Combination of GNS561 and Trametinib in Patients With Advanced KRAS Mutation Cholangiocarcinoma

Cholangiocarcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05874414
• Other study ID #: GNS561-222-1
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 21, 2023
• Est. completion date: October 2026

Study information

• Verified date: March 2024
• Source: Genfit
• Contact: Carol ADDY, M.D.
• Phone: +333 20 16 40 00
• Email: clinicaltrial[@]genfit.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 74
• Est. completion date: October 2026
• Est. primary completion date: May 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

1. Histologically confirmed 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 at least one line 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 =1500 cells/µL, platelet count =100,000 cells/µL, hemoglobin =9 g/dL, aspartate aminotransferase or alanine aminotransferase less than or equal to 5 × 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. 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, history of coronary disease (including myocardial infarction, unstable angina), history of angioplasty or stenting within 6 months prior to enrollment.

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 another malignancy with the exception of patients who have been disease-free for at least 3 years.

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).

3. Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, or inherited liver disease as well as active viral disease including HBV and HCV.

4. Patients with known allergic reaction to quinoline derivatives (e.g., quinine, chloroquine, mefloquine) and/or hypersensitivity to study drugs.

5. Female patients who are pregnant or lactating at the time of enrollment.

Related Conditions & MeSH terms

• Cholangiocarcinoma

Intervention

Drug:
• GNS561 + Trametinib
GNS561: 50mg, 100mg, 150mg, 200mg and trametinib: 1mg, 1.5mg and 2mg

Locations

Country	Name	City	State
Puerto Rico	Pan American Center for Oncology Trials, LLC	Rio Piedras
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Virginia Comprehensive Cancer Center	Charlottesville	Virginia
United States	University Of Chicago Medical Center	Chicago	Illinois
United States	University of Texas, MD Anderson Cancer Center	Houston	Texas
United States	USC Norris Comprehensive Cancer Center	Los Angeles	California
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Genfit

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of dose limiting toxicity (DLT) of GNS561 with trametinib (Phase 1b)	Defined as at least possibly related adverse event and treatment-related adverse event (TRAE) of = Grade 3 using National Cancer Institute Toxicity Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0)	At the end of Cycle 1 (each Cycle is 21 days)
Primary	Objective response rate (ORR) of the combination of GNS561 with trametinib (Phase 2a)	Defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)	Up to 11 months (estimated)
Secondary	Duration of response (DoR)	Defined as the duration between first documentation of CR or PR to first documentation of disease progression or death using RECIST v1.1	Up to 11 months (estimated)
Secondary	Progression-free survival (PFS)	Defined as the time from the date of first dose of study drug to the date of first documented disease progression or death	Up to 11 months (estimated)
Secondary	Time To Progression (TTP)	Defined as the time from first dose of study drug to the date of first documented disease progression.	Up to 11 months (estimated)
Secondary	Disease Control Rate (DCR)	defined as the proportion of patients with a best overall response of CR or PR or stable disease (SD) using RECIST v1.1	Up to 11 months (estimated)
Secondary	Time To Response (TTR)	Defined as the time from first dose of study drug to first documentation of CR or PR using RECIST v1.1	Up to 11 months (estimated)
Secondary	Overall Survival (OS) time	Defined as the time from the date of first dose of study drug to the date of death due to any cause.	Up to approximately 42 months
Secondary	Incidence and severity of treatment emergent adverse event (TEAEs), incidence of serious adverse events (SAEs), incidence of TRAEs, incidence of adverse events of special interest (AESIs), rate of treatment discontinuation or interruption for TRAEs	graded according to NCI CTCAE v5.0	Up to 11 months (estimated)
Secondary	Incidence of clinically significant changes or abnormalities from physical examinations, ophthalmologic assessments, vital signs, performance scores, laboratory results, ECGs, echocardiograms or multigated acquisition scans		Up to 11 months (estimated)
Secondary	Drug concentration in plasma for GNS561 and trametinib		Predose to Day 21 of Cycle 1 and predose to Day 21 of Cycle 2 (each Cycle is 21 days)