Preliminary safety and pharmacokinetics of a new lysosomotropic oral agent, GNS561, in a first-in-human study in advanced primary liver cancer patients

Abstract

Background: Lysosome has been described as target of interest for cancer therapy. GNS561 is a new lysosomotropic small molecule which displays meaningful activity against several tumor types, specifically in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Herein, we report preliminary results of the Phase 1b/2a study of GNS561 in advanced primary liver cancer patients. Methods: The Phase 1b portion is a non-randomized, one arm (3 + 3 design) clinical trial with a maximum enrolment of 36 patients. GNS561 was administered orally to histologically confirmed HCC or iCCA adult patients not eligible for curative therapy in 4 week cycles. The objectives are to assess the safety and pharmacokinetics (PK) of GNS561 and to determine the recommended phase 2 dose. Early safety, PD and PK data from patients of the 4 first dose levels are reported. Results: As of May 2019, 13 patients were enrolled with 10 patients having completed the study with at least one cycle of treatment. Median patient age was 66 years (range 31 - 80), 3 (23%) were female, 6 (46%) had HCC; median number of prior systemic therapies was 1 (range 1-5). Patients received a median number of 2 cycles of GNS561. Six (46%) patients interrupted treatment because of tumor progression, 31% (n = 4) for investigator decision, and 7.7% (n = 1) for serious adverse event. Thus far, no dose limiting toxicity (DLT), or DLT equivalent toxicity have been observed. Most of related-AEs are digestive toxicities (grade 1-2 nausea, vomiting and diarrhea), fatigue and blood parameters abnormalities. The 400 mg cohort is currently ongoing. 70% (n = 7) patients were evaluable for tumor imaging assessment: 43% of them (n = 3) were stable at the beginning of Cycle 3, among which 2 patients had stable disease at the beginning of Cycle 5. Patients showed increasing exposure to GNS561 along with the dose in blood and liver, with dose-proportionality in plasma. Liver concentrations are at least 200 fold higher than in plasma. Conclusions: Current data show patients that oral GNS561 displays a favorable safety profile, and exposure in blood and liver throughout the dosing interval. Enrollment in Phase 1b is continuing before extension to Phase 2a. Clinical trial identification: 2017-003585-27. Legal entity responsible for the study: Genoscience Pharma. Funding: Genoscience Pharma. Disclosure: A.H. Awada: Honoraria (institution), Advisory / Consultancy: Genoscience Pharma. J.J. Harding: Honoraria (institution), Advisory / Consultancy: Genoscience Pharma. N. Kotecki: Honoraria (institution): Genoscience Pharma. P.G. Aftimos: Honoraria (institution): Genoscience Pharma. T. Decaens: Honoraria (institution): Genoscience Pharma. C. Dreyer: Honoraria (institution): Genoscience Pharma. C. Ansaldi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genoscience Pharma. M. Rachid: Full / Part-time employment: Genoscience Pharma. C. Serdjebi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genoscience Pharma. P. Halfon: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Genoscience Pharma. G.K. Abou-Alfa: Honoraria (institution), Advisory / Consultancy: Genoscience Pharma. E. Raymond: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Full / Part-time employment: Genoscience Pharma.