Neoplasms, ColorectalPhase 1/2SYLVERNCT06710847
A Study to Investigate the Safety, Pharmacokinetics, and Preliminary Effectiveness of GSK4418959 Alone or in Combination With Other Anti-cancer Agents in Participants With Solid Tumors
A Phase 1/2 study testing GSK4418959 and PD-1 inhibitor in people with Neoplasms, Colorectal and Solid Tumor, run by GlaxoSmithKline at 22 sites in 7 countries.
Trial summary
Solid tumours are abnormal lumps of tissue that can occur in different parts of the body. The tumours involved in this study have specific genetic characteristics that can make them more aggressive and challenging to treat. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Neoplasms, Colorectal, Solid Tumor, Colon Cancer
- What is being tested?
- GSK4418959 and PD-1 inhibitor
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 22 sitesin 7 countries
- Study dates
- 13 Dec 2024to 22 Jun 2026
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Parts 1, 2, and 3 inclusion criteria:
- Has a histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor
- Has a known dMMR/MSI-H status as determined by a certified local laboratory at the time of Pre-screening or has an unknown Mismatch repair (MMR)/ Microsatellite Instability (MSI) status at the time of Pre-screening and MMR/MSI status will be determined by central reference laboratory
- Provides an archival or fresh (preferred) formalin fixed, paraffin embedded (FFPE) sample
- Intends to receive GSK4418959 (alone or in combination with PD-1 inhibitor, as determined between Investigator and sponsor) as next line of treatment
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
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- Is expected to have a minimum of 3 months life expectancy
- Has adequate organ function, as defined in the protocol
- Parts 1 and 3 inclusion criteria:
- Has histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor and has exhausted all standard of care treatment options
- Part 2 inclusion criteria:
- Has histologically diagnosed advanced (unresectable, metastatic or recurrent) Colorectal cancer (CRC) or Endometrial cancer (EC)
- Has received at least 1 but no more than 3 lines of systemic anticancer therapy for their advanced (unresectable, metastatic or recurrent) disease including at least one line of Immune checkpoint inhibitors (ICI) therapy
- Has measurable disease (i.e., at least 1 target lesion) during the Screening period per RECIST 1.1, as determined by the investigator
Who cannot join
- Parts 1, 2, and 3 exclusion criteria:
- Has not recovered (i.e., to Grade ≤1 or to baseline) from prior anticancer therapy-induced AEs
- Has received prior treatment with a WRN inhibitor
- Is unable to swallow and retain orally administered study treatment
- Has symptomatic uncontrolled brain or leptomeningeal metastases
- Has a known additional malignancy that progressed or required active treatment within the last 2 years because reoccurrence of another malignancy would confound interpretation by RECIST 1.1 criteria. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cancer that is considered to be low risk for progression by the investigator
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- Has any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs
- Has severe liver fibrosis
- Has cirrhosis or current unstable liver or biliary disease
- Has known hypersensitivity to any of the study interventions or any of their excipients
- Has known WRN syndrome
- Has an active autoimmune disease that has required systemic treatment in the past 2 years
- Part 3 exclusion criteria:
- Has experienced any of the following with prior immunotherapy: any immune mediated adverse events (imAE) of Grade ≥3, immune-related severe neurologic events of any grade, exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or Drug rash with eosinophilia and systemic signs syndrome [DRESS] syndrome), or myocarditis of any grade. Non-clinically significant laboratory abnormalities are not exclusionary
- Has any history of interstitial lung disease or pneumonitis
Trial locations and contacts
22 sites in 7 countries.
22 sites in 7 countries
United States6 sites
GSK Investigational Site
Denver, Colorado, 80218
GSK Investigational Site
Detroit, Michigan, 48201
GSK Investigational Site
Los Angeles, California, 90095
GSK Investigational Site
New York, New York, 10016
GSK Investigational Site
Philadelphia, Pennsylvania, 19104
GSK Investigational Site
Philadelphia, Pennsylvania, 19107
Japan4 sites
GSK Investigational Site
Chiba, 277-8577
GSK Investigational Site
Shizuoka, 411-8777
GSK Investigational Site
Tokyo, 104-0045
GSK Investigational Site
Tokyo, 135-8550
Spain4 sites
GSK Investigational Site
Barcelona, 08023
GSK Investigational Site
Barcelona, 08035
GSK Investigational Site
Madrid, 28040
GSK Investigational Site
Málaga, 29010
Belgium3 sites
GSK Investigational Site
Brussels, 1200
GSK Investigational Site
Ghent, 9000
GSK Investigational Site
Leuven, 3000
South Korea3 sites
GSK Investigational Site
Daegu, 41404
GSK Investigational Site
Gyeonggi-do, 10408
GSK Investigational Site
Seoul, 03080
About this study
Official title: A Phase 1/2 First-Time-in-Human, Open-label, Multicenter, Dose Escalation and Expansion Study of the Oral DNA Helicase Werner Inhibitor (WRNi) GSK4418959 Alone or in Combination With Other Anti-cancer Agents in Adult Participants With Mismatch Repair-deficient (dMMR) or Microsatellite Instability-High (MSI-H) Solid Tumors (SYLVER)
Solid tumours are abnormal lumps of tissue that can occur in different parts of the body. The tumours involved in this study have specific genetic characteristics that can make them more aggressive and challenging to treat. The study will test whether GSK4418959 alone or in combination with a PD-1 inhibitor agent can decrease tumor size, is safe, well-tolerated, and how amounts of the study drug decrease in the body over time.
- Being tested
- GSK4418959, PD-1 inhibitor
- Keywords
- GSK4418959, DNA Helicase Werner Inhibitor (WRNi), PD-1 inhibitor, Solid tumors, Colon cancer, Rectal cancer, Colorectal cancer, Endometrial cancer, Mismatch repair deficient, dMMR, microsatellite instability high, MSI-H
- Medical subject headings
- Colorectal Neoplasms, Colonic Neoplasms, Rectal Neoplasms, Endometrial Neoplasms, Turcot syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GSK4418959Drug
GSK4418959 will be administered.
PD-1 inhibitorBiological
PD-1 inhibitor will be administered.
| Study group | Role | What they receive |
|---|---|---|
| Part 1: Dose escalation of GSK4418959 monotherapy | Experimental | Participants will receive GSK4418959 as monotherapy. Receives: Drug: GSK4418959 |
| Part 2: Dose expansion of GSK4418959 monotherapy | Experimental | Participants will receive GSK4418959 as monotherapy. Receives: Drug: GSK4418959 |
| Part 3: Dose escalation of GSK4418959 plus PD-1 inhibitor | Experimental | Participants will receive GSK4418959 plus PD-1 inhibitor. Receives: Drug: GSK4418959; Biological: PD-1 inhibitor |
What is being measured
The primary outcome is the main question the study is designed to answer.
Part 1: Number of participants with dose limiting toxicities (DLTs) during DLT observation period
Measured: Up to 21 days
Part 3: Number of participants with dose limiting toxicities (DLTs) during DLT observation period
Measured: Up to 21 days
Part 1: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period
Measured: Up to 21 days
Part 3: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period
Measured: Up to 21 days
Part 1: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period
Measured: Up to 21 days
Part 3: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period
Measured: Up to 21 days
Part 2: Objective Response Rate (ORR)
ORR is defined as percentage of participants with confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) by investigator assessment.
Measured: Up to approximately 26 months
Secondary outcomes (18)
Part 1: Area under the concentration-time curve (AUC) for GSK4418959
Measured: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 1: Maximum concentration (Cmax) for GSK4418959
Measured: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 1: Time to maximum concentration (Tmax) for GSK4418959
Measured: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 3: AUC for GSK4418959
Measured: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 3: Cmax for GSK4418959
Measured: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 3: Tmax for GSK4418959
Measured: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 1: Number of participants with TEAEs
Measured: Up to approximately 42 months
Part 2: Number of participants with TEAEs
Measured: Up to approximately 42 months
Part 3: Number of participants with TEAEs
Measured: Up to approximately 42 months
Part 1: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
Measured: Up to approximately 42 months
Part 2: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
Measured: Up to approximately 42 months
Part 3: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
Measured: Up to approximately 42 months
Part 1: Number of participants with clinical laboratory abnormalities
Measured: Up to approximately 42 months
Part 2: Number of participants with clinical laboratory abnormalities
Measured: Up to approximately 42 months
Part 3: Number of participants with clinical laboratory abnormalities
Measured: Up to approximately 42 months
Part 2: Progression-free Survival (PFS)
PFS is defined as time from first dose to progressive disease (as assessed per RECIST 1.1 by Investigator assessment) or death from any cause, whichever is earlier.
Measured: Up to approximately 42 months
Part 2: Duration of Response (DoR)
DoR is defined as time from first documented PR or CR to progressive disease (as assessed per RECIST 1.1 by investigator assessment) or death from any cause, whichever is earlier for participants who have achieved a confirmed CR or PR.
Measured: Up to approximately 42 months
Part 2: Plasma concentration of GSK4418959
Measured: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Nov 2024
- Study start13 Dec 2024
- Primary completion22 Jun 2026 (estimated)
- Study completion22 Jun 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Neoplasms, ColorectalStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- IDEAYA Biosciences
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06710847
- Sponsor's protocol ID
- 221971
- Other IDs
- 2024-519721-37-00
- Acronym
- SYLVER
- Status last verified
- Jan 2026
- First submitted
- 26 Nov 2024
- Last updated
- 2 Feb 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/
Study at a glance
From the registry record, last updated by the sponsor on 2 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1/2 First-Time-in-Human, Open-label, Multicenter, Dose Escalation and Expansion Study of the Oral DNA Helicase Werner Inhibitor (WRNi) GSK4418959 Alone or in Combination With Other Anti-cancer Agents in Adult Participants With Mismatch Repair-deficient (dMMR) or Microsatellite Instability-High (MSI-H) Solid Tumors (SYLVER)
- ClinicalTrials.gov ID
- NCT06710847
- Acronym / sponsor ID
- SYLVER / 221971
- Keywords
- GSK4418959, DNA Helicase Werner Inhibitor (WRNi), PD-1 inhibitor, Solid tumors, Colon cancer, Rectal cancer, Colorectal cancer, Endometrial cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 14 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Collaborators
- IDEAYA Biosciences
- Study start
- 13 Dec 2024 (actual)
- Primary completion
- 22 Jun 2026 (estimated)
- Study completion
- 22 Jun 2026 (estimated)
- First posted
- 29 Nov 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Solid tumours are abnormal lumps of tissue that can occur in different parts of the body. The tumours involved in this study have specific genetic characteristics that can make them more aggressive and challenging to treat. The study will test whether GSK4418959 alone or in combination with a PD-1 inhibitor agent can decrease tumor size, is safe, well-tolerated, and how amounts of the study drug decrease in the body over time.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Part 1: Dose escalation of GSK4418959 monotherapy | Experimental | Drug: GSK4418959Participants will receive GSK4418959 as monotherapy. |
| Part 2: Dose expansion of GSK4418959 monotherapy | Experimental | Drug: GSK4418959Participants will receive GSK4418959 as monotherapy. |
| Part 3: Dose escalation of GSK4418959 plus PD-1 inhibitor | Experimental | Drug: GSK4418959, Biological: PD-1 inhibitorParticipants will receive GSK4418959 plus PD-1 inhibitor. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Has a histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor
- Has a known dMMR/MSI-H status as determined by a certified local laboratory at the time of Pre-screening or has an unknown Mismatch repair (MMR)/ Microsatellite Instability (MSI) status at the time of Pre-screening and MMR/MSI status will be determined by central reference laboratory
- Provides an archival or fresh (preferred) formalin fixed, paraffin embedded (FFPE) sample
- Intends to receive GSK4418959 (alone or in combination with PD-1 inhibitor, as determined between Investigator and sponsor) as next line of treatment
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Key exclusion criteria (15 listed)
- Has not recovered (i.e., to Grade ≤1 or to baseline) from prior anticancer therapy-induced AEs
- Has received prior treatment with a WRN inhibitor
- Is unable to swallow and retain orally administered study treatment
- Has symptomatic uncontrolled brain or leptomeningeal metastases
- Has a known additional malignancy that progressed or required active treatment within the last 2 years because reoccurrence of another malignancy would confound interpretation by RECIST 1.1 criteria. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cancer that is considered to be low risk for progression by the investigator
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GSK4418959GSK4418959 will be administered. | Drug | Part 1: Dose escalation of GSK4418959 monotherapy, Part 2: Dose expansion of GSK4418959 monotherapy, Part 3: Dose escalation of GSK4418959 plus PD-1 inhibitor |
| PD-1 inhibitorPD-1 inhibitor will be administered. | Biological | Part 3: Dose escalation of GSK4418959 plus PD-1 inhibitor |
Primary outcome
Part 1: Number of participants with dose limiting toxicities (DLTs) during DLT observation period
Time frame: Up to 21 days
Part 3: Number of participants with dose limiting toxicities (DLTs) during DLT observation period
Time frame: Up to 21 days
Part 1: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period
Time frame: Up to 21 days
Part 3: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period
Time frame: Up to 21 days
Part 1: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period
Time frame: Up to 21 days
Part 3: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period
Time frame: Up to 21 days
Part 2: Objective Response Rate (ORR)
Time frame: Up to approximately 26 months
ORR is defined as percentage of participants with confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) by investigator assessment.
18 secondary outcomes
Part 1: Area under the concentration-time curve (AUC) for GSK4418959
Time frame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 1: Maximum concentration (Cmax) for GSK4418959
Time frame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 1: Time to maximum concentration (Tmax) for GSK4418959
Time frame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 3: AUC for GSK4418959
Time frame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 3: Cmax for GSK4418959
Time frame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 3: Tmax for GSK4418959
Time frame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 1: Number of participants with TEAEs
Time frame: Up to approximately 42 months
Part 2: Number of participants with TEAEs
Time frame: Up to approximately 42 months
Part 3: Number of participants with TEAEs
Time frame: Up to approximately 42 months
Part 1: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
Time frame: Up to approximately 42 months
Part 2: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
Time frame: Up to approximately 42 months
Part 3: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
Time frame: Up to approximately 42 months
Part 1: Number of participants with clinical laboratory abnormalities
Time frame: Up to approximately 42 months
Part 2: Number of participants with clinical laboratory abnormalities
Time frame: Up to approximately 42 months
Part 3: Number of participants with clinical laboratory abnormalities
Time frame: Up to approximately 42 months
Part 2: Progression-free Survival (PFS)
Time frame: Up to approximately 42 months
Part 2: Duration of Response (DoR)
Time frame: Up to approximately 42 months
Part 2: Plasma concentration of GSK4418959
Time frame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Feb 2026.
- Individual participant dataSharing planned: Yes. Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
22 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing GSK4418959 and PD-1 inhibitor in people with Neoplasms, Colorectal and Solid Tumor, run by GlaxoSmithKline at 22 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 2 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 22 sites in United States, Japan, Spain, Belgium, South Korea and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part 1: Number of participants with dose limiting toxicities (DLTs) during DLT observation period (time frame: Up to 21 days). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Feb 2026.