Study on the Safety and Effects of GSK4418959 and Dostarlimab for Adults with Colorectal Cancer with Mismatch Repair Deficiency or High Microsatellite Instability

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What is this study about?

This study is researching a new medication called GSK4418959 for treating solid tumors that have specific genetic characteristics called Mismatch Repair-deficient (dMMR) or Microsatellite Instability-High (MSI-H). These genetic features are found in certain types of cancers, including colorectal cancer and endometrial cancer. The purpose of this research is to determine if this medication is safe and effective for treating these types of cancer, either alone or in combination with other cancer treatments.

The medication being studied, GSK4418959, works by inhibiting a protein called DNA Helicase Werner, which some cancer cells rely on to repair their DNA. In some parts of the study, GSK4418959 will be tested in combination with a type of immunotherapy called a PD-1 inhibitor, which helps the immune system recognize and attack cancer cells.

The study is divided into three parts. The first part will determine the appropriate dose of GSK4418959 when used alone. The second part will evaluate how well the medication works against colorectal and endometrial cancers. The third part will test GSK4418959 in combination with immunotherapy to determine the best dose for this combination approach.

1 Study Overview

You are participating in a clinical trial called SYLVER, which tests a new medication called GSK4418959. This medication is a DNA Helicase Werner Inhibitor (WRNi), which targets specific cancer cells.

The study is divided into three parts. Depending on which part you are in, you may receive either GSK4418959 alone or in combination with a PD-1 inhibitor (a type of immunotherapy medication called dostarlimab, also known as JEMPERLI).

This study is for patients with advanced solid tumors that have a specific characteristic called Mismatch Repair-deficient (dMMR) or Microsatellite Instability-High (MSI-H). These terms describe specific genetic features of your cancer.

2 Initial Assessments

Before starting treatment, you will undergo several assessments to confirm your eligibility for the study. This includes confirming your cancer type and its genetic characteristics.

If your tumor can be biopsied safely, you will provide a fresh tumor sample during screening. This helps researchers understand your cancer better.

3 Treatment – Part 1 (Dose Finding for GSK4418959 Alone)

If you are in Part 1 of the study, you will receive only GSK4418959. This part is for patients who have exhausted all standard treatment options.

The medication is given as a film-coated tablet that you take by mouth. The dose will depend on which dose level group you are assigned to.

During this part, doctors are trying to find the best dose that can be tolerated with manageable side effects.

You will be closely monitored for side effects, especially during the initial dose-limiting toxicity (DLT) observation period.

4 Treatment – Part 2 (Testing Effectiveness)

If you are in Part 2, you will receive GSK4418959 to evaluate how effective it is against colorectal cancer or endometrial cancer.

To participate in this part, you must have received 1-3 previous lines of therapy for your advanced cancer, including at least one immunotherapy treatment.

Your cancer must be measurable using imaging scans.

You will take GSK4418959 tablets according to the recommended dose established in Part 1.

Regular scans will be performed to assess if your tumors are responding to treatment.

5 Treatment – Part 3 (Combination Therapy)

If you are in Part 3, you will receive GSK4418959 tablets in combination with a PD-1 inhibitor called dostarlimab (JEMPERLI).

JEMPERLI is given as a solution for infusion at a dose of 500 mg through an intravenous (IV) line. The frequency and duration will be determined by your doctor.

Like in Part 1, this part aims to find the best dose of the combination that can be tolerated with manageable side effects.

This part is for patients who have exhausted all standard treatment options.

6 Treatment Cycles and Monitoring

Your treatment will be given in cycles. During each cycle, you will have regular check-ups to monitor your health and how you’re responding to treatment.

Blood tests will be taken to check your general health and how your body is processing the medication.

If medically feasible, you will undergo another tumor biopsy during treatment to see how the cancer is responding at the cellular level.

You will have regular imaging scans to measure if your tumors are shrinking, staying the same, or growing.

7 Side Effect Management

Throughout the study, any side effects you experience will be carefully monitored and managed.

If needed, your medication dose may be adjusted, temporarily interrupted, or discontinued based on how you tolerate the treatment.

All side effects, regardless of severity, should be reported to your study doctor.

8 Treatment Duration

You will continue receiving treatment as long as you are benefiting from it and not experiencing unacceptable side effects.

If your cancer progresses or you experience severe side effects that cannot be managed, your participation in the treatment phase of the study may end.

The entire study is expected to run until August 2025, with follow-up possibly continuing until June 2028.

9 Response Evaluation

Your response to treatment will be evaluated regularly using imaging scans.

A complete response means all detectable tumor has disappeared.

A partial response means your tumors have shrunk by a significant amount.

If you achieve a complete or partial response, this will be confirmed by a second scan.

The duration of your response (how long your cancer remains controlled) will be tracked.

Who Can Join the Study?

You must be at least 18 years old.
You must have an advanced solid tumor (cancer that has spread, cannot be surgically removed, or has come back) that has been confirmed by examining tissue samples.
Your tumor must show either:
- Mismatch repair deficiency (dMMR) – a condition where certain proteins that repair DNA errors are missing, OR
- Microsatellite instability-high (MSI-H) – a characteristic where specific areas in your DNA show instability
You must have an ECOG performance status of 0-1 (meaning you are either fully active or restricted in physically strenuous activity but able to walk and carry out light work), with no worsening in the 2 weeks before starting treatment.
Your doctor must expect that you have at least 3 months life expectancy.
If your tumor can be safely biopsied, you must provide a tissue sample during screening and be willing to have another biopsy during treatment.
For Parts 1 and 3 of the study: You must have tried all standard treatment options for your type of cancer.
For Part 2 of the study:
- You must have colorectal cancer (CRC) or endometrial cancer (EC).
- You must have received at least 1 but no more than 3 previous treatments for your advanced disease.
- You must have received at least one immune checkpoint inhibitor (ICI) therapy (a type of immunotherapy).
- You must have measurable disease (at least one tumor that can be accurately measured) during screening.

Who Cannot Join the Study?

You must be 18 years or older to participate in this study.
You cannot participate if you have had major surgery within 4 weeks before starting the study treatment.
If you have active or untreated brain metastases (cancer that has spread to the brain), you cannot participate.
Individuals with symptomatic heart failure or a history of significant heart conditions are not eligible.
If you have an active infection requiring treatment, you cannot join the study.
People with known human immunodeficiency virus (HIV) infection cannot participate.
If you have active hepatitis B or hepatitis C (liver infections), you are not eligible.
Individuals receiving treatment with medications that can significantly affect how the study drug works in your body are excluded.
If you are pregnant, breastfeeding, or planning to become pregnant during the study period, you cannot participate.
You cannot join if you have participated in another clinical trial with an investigational drug within 14 days before starting this study.
If you have any condition that the study doctor believes would make it unsafe for you to participate, you will be excluded.

Where you can join this trial?

Verified and Recommended Sites

No sites found in this category

Verified Sites

Site Name	City	Country	Status
Katholieke Universiteit te Leuven	Leuven	Belgium

Other Sites

Site Name	City	Country
Universitair Ziekenhuis Gent	Gent	Belgium
Stichting Radboud University Medical Center	Nijmegen	The Netherlands
Hospital Hm Nou Delfos	Barcelona	Spain
Netherlands Cancer Institute	Amsterdam	The Netherlands
Hospital Universitario Virgen De La Victoria	Malaga	Spain
Cxglmgsjd Ureiivzidtdfuv Sqfgqpyfz	Woluwe-Saint-Lambert	Belgium
Eyzmiwq Umzpgjstwzie Mljovhv Cpdhkso Rgzbpshqh (pbkfaqj Mxl	Rotterdam	The Netherlands

Trial status

Country	Status	Recruitment Start
Belgium	Not recruiting	29.08.2025
Spain	Not recruiting	29.08.2025
The Netherlands	Not recruiting	29.08.2025

Trial locations

Investigated drugs:

GSK4418959 is an oral DNA Helicase Werner Inhibitor (WRNi). This medication is being studied for its potential anti-cancer effects in patients with certain types of solid tumors that have specific genetic characteristics called Mismatch Repair-deficient (dMMR) or Microsatellite Instability-High (MSI-H). It works by targeting a specific protein involved in DNA repair.

PD-1 inhibitor is a type of immunotherapy that helps your immune system fight cancer. PD-1 inhibitors work by blocking a protein called PD-1, which normally helps keep immune cells from attacking normal cells in the body. By blocking PD-1, these medications help the immune system recognize and attack cancer cells more effectively.

Investigated diseases:

Colorectal neoplasms – Abnormal growths that occur in the colon or rectum, which make up the large intestine. These neoplasms typically begin as small, noncancerous clumps of cells called polyps that form on the inner lining of the colon or rectum. Over time, some of these polyps can develop into colorectal cancer. The disease often progresses slowly and may not cause symptoms until it reaches advanced stages. As it advances, common signs include changes in bowel habits, rectal bleeding, persistent abdominal discomfort, and unexplained weight loss. The progression typically follows a sequence from polyp to adenoma to carcinoma, with the cancer potentially spreading through the bowel wall and to nearby lymph nodes or distant organs if left untreated.

Trial ID:

2024-519721-37-00

Protocol code:

221971

NCT ID:

NCT06710847

Trial Phase:

Phase I and Phase II (Integrated) – First administration to humans

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Study on the Safety and Effects of GSK4418959 and Dostarlimab for Adults with Colorectal Cancer with Mismatch Repair Deficiency or High Microsatellite Instability

What is this study about?

Who Can Join the Study?

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