GSK4418959 for Colorectal Cancer

(SYLVER Trial)

Recruiting at 11 trial locations

Overseen By EU GSK Clinical Trials Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: GlaxoSmithKline

Must not be taking: WRN inhibitors

Disqualifiers: Uncontrolled brain metastases, Severe liver fibrosis, Active autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

73 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug GSK4418959 for colorectal cancer?

Research shows that PD-1 inhibitors, a type of drug that helps the immune system fight cancer, are effective for colorectal cancer with certain genetic features called high microsatellite instability (MSI-H). In studies, patients with MSI-H colorectal cancer responded well to PD-1 inhibitors, with some showing no further disease progression. ^{1 2 3 4 5}

What safety data exists for PD-1 inhibitors like GSK4418959 in humans?

PD-1 inhibitors, including GSK4418959, can cause colitis (inflammation of the colon) as a side effect, which is more common and severe when used in combination with other treatments. While most patients recover from these side effects, they can be serious and require treatment with medications like steroids. ^{6 7 8 9 10}

How is the drug GSK4418959 different from other treatments for colorectal cancer?

GSK4418959, a PD-1 inhibitor, is unique because it targets the immune system to fight colorectal cancer, particularly effective in cases with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR), unlike traditional chemotherapy which directly targets cancer cells. ^{1 2 11 12 13}

Eligibility Criteria

This trial is for individuals with aggressive solid tumors, specifically colorectal cancer that shows microsatellite instability. Participants should have specific genetic features making their cancer hard to treat. The study excludes details not provided.

Inclusion Criteria

My organs are functioning well.

My cancer's MMR/MSI status is known or will be tested.

Is expected to have a minimum of 3 months life expectancy

Exclusion Criteria

Has known hypersensitivity to any of the study interventions or any of their excipients

I have been treated with a WRN inhibitor before.

I have an autoimmune disease treated with drugs in the last 2 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive GSK4418959 as monotherapy to determine the appropriate dose

Up to 26 months

Dose Expansion

Participants receive GSK4418959 as monotherapy to further evaluate safety and effectiveness

Up to 26 months

Combination Treatment

Participants receive GSK4418959 plus PD-1 inhibitor to assess combined treatment effects

Up to 26 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 42 months

Treatment Details

Interventions

• GSK4418959
• PD-1 inhibitor

Trial Overview The study is testing GSK4418959 alone or combined with a PD-1 inhibitor to see if they can shrink the tumors, are safe and tolerated by patients, and how the drug levels decrease in the body over time.

Participant Groups

Group I: Part 3: Dose escalation of GSK4418959 plus PD-1 inhibitor Experimental Treatment 2 Interventions

Participants will receive GSK4418959 plus PD-1 inhibitor.

Group II: Part 2: Dose expansion of GSK4418959 monotherapy Experimental Treatment 1 Intervention

Participants will receive GSK4418959 as monotherapy.

Group III: Part 1: Dose escalation of GSK4418959 monotherapy Experimental Treatment 1 Intervention

Participants will receive GSK4418959 as monotherapy.

Who Is Running the Clinical Trial?

GlaxoSmithKline

Lead Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

IDEAYA Biosciences

Industry Sponsor

Trials

6

Recruited

1,300+

Findings from Research

In a study of 75 Lynch syndrome patients with colorectal cancer, PD-1 inhibitors showed a high objective response rate of 70.7%, indicating their effectiveness particularly in tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H).

The treatment was less effective in tumors with proficient MMR (pMMR) or microsatellite stable (MSS) characteristics, and mucinous/signet-ring cell differentiation was linked to a lower response rate, highlighting the need for tailored therapies based on tumor characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients. Yu, JH., Xiao, BY., Tang, JH., et al.[2023]

Immunotherapy using PD-1 inhibitors shows promising efficacy in treating high-level microsatellite instability (MSI-H) colorectal cancers (CRCs), with a 40% objective response rate in MSI-H patients compared to 0% in microsatellite stable (MSS) patients.

The studies indicate that while PD-1 inhibitors may benefit MSI-H mCRC patients, there is currently no evidence supporting their effectiveness in MSS CRCs, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Potential Value of Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 Inhibitor Therapy. Toh, JWT., de Souza, P., Lim, SH., et al.[2022]

Programmed cell death 1 (PD-1) and its ligand (PD-L1) are promising targets for treating gastrointestinal cancers, which are a leading cause of cancer-related deaths, highlighting the need for new biomarkers and therapies.

Several PD-1/PD-L1 inhibitors, including pembrolizumab, have been developed and approved for use in other cancers, showing potential for improving treatment efficacy in gastrointestinal cancers, although resistance mechanisms to these therapies are still being studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed cell death 1 as prognostic marker and therapeutic target in upper gastrointestinal cancers. Khoshghamat, N., Jafari, N., Moetamani-Ahmadi, M., et al.[2021]

Immune checkpoint inhibitors, targeting CTLA-4 and PD-1/PD-L1, are showing promising results in treating colorectal cancer, particularly in patients with microsatellite instability (MSI).

Ongoing clinical trials aim to confirm these early findings, explore combination therapies, and identify biomarkers that can predict patient responses to these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoints as a Target for Colorectal Cancer Treatment. Passardi, A., Canale, M., Valgiusti, M., et al.[2022]

Anti-PD-1 therapies, specifically nivolumab and pembrolizumab, show promising efficacy and acceptable safety in treating gastrointestinal cancers, particularly in advanced gastroesophageal cancer and refractory MSI positive metastatic colorectal cancer.

The effectiveness of these therapies appears to be linked to tumor PD-L1 levels, although clinical benefits in patients with MSI positive advanced colorectal cancer have been limited according to recent phase 2 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the PD-1 pathway: a new hope for gastrointestinal cancers. Bilgin, B., Sendur, MA., Bülent Akıncı, M., et al.[2022]

In a study of 1261 patients with advanced melanoma receiving anti-PD-1 therapy, colitis occurred in 109 patients, with a significantly higher incidence of 24.4% in those receiving combination therapy with ipilimumab compared to 3.2% in those on monotherapy.

Patients on combination therapy experienced earlier onset of colitis symptoms and required higher doses and longer tapering of steroids, indicating that combination therapy may lead to more severe immune-related adverse events, highlighting the need for improved management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical characterization of colitis arising from anti-PD-1 based therapy. Wang, DY., Mooradian, MJ., Kim, D., et al.[2023]

Anti-CTLA-4 therapy (ipilimumab) is associated with a significantly higher risk of severe colitis compared to anti-PD-1 therapies (nivolumab and pembrolizumab), with a three-fold increase in adverse event reports related to colitis.

The study utilized a novel data analysis platform to explore the molecular mechanisms behind these adverse reactions, but found no significant evidence that the increased colitis rates were due to greater T-cell activation from anti-CTLA-4 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of a patient-centered reverse translational systems-based approach to understand mechanisms of an adverse drug reaction of immune checkpoint inhibitors. Kim, S., Lahu, G., Vakilynejad, M., et al.[2022]

PD-1/PD-L1 inhibitors show a promising objective response rate of 33% in treating colorectal cancer (CRC), particularly effective in patients with deficient mismatch repair, achieving a response rate of 43%.

The treatment is associated with an overall survival rate of 56% and a progression-free survival rate of 46%, indicating its efficacy, while the adverse event rate is manageable at 59%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in colorectal cancer: a meta-analysis. Jin, C., Zhu, X., Huang, X., et al.[2022]

A study analyzing 70,330 adverse events reported to the FDA found that immune checkpoint inhibitors (ICIs) significantly increase the risk of gastrointestinal (GI) toxicities, particularly colitis, hepatobiliary disorders, and pancreatitis, with colitis showing the highest reporting odds ratio of 17.2.

The risk of these GI adverse events was notably higher with anti-CTLA-4 treatments compared to anti-PD-1 and anti-PD-L1 therapies, and factors such as female gender and polytherapy were identified as strong risk factors for these complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System. Bai, X., Jiang, S., Zhou, Y., et al.[2021]

In a meta-analysis of clinical trials, PD-1 inhibitors (like nivolumab and pembrolizumab) were found to have a higher incidence of colitis compared to PD-L1 inhibitors (like atezolizumab and durvalumab), with rates of 1.49% for all grade colitis and 0.85% for grade 3-4 colitis.

The analysis indicated that the relative risk of developing colitis with PD-1 inhibitors was significantly higher (1.80 for all grade colitis and 2.52 for grade 3-4 colitis), suggesting that patients receiving PD-1 inhibitors may need closer monitoring for this adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and Risk of Colitis With Programmed Death 1 Versus Programmed Death Ligand 1 Inhibitors for the Treatment of Cancer. Miyashita, H., Mikami, T., Satoi, S., et al.[2021]

In a phase 2 study involving 94 patients with advanced colorectal cancer, the combination of regorafenib and nivolumab resulted in a modest objective response rate of 7%, with all responders having no liver metastases at baseline.

The treatment was associated with a high incidence of adverse events (97%), with the majority being mild to moderate (grade 1 or 2), indicating that while the combination therapy shows some potential, it also carries significant safety concerns that need to be addressed in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib plus nivolumab in patients with mismatch repair-proficient/microsatellite stable metastatic colorectal cancer: a single-arm, open-label, multicentre phase 2 study. Fakih, M., Raghav, KPS., Chang, DZ., et al.[2023]

In a case series of three patients with mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer, combination therapy with nivolumab and ipilimumab led to durable responses after initial progression on pembrolizumab, suggesting that CTLA-4 blockade may be effective following PD-1 inhibition.

The study highlights the potential of using circulating tumor DNA (ctDNA) as a reliable biomarker for monitoring treatment response and disease progression, indicating its value in assessing therapy effectiveness in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating tumor DNA (ctDNA) serial analysis during progression on PD-1 blockade and later CTLA-4 rescue in patients with mismatch repair deficient metastatic colorectal cancer. Kasi, PM., Budde, G., Krainock, M., et al.[2022]

A case study of a patient with primary colon squamous cell carcinoma (SCC) showed a significant response to a combination of immunotherapy (sintilimab) and chemotherapy (mFOLFOX6), suggesting this approach may be effective for treating pMMR/MSS colon SCC with high PD-L1 expression.

The patient's treatment led to a durable response and improved quality of life, indicating that PD-L1 expression could serve as a potential biomarker for immunotherapy effectiveness in colorectal SCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Squamous cell carcinoma of ascending colon with pMMR/MSS showed a partial response to PD-1 blockade combined with chemotherapy: A case report. Liu, Y., Du, J., Zhang, P., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

The Potential Value of Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 Inhibitor Therapy. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Programmed cell death 1 as prognostic marker and therapeutic target in upper gastrointestinal cancers. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Immune Checkpoints as a Target for Colorectal Cancer Treatment. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Targeting the PD-1 pathway: a new hope for gastrointestinal cancers. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Clinical characterization of colitis arising from anti-PD-1 based therapy. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Application of a patient-centered reverse translational systems-based approach to understand mechanisms of an adverse drug reaction of immune checkpoint inhibitors. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in colorectal cancer: a meta-analysis. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Incidence and Risk of Colitis With Programmed Death 1 Versus Programmed Death Ligand 1 Inhibitors for the Treatment of Cancer. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Regorafenib plus nivolumab in patients with mismatch repair-proficient/microsatellite stable metastatic colorectal cancer: a single-arm, open-label, multicentre phase 2 study. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Circulating tumor DNA (ctDNA) serial analysis during progression on PD-1 blockade and later CTLA-4 rescue in patients with mismatch repair deficient metastatic colorectal cancer. [2022]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Squamous cell carcinoma of ascending colon with pMMR/MSS showed a partial response to PD-1 blockade combined with chemotherapy: A case report. [2023]