GSK4381562 for Cancer

Recruiting at 24 trial locations

Overseen By US GSK Clinical Trials Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: GlaxoSmithKline

Must not be taking: Immunotherapy, Chemotherapy

Disqualifiers: Organ transplant, Recent malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

141 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new drug called GSK4381562 in patients with recurring or spreading tumors who have no other treatment options. It will see how the drug is processed by the body, its safety, and any immune responses it might cause.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that certain prior treatments and therapies are not allowed within specific time frames before starting the study. It's best to discuss your current medications with the trial team to get a clear answer.

What makes the drug GSK4381562 unique for cancer treatment?

GSK4381562 is unique because it targets glycogen synthase kinase-3 beta (GSK-3β), a protein involved in cancer cell growth and immune response. This drug may offer a novel approach by potentially altering the tumor microenvironment and enhancing immune cell activity, which is different from traditional cancer treatments that primarily focus on directly killing cancer cells. ^{1 2 3 4 5}

Research Team

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Eligibility Criteria

This trial is for adults with certain advanced solid tumors, like lung, breast, or colorectal cancer, that have worsened after standard treatments or when such treatments aren't suitable. Participants must not be pregnant or breastfeeding and should use effective contraception. They need to have a life expectancy of at least 12 weeks and good organ function.

Inclusion Criteria

I agree to have two tumor biopsies: one before and one 6 weeks after starting treatment.

I am not pregnant or breastfeeding.

My organs are functioning well.

Exclusion Criteria

I have experienced side effects from previous cancer treatments.

I have another cancer that has worsened or needed treatment in the last 2 years.

My side effects from previous treatments have mostly gone away.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive GSK4381562 as monotherapy or in combination with other anticancer agents

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Long-term follow-up

Participants are monitored for long-term safety and overall response rate

27 months

Treatment Details

Interventions

• Dostarlimab
• GSK4381562
• GSK4428859A

Trial Overview The study tests GSK4381562's safety and effects in humans for the first time. It will also look at how the body processes it (pharmacokinetics) and if it triggers immune responses (immunogenicity). Dostarlimab and GSK4428859A are other interventions under investigation.

Participant Groups

Group I: Participants receiving dostarlimab plus belrestotug plus nelistotug (Arm F) Experimental Treatment 3 Interventions

Group II: Participants receiving dostarlimab plus belrestotug plus GSK4381562 (Arm E) Experimental Treatment 3 Interventions

Group III: Participants receiving dostarlimab plus belrestotug (Arm D) Experimental Treatment 2 Interventions

Group IV: Participants receiving GSK5764227 plus dostarlimab (Arm I) Experimental Treatment 2 Interventions

Group V: Participants receiving GSK4381562 plus dostarlimab plus belrestotug (Arm C) Experimental Treatment 3 Interventions

Group VI: Participants receiving GSK4381562 plus dostarlimab (Arm B) Experimental Treatment 2 Interventions

Group VII: Participants receiving GSK4381562 monotherapy (Arm A) Experimental Treatment 1 Intervention

Group VIII: China Cohort: Participants receiving dostarlimab plus belrestotug (Arm H) Experimental Treatment 2 Interventions

Group IX: China Cohort: Participants receiving dostarlimab (Arm G) Experimental Treatment 1 Intervention

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

Findings from Research

SGI-1776 demonstrated significant anti-tumor effects on human ovarian cancer HO-8910 cells, inhibiting cell proliferation, migration, and invasion in a dose-dependent manner, and causing cell cycle arrest in the G1 phase.

The mechanism of action involves the down-regulation of Pim-1 kinase activity and its downstream targets, indicating that Pim-1 could be a potential therapeutic target for treating ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SGI-1776, an imidazo pyridazine compound, inhibits the proliferation of ovarian cancer cells by inactivating Pim-1. Xie, J., Bai, J.[2018]

NT157, a tyrosine kinase inhibitor, effectively inhibits glioma cell growth in vitro by causing cell cycle arrest and inducing apoptosis through mechanisms involving p21, p27, and the DR5 pathway.

Combining NT157 with TRAIL enhances apoptosis in glioma cells and significantly reduces tumor growth in vivo, suggesting that this combination therapy could be a promising strategy for treating human glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NT157 inhibits cell proliferation and sensitizes glioma cells to TRAIL-induced apoptosis by up-regulating DR5 expression. Hou, YJ., Li, D., Wang, W., et al.[2022]

Elraglusib, a GSK-3 inhibitor, enhances immune cell-mediated killing of colorectal cancer (CRC) cells by sensitizing them to immune attacks and promoting immune cell function, which could improve treatment outcomes.

In a murine model, elraglusib combined with immune checkpoint blockade (anti-PD-1/L1) led to improved survival rates, increased tumor-infiltrating T cells, and a favorable shift in cytokine profiles, suggesting its potential as an effective therapy for CRC and possibly other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GSK-3 Inhibitor Elraglusib Enhances Tumor-Infiltrating Immune Cell Activation in Tumor Biopsies and Synergizes with Anti-PD-L1 in a Murine Model of Colorectal Cancer. Huntington, KE., Louie, AD., Srinivasan, PR., et al.[2023]

LKB1/KRAS mutant non-small-cell lung cancer (NSCLC) cell lines show a significant sensitivity to the MEK inhibitor CI-1040, indicating a potential targeted treatment option for this specific cancer subtype.

These LKB1/KRAS mutant NSCLCs are also responsive to the mTOR inhibitor rapamycin, suggesting that targeting both the MAPK and mTOR pathways could be an effective therapeutic strategy for this genetically distinct group of lung cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. Mahoney, CL., Choudhury, B., Davies, H., et al.[2022]

GSK-3β mutations were found in about 1% of over 100,000 tumors analyzed, with uterine endometrioid carcinoma showing the highest mutation rate at 4%, indicating its potential role in cancer development.

Tumors with GSK-3β mutations exhibited increased PD-L1 expression and a higher infiltration of immune cells, suggesting that these mutations may influence the tumor microenvironment and immune response, which could have implications for targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Landscape of Glycogen Synthase Kinase-3 Beta Genomic Alterations in Cancer. Borden, BA., Baca, Y., Xiu, J., et al.[2021]

References

1. China pubmed.ncbi.nlm.nih.gov

SGI-1776, an imidazo pyridazine compound, inhibits the proliferation of ovarian cancer cells by inactivating Pim-1. [2018]

2. France pubmed.ncbi.nlm.nih.gov

NT157 inhibits cell proliferation and sensitizes glioma cells to TRAIL-induced apoptosis by up-regulating DR5 expression. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

GSK-3 Inhibitor Elraglusib Enhances Tumor-Infiltrating Immune Cell Activation in Tumor Biopsies and Synergizes with Anti-PD-L1 in a Murine Model of Colorectal Cancer. [2023]

4. England pubmed.ncbi.nlm.nih.gov

LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. [2022]

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

The Landscape of Glycogen Synthase Kinase-3 Beta Genomic Alterations in Cancer. [2021]