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

Study Overview
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Brief Summary
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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

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

Conditions
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Cholangiocarcinoma

Intervention / Treatment
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* Drug: GNS561 + Trametinib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically confirmed CCA with a documented KRAS mutation. Patients greater than or equal to 18 years of age. Patients must have disease progression that is not amenable to potentially curative treatment. Patients must have received at least one line of chemotherapy. Patients must have at least one measurable disease by RECIST v1.1. Performance status (ECOG) 0-1. 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. 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. Patients must be able to understand and be willing to comply with the requirements of the study protocol. Patients participate voluntarily and sign informed consent form(s). Exclusion criteria: Previous treatment with a MEK inhibitor or autophagy inhibitor. Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions: 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. Patients who have retinal condition (retinal tear, exudate, hemorrhage) or history of retinal vein occlusion or central serous retinopathy or retinal pigment epithelial detachment. History of interstitial lung disease or pneumonitis. Patients who have clinically significant pleural effusion or ascites. Patients who have neurological condition (e.g., tremor, ataxia, hypotension, confusion), history of seizures or active central nervous system metastases. 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). 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. 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). Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, or inherited liver disease as well as active viral disease including HBV and HCV. Patients with known allergic reaction to quinoline derivatives (e.g., quinine, chloroquine, mefloquine) and/or hypersensitivity to study drugs. Female patients who are pregnant or lactating at the time of enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GNS561+Trametinib<br>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<br>* GNS561: 50mg, 100mg, 150mg, 200mg and trametinib: 1mg, 1.5mg and 2mg<br>* Other names: Ezurpimtrostat (GNS561);|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GNS561, Cholangiocarcinoma, Trametinib, Phase1b/2a