GNS561 + Trametinib for Bile Duct Cancer

Recruiting at 7 trial locations

Overseen By Carol ADDY, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Genfit

Must not be taking: MEK inhibitors, Autophagy inhibitors

Disqualifiers: Cardiovascular disorders, Retinal conditions, Lung disease, others

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

Compensation: Varies

Number of Visits: Unknown

74 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label, multicenter Phase 1b/2a study to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of GNS561 in combination with trametinib in Advanced KRAS Mutated Cholangiocarcinoma after failure of standard-of-care first line therapy

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, you cannot participate if you are taking antineoplastic drugs for another cancer or have taken a MEK inhibitor or autophagy inhibitor before.

What data supports the effectiveness of the drug combination GNS561 and Trametinib for bile duct cancer?

Research shows that Trametinib, a part of the treatment, has been studied in bile duct cancer and other cancers, showing some ability to slow disease progression, especially in cases with specific genetic mutations. Additionally, combining MEK inhibitors like Trametinib with other treatments has shown potential in enhancing treatment responses in similar cancers. ^{1 2 3 4 5}

Is the combination of GNS561 and Trametinib safe for humans?

Trametinib, also known as Mekinist, has been studied in patients with biliary tract cancers and other solid tumors, showing a safety profile consistent with known side effects, without new safety concerns. No specific safety data for GNS561 (ezurpimtrostat) in humans is provided in the available research. ^{2 3 5 6 7}

What makes the drug combination of GNS561 and Trametinib unique for bile duct cancer?

The combination of GNS561 and Trametinib is unique for bile duct cancer because it targets the MAPK pathway, which is often abnormally activated in these cancers. Trametinib is a selective inhibitor of MEK1/MEK2, part of the MAPK pathway, and this approach is novel as there are no established second-line treatments for bile duct cancer after gemcitabine-based therapy. ^{1 2 5 8 9}

Research Team

Carol ADDY, M.D.

Principal Investigator

Genfit

Eligibility Criteria

This trial is for adults over 18 with advanced bile duct cancer (cholangiocarcinoma) that has a KRAS mutation and has worsened despite chemotherapy. Participants must have at least one measurable disease, be in good physical condition (ECOG 0-1), and have normal organ function. Women of childbearing age must test negative for pregnancy and use birth control; men must agree to contraception methods.

Inclusion Criteria

I am fully active or can carry out light work.

My bile duct cancer has a KRAS mutation.

My condition cannot be cured with current treatments.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Dose Finding

Patients will receive GNS561 and trametinib in a dose escalation/de-escalation design to determine the maximum tolerated dose (MTD) of the combination.

3 weeks per cycle

Phase 2a Treatment

Patients will receive GNS561 and trametinib at the recommended dose of the combination determined during Phase 1b.

Up to 11 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 11 months

Treatment Details

Interventions

• GNS561
• Trametinib

Trial Overview The study tests the combination of two drugs, GNS561 and Trametinib, on patients with cholangiocarcinoma who've had no success with first-line therapy. It's an early-phase trial assessing safety, how the body processes the drugs, their effects on the body, and their effectiveness against this type of cancer.

Participant Groups

Group I: GNS561+Trametinib Experimental Treatment 1 Intervention

Phase 1b Dose Finding Patients will receive GNS561 (50mg QD; 100mg QD; 150mg; 200mg QD) and trametinib (2mg QD; 1.5mg QD; 1mg QD) in a dose escalation/de-escalation design to determine the maximum tolerated dose (MTD) of the combination. Experimental: Phase 2a Patients will receive GNS561 and trametinib at the recommended dose of the combination determined during Phase 1b

GNS561 is already approved in United States for the following indications:

Approved in United States as ezurpimtrostat for:

• Cholangiocarcinoma (Orphan Drug Designation)

Who Is Running the Clinical Trial?

Genfit

Lead Sponsor

Trials

20

Recruited

3,500+

Findings from Research

In a phase II study involving 77 patients with unresectable biliary tract cancers, the combination of atezolizumab (anti-PD-L1) and cobimetinib (MEK inhibitor) significantly improved progression-free survival (PFS) to a median of 3.65 months compared to 1.87 months for atezolizumab alone.

Despite the improved PFS, the overall response rates were low in both treatment groups, indicating that biliary tract cancers may be resistant to immune therapies, and combination therapy was associated with increased side effects such as rash and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. Yarchoan, M., Cope, L., Ruggieri, AN., et al.[2023]

In a phase IIa study involving 20 Japanese patients with advanced biliary tract cancers who were resistant to gemcitabine-based therapy, trametinib showed a 12-week non-progression rate of only 10%, which was below the target threshold of 25%.

Despite not meeting the primary endpoint, the study found a median progression-free survival of 10.6 weeks and identified potential biomarkers for sensitivity to trametinib, suggesting that further research into genetic mutations could help improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine. Ikeda, M., Ioka, T., Fukutomi, A., et al.[2022]

In a study involving 43 patients with BRAFV600E-mutated biliary tract cancer, the combination of dabrafenib and trametinib showed promising efficacy, with an overall response rate of 51% as assessed by investigators.

The treatment was generally well-tolerated, with manageable side effects; the most common serious adverse event was pyrexia, and no treatment-related deaths occurred, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Subbiah, V., Lassen, U., Élez, E., et al.[2021]

In a trial involving 25 patients with advanced cholangiocarcinoma, the combination of pazopanib and trametinib showed a median progression-free survival (PFS) of 3.6 months, indicating some clinical activity despite not reaching statistical significance compared to the expected PFS.

The treatment was associated with a 75% disease control rate, but also resulted in significant adverse events in over half of the participants, highlighting the need for careful monitoring of side effects like thrombocytopenia and hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma. Shroff, RT., Yarchoan, M., O'Connor, A., et al.[2022]

Trametinib, a MEK1/2 inhibitor, showed significant anti-tumor effects in K-RAS mutated biliary tract carcinoma (BTC) models, effectively slowing tumor growth and reducing cell proliferation, while Panitumumab, an anti-EGFR therapy, had limited effects on its own.

The combination of Trametinib and Panitumumab enhanced the efficacy of treatment in K-RAS wild type BTC models, suggesting a potential strategy for overcoming resistance to anti-EGFR therapies in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical activity of EGFR and MEK1/2 inhibitors in the treatment of biliary tract carcinoma. Cavalloni, G., Peraldo-Neia, C., Varamo, C., et al.[2018]

The pediatric oral solution of trametinib showed improved bioavailability compared to the tablet formulation, with significant increases in key pharmacokinetic measures such as Cmax and AUC, indicating it may be more effective in delivering the drug to patients.

The safety profile of the trametinib pediatric oral solution was consistent with existing data, with no serious adverse events leading to withdrawal from the study, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. Cox, DS., Allred, A., Zhou, Y., et al.[2018]

In a study of pancreatic ductal adenocarcinoma (PDAC) cell lines, gefitinib showed biphasic inhibition, effectively reducing cell growth at low concentrations, while cetuximab exhibited a single-phase inhibition in some cells, indicating different mechanisms of action for these EGFR inhibitors.

The combination of EGFR inhibitors (gefitinib or cetuximab) with trametinib, a MEK1/2 inhibitor, resulted in an additive effect in all EGFR-sensitive PDAC cell lines, suggesting a promising new treatment strategy for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mesothelin and TGF-α predict pancreatic cancer cell sensitivity to EGFR inhibitors and effective combination treatment with trametinib. Poteet, E., Liu, D., Liang, Z., et al.[2022]

The recommended dose (RD) for the combination chemotherapy of gemcitabine, cisplatin, and S-1 in patients with advanced biliary tract cancer was established as gemcitabine 1000 mg/m², cisplatin 25 mg/m², and S-1 80 mg/m², administered every 4 weeks.

In a study involving 12 patients, dose-limiting toxicities (DLTs) were observed, but the maximum-tolerated dose (MTD) was not reached, indicating that the treatment regimen is potentially safe for further evaluation in a phase II study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of combination chemotherapy with gemcitabine, cisplatin, and S-1 in patients with advanced biliary tract cancer. Watanabe, A., Kida, M., Miyazawa, S., et al.[2022]

In a phase I study involving 12 patients with unresectable advanced biliary tract cancer, the combination of gemcitabine, cisplatin, and oral S-1 was found to be safe, with no dose-limiting toxicities reported.

The recommended doses of S-1 were established at 80, 100, and 120 mg per day based on patient body surface area, and one patient even achieved conversion to curative surgery, indicating potential efficacy of the treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of S-1 every other day in combination with gemcitabine/cisplatin for inoperable biliary tract cancer. Uwagawa, T., Sakamoto, T., Abe, K., et al.[2022]

References

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

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. [2021]

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

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma. [2022]

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

Preclinical activity of EGFR and MEK1/2 inhibitors in the treatment of biliary tract carcinoma. [2018]

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

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. [2018]

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

Mesothelin and TGF-α predict pancreatic cancer cell sensitivity to EGFR inhibitors and effective combination treatment with trametinib. [2022]

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

Phase I trial of combination chemotherapy with gemcitabine, cisplatin, and S-1 in patients with advanced biliary tract cancer. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Phase I trial of S-1 every other day in combination with gemcitabine/cisplatin for inoperable biliary tract cancer. [2022]