive disease is documented, if treatment‑emergent adverse events reach predefined severity thresholds, or if the investigator deems continued participation unsafe.

Denikitug is supplied as a 150 mg/vial concentrate for solution for infusion. The active substance is a humanised IgG1 monoclonal antibody against CCR8. The prescribed dose is 30 mg administered intravenously as an infusion. Dosing is scheduled on day 1 of each 14‑day cycle and may be repeated according to the protocol‑defined treatment duration.

Bevacizumab is provided as a 25 mg/mL concentrate for solution for infusion. The dose is 5 mg/kg given by intravenous infusion. The infusion is performed on day 1 of each 14‑day cycle. Administration follows standard infusion‑rate guidelines and infusion records are maintained for compliance monitoring.

Nivolumab is supplied as a 10 mg/mL concentrate for solution for infusion. The dose is 480 mg administered intravenously as a single infusion. The infusion is given on day 1 of each 14‑day cycle. Infusion details, including start and end times, are documented to ensure adherence to the dosing schedule.

Trifluridine‑tipiracil (Lonsurf) is provided as film‑coated tablets containing 15 mg trifluridine and 6.14 mg tipiracil hydrochloride per tablet. The dose is 70 mg/m² administered orally. Tablets are taken twice daily on days 1 through 5 of each 14‑day cycle. Pill counts and patient diaries are used to verify oral compliance.

Efficacy will be evaluated primarily by the objective response rate (RECIST Version 1.1), defined as the proportion of participants achieving a complete response or partial response as determined by the investigator.

Secondary efficacy assessments include:

• Duration of response, measured from the first documented response until progressive disease or death.
• Progression‑free survival, calculated from randomization to the first occurrence of progressive disease or death.
• Overall survival, measured from randomization to death from any cause.
• Pharmacokinetic analysis of serum denikitug concentrations and derived parameters such as Cmax and AUCall.
• Incidence of treatment‑emergent anti‑drug antibodies, reported as positive or negative.
• Safety evaluation encompassing the incidence, severity, and relatedness of treatment‑emergent adverse events and laboratory abnormalities graded per NCI‑CTCAE v5.0.