Combining GNS561 and Trametinib for Advanced Cholangiocarcinoma with KRAS Mutation

Phase 1b/2a Study of GNS561 in Combination With Trametinib in Advanced KRAS Mutated Cholangiocarcinoma

This study is testing if a new combination of two drugs, GNS561 and trametinib, can help people with advanced bile duct cancer and a specific gene mutation who haven't had success with standard treatments.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 74 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Genfit (industry)
• Drugs / interventions: chemotherapy, trametinib
• Locations: 11 sites (Los Angeles, California and 10 other locations)
• Trial ID: NCT05874414 on ClinicalTrials.gov

What this trial studies

This open-label, multicenter Phase 1b/2a study aims to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of GNS561 in combination with trametinib in patients with advanced cholangiocarcinoma harboring a KRAS mutation. Participants must have experienced disease progression after standard first-line therapy and have measurable disease. The study will assess how well this combination therapy works in this specific patient population.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with histologically confirmed cholangiocarcinoma and a documented KRAS mutation who have progressed after at least one line of chemotherapy.

Not a fit: Patients with cholangiocarcinoma that does not have a KRAS mutation or those who have not received prior chemotherapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with advanced KRAS mutated cholangiocarcinoma who have limited treatment options.

How similar studies have performed: While this approach is novel in the context of cholangiocarcinoma, similar combinations targeting KRAS mutations have shown promise in other cancer types.

Eligibility criteria

Inclusion criteria:

1. Histologically confirmed intrahepatic CCA with a documented KRAS mutation.
2. Patients greater than or equal to 18 years of age.
3. Patients must have disease progression that is not amenable to potentially curative treatment.
4. Patients must have received one or two lines of chemotherapy.
5. Patients must have at least one measurable disease by RECIST v1.1.
6. Performance status (ECOG) 0-1.
7. Adequate organ baseline function defined as follows: absolute neutrophil count ≥1000 cells/μL, platelet count ≥75,000 cells/μL, hemoglobin ≥9 g/dL, aspartate aminotransferase or alanine aminotransferase less than or equal to 3 × upper limit of normal, estimated glomerular filtration rate ≥60 mL/min, corrected QT interval by Fridericia's (QTcF) interval ≤470 msec.
8. Women of childbearing potential must present with a negative serum pregnancy test and agree to use adequate contraception during the study and until 6 months after the end of treatment. Male patients with women partners of childbearing potential must agree with the contraception procedures of the study protocol.
9. Patients must be able to understand and be willing to comply with the requirements of the study protocol.
10. Patients participate voluntarily and sign informed consent form(s).

Exclusion criteria:

1. Previous treatment with a MEK inhibitor or autophagy inhibitor.
2. Previous treatment with three or more lines of prior chemotherapy.
3. Extrahepatic CCA with
4. Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:

   1. Cardiovascular disorders: congestive heart failure New York Heart Association ≥ class 2 or left ventricular ejection fraction (LVEF) \<50%, arrythmias or cardiac conduction abnormalities. Uncontrolled arterial hypertension or inadequately controlled arterial hypertension, at the discretion of the investigator, based on an average of = \>3 BP readings over = \>2 sessions.
   2. Patients who have retinal condition (retinal tear, exudate, hemorrhage) or history of retinal vein occlusion or central serous retinopathy or retinal pigment epithelial detachment.
   3. History of interstitial lung disease or pneumonitis.
   4. Patients who have clinically significant pleural effusion or ascites.
   5. Patients who have neurological condition (e.g., tremor, ataxia, hypotension, confusion), history of seizures or active central nervous system metastases.
   6. Impairment of gastrointestinal function or gastrointestinal disease (e.g., diarrhea, active ulcer disease, history of gastrointestinal perforation/hemorrhage, malabsorption or other conditions that under the judgment of the principal investigator (PI) may impair absorption of study drugs).
   7. Patients who are taking antineoplastic drugs for concomitant cancer or history of malignancy other than CCA within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate \> 90%) such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
   8. Any other condition that would, in the Investigator s judgment, contraindicate the patients' participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection, unable to swallow medication, social/psychological issues, etc).
5. Known active viral hepatitis, including HBV and HCV.
6. Patients with known allergic reaction to quinoline derivatives (e.g., quinine, chloroquine, mefloquine) and/or hypersensitivity to study drugs.
7. Patients who have not recovered for certain AEs due to previous lines of therpay.
8. Female patients who are pregnant or lactating at the time of enrollment.

Where this trial is running

Los Angeles, California and 10 other locations

• USC Norris Comprehensive Cancer Center — Los Angeles, California, United States (RECRUITING)
• LA Cancer Network — Los Angeles, California, United States (RECRUITING)
• Orlando Health — Orlando, Florida, United States (RECRUITING)
• Moffitt Cancer Center — Tampa, Florida, United States (RECRUITING)
• University Of Chicago Medical Center — Chicago, Illinois, United States (RECRUITING)
• Roswell Park Cancer Institute — Buffalo, New York, United States (TERMINATED)
• Hospital of the University of Pennsylvania — Philadelphia, Pennsylvania, United States (TERMINATED)
• University of Texas, MD Anderson Cancer Center — Houston, Texas, United States (RECRUITING)
• University of Virginia Comprehensive Cancer Center — Charlottesville, Virginia, United States (RECRUITING)
• Froedtert Hospital and the Medical College of Wisconsin — Milwaukee, Wisconsin, United States (RECRUITING)
• Pan American Center for Oncology Trials, LLC — Rio Piedras, Puerto Rico, Puerto Rico (RECRUITING)

Study contacts

• Study coordinator: Pejvack MOTLAGH, CMO

Conditions: Cholangiocarcinoma, GNS561, Trametinib, Phase1b/2a, Bile Duct cancer