Clinical trial NCT05874414: Combination of GNS561 and Trametinib in Patients With Advanced KRAS Mutated Cholangiocarcinoma
Official title: Phase 1b/2a Study of GNS561 in Combination With Trametinib in Advanced KRAS Mutated Cholangiocarcinoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Cholangiocarcinoma
Keywords: GNS561
Cholangiocarcinoma
Trametinib
Phase1b/2a
Lead sponsor: Genfit
Sponsor class: INDUSTRY
First posted: 2023-05-24
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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


Eligibility criteria: 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 ≥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. 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).
3. Known active viral hepatitis, 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.

Primary outcomes:
measure: Incidence of dose limiting toxicity (DLT) of GNS561 with trametinib (Phase 1b)
timeFrame: At the end of Cycle 1 (each Cycle is 21 days)
measure: Objective response rate (ORR) of the combination of GNS561 with trametinib (Phase 2a)
timeFrame: Up to 11 months (estimated)
Secondary outcomes:
measure: Duration of response (DoR)
timeFrame: Up to 11 months (estimated)
measure: Progression-free survival (PFS)
timeFrame: Up to 11 months (estimated)
measure: Time To Progression (TTP)
timeFrame: Up to 11 months (estimated)
measure: Disease Control Rate (DCR)
timeFrame: Up to 11 months (estimated)
measure: Time To Response (TTR)
timeFrame: Up to 11 months (estimated)
measure: Overall Survival (OS) time
timeFrame: Up to approximately 42 months
measure: 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
timeFrame: Up to 11 months (estimated)
measure: Incidence of clinically significant changes or abnormalities from physical examinations, ophthalmologic assessments, vital signs, performance scores, laboratory results, ECGs, echocardiograms or multigated acquisition scans
timeFrame: Up to 11 months (estimated)
measure: Drug concentration in plasma for GNS561 and trametinib
timeFrame: Predose to Day 21 of Cycle 1 and predose to Day 21 of Cycle 2 (each Cycle is 21 days)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: LA Cancer Network
state: California
city: Chicago
country: United States
facility: University Of Chicago Medical Center
state: Illinois
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas, MD Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Comprehensive Cancer Center
state: Virginia
city: Milwaukee
country: United States
facility: Froedtert Hospital and the Medical College of Wisconsin
state: Wisconsin
city: Rio Piedras
country: Puerto Rico
facility: Pan American Center for Oncology Trials, LLC
Study officials:
affiliation: Genfit
name: Carol ADDY, M.D.
role: STUDY_DIRECTOR
References: