Clinical Trial 22483

• Overview

  Study Title:

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

  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

  Objective:

  Primary: Phase 1b To determine the maximum tolerated dose (MTD) of the combination of GNS561 with trametinib. Phase 2a To evaluate the efficacy of the combination of GNS561 with trametinib. Secondary: Efficacy Phase 1b To evaluate tumor response. Phase 1b/2a To further evaluate the efficacy of the combination. Safety Phase 1b and 2a To further assess the safety and tolerability of the combination of GNS561 given with trametinib. Pharmacokinetics Phase 1b and Phase 2a Stage 1 To characterize full PK profile of GNS561 and trametinib. Phase 2a Stage 2 To measure selected GNS561 and trametinib PK parameters. Exploratory: To assess PD biomarkers in PBMCs and tumor tissue following exposure to GNS561 in combination with trametinib. To explore KRAS mutation status in circulating free tumor DNA To measure GNS561 and trametinib concentration in tumor tissue. If sufficient data are available, correlations between PD and PK parameters may be examined To assess CYP2D6 polymorphisms and, if sufficient data, to explore the correlation with GNS561 PK, safety, and efficacy results

• Treatments

  Therapies:

  Autophagy Inhibitor; MEK Inhibitor

  Medications:

  Ezurpimtrostat (GNS561) (); GSK1120212 (Trametinib); Trametinib ()

• Inclusion Criteria

  Key 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 ≥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.
  • 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

  Key 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) 3 BP readings over = >2 sessions.
  • 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 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.
  • 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 active viral hepatitis, 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.

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