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Study of denikitug alone or in drug combination in adults with advanced microsatellite stable colorectal cancer

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on adults with advanced colorectal cancer that is microsatellite stable. Participants will receive the investigational drug denikitug either by itself, together with the immune‑boosting agent nivolumab, or combined with a chemotherapy pill containing trifluridine and tipiracil plus an anti‑angiogenic medicine called bevacizumab. The investigational drug is given through an IV infusion, while the chemotherapy pills are taken by mouth.

The purpose of the study is to evaluate how the treatment affects the objective response rate, which is the proportion of patients whose tumors shrink or disappear. After enrollment, participants are randomly assigned to one of the three treatment groups and receive the assigned therapy in repeated cycles over several months, with regular clinic visits for safety checks and blood draws. Tumor changes are measured using the standard imaging criteria known as RECIST, and any adverse events are closely monitored. Blood samples are also taken to assess the drug’s pharmacokinetics, meaning how the body absorbs and clears the medication.

Key outcomes include the percentage of patients achieving tumor shrinkage, the time until the disease shows progressive disease (when the cancer grows again), and the length of time patients remain alive, referred to as overall survival. Safety information and laboratory test results are collected throughout the study to understand the treatment’s risk profile.

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Randomization to treatment group
After joining, you are assigned to one of three groups: denikitug alone, denikitug plus nivolumab, or denikitug plus trifluridine‑tipiracil and bevacizumab.
Step 2
Initial treatment administration
You receive an intravenous infusion of denikitug at a dose of 30 mg.
If you are in the combination with nivolumab, you also receive an intravenous infusion of nivolumab at a dose of 480 mg.
If you are in the chemotherapy combination, you also receive an intravenous infusion of bevacizumab at a dose of 5 mg per kilogram of body weight and you start oral tablets of trifluridine‑tipiracil (lonsurf) at a dose of 70 mg per square meter of body‑surface area.
Step 3
Treatment cycle repetition
The same set of medications is given again at each scheduled visit, typically every two weeks, as defined by the study protocol.
The infusion is performed over the time required by the clinical staff, and oral tablets are taken as directed each day of the cycle.
Step 4
Monitoring and assessments
Regular imaging scans and laboratory tests are performed to evaluate tumor response and safety.
The investigator records any side effects and any changes in laboratory values.
Step 5
Continuation or discontinuation
Treatment continues until disease progression, unacceptable side effects, or the planned end of the study period.
If progression or toxicity occurs, treatment stops and final assessments are made.
Step 6
Final follow‑up
After stopping treatment, a final visit records overall survival and any lasting effects.
The study concludes when all follow‑up visits are completed.

Who can join the trial?

8 criteria

You must have colorectal cancer that cannot be removed by surgery, has returned, is locally advanced, or has spread to other parts of the body, and the tumor must be microsatellite stable (MSS) or have proficient mismatch repair (pMMR). Microsatellite stable means the DNA pattern is normal, and proficient mismatch repair means the cells can fix DNA errors correctly; both are confirmed with special lab tests called PCR (a test that looks at DNA) or immunohistochemistry (IHC) (a test that uses antibodies to see proteins).
You may have had up to two previous courses of systemic (whole‑body) chemotherapy for advanced disease. These courses must have included at least one of the following drug groups if they were available to you: fluoropyrimidine, oxaliplatin, or irinotecan. Depending on the specific features of your tumor, you might also have received targeted medicines such as an anti‑VEGF agent (which blocks blood‑vessel growth) or an anti‑EGFR agent (which blocks a growth signal), especially if your tumor is on the left side of the colon and does not have mutations in the BRAF or RAS genes. Certain mutations (e.g., BRAF V600E or KRAS G12C) allow use of specific drugs like encorafenib or adagrasib/sotorasib together with an anti‑EGFR agent. Patients whose tumors are HER2‑positive are not eligible.
Your cancer must have shown progressive disease (PD), meaning it has grown or spread, on a recent CT (computed tomography) or MRI (magnetic resonance imaging) scan, as judged by the doctor using the standard RECIST Version 1.1 criteria.
You need an ECOG performance status score of 0 or 1. This scale measures how well you are able to carry out daily activities: 0 means fully active, and 1 means you are restricted in physically demanding work but can do light work.
Your laboratory tests must show that your blood, liver, kidneys, and clotting system are working well enough. This includes:
- Hematologic (blood) function: absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, platelets ≥ 100 × 10⁹/L, and hemoglobin ≥ 9 g/dL, without needing a transfusion or growth‑factor medication in the past two weeks.
- Liver function: total bilirubin ≤ 1.5 times the normal upper limit (or ≤ 3 times if you have liver metastases or Gilbert’s syndrome) and AST/ALT enzymes ≤ 2.5 times normal (or ≤ 5 times if you have known liver metastases).
- Kidney function: creatinine clearance ≥ 50 mL/min (calculated by the Cockcroft‑Gault method) and urine protein ≤ 1+ on a dipstick test; if protein is higher, a 24‑hour urine collection must show less than 1000 mg protein.
- Clotting ability: if you are taking blood‑thinning medication (other than platelet anti‑aggregates), your INR (international normalized ratio) must be ≤ 1.5 times normal, and aPTT (activated partial thromboplastin time) must also be ≤ 1.5 times normal.

Who cannot join the trial?

5 criteria

Heart and blood‑vessel problems: You cannot join if you have recent (within the last 6 months) serious heart or brain blood‑vessel events such as a heart attack, stroke, unstable chest pain, or deep blood‑clot problems. Also excluded are serious irregular heart rhythms (like fast ventricular beats or dangerous heart‑block problems) that need medication, and heart failure that is moderate or worse (called NYHA Class II or higher) or a weak heart pumping ability (left‑ventricle ejection fraction less than 40%).
Autoimmune diseases: Anyone who has had an autoimmune condition (where the immune system attacks the body) that needed strong medicines such as steroids, disease‑modifying drugs, or other immune‑suppressing drugs in the past 2 years cannot participate. This includes conditions like non‑infectious inflammation of the intestine (enteritis/colitis), Crohn’s disease, ulcerative colitis, or Celiac disease. Simple hormone replacement (like thyroid or insulin) is not considered a disqualifier.
Lung inflammation (pneumonitis or interstitial lung disease): A history of, or current, non‑infectious lung inflammation—whether from radiation, medication, or other causes—excludes you, especially if it required steroids.
Serious gastrointestinal problems: You cannot be in the study if you have had a gut perforation, a permanent ileostomy (surgical opening of the small intestine), an abdominal abscess or fistula within the past 6 months, or active uncontrolled bleeding in the digestive tract within the past 4 weeks. Conditions that greatly increase the risk of bleeding or perforation, such as untreated varices (enlarged veins), tumor erosion into the gut, or recent major gut surgery, also exclude you.
Previous cancer treatments that conflict with the study: If you have already been treated with the drugs trifluridine‑tipiracil, regorafenib, or fruquitinib, you are not eligible. Any prior use of immune‑checkpoint inhibitors (medicines that target PD‑1/PD‑L1, CTLA‑4, CD137, OX‑40, CD40, or similar) also excludes you. Receiving an anticancer biologic agent within 4 weeks before randomization, or chemotherapy, targeted therapy, or radiation within 2 weeks that has not fully healed (still causing side effects grade 2 or higher) makes you ineligible. Finally, anyone who has had an allogeneic (donor) organ or stem‑cell transplant is excluded, except for a cornea transplant that does not require ongoing immune‑suppressing drugs.

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Verified sites

All sites with verified contact details – recruitment status may not be available; ask directly

Hospital Universitario Hm Sanchinarro
Responsive
Madrid, Spain
Istituto Europeo Di Oncologia S.r.l.
Responsive
Milan, Italy
Istituto Oncologico Veneto
Responsive
Padua, Italy

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Investigated drugs

Denikitug
is a human‑engineered antibody that targets a protein called CCR8. By binding to this protein, it is intended to change how the immune system interacts with the cancer, helping the body’s defenses to recognize and fight advanced colorectal cancer.
Nivolumab
is an immunotherapy drug that blocks a checkpoint called PD‑1 on immune cells. This blockage lets the immune system stay active against cancer cells, allowing it to better detect and destroy tumors.
Trifluridine‑tipiracil
is an oral chemotherapy combination. Trifluridine works by getting incorporated into the DNA of cancer cells, which disrupts their ability to grow and divide. Tipiracil is included to keep trifluridine active in the body for a longer time, making the treatment more effective.
Bevacizumab
is a monoclonal antibody that attaches to a protein called VEGF. By blocking VEGF, it reduces the formation of new blood vessels that supply the tumor, which can slow tumor growth and help other treatments work better.

What is already known about the treatment

Denikitug
Denikitug is given as an intravenous infusion of a clear solution. It is a humanised IgG1 monoclonal antibody that is still being studied in clinical trials and is not yet approved for general use. The drug is being tested for advanced microsatellite stable colorectal cancer and works by attaching to the CCR8 protein on certain immune cells, blocking signals that can help the tumor grow. It belongs to the class of monoclonal antibody immunotherapies.
Lonsurf (trifluridine & tipiracil)
Lonsurf is taken as oral film‑coated tablets. It is an approved cancer medicine used for metastatic colorectal cancer and other solid tumors. In the trial it is used for advanced microsatellite stable colorectal cancer; trifluridine is incorporated into DNA of cancer cells causing faulty DNA, while tipiracil stops trifluridine from being broken down, together slowing tumor growth. It is classified as an antimetabolite chemotherapy.
Bevacizumab (Avastin)
Bevacizumab is administered by intravenous infusion of a sterile solution. It is an approved anti‑angiogenic antibody that has been used for many cancers, including colorectal cancer. In this study it helps treat advanced microsatellite stable colorectal cancer by binding to VEGF and preventing new blood vessels that feed the tumor. It belongs to the monoclonal antibody anti‑angiogenic drug class.
Nivolumab (Opdivo)
Nivolumab is given as an intravenous infusion of a sterile solution. It is an approved immune‑checkpoint inhibitor used for several cancers, such as melanoma and certain colorectal cancers. For the trial it is used in advanced microsatellite stable colorectal cancer and works by blocking the PD‑1 receptor on T‑cells, allowing the immune system to recognize and attack cancer cells. It is classified as a monoclonal antibody immune‑checkpoint inhibitor.

Investigated diseases

Advanced Microsatellite Stable Colorectal Cancer - This is a cancer that starts in the lining of the colon or rectum and shows a stable pattern of microsatellites, meaning it does not have many genetic changes in those regions. Being advanced means the tumor has grown beyond its original location, often reaching nearby lymph nodes or other parts of the body. The disease begins with abnormal cells multiplying in the bowel wall, forming a mass that can become larger over time. As the cancer progresses, it may spread locally to surrounding tissues and travel through the bloodstream or lymphatic system to distant sites. The growth continues as cells keep dividing, leading to an increase in tumor size and extent.