Study of VS-7375 alone and with drug combination in patients with advanced KRAS G12D‑mutated solid tumors

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What is this study about?

The study looks at patients with advanced KRAS G12D solid tumors, which are cancers that have a specific genetic change in the KRAS gene. Types of cancer included are pancreatic cancer, non‑small cell lung cancer, and colorectal adenocarcinoma. The investigational medicine is an oral tablet called VS-7375, designed to block the activity of the KRAS G12D change. The purpose of the study is to determine how safe the medicine is and what dose can be used in future research.

The trial is divided into several parts. In the first part, participants take only the study tablet, beginning with low amounts that are gradually increased to see how the body handles it. In later parts, the tablet is given together with other cancer medicines such as cetuximab, carboplatin, pembrolizumab, pemetrexed, gemcitabine and nab-paclitaxel to see if the combination works better. Some participants also receive a small dose of medicines like midazolam or repaglinide to check whether the study drug changes how these other drugs are processed by the body; these other drugs are broken down by enzymes called CYP3A4 and CYP2C8. Throughout the study, patients have regular visits for safety checks, simple scans to see if the tumor is shrinking, and blood tests. The study continues until enough information about safety and early signs of benefit is collected.

1 baseline assessments

after joining, you will undergo a series of examinations to record your health status. this includes a physical exam, blood tests, urine tests, and imaging studies such as scans to measure tumor size. your performance status, which describes how well you are able to carry out daily activities, will also be recorded.

2 assignment to study part

based on the type of tumor you have and the treatments you have received before, you will be placed in one of the study sections named part a, b, c, d, or e. each part has a specific treatment plan.

3 part a – dose escalation with <b>vs-7375</b> alone

you will take vs-7375 tablets by mouth each day. the amount of the tablet may be increased in steps, a process called dose escalation, to find the highest dose that can be tolerated safely. each dose level is usually given for a period of about three weeks before the next level is considered. during this time you will be checked regularly for side effects, called adverse events, and for any changes in laboratory results.

4 part b – dose expansion with optimal <b>vs-7375</b> regimen

once the safe dose of vs-7375 has been identified in part a, you will receive that dose daily by mouth for multiple treatment cycles. the cycles continue until the disease progresses, side effects become unacceptable, or the study ends. tumor scans are performed periodically to evaluate the effectiveness of the drug.

5 part c – combination dose escalation

in this section you will receive vs-7375 daily together with one of several partner medicines given by intravenous infusion. the possible partners are:

cetuximab – an antibody given by infusion,

carboplatin, pembrolizumab and pemetrexed – three drugs given together by infusion,

or gemcitabine plus nab-paclitaxel – two drugs given by infusion.

the partner drugs are administered on the first day of each treatment cycle as defined by the protocol. the amount of vs-7375 may be increased in steps while the partner drug dose remains fixed, to determine a safe combination dose.

6 part d – combination dose expansion

after the safe combination dose has been identified in part c, you will receive the recommended combination for an extended period. the schedule is the same as in part c, with daily oral vs-7375 and the partner drug(s) given by infusion on the designated day of each cycle. treatment continues until disease progression, unacceptable toxicity, or study completion.

7 part e – drug‑drug interaction study

in this part you will take a fixed dose of vs-7375 (600 mg) once daily. on a specific study day you will also receive a single dose of either midazolam (a medication that is processed by the liver enzyme cyp3a4) or repaglinide (a medication processed by the liver enzyme cyp2c8). blood samples are taken to measure how the presence of vs-7375 changes the levels of these drugs.

8 regular monitoring and reporting

throughout all parts of the study you will attend scheduled clinic visits. at each visit you will have vital signs checked, blood drawn for laboratory tests, and an electrocardiogram (ecg) to examine heart rhythm. you will be asked to report any new symptoms or side effects. imaging studies will be repeated at defined intervals to track tumor changes.

9 completion of treatment

treatment ends when the disease shows growth on scans, when side effects become too severe, or when the study reaches its planned end date. after the last dose you will have a final set of assessments, including blood tests, imaging, and a physical exam, to document your condition at the end of the trial.

Who Can Join the Study?

Be 18 years of age or older.
Agree to sign an informed consent form showing you understand the study and will follow its procedures.
Have cancer that can be measured on scans according to the RECIST (Response Evaluation Criteria in Solid Tumors) guidelines, with imaging done within the last 28 days.
Have a solid tumor that tests positive for a KRAS G12D mutation (a specific genetic change that drives the cancer) using a validated laboratory test such as next‑generation sequencing or PCR, with results available before screening.
Have an ECOG performance status of 0 or 1 (meaning you are fully active or able to carry out light work).
Have adequate organ function, including:
- White blood cells (neutrophils) ≥1,000 per microliter without growth‑factor support.
- Platelet count ≥100,000 per microliter (stable for at least 72 hours after any transfusion).
- Hemoglobin ≥9 g/dL (stable for at least 72 hours after any transfusion).
- Liver function: total bilirubin ≤1.5 × the normal limit (up to 3.0 mg/dL if you have Gilbert syndrome), and ALT/AST ≤2.5 × normal (or ≤5 × normal if you have liver metastases).
- Kidney function: creatinine clearance ≥60 mL/min (calculated by standard formulas).
- Blood clotting: INR ≤1.5 and PTT ≤1.5 × normal (or therapeutic if you are on anticoagulants).
- Albumin ≥3.0 g/dL.
- Heart function: left‑ventricular ejection fraction ≥50% measured by echo or MUGA scan.
- Heart rhythm: baseline QTc interval <470 ms (unless you have a bundle‑branch block).
Have recovered from any side effects of previous cancer treatments to mild (grade ≤1) levels, except certain mild hair loss, nerve problems, or hormone‑related effects that may be grade ≤2.
Not be a person who could become pregnant, unless you agree to use highly effective birth control (two methods or one method plus a barrier) and have a negative pregnancy test at screening and within 7 days before starting treatment. If you are post‑menopausal or surgically sterilized, this requirement does not apply.
Agree not to donate sperm and, if you have a partner who could become pregnant, agree to use a condom in addition to your partner’s contraceptive method for at least 90 days after the last dose.
For metastatic colorectal cancer, have received at least one but no more than three prior treatment regimens and have previously been treated with fluoropyrimidine, oxaliplatin, irinotecan, and an anti‑VEGF (anti‑vascular endothelial growth factor) drug.
For metastatic pancreatic cancer (PDAC), have a confirmed diagnosis and be a suitable candidate for treatment with gemcitabine and nab‑paclitaxel.
For metastatic non‑small cell lung cancer (NSCLC), have a confirmed diagnosis and be a suitable candidate for treatment with carboplatin, pemetrexed, and pembrolizumab.
Have received prior platinum‑based chemotherapy and an immune‑checkpoint inhibitor (if not medically contraindicated) for advanced, non‑resectable disease.
Have received prior appropriate therapy for an activating mutation (except prior RAS inhibitors) when such therapy is approved for your cancer type.
Have received one or two prior standard systemic therapy lines for advanced or metastatic disease, or for pancreatic cancer, have progressed during adjuvant therapy (treatment given after surgery) and have no other proven options.
Have a solid tumor (other than PDAC, NSCLC, or colorectal adenocarcinoma) that is locally advanced or metastatic, carries the KRAS G12D mutation, and includes types such as small‑bowel, biliary tract (including intrahepatic cholangiocarcinoma), appendiceal, endometrial, or ovarian cancers (excluding low‑grade serous ovarian cancer).
Be treatment‑naïve or have received no more than one cycle of standard systemic therapy for metastatic disease.
Have received 2 or 3 prior lines of therapy (or progressed during adjuvant therapy) for pancreatic cancer, 3 or 4 prior lines for NSCLC, 4 prior lines for colorectal adenocarcinoma, or 4 or more prior lines for other KRAS G12D‑mutated solid tumors.
Be ineligible for enrollment in any other cohort of this study; if other expansion cohorts are full, you may be allowed to join the drug‑interaction (Part E) cohort.

Who Cannot Join the Study?

Had a major surgery (other than a diagnostic test) within 4 weeks before the first study dose, or plans to have such surgery during the study. (Minor procedures like biopsies are allowed up to 7 days before.)
Used a strong blocker (inhibitor) or activator (inducer) of the enzyme CYP3A4 within 14 days before the first dose, or used medicines that are very sensitive to this enzyme within the same time frame. This also includes drinking grapefruit juice, which can block CYP3A4; avoid grapefruit for at least 1 week before starting.
Took a proton pump inhibitor (a medicine that reduces stomach acid) within 7 days, or an H2‑blocker (another acid‑reducing drug) within 1 day before the first dose.
Has active or untreated cancer that has spread to the brain (central nervous system metastases) and is getting worse. If brain metastases were treated and are stable, you may be allowed.
Has an active flare‑up of an autoimmune disease that needs systemic (whole‑body) treatment such as strong steroids or immune‑suppressing drugs during screening.
Cannot swallow pills. (If you have a stomach condition that might affect pill absorption, special approval may be needed.)
Has an uncontrolled illness such as an infection that needs treatment, ongoing drug abuse, or a social situation that would make it hard to follow study rules.
Has 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 have shorter required periods).
Is pregnant or breastfeeding.
Has a known allergy or severe reaction to any of the study drugs or their inactive ingredients.
Has a diagnosis of low‑grade serous ovarian cancer (LGSOC).
Had a severe COVID‑19 infection that still requires extra oxygen to keep blood oxygen levels above 90% at rest.
For the lung‑cancer group only: has a tumor with an ALK mutation or an EGFR mutation (these are specific genetic changes not allowed in this study).
For several groups (including lung, pancreas, and colorectal cancers): has a history or current diagnosis of interstitial lung disease (ILD) or pneumonitis (inflammation of the lung tissue).
For the drug‑interaction group only: carries the genetic variant CYP2C8*3 (either one or two copies).
Has high liver test results: total bilirubin ≥1.5 times the normal upper limit (except if you have Gilbert syndrome and bilirubin is >3.0 mg/dL), or ALT or AST enzymes ≥2.5 times the normal limit.
Uses any medicines that are known to block or activate CYP3A4 or CYP2C8 (including St. John’s Wort) within 14 days before the first dose of the special test drugs and during the first study cycle.
Has had gastrointestinal surgery that could affect how the study drug is absorbed, such as partial stomach removal, bariatric (weight‑loss) surgery, or gallbladder removal (except a simple appendix removal).
Cannot avoid alcohol for at least 72 hours before and during the first cycle of the special test drugs.
Cannot avoid all tobacco products (cigarettes, cigars, vaping, etc.) for at least 7 days before and during the first cycle of the special test drugs.
Cannot avoid all recreational drugs, including cannabis products (THC or CBD), for at least 30 days before and during the first cycle of the special test drugs.
Has an active infection with hepatitis B, hepatitis C, or HIV that needs treatment. Chronic or uncertain cases need discussion with the study doctor.
Has received an organ or tissue transplant from another person.
Has serious heart problems such as congestive heart failure, class III/IV heart disease (according to the NYHA classification), a heart attack within the last 6 months, unstable heart rhythm, unstable chest pain, or severe obstructive lung disease.
Has uncontrolled or serious problems with blood, kidneys, liver, hormones, lungs, stomach, heart, mental health, clotting, skin, autoimmune disease, or severe drug allergies that would put you at high risk for side effects.
Received chemotherapy, targeted therapy, or radiation (except palliative radiation) within 4 weeks (or 5 drug half‑lives, whichever is shorter) before the first dose, or immunotherapy within 4 weeks before the first dose.
Taken any experimental (investigational) drug within 4 weeks (or 5 half‑lives) before the first dose, or is currently enrolled in another interventional study.
Has ever been treated with direct RAS inhibitors (a type of drug that targets the RAS pathway), which are not allowed in any part of this study.

Where you can join this trial?

Verified and Recommended Sites

No sites found in this category

Verified Sites

Site Name	City	Country
Comite Entreprise Paul Papin	Angers	France
Universitaet Leipzig	Leipzig	Germany
Technische Universitaet Dresden	Dresden	Germany
Katholieke Universiteit te Leuven	Leuven	Belgium
Hospital Universitario Hm Sanchinarro	Madrid	Spain
Institut Curie – Site Paris	Paris	France

Other Sites

Site Name	City	Country
Universitair Medisch Centrum Utrecht	Utrecht	The Netherlands
Stichting Radboud University Medical Center	Nijmegen	The Netherlands
Hospital Universitario Fundacion Jimenez Diaz	Madrid	Spain
Klinikum der Technischen Universitaet Muenchen (TUM Klinikum)	Munich	Germany
Netherlands Cancer Institute	Amsterdam	The Netherlands
Istituto Europeo Di Oncologia S.r.l.	Milan	Italy
Centre hospitalier universitaire de Liege	Liege	Belgium
Vrije Universiteit Brussel	Jette	Belgium
Hnzcpkof Vfsf dtddoxah	Barcelona	Spain
Herkqvan Udianzxepbowh dh A Crvqkx	A Coruna Galicia	Spain
Ahbpymemrl Pptvxfta Hidmquoe De Mtfhoqeyo	Marseille	France
Aflrxtl Oysftwderzd Ufprojjniwfvb Pswcq	Parma	Italy
Cpkttx Lecu Btwfyg	Lyon	France

Trial status

Country	Status	Recruitment Start
Belgium	Not yet recruiting	01.06.2026
France	Not yet recruiting	01.06.2026
Germany	Not yet recruiting	01.06.2026
Italy	Not yet recruiting	01.06.2026
Spain	Not yet recruiting	01.06.2026
The Netherlands	Not yet recruiting	01.06.2026

Trial locations

Investigated drugs:

VS-7375 is an experimental oral tablet that targets a specific mutation called KRAS G12D, which can help stop the growth of certain cancer cells. In this study the drug is taken once a day by mouth, and researchers are looking at how safe it is and how well it works when used alone or together with other treatments.

Gemcitabine is a chemotherapy medicine that is given through an IV infusion. It works by interfering with the DNA of cancer cells, which can slow or stop their growth. In the trial it is used together with other drugs for patients with pancreatic cancer.

Pembrolizumab (brand name Keytruda) is an immunotherapy drug that is given by IV infusion. It helps the body’s own immune system recognize and attack cancer cells. In this study it is combined with other chemotherapy drugs for patients with lung cancer.

Cetuximab (brand name Erbitux) is a targeted therapy given by IV infusion. It attaches to a protein on the surface of some cancer cells and blocks signals that tell the cells to grow. The trial tests cetuximab alone and together with the experimental drug VS-7375.

Pemetrexed is a chemotherapy agent administered by IV infusion. It stops cancer cells from making the building blocks they need to grow. In the study it is used together with carboplatin, pembrolizumab and VS-7375 for patients with lung cancer.

Carboplatin is a chemotherapy drug given by IV infusion. It damages the DNA of cancer cells, which can lead to cell death. The trial includes carboplatin as part of a combination regimen with VS-7375, pembrolizumab and pemetrexed for lung cancer patients.

Nab‑paclitaxel (brand name Abraxane) is a form of the chemotherapy drug paclitaxel that is bound to albumin, allowing it to be given as an IV infusion. It stops cancer cells from dividing. In this study it is combined with VS-7375 and gemcitabine for patients with pancreatic cancer.

VS-7375 plus cetuximab is a combination therapy where the experimental oral KRAS G12D inhibitor is taken together with the IV‑infused targeted drug cetuximab. This pairing is being tested to see if blocking KRAS and the growth‑signal protein at the same time improves outcomes for various solid tumors.

VS-7375 plus carboplatin, pembrolizumab, and pemetrexed is a four‑drug regimen. The oral VS-7375 is taken with three IV drugs: carboplatin (chemotherapy), pembrolizumab (immunotherapy), and pemetrexed (chemotherapy). Researchers are studying whether this mix can safely treat patients with newly diagnosed metastatic lung cancer.

VS-7375 plus gemcitabine and nab‑paclitaxel combines the oral KRAS inhibitor with two IV chemotherapies, gemcitabine and nab‑paclitaxel. This combination is being evaluated for safety and effectiveness in patients with locally advanced or metastatic pancreatic cancer.

Investigated diseases:

Malignant mast cell neoplasm

KRAS G12D‑mutated solid tumor – These cancers arise in various organs and carry a specific KRAS gene change known as G12D. The mutation drives uncontrolled cell growth, allowing the tumor to expand locally. Over time the mass can invade surrounding tissues and spread to nearby lymph nodes. As the disease advances, cancer cells may travel through the bloodstream to distant sites. The presence of the KRAS G12D alteration is linked to a tendency for continued tumor expansion.

Pancreatic ductal adenocarcinoma – This cancer begins in the ducts of the pancreas that produce digestive enzymes. It typically starts as a small lesion that gradually enlarges within the pancreatic tissue. As it grows, it can block the duct and cause swelling of the organ. The tumor often invades nearby blood vessels and can spread to the liver and other organs. Its growth pattern is usually aggressive, with a propensity to infiltrate surrounding structures.

Non‑small cell lung cancer – This group of lung cancers, including adenocarcinoma, squamous cell carcinoma, and large‑cell carcinoma, arises from the lining of the airways. It usually starts as a small nodule in lung tissue and expands slowly. The cancer can erode into nearby bronchi and blood vessels, leading to local spread. Over time, cells may travel through the bloodstream to distant sites such as the brain, bones, or adrenal glands. The disease often progresses stepwise from localized growth to wider dissemination.

Colorectal adenocarcinoma – This cancer originates from the glandular cells that line the colon or rectum. It often begins as a benign polyp that slowly transforms into an invasive tumor. As it enlarges, it can penetrate the bowel wall and involve regional lymph nodes. The tumor may later disseminate to the liver, lungs, or other organs through the bloodstream. Its progression follows a stepwise pattern from localized growth to distant spread.

Trial ID:

2025-523432-39-01

Protocol code:

VS-7375-101

NCT ID:

NCT07020221

Trial Phase:

Human Pharmacology (Phase I) – Other

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Study of VS-7375 alone and with drug combination in patients with advanced KRAS G12D‑mutated solid tumors

What is this study about?

Who Can Join the Study?

Who Cannot Join the Study?