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

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

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

Study Overview

• Status: Recruiting
• Conditions: Cholangiocarcinoma
• Intervention / Treatment: Drug: GNS561 + Trametinib

• Study Type: Interventional
• Enrollment (Estimated): 74
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Carol ADDY, M.D.; Phone Number: +01 6179536469; Email: clinicaltrial@genfit.com

Study Locations

• Puerto Rico
  • Rio Piedras, Puerto Rico, 00935
    • Recruiting
    • Pan American Center for Oncology Trials, LLC
    • Contact: Pan American Center for Oncology Trials, LLC
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • USC Norris Comprehensive Cancer Center
      • Contact: USC Norris Comprehensive Cancer Center
  • New York
    • Buffalo, New York, United States, 14263
      • Recruiting
      • Roswell Park Cancer Institute
      • Contact: Roswell Park Cancer Institute
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • University of Texas, MD Anderson Cancer Center
      • Contact: The University of Texas, MD Anderson Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Recruiting
      • University of Virginia Comprehensive Cancer Center
      • Contact: University of Virginia Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: GNS561+Trametinib; 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

Drug: GNS561 + Trametinib; GNS561: 50mg, 100mg, 150mg, 200mg and trametinib: 1mg, 1.5mg and 2mg; Other Names: Ezurpimtrostat (GNS561)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)
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)
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)
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)
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
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)
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)
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)

Collaborators and Investigators

• Sponsor: Genfit
• Investigators: Study Director: Carol ADDY, M.D., Genfit

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2023
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: April 27, 2023
• First Submitted That Met QC Criteria: May 22, 2023
• First Posted (Actual): May 24, 2023

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Trametinib; Cholangiocarcinoma; GNS561; Phase1b/2a
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib
• Other Study ID Numbers: GNS561-222-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No