GIM-531 for Solid Tumors

Recruiting at 9 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Georgiamune Inc

Must be taking: Anti-PD-1 therapy

Must not be taking: Steroids, Immunosuppressants, PPIs, H2 blockers

Disqualifiers: Cardiac disease, Autoimmune, Infections, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

GIM-531 is a first-in-class, orally bioavailable small molecule that is being developed for the treatment of advanced solid tumors as a single agent and rescue therapy. GIM-531 exhibits its primary effect through selective inhibition of regulatory T-cells (Tregs).

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

The trial requires you to stop taking certain medications, specifically those that are strong inducers or inhibitors of specific enzymes (CYP2C8 or CYP3A4/5) and certain drugs that modify stomach acid, like proton-pump inhibitors. You must discontinue these at least 1 week before starting the study drug and for the duration of the study.

What safety data exists for GIM-531 in humans?

The research does not provide specific safety data for GIM-531, but it highlights that some novel cancer drugs can cause serious gastrointestinal issues, like perforation, which should be monitored. It's important to discuss potential risks with your doctor. ^{1 2 3 4 5}

How does the drug GIM-531 differ from other treatments for solid tumors?

GIM-531 is unique because it likely targets the p53-HDM2 interaction, similar to other MDM2 inhibitors like CGM097 and nutlin-3, which activate the p53 pathway to suppress tumor growth. This approach is novel as it focuses on reactivating the body's natural tumor suppressor mechanisms, potentially offering benefits for tumors with wild-type p53, where traditional treatments may not be as effective. ^{6 7 8 9 10}

Eligibility Criteria

This trial is for adults with advanced solid tumors, including melanoma, that have worsened after standard treatment or who can't tolerate it. They must not have taken experimental drugs recently and should be in good physical condition (ECOG 0-1). Participants need functioning major organs and agree to a tumor biopsy. Women of childbearing age and men must use effective contraception.

Inclusion Criteria

I have signed the consent form.

I haven't taken any experimental drugs recently or am not in another study.

My recent tests show my heart, kidneys, and liver are functioning well.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Dose escalation with GIM-531 administered as a single agent to determine safety profile, PK, PD effects, and early anti-tumor activity

21 days

Multiple visits for dose escalation and monitoring

Phase 2 Treatment

GIM-531 administered in combination with anti-PD-1 therapy to participants with advanced/metastatic cutaneous melanoma

Approximately 2 years

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• GIM-531 (Small Molecule)

Trial Overview The study tests GIM-531, an oral drug designed to block certain immune cells (Tregs) that may allow tumors to grow. It's given as a single agent or rescue therapy for those whose cancer has progressed on anti-PD-1 therapy, which they will continue during the trial.

Participant Groups

Group I: Phase 2 Combination Treatment Experimental Treatment 2 Interventions

GIM-531 administered orally daily in combination with anti-PD-1 therapy

Group II: Phase 1 Single Agent Experimental Treatment 1 Intervention

GIM-531 administered orally daily

Who Is Running the Clinical Trial?

Georgiamune Inc

Lead Sponsor

Trials

3

Recruited

310+

Findings from Research

A comprehensive analysis of the FDA Adverse Event Reporting System identified 5226 cases of gastrointestinal perforation (GIP) linked to 37 novel antineoplastic drugs, highlighting a significant safety concern associated with these medications.

Out of the 37 drugs analyzed, 22 showed statistically significant signals for GIP, particularly those targeting vascular endothelial growth factor and immune checkpoints, indicating a need for careful monitoring and management of this adverse event in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal perforation associated with novel antineoplastic agents: A real-world study based on the FDA Adverse Event Reporting System. Yu, Z., Zhu, H., Chen, H., et al.[2023]

In a study of 307 Chinese patients with gastrointestinal stromal tumors (GISTs) receiving imatinib, the plasma trough concentrations (Cmin) were found to be significantly higher than those reported in Western populations, particularly at higher doses (400 mg, 600 mg, and 800 mg).

Higher imatinib Cmin levels were correlated with severe adverse reactions such as periorbital and limb edema, anemia, and rash, indicating that monitoring these concentrations could help manage and mitigate side effects in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlations between imatinib plasma trough concentration and adverse reactions in Chinese patients with gastrointestinal stromal tumors. Xia, Y., Chen, S., Luo, M., et al.[2022]

Gilteritinib is an effective treatment for adults with relapsed or refractory acute myeloid leukemia (AML) with FLT3 mutations, showing advantages in survival and a generally favorable safety profile.

While gilteritinib is associated with common side effects like diarrhea and nausea, serious gastrointestinal events such as GI hemorrhage and perforation have been reported, highlighting the need for careful monitoring in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data. Gozzo, L., Nardo, A., Brancati, S., et al.[2023]

Imatinib (Gleevec) has shown high efficacy in treating chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST), with over 12,000 patients involved in clinical trials, indicating its effectiveness as a treatment option.

The drug is generally well tolerated, with manageable common side effects such as nausea and rash, and ongoing studies have helped identify rarer toxicities and predictors of common side effects, as well as its impact on male fertility and pregnancy outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib treatment: specific issues related to safety, fertility, and pregnancy. Hensley, ML., Ford, JM.[2022]

Immune checkpoint antibodies targeting the PD-1/PD-L1 pathway have shown significant antitumor activity and have been approved for use as single-agent therapies in metastatic malignant melanoma and nonsmall-cell lung cancer.

Understanding the toxicities associated with PD-1/PD-L1 blockade and having effective management strategies is crucial for maximizing both the safety and efficacy of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Naidoo, J., Page, DB., Li, BT., et al.[2023]

Nutlin-3 effectively stabilizes the tumor suppressor p53 in gastric cancer cells with wild-type p53, leading to increased expression of important proteins that promote cell cycle arrest and apoptosis.

In combination with traditional chemotherapy drugs like 5-fluorouracil and cisplatin, nutlin-3 enhances cytotoxic effects against gastric cancer cells, demonstrating its potential as a promising treatment option for patients with wild-type p53.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent in vitro and in vivo antitumor effects of MDM2 inhibitor nutlin-3 in gastric cancer cells. Endo, S., Yamato, K., Hirai, S., et al.[2021]

The small-molecule MDM2 antagonist nutlin-3 preserves the cell-cycle arrest function of the p53 pathway in various tumor-derived cell lines with wild-type p53, indicating potential therapeutic benefits for these tumors.

Cancer cells with amplified mdm2 genes showed heightened sensitivity to nutlin-3, suggesting that targeting the p53-MDM2 interaction could be an effective treatment strategy for many patients with tumors retaining wild-type p53.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Tovar, C., Rosinski, J., Filipovic, Z., et al.[2018]

The study found that combining MDM2 inhibitors like Nutlin-3 or RG7388 with cisplatin can enhance the effectiveness of treatment in ovarian cancer cell lines, leading to increased activation of the p53 protein, which is crucial for cell cycle arrest and apoptosis.

This combination therapy showed synergistic effects, meaning it worked better together than separately, particularly in cells with a functional p53 gene, suggesting a promising new approach to overcome resistance to standard chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-clinical efficacy and synergistic potential of the MDM2-p53 antagonists, Nutlin-3 and RG7388, as single agents and in combined treatment with cisplatin in ovarian cancer. Zanjirband, M., Edmondson, RJ., Lunec, J.[2022]

Restoring wild-type TP53 activity in pancreatic cancer cells (MIA-PaCa-2) enhances their sensitivity to the MDM2 inhibitor nutlin-3a, suggesting a potential therapeutic strategy for targeting TP53 mutations in pancreatic ductal adenocarcinoma (PDAC).

Co-treatment with nutlin-3a and certain chemotherapeutic agents like irinotecan and oxaliplatin showed antagonistic effects, indicating that while nutlin-3a can sensitize cancer cells, it may not always work well in combination with all therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of the MDM-2 inhibitor Nutlin-3a on PDAC cells containing and lacking WT-TP53 on sensitivity to chemotherapy, signal transduction inhibitors and nutraceuticals. Candido, S., Abrams, SL., Steelman, LS., et al.[2020]

In a first-in-human phase I study involving 51 patients with advanced solid tumors, CGM097 was found to be tolerable with no dose-limiting toxicities, although delayed-onset thrombocytopenia was a common side effect.

The disease control rate was 39%, with one patient achieving a partial response and 19 patients maintaining stable disease, indicating limited but notable antitumor activity and providing insights for optimizing dosing regimens for future HDM2 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic-pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies. Bauer, S., Demetri, GD., Halilovic, E., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Gastrointestinal perforation associated with novel antineoplastic agents: A real-world study based on the FDA Adverse Event Reporting System. [2023]

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

Correlations between imatinib plasma trough concentration and adverse reactions in Chinese patients with gastrointestinal stromal tumors. [2022]

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

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data. [2023]

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

Imatinib treatment: specific issues related to safety, fertility, and pregnancy. [2022]

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

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Potent in vitro and in vivo antitumor effects of MDM2 inhibitor nutlin-3 in gastric cancer cells. [2021]

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

Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. [2018]

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

Pre-clinical efficacy and synergistic potential of the MDM2-p53 antagonists, Nutlin-3 and RG7388, as single agents and in combined treatment with cisplatin in ovarian cancer. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Effects of the MDM-2 inhibitor Nutlin-3a on PDAC cells containing and lacking WT-TP53 on sensitivity to chemotherapy, signal transduction inhibitors and nutraceuticals. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetic-pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies. [2023]