GNS561 + Trametinib for Bile Duct Cancer

Recruiting at 7 trial locations

Overseen By Peter Lichten, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for individuals with advanced bile duct cancer, specifically those with a KRAS gene mutation who haven't responded to standard treatments. The study examines the safety and effectiveness of combining two drugs, GNS561 (ezurpimtrostat) and trametinib (Mekinist), for this condition. Participants should have previously undergone one or two rounds of chemotherapy and have bile duct cancer that has progressed despite treatment. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants early access to potentially beneficial therapies.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that GNS561, also known as Ezurpimtrostat, is under study for its safety and effectiveness in treating liver cancer and other conditions. Currently, specific safety information about GNS561 in humans is limited.

In contrast, the FDA has approved trametinib, and its safety in humans is well-established. Researchers are examining the safety and tolerability of GNS561 when combined with trametinib, aiming to determine the highest dose patients can tolerate without serious side effects.

As this trial is in the early stages, it seeks to understand patient tolerance and identify any potential side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of GNS561 and trametinib for treating bile duct cancer because it targets the disease in a way that current treatments, like chemotherapy and surgery, do not. GNS561 is unique because it inhibits the lysosomal pathway, which is crucial for cancer cell survival, while trametinib targets the MAPK/ERK pathway, a key driver in the growth of cancer cells. This dual-action approach could potentially overcome the resistance seen in standard treatments and offer a more effective option for patients with this challenging cancer.

What evidence suggests that this trial's treatments could be effective for bile duct cancer?

This trial will study the combination of GNS561 and trametinib for patients with bile duct cancer. Research shows that this combination might benefit patients with bile duct cancer, especially those with KRAS mutations. Although the treatment did not achieve its main goal, patients experienced a median progression-free survival of 10.6 weeks, meaning the cancer did not worsen for about two and a half months on average. The study also identified certain biological markers that might help predict who will respond well to the treatment. Researchers are studying GNS561 for its potential in treating liver cancers due to its promising early results. Trametinib is already known to help in some cancers by targeting specific growth signals in cancer cells. ^{1 2 3 4 5}

Who Is on the Research Team?

Peter Lichten, M.D.

Principal Investigator

Genfit

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05874414

NCT05874414 | Combination of GNS561 and Trametinib in ... This is an open-label, multicenter Phase 1b/2a study to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of GNS561 in combination ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05874414?id=GNS561-222-1&rank=1

Study Details | Combination of GNS561 and Trametinib in ... Patients who are taking antineoplastic drugs for concomitant cancer or history of malignancy other than CCA within 5 years prior to screening, with the ...

3. withpower.com withpower.com/trial/phase-2-cholangiocarcinoma-5-2023-94733

GNS561 + Trametinib for Bile Duct Cancer Despite not meeting the primary endpoint, the study found a median progression-free survival of 10.6 weeks and identified potential biomarkers for sensitivity ...

4. moffitt.org moffitt.org/clinical-trials-and-studies/clinical-trial-22483/

Clinical Trial 22483 Phase 2a To evaluate the efficacy of the combination of GNS561 with trametinib. ... Bile Duct Cancer / Cholangiocarcinoma, Bones and Joints, Brain and ...

5. clinicaltrials.eu clinicaltrials.eu/inn/gns561/

GNS561: A Promising Drug for Liver Cancer and COVID- ... GNS561: A Promising Drug for Liver Cancer and COVID-19 Treatment. GNS561, also known as Ezurpimtrostat, is an investigational drug currently being studied ...