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A Phase 2 Study of VS-7375 Alone or with Drug Combination in Patients with Metastatic KRAS G12D‑Mutated Colorectal Cancer

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 carries a KRAS G12D mutation. This type of cancer has spread beyond the colon and has a specific genetic change that can affect how it responds to treatment. The investigational oral medicine VS-7375 will be given as a tablet taken each day. In some groups, the tablet will be combined with an intravenously delivered anti‑EGFR antibody such as cetuximab or panitumumab, and with standard chemotherapy drugs including fluorouracil, calcium folinate, and oxaliplatin.

The purpose of the study is to see how well the new medicine works and how safe it is when used alone or together with these other treatments. Participants will receive the oral tablet daily for several cycles, and the IV medicines will be given on scheduled clinic days. Throughout the study, patients will have regular doctor visits, blood tests, and imaging scans to check the tumor and monitor any side effects.

The study will continue until the treatment is stopped because of disease progression, unacceptable side effects, or completion of the planned treatment period. All information collected will be kept confidential, and the study follows strict safety rules to protect participants.

The research process

The trial runs in 5 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Start Daily Oral Medication

    You will begin taking VS‑7375 by mouth each day. The dose is 900 mg taken once daily.

    The medication is swallowed with water and should be taken at the same time each day unless the study team advises otherwise.

  2. Step 2

    Receive Intravenous Anti‑EGFR Antibody

    On scheduled treatment days you will receive an intravenous (IV) infusion of an anti‑EGFR antibody. Depending on the study arm you will receive either cetuximab at a dose of 500 mg per square meter of body surface area, or panitumumab at a dose of 6 mg per kilogram of body weight.

    The infusion is administered through a vein in your arm and takes about one hour. The exact timing of each infusion follows the study schedule.

  3. Step 3

    Receive Chemotherapy Infusion

    During the same visit as the anti‑EGFR antibody, you will also receive a chemotherapy infusion that includes three drugs:

    Oxaliplatin – 85 mg per square meter, given IV;

    Fluorouracil – 1200 mg per square meter, given IV;

    Calcium folinate – 400 mg per square meter, given IV.

    All three medicines are delivered through a vein in a single infusion session as directed by the study protocol.

  4. Step 4

    Continue Treatment Cycles

    You will keep taking the daily oral dose of VS‑7375 throughout the study.

    The intravenous antibody and chemotherapy infusions will be repeated on each treatment cycle according to the study schedule, which is typically every two weeks, until the study ends or the investigator decides to stop treatment.

  5. Step 5

    Attend Follow‑Up Visits

    Regular clinic visits are required to check your health, monitor any side effects, and evaluate how the cancer is responding.

    During these visits blood samples may be taken, and imaging tests such as scans may be performed, all as described in the study protocol.

Who can join the trial?

15 criteria

  • Be at least 18 years old.
  • Agree to sign a consent form that explains the study and your role.
  • Have a diagnosis of metastatic colorectal adenocarcinoma (colon cancer that has spread) confirmed by a tissue test.
  • Have tumors that can be measured on scans using the RECIST system (a standard way doctors track tumor size).
  • Test positive for a specific genetic change called the KRAS G12D mutation (a change in the KRAS gene that can affect treatment).
  • Have an ECOG performance status of 0 or 1, meaning you are fully active or able to do light work.
  • Have received at least one standard chemotherapy regimen for metastatic disease that includes the drugs fluoropyrimidines, irinotecan, and oxaliplatin, and may include a VEGF‑targeting medicine; you must not have received trifluridine/tipiracil (TAS‑102), regorafenib, fruquintinib, or more than one experimental therapy.
  • If you received oxaliplatin as part of treatment after surgery (adjuvant therapy) and your cancer returned within 6 months, you can join even if you did not get oxaliplatin for metastatic disease; otherwise you must have had oxaliplatin in the metastatic setting.
  • Must have disease that got worse (progressed) during or after your most recent line of therapy.
  • Must have had a best overall response of stable disease, partial response, or complete response to prior therapy (you should not have only progressive disease as your best result).
  • If you are enrolling in Part C of the study, you must be either treatment‑naïve (no prior therapy) or have received no more than one cycle of standard therapy for metastatic disease.
  • Must have adequate organ function, meaning recent blood tests and other lab results show your liver, kidneys, bone marrow, and other organs are working well enough for the study.
  • Must have recovered from side effects of previous treatments to a mild level (grade 1 or less), except for hair loss or mild nerve problems; certain hormone‑related side effects that are stable at grade 2 are allowed.
  • Female participants must either be unable to become pregnant (for example, surgically sterile or post‑menopausal) or must agree to use effective birth control (two highly effective methods, or one method plus a barrier) before, during, and for several months after the study, and must have a negative pregnancy test before starting.
  • Male participants must agree not to donate sperm and, if they have a partner who could become pregnant, must use a condom plus a highly effective contraceptive method for the partner during the study and for at least 100 days after the last dose.

Who cannot join the trial?

24 criteria

  • Recent major surgery: If you had a large operation (other than a simple diagnostic test) within the last 4 weeks, or you are expected to need one during the study, you cannot join. Small procedures like a skin biopsy are allowed up to 7 days before the study starts.
  • Recent cancer treatments: You cannot have received chemotherapy, targeted cancer drugs, or regular radiation (except palliative radiation) within 4 weeks (or five drug half‑lives, whichever is shorter). Palliative radiation is allowed up to 7 days before, but radiation to the lung or brain needs a 2‑week gap. Steroids used after radiation must be reduced to ≤10 mg prednisone (or equivalent) before the study.
  • Use of investigational drugs: Taking any experimental medication within 4 weeks (or five half‑lives) or being in another interventional trial at the same time makes you ineligible.
  • More than one investigational therapy: Receiving two or more experimental treatments at once disqualifies you.
  • Specific prior medications: If you have taken trifluridine/tipiracil (TAS‑102), regorafenib, or fruquintinib, you cannot participate.
  • Other RAS mutations: Having any additional common RAS gene changes besides the required KRAS G12D mutation excludes you.
  • Previous direct RAS inhibitors: If you have ever been treated with drugs that directly inhibit RAS proteins, you are not eligible.
  • Microsatellite instability‑high (MSI‑H) or deficient mismatch repair (dMMR): Tumors that show these genetic features are not allowed in the study.
  • Strong CYP3A4 interactions: Use of strong inhibitors or inducers of the liver enzyme CYP3A4 (or related transporters) within 14 days (or three drug half‑lives) prevents enrollment. This also includes avoiding grapefruit or grapefruit juice for at least 1 week before the study.
  • Proton pump inhibitors (PPIs) and H2 blockers: Taking PPIs within 5 days or H2‑receptor antagonists within 1 day before the first dose excludes you.
  • Active brain metastases: Untreated or worsening cancer spread to the brain disqualifies you, unless the brain lesions have been treated, you are neurologically stable, and steroid use has been tapered to ≤10 mg prednisone (or equivalent) for at least 2 weeks.
  • Inability to swallow oral medication or serious gastrointestinal conditions (such as major stomach surgery) that could affect drug absorption make you ineligible.
  • Need for supplemental oxygen: Requiring oxygen to keep resting blood‑oxygen levels at or above 90 % excludes you.
  • Hepatitis B, hepatitis C, or HIV infection: Known infection with these viruses prevents participation, except HIV may be allowed if it is well‑controlled, with a stable viral load, no symptoms, and a lymphocyte count >500 cells/µL.
  • Allogeneic transplant: Having received a tissue, solid‑organ, or bone‑marrow transplant from another person excludes you.
  • Serious heart or lung disease: Current congestive heart failure, a history of severe (NYHA class III/IV) heart disease, a heart attack within 3 months, unstable heart rhythm, unstable chest pain, or severe obstructive lung disease make you ineligible.
  • Uncontrolled serious medical conditions: Ongoing, uncontrolled problems with blood clotting, kidneys, liver, hormones, lungs, digestive system, heart, mental health, nerves, skin, autoimmune disease, or severe drug allergies increase the risk of toxicity and exclude you.
  • Uncontrolled intercurrent illness: Active infections needing treatment, drug abuse, or a social situation that would prevent you from following study requirements disqualifies you.
  • Prior cancer history: Having had another cancer, unless it was treated with curative intent and you have been disease‑free for at least 3 years (with certain exceptions for low‑risk skin cancers, in‑situ cancers, indolent cancers, or early‑stage prostate cancer), excludes you.
  • Pregnancy or breastfeeding: If you are pregnant or nursing, you cannot join the study.
  • Allergy to study drugs: Any known allergy or hypersensitivity to the study medications or their ingredients, or a contraindication listed in their prescribing information, excludes you.
  • Interstitial lung disease (ILD) or pneumonitis: A past or current diagnosis of ILD or lung inflammation (pneumonitis) that required systemic steroids, or drug‑induced ILD/pneumonitis, disqualifies you. Prior radiation‑related lung scarring is allowed if it has resolved to mild (Grade 1) at least 4 weeks before the study.
  • DPD deficiency: Being deficient in the enzyme dihydropyrimidine dehydrogenase (DPD) excludes you.
  • High anti‑α‑galactose IgE antibodies: Having an anti‑α‑galactose IgE level greater than 0.10 kUA/L (which raises the risk of a severe reaction to cetuximab) makes you ineligible, especially if you live in areas with Lone Star ticks.
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Investigated drugs

  • VS‑7375

    is an experimental oral medicine that blocks a specific mutation called KRAS G12D, which can help cancer cells grow. In this study the drug is taken by mouth every day. Researchers are testing it alone and also together with other medicines to see if it can shrink tumors and how safe it is for patients with advanced colorectal cancer that has the KRAS G12D change.

  • Cetuximab

    is a medication that targets a protein called EGFR on the surface of cancer cells. By binding to EGFR, it can slow down the growth of the tumor. In the trial cetuximab is given through an IV infusion and is combined with VS‑7375 to see if the two drugs work better together than VS‑7375 alone.

  • Panitumumab

    works in a similar way to cetuximab by blocking the EGFR protein on cancer cells. It is also given by IV infusion. The study uses panitumumab together with VS‑7375 to test whether this combination can improve treatment outcomes for patients with the KRAS G12D mutation.

  • Fluorouracil

    is a chemotherapy drug that interferes with the DNA building blocks that cancer cells need to multiply. It is administered through an IV infusion. In the trial fluorouracil is part of the standard chemotherapy regimen that may be given alongside the anti‑EGFR antibodies and VS‑7375.

  • Calcium folinate

    (also known as folinic acid) is a supportive medication that helps protect normal cells from the side effects of fluorouracil and can make the chemotherapy work better. It is given by IV injection and is used together with fluorouracil in the combination treatment arms of the study.

  • Oxaliplatin

    is another chemotherapy drug that damages the DNA of cancer cells, preventing them from growing and spreading. It is given as an IV infusion. In this trial oxaliplatin is included in the chemotherapy backbone that is combined with the anti‑EGFR antibodies and VS‑7375 to evaluate the overall effectiveness of the full treatment regimen.

What is already known about the treatment

  • Fluorouracil

    Fluorouracil is given as a solution for intravenous injection and is an approved chemotherapy drug used mainly for colorectal and other solid cancers. It works by mimicking the natural building block uracil, which interferes with DNA synthesis and stops rapidly dividing cells from growing. In medical literature it is well‑studied and listed as an antimetabolite chemotherapy. Its main therapeutic use is to treat advanced colorectal adenocarcinoma, often together with other agents.

  • Calcium Folinate

    Calcium folinate is supplied as a solution for intravenous use and is an approved medication that supports chemotherapy, especially fluorouracil‑based regimens. It provides a reduced form of folic acid that helps normal cells repair DNA and reduces some toxic side effects of fluorouracil. It is classified as a folate analog and a rescue agent. Its primary indication is to enhance the effectiveness and safety of fluorouracil treatment in colorectal cancer.

  • Oxaliplatin

    Oxaliplatin is administered as a solution for intravenous infusion and is an approved platinum‑based chemotherapy for colorectal cancer. It creates cross‑links in DNA strands, which prevents cancer cells from dividing and leads to their death. It belongs to the class of platinum compounds, also called alkylating agents. Oxaliplatin is used mainly to treat metastatic colorectal adenocarcinoma, often in combination with other drugs.

  • Cetuximab

    Cetuximab is given as an intravenous infusion solution and is an approved monoclonal antibody for cancers that express the EGFR protein, such as colorectal cancer. It binds to the EGFR on the cell surface, blocking signals that tell the cell to grow and divide. It is classified as an anti‑EGFR monoclonal antibody. Its main therapeutic indication is to treat metastatic colorectal adenocarcinoma, especially when combined with chemotherapy.

  • Panitumumab

    Panitumumab is supplied as a concentrate for intravenous infusion and is an approved anti‑EGFR monoclonic antibody used in colorectal cancer. It attaches to the EGFR receptor, stopping growth signals and slowing tumor progression. It belongs to the anti‑EGFR antibody class. It is indicated for metastatic colorectal adenocarcinoma, often in patients whose tumors lack certain resistance mutations.

  • VS‑7375

    VS‑7375 is taken as an oral tablet and is currently an investigational drug being studied in clinical trials for KRAS G12D‑mutated colorectal cancer. It works by selectively blocking the mutant KRAS protein that drives tumor growth, thereby reducing cancer cell proliferation. It is classified as a KRAS G12D small‑molecule inhibitor. The drug is not yet approved but is being evaluated for use in patients with metastatic KRAS G12D‑mutated colorectal adenocarcinoma.

Investigated diseases

Metastatic KRAS G12D‑mutated colorectal adenocarcinoma - This cancer starts in the glandular cells of the colon or rectum and is driven by a KRAS gene change at position G12D. The mutation makes the tumor cells grow and divide quickly. In the metastatic stage the disease has spread from the original site to other organs such as the liver, lungs, or peritoneum. As it progresses, additional tumor sites can develop and existing lesions may enlarge, leading to increasing symptoms.
Trial detailsLast updated 22 Oct 2026
Age18+ yearsPhasePhase IITrial ID2026-526473-42-00Protocol codeVS-7375-203Estimated enrolment94 patientsSponsorVerastem Inc.

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