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Second‑line ivonescimab plus chemotherapy drug combination versus bevacizumab in patients with metastatic colorectal cancer without liver metastases

Verified siteRegistered drugNo placebo
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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 patients with metastatic colorectal cancer that is Microsatellite Stable, has pMMR, and is BRAF wild type. These cancers have spread beyond the colon but do not involve the liver. After first‑line chemotherapy, a second‑line treatment is being tested that combines a standard chemotherapy regimen called FOLFIRI (which includes fluorouracil, irinotecan, and folinic acid) with either ivonescimab or bevacizumab, both given by IV infusion.

The purpose of the trial is to see whether the combination with ivonescimab can keep the disease from getting worse longer than the combination with bevacizumab. Participants are randomly placed into one of the two groups, receive the assigned medicines by IV every two weeks for several cycles, and attend regular clinic visits for monitoring and safety checks.

The main outcome being watched is Progression-Free Survival, which means the length of time the cancer does not grow or spread. Additional observations include side effects, overall health, and quality of life, which are recorded throughout the treatment and follow‑up period.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization to treatment group

    After you agree to join the study, you are assigned by chance to one of two treatment groups. one group receives ivonescimab together with standard chemotherapy, and the other group receives bevacizumab together with the same chemotherapy.

  2. Step 2

    Baseline medical assessments

    Before the first dose, doctors perform tests such as blood work, imaging scans, and questionnaires to record your health status. these results serve as a reference point for later comparisons.

  3. Step 3

    First treatment cycle

    On the first treatment day you receive a combination of medicines through an intravenous (IV) line.

    The chemotherapy part, called FOLFIRI, includes:

    - irinotecan at a dose of 180 mg per square meter of body‑surface area (mg/m²).

    - levoleucovorin at 200 mg/m².

    - fluorouracil at 2400 mg/m².

    - folinic acid at 400 mg/m².

    In addition, depending on your assigned group you receive either:

    - ivonescimab at 20 mg per kilogram of body weight (mg/kg) given as an injection, or

    - bevacizumab at 5 mg per kilogram (mg/kg).

    All medicines are given by IV infusion on the same day.

  4. Step 4

    Repeating treatment cycles

    The same set of medicines is given in each subsequent cycle as scheduled by the study protocol.

    Each cycle repeats the doses listed in step 3 and continues until the doctor decides to stop because of disease progression, side effects, or completion of the planned treatment period.

  5. Step 5

    Regular safety and disease monitoring

    Throughout the study you have regular visits where doctors check blood tests, record any side effects, and perform imaging scans to see whether the cancer is growing or shrinking.

    These assessments are used to measure progression‑free survival, which means the time you remain alive without the cancer getting worse.

  6. Step 6

    Dose adjustments or treatment interruptions

    If side effects become severe, the doctor may lower the dose of one or more medicines or pause treatment for a short period.

    The decision is made to keep you as safe as possible while still trying to treat the cancer.

  7. Step 7

    End of treatment

    Treatment ends when the doctor determines that the cancer has progressed, the side effects are no longer manageable, or the planned number of cycles has been completed.

    After the last dose you continue to have follow‑up visits.

  8. Step 8

    Post‑treatment follow‑up

    After stopping the study drugs you attend regular follow‑up appointments where health status, quality of life, and any late side effects are recorded.

    These visits may include questionnaires such as the EORTC QLQ‑C30 and QLQ‑CR29, which ask about everyday functioning and symptoms.

Who can join the trial?

15 criteria

  • Sign a written informed consent form before any study procedures begin.
  • Women who could become pregnant must have a negative blood pregnancy test within 3 days before joining and a negative urine pregnancy test on the day of the first dose.
  • Be willing and able to follow the study schedule, including clinic visits, treatments, lab tests, and other required procedures.
  • Have coverage through a Social Security system or a similar health‑insurance program.
  • Have a confirmed diagnosis of metastatic colorectal cancer that cannot be removed by surgery, with laboratory results showing pMMR (by tissue staining), MSS (by DNA testing), and BRAF wild‑type, and no cancer spread to the liver.
  • Have already received first‑line treatment with FOLFOX chemotherapy, with or without anti‑VEGF or EGFR targeted therapy, or have received FOLFIRINOX chemotherapy under specific conditions (no progression on the triplet regimen, progression only after maintenance therapy, and a break from irinotecan for at least 3 months).
  • Have at least one tumor that can be measured by the doctor using standard criteria (RECIST v1.1).
  • Have an ECOG performance status of 0 or 1, meaning you are fully active or able to carry out light work but are up and about most of the day.
  • Be 18 years of age or older.
  • Show adequate organ function within the past 14 days, including:
    • Blood counts: enough white blood cells (neutrophils ≥ 1.5 × 10⁹/L), platelets ≥ 100 × 10⁹/L, and hemoglobin ≥ 10 g/dL.
    • Kidney function: creatinine clearance ≥ 50 mL/min or eGFR ≥ 50 mL/min.
    • Liver function: total bilirubin ≤ 1.5 times the normal limit, and liver enzymes (AST and ALT) ≤ 2.5 times the normal limit.
    • Blood clotting: prothrombin time/INR and partial thromboplastin time ≤ 1.5 times the normal limit.
    • Have a life expectancy of at least 3 months.
    • Agree to use an effective method of contraception for the entire study period and for 6 months after the last dose; men must not donate sperm and women must not donate eggs during this time.

Who cannot join the trial?

34 criteria

  • Presence of liver metastases (cancer spread to the liver) on a CT scan or MRI performed within the last 28 days.
  • Ongoing HIV infection that is not well‑controlled (detectable virus or CD4 count below 350 cells/µL).
  • Active hepatitis C or hepatitis B infection that has not been successfully treated.
  • History of Gilbert’s syndrome or a deficiency of the enzyme UGT1A1.
  • Complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD).
  • Known allergy (hypersensitivity) to ivonescimab, any study drug, or their ingredients.
  • Previous organ transplant, including stem‑cell transplant.
  • Use of the antiviral drug brivudine within the last 4 weeks.
  • Use of live weakened (attenuated) vaccines or the herbal supplement St John’s Wort.
  • Any currently serious infection.
  • Poor nutritional status (for example, severe weight loss or malnutrition).
  • Significant blockage of the gastrointestinal (GI) tract seen on imaging or causing symptoms.
  • Any other cancer diagnosed within the past 3 years, except for non‑melanoma skin cancer that was removed.
  • Tumors that have high microsatellite instability (MSI‑H), mismatch repair deficiency (dMMR), or a BRAF V600E mutation.
  • Ongoing side effects from previous cancer treatment that are worse than mild (grade > 1), except nerve damage (neuropathy) or hair loss.
  • Major surgery or serious injury within 4 weeks before randomization, or planned major surgery within 4 weeks after the first dose.
  • Bleeding problems or clotting disorders, recent significant GI bleeding, or use of blood‑thinners that are not stable.
  • High blood pressure (systolic ≥150 mmHg or diastolic ≥100 mmHg) despite medication.
  • Serious heart or blood‑vessel disease in the past year (unstable angina, heart attack, heart failure NYHA ≥ II, aortic aneurysm, uncontrolled arrhythmia, or heart‑muscle ischemia).
  • Severe stomach or intestinal problems within 6 months (large ulcers, varices, wounds that don’t heal, fistulas, abscesses, major bleeding).
  • Recent clotting events (arterial or venous thrombosis), stroke, transient ischemic attack, severe high‑blood‑pressure crisis, or worsening chronic lung disease (COPD) within the last weeks.
  • History of perforation or severe obstruction of the gastrointestinal tract, or extensive bowel surgery within 6 months.
  • Allergy to products made from Chinese Hamster Ovary (CHO) cells or other similar laboratory‑produced antibodies.
  • Pregnancy or breastfeeding.
  • Fluid buildup in the abdomen (ascites) that needed drainage (paracentesis) within the last 30 days.
  • Participation in another treatment trial within the last 30 days (observational studies are allowed).
  • Inability or unwillingness to follow study visits because of distance, family, social, or psychological reasons.
  • Being incarcerated, under protective custody, or lacking a legal guardian.
  • Active symptoms from cancer that has spread to the brain or spinal cord, or leptomeningeal disease, unless stable and not requiring steroids or seizure medication.
  • Presence of metastases in the brainstem, meninges, spinal cord, or compression of these areas.
  • Current or past inflammatory bowel disease such as Crohn’s disease or ulcerative colitis.
  • Use of strong immune‑suppressing drugs (more than 10 mg prednisone daily) within 2 weeks before starting study medication.
  • Active autoimmune disease that needs systemic therapy (for example, high‑dose steroids or disease‑modifying drugs) within the past 2 years, except for hormone replacement.
  • Known interstitial lung disease (a group of lung disorders causing scarring).
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Investigated drugs

  • Bevacizumab

    is a medication given through an IV that helps stop new blood vessels from forming around cancer cells. By preventing these blood vessels, it can slow the growth of tumors. In this trial, it is used as a comparison treatment combined with standard chemotherapy to see how well it works for patients with advanced colorectal cancer.

  • Folinic acid

    is a form of vitamin B9 that is given by IV to help protect normal cells from the effects of chemotherapy. It works together with certain chemotherapy drugs to make the treatment more effective and to reduce side‑effects. In this study, it is part of the standard chemotherapy regimen used for all patients.

  • Ivonescimab

    is an experimental drug that is given by IV injection. It is designed to target specific proteins on cancer cells, helping the immune system recognize and attack the tumor. In this trial, it is tested together with standard chemotherapy to see if it can improve how long patients live without their disease getting worse.

  • Fluorouracil

    (often called 5‑FU) is a chemotherapy medicine given through an IV. It works by interfering with the cancer cells’ ability to make DNA, which stops them from growing and dividing. In this study, it is a key part of the standard chemotherapy regimen used for all participants.

  • Levoleucovorin

    is a medication similar to folinic acid that is given by IV to enhance the effect of fluorouracil. It helps the chemotherapy work better against cancer cells while protecting normal cells. It is included in the standard chemotherapy combination used in both treatment groups.

  • Irinotecan

    is an IV chemotherapy drug that stops cancer cells from dividing by blocking an enzyme they need to copy their DNA. It is a core component of the standard chemotherapy regimen (FOLFIRI) given to all patients in the trial.

What is already known about the treatment

  • Bevacizumab

    Bevacizumab is given by intravenous infusion as a sterile injection. It is an approved drug used for several cancers, including colorectal cancer, and is listed in medical literature as a standard therapy. The medicine works by attaching to a protein called VEGF, stopping new blood vessels from feeding the tumor, which slows tumor growth. It belongs to the class of monoclonal antibodies that act as anti‑angiogenic agents.

  • Folinic Acid

    Folinic acid is administered intravenously as a sterile solution. It is an approved medication that is commonly used to lessen the side effects of chemotherapy drugs like fluorouracil. The compound supplies a ready‑made form of folate that helps normal cells make DNA and recover from chemotherapy damage. It is classified as a folate analog rescue agent.

  • Ivonescimab

    Ivonescimab is given by intravenous injection. It is currently an investigational drug being studied in clinical trials for advanced colorectal cancer and is not yet approved for general use. The antibody is designed to bind a specific growth‑factor receptor on cancer cells, blocking signals that tell the tumor to grow and spread. It falls under the class of experimental monoclonal antibodies targeting tumor‑growth pathways.

  • Fluorouracil

    Fluorouracil is delivered through an intravenous infusion. It is a well‑established chemotherapy drug widely used for colorectal and other solid tumors. The drug mimics the natural building block uracil, getting incorporated into DNA and causing the cancer cells to stop dividing. It is classified as an antimetabolite chemotherapy agent.

  • Levoleucovorin

    Levoleucovorin is administered intravenously as a sterile injection. It is an approved medication that is given together with fluorouracil to boost the cancer‑killing effect of the chemotherapy. The agent provides a stable form of folate that helps the chemotherapy bind more tightly to its target enzyme in tumor cells. It belongs to the class of folate analogs used as chemotherapy enhancers.

  • Irinotecan

    Irinotecan is given by intravenous infusion. It is an approved chemotherapy drug for colorectal cancer and is listed in standard treatment guidelines. The drug blocks an enzyme called topoisomerase I, which cancer cells need to unwind DNA for replication, leading to cell death. It is classified as a topoisomerase I inhibitor.

Investigated diseases

Metastatic colorectal cancer, proficient mismatch repair/microsatellite stable, BRAF wild‑type, non‑resectable, without liver metastasis – It is a cancer that began in the colon or rectum and has spread beyond the original organ. The tumor cells retain normal DNA‑repair mechanisms and do not carry the BRAF mutation. Because the disease cannot be removed surgically, the cancer remains in place and may enlarge in the existing sites. It can also appear in new locations as the illness advances. Patients have already completed first‑line chemotherapy and are now in a second‑line treatment phase.
Trial detailsLast updated 2 Oct 2026
Age18+ yearsPhasePhase IITrial ID2025-524215-36-00Protocol codeUC-GIG-2518Estimated enrolment130 patientsSponsorUnicancer

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