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Phase 1/2 Study of VS-7375 with Drug Combination in Patients with Advanced KRAS G12D‑Mutated Solid Tumors

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What is this trial about?

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

The study examines patients with advanced cancers that carry a specific genetic change called the KRAS G12D mutation. These cancers include solid tumors such as pancreatic cancer, non‑small cell lung cancer, and colorectal adenocarcinoma. The experimental drug being tested is an oral tablet named VS-7375, which will also be evaluated together with other medicines including cetuximab, carboplatin, pembrolizumab, pemetrexed, gemcitabine, and nab‑paclitaxel.

The purpose of the trial is to identify a safe and effective dose of the new medication, to see how well it works against these cancers, and to understand how it interacts with other treatments. Early parts of the study increase the dose to find the highest amount patients can tolerate, followed by later parts that treat specific cancer types either alone or combined with the listed drugs. A small group of participants will also receive medicines that are processed by the enzymes CYP3A4 and CYP2C8 to check for possible drug‑interaction effects.

Participants will take the study tablet each day and receive the other medicines by intravenous infusion, meaning the drugs are given through a vein. Regular clinic visits will include physical checks, blood tests, and imaging scans that are evaluated using RECIST criteria, a system that measures how tumor size changes over time. The trial will continue for several months, with close monitoring for side effects, dose adjustments if needed, and assessments of tumor response.

The research process

The trial runs in 9 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Study enrollment

    After providing informed consent, you are assigned a study identification number and scheduled for baseline assessments.

  2. Step 2

    Baseline assessments

    A complete medical history, physical examination, vital signs, electrocardiogram, and laboratory tests are performed.

    Imaging studies are obtained to document the extent of the tumor.

  3. Step 3

    Part a – single‑agent dose escalation

    You receive vs-7375 tablets taken by mouth once daily.

    The dose is increased in a stepwise manner according to a predefined schedule to find the maximum tolerated dose.

    Each dose level is given for a period of several weeks while safety is monitored.

    The dose‑limiting toxicity (dlt) assessment period runs from day 1 of the cycle through day 21.

  4. Step 4

    Part b – single‑agent dose expansion

    Once the optimal dose from part a is identified, you continue to take vs-7375 daily at that dose.

    Treatment continues until disease progression, unacceptable toxicity, or withdrawal from the study.

  5. Step 5

    Part c – combination dose escalation

    You receive vs-7375 orally each day together with one of the following intravenous combinations, depending on the cohort:

    cetuximab – administered by infusion according to the protocol schedule.

    carboplatin, pembrolizumab and pemetrexed – all given by infusion according to the protocol schedule.

    gemcitabine and nab‑paclitaxel – both given by infusion according to the protocol schedule.

  6. Step 6

    Part d – combination dose expansion

    The recommended dose identified in part c is used.

    You continue the same oral vs-7375 and the chosen intravenous combination (either cetuximab, or carboplatin with pembrolizumab and pemetrexed, or gemcitabine with nab‑paclitaxel).

    Treatment proceeds until disease progression, unacceptable toxicity, or withdrawal.

  7. Step 7

    Part e – drug‑drug interaction assessment

    You receive a fixed dose of vs-7375 (600 mg once daily).

    On designated days, a single dose of either midazolam (a medication that is processed by the enzyme cyp3a4) or repaglinide (a medication that is processed by the enzyme cyp2c8) is administered to evaluate how vs-7375 affects their blood levels.

    Blood samples are collected at multiple time points to measure drug concentrations.

  8. Step 8

    Ongoing safety monitoring

    Throughout all parts of the study, regular visits are scheduled to record adverse events, perform physical examinations, check vital signs, repeat laboratory tests, and obtain imaging as needed.

    Dose interruptions or reductions may be applied based on the severity of any toxicity.

  9. Step 9

    Study completion

    The study ends when the predetermined end date is reached, when you discontinue treatment, or when the investigator determines that continued participation is no longer appropriate.

    Final assessments are performed to document the overall outcome.

Who can join the trial?

22 criteria

  • Be 18 years of age or older.
  • Agree to sign an informed consent form, which means you understand the study and agree to follow its procedures.
  • Have a solid tumor that can be measured on scans (called measurable disease) and have recent imaging done within the last 28 days.
  • Have a tumor that tests positive for a KRAS G12D mutation. This mutation is identified using a laboratory test such as next‑generation sequencing (NGS) or polymerase chain reaction (PCR).
  • Have an ECOG performance status of 0 or 1, meaning you are fully active or able to carry out light work but are still able to walk around.
  • Have adequate organ function, including:
    • White blood cell count (neutrophils) ≥ 1,000 per microliter.
    • Platelet count ≥ 100,000 per microliter.
    • Hemoglobin ≥ 9 g/dL.
    • Liver tests (bilirubin, ALT, AST) within the limits specified by the study.
    • Kidney function (creatinine clearance) ≥ 60 mL/min.
    • Blood clotting tests (INR ≤ 1.5, PTT ≤ 1.5 × upper limit) if not on blood thinners.
    • Albumin ≥ 3.0 g/dL.
    • Heart function with an ejection fraction ≥ 50% and a QTc interval < 470 ms.
    • Have recovered from side effects of previous cancer treatments to low levels (grade ≤ 1), with only mild hair loss or nerve symptoms allowed.
    • Have received between 1 and 3 prior lines of standard systemic therapy for advanced or metastatic disease (the exact number may vary by cancer type).
    • If you have metastatic colorectal cancer, you must have already received the following drugs: a fluoropyrimidine, oxaliplatin, irinotecan, and a medicine that blocks blood vessel growth (anti‑VEGF agent).
    • If you have metastatic pancreatic cancer, you must be a candidate for treatment with gemcitabine and nab‑paclitaxel.
    • If you have metastatic non‑small cell lung cancer (NSCLC), you must have received a platinum‑based chemotherapy and an immune checkpoint inhibitor, unless these are not suitable for you.
    • Be ineligible for enrollment in any other cohort of this study.
    • Not be pregnant and agree to use effective birth control methods:
      • If you are not able to become pregnant (e.g., surgically sterilized or post‑menopausal), no contraception is needed.
      • If you could become pregnant, you must have a negative pregnancy test and use two forms of highly effective contraception, or one highly effective method plus a barrier method, during the study and for at least 6 months after the last dose.
      • Agree not to donate sperm or eggs during the study, and if you have sexual activity that could lead to pregnancy, you must use a condom in addition to the partner’s contraception for at least 90 days after the last dose.

Who cannot join the trial?

30 criteria

  • You had a major operation (an invasive surgery, not just a diagnostic test) within the last 4 weeks, or you are expected to need one while the study is running.
  • You have taken a strong blocker of the enzyme CYP3A4 within 14 days before the study starts, or a strong activator of this enzyme within the same time.
  • You have taken medicines that are processed by CYP3A4, OAT1, CYP2C8, or the drug transporter P‑gp and have a very narrow safety range, within 14 days before the study starts.
  • You have consumed grapefruit or grapefruit juice within 1 week before the study starts (grapefruit can strongly block CYP3A4).
  • You used a proton‑pump inhibitor (a drug that reduces stomach acid) within 7 days, or an H2‑blocker (another type of acid‑reducing drug) within 1 day before the study starts.
  • You have active or untreated cancer that has spread to the brain or spinal cord, or your brain metastases are still getting worse.
  • You have an ongoing flare‑up of an autoimmune disease that needs systemic medicines such as steroids or other immune‑suppressing drugs during screening.
  • You cannot swallow pills, or you have a stomach condition (like major gastric surgery) that might prevent the study drug from being absorbed.
  • You have an uncontrolled illness right now, such as an infection that needs treatment, ongoing drug abuse, or a social situation that would make it hard to follow study rules.
  • You have had another cancer in the past, unless it was treated with curative intent and you have been disease‑free for at least 3 years (some low‑risk cancers are allowed).
  • You are currently pregnant or breastfeeding.
  • You have a known allergy or severe reaction to any of the study drugs or their inactive ingredients.
  • You have low‑grade serous ovarian cancer (LGSOC).
  • You had a severe COVID‑19 infection that still requires extra oxygen to keep your blood oxygen level at 90% or higher.
  • If you are in the lung cancer group (Cohort B2), your tumor has an ALK mutation or an EGFR mutation, which are not allowed.
  • If you are in any of the solid‑tumor groups (Cohorts C1, C2, C3, D1/D1R, D2, D3), you have a current or past diagnosis of interstitial lung disease or pneumonitis.
  • If you are in the drug‑interaction group (Cohort E), you carry the genetic variant CYP2C8*3 (either one or two copies).
  • Your blood tests show a total bilirubin level 1.5 times higher than the normal upper limit (unless you have Gilbert syndrome and bilirubin is under 3.0 mg/dL), or liver enzymes ALT or AST are 2.5 times above the normal upper limit.
  • You are taking any medicines that strongly block or activate CYP3A4 or CYP2C8 (including St. John’s Wort) within 14 days before the first dose of the study’s interaction test.
  • You have had gastrointestinal surgery that could affect drug absorption, such as partial removal of the stomach, weight‑loss (bariatric) surgery, or removal of the gallbladder (except a simple appendix removal).
  • You cannot avoid all alcohol‑containing products for at least 72 hours before and during the first part of the study.
  • You cannot avoid all tobacco products (cigarettes, cigars, heated tobacco, vaping) for at least 7 days before and during the first part of the study.
  • You cannot avoid all recreational drugs, including cannabis products (THC or CBD), for at least 30 days before and during the first part of the study.
  • You have an active hepatitis B, hepatitis C, or HIV infection that needs treatment.
  • You have received an organ or tissue transplant from another person.
  • You have serious heart problems, such as congestive heart failure, advanced heart disease (NYHA class III/IV), a heart attack within the last 6 months, unstable heart rhythm, or unstable chest pain, or you have severe obstructive lung disease.
  • You have uncontrolled or serious blood, kidney, liver, hormone, lung, digestive, heart, mental health, clotting, nerve, skin, autoimmune, or allergy conditions that would put you at high risk for side effects.
  • You received chemotherapy, targeted therapy, or radiation (except palliative radiation) within 4 weeks (or 5 drug half‑lives, whichever is shorter) before the study starts, or immunotherapy within the same time frame.
  • You took any experimental (investigational) drug within 4 weeks (or 5 half‑lives) before the study starts, or you are currently enrolled in another interventional trial.
  • You have ever been treated with direct RAS inhibitors (drugs that block the RAS protein pathway) at any time.
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Investigated drugs

  • VS-7375

    is an experimental oral tablet that targets a specific KRAS G12D mutation found in some solid tumors. In the study it is taken every day by mouth, either alone or together with other cancer medicines, to see how safe it is and whether it can shrink tumors.

  • Gemcitabine

    is a chemotherapy drug given through a vein as an infusion. It works by stopping cancer cells from making DNA, which can slow or stop tumor growth. In the trial it is used together with other drugs for patients with pancreatic cancer.

  • Pembrolizumab

    (marketed as Keytruda) is an immunotherapy that is given by intravenous infusion. It helps the body’s immune system recognize and attack cancer cells. The study combines it with other treatments to see if it improves outcomes for lung cancer patients.

  • Cetuximab

    (marketed as Erbitux) is a monoclonal antibody delivered by IV infusion. It blocks a protein called EGFR that many cancers use to grow. In the trial it is tested in combination with VS-7375 for tumors that have the KRAS G12D mutation.

  • Pemetrexed

    is a chemotherapy agent given by IV infusion. It interferes with the production of DNA and RNA in cancer cells, slowing their growth. The study uses it together with other drugs for patients with non‑small cell lung cancer.

  • Carboplatin

    is a platinum‑based chemotherapy given by IV infusion. It damages the DNA of cancer cells, which can cause them to die. In the trial it is combined with VS-7375, pembrolizumab, and pemetrexed for untreated metastatic lung cancer.

What is already known about the treatment

  • VS-7375

    This drug is taken as a tablet taken by mouth once daily. It is an experimental small‑molecule that blocks the mutated KRAS G12D protein, stopping the signal that makes cancer cells grow. The medicine is being studied in early‑phase clinical trials for solid tumors that have the KRAS G12D mutation. It belongs to the class of KRAS inhibitors.

  • Gemcitabine

    Gemcitabine is given as an intravenous infusion of a sterile solution. It is a nucleoside analog that is incorporated into DNA and stops cancer cells from copying their genetic material. The drug is approved for many cancers, especially pancreatic, lung and bladder cancers. It is classified as an antimetabolite chemotherapy agent.

  • Pembrolizumab

    Pembrolizumab is administered by intravenous infusion into a vein. It is a monoclonal antibody that blocks the PD‑1 protein on immune cells, allowing the body’s immune system to attack cancer. The medicine is approved for many solid tumors, including lung, melanoma and colorectal cancers. It is classified as an immune‑checkpoint inhibitor.

  • Cetuximab

    Cetuximab is given as an intravenous infusion. It is a monoclonal antibody that binds to the EGFR on the surface of cancer cells, preventing signals that cause the cells to grow. The drug is approved for colorectal cancer and head‑and‑neck cancers. It belongs to the class of EGFR‑targeting antibodies.

  • Pemetrexed

    Pemetrexed is administered as an intravenous infusion of a concentrate that is diluted before use. It works by blocking several enzymes needed to make DNA and RNA, which slows the growth of cancer cells. The medicine is approved for non‑small cell lung cancer and malignant pleural mesothelioma. It is classified as an antifolate chemotherapy agent.

  • Carboplatin

    Carboplatin is given as an intravenous infusion of a solution. It is a platinum‑based compound that creates cross‑links in DNA, which stops cancer cells from dividing. The drug is approved for many cancers, including ovarian, lung and head‑and‑neck cancers. It belongs to the class of platinum chemotherapy agents.

Investigated diseases

  • KRAS G12D‑mutated solid tumor

    A solid tumor that carries a specific change in the KRAS gene where glycine is replaced by aspartic acid at position 12. This mutation drives abnormal cell growth and can be found in cancers of many organs. Tumors with this alteration tend to enlarge and may spread to nearby tissues over time. The disease course is marked by gradual increase in tumor size and potential spread to distant sites.

  • Pancreatic ductal adenocarcinoma

    A cancer that begins in the ducts of the pancreas and forms malignant glands. It usually starts as a small lesion that grows slowly at first, then rapidly invades surrounding tissue. As it expands, it can extend into nearby blood vessels and lymph nodes. Over time, cancer cells may travel to the liver, lungs, or other organs.

  • Non‑small cell lung cancer

    A type of lung cancer that arises from the larger airways and includes several subtypes such as adenocarcinoma and squamous cell carcinoma. It typically begins as a localized mass within the lung and can enlarge to obstruct airways. The tumor may infiltrate the chest wall, lymph nodes, and eventually spread through the bloodstream. Disease progression is often marked by increasing tumor size and spread to distant organs.

  • Colorectal adenocarcinoma

    A cancer that develops from the lining of the colon or rectum and forms glandular structures. It often starts as a small polyp that slowly enlarges and becomes invasive. The tumor can grow through the bowel wall and involve nearby lymph nodes. With time, cancer cells may disseminate to the liver, lungs, or other sites.

Trial detailsLast updated 2 Oct 2026
Age18+ yearsPhasePhase ITrial ID2025-523432-39-01Protocol codeVS-7375-101Estimated enrolment804 patientsSponsorVerastem Inc.

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