384P - Initial first-in-human phase 1 results of PTC596, a novel small molecule that targets cancer stem cells (CSCs) by reducing BMI1 protein levels

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Clinical Research
Basic Scientific Principles
Presenter Geoffrey Shapiro
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors G. Shapiro1, J. Infante2, T.M. Bauer3, A. Prawira4, P. Bedard5, O. Laskin6, M. Weetall7, J. Baird8, E. O'Mara6, R. Spiegel9
  • 1Oncology, Dana Farber Cancer Institute, 02115 - Boston/US
  • 2Other, Sarah Cannon Research Institute, Nashville/US
  • 3Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville/US
  • 4Department Of Medical Oncology And Hematology, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
  • 5Medical Oncology, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
  • 6Clinical, PTC Therapeutics, South Plainfield/US
  • 7Pharmacology, PTC Therapeutics, Inc., South Plainfield/US
  • 8Clinical, PTC Therapeutics, inc., South Plainfield/US
  • 9Clinical, PTC Therapeutics, Inc., South Plainfield/US



PTC596 is a novel, oral investigational drug that reduces the levels of BMI1, a protein that is required for CSC survival. PTC596 reduced the number of CSCs in preclinical models and reduced growth of tumor xenografts in mouse models. The primary objectives of this first in human trial are to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives will include an initial assessment of biological efficacy and pharmacodynamic changes and to evaluate anti-tumor activity.


A phase I multi-center study comprising 2 stages is being conducted in patients with advanced solid tumors. PTC596 is administered in 4 week cycles using body-weight-adjusted twice-per-week (biw) oral capsule dosing. Stage 1 is an escalation using a modified 3 + 3 design. Anti-tumor activity is assessed by RECIST 1.1. Expansion cohorts are being enrolled to obtain pre- and post-treatment tumor biopsies for markers of target engagement. In stage 2, up to 40 patients with a limited number of tumor types will be enrolled at the MTD. Patients who appear to be deriving benefit may stay on PTC596.


To date, 19 patients have been enrolled at doses of 0.65, 1.3, 2.6, 5.2, and 10 mg/kg. No DLTs or drug related grade 2 toxicities were observed in the first 4 cohorts. Grade 1 Nausea and vomiting were seen at these lower doses. Though a protocol defined MTD was not obtained, the dose of 10 mg/kg was deemed intolerable due to Grade 4 neutropenia and thrombocytopenia (n = 1 patient) and intolerable Grade 2 nausea, vomiting, and diarrhea. An intermediate dose of 7 mg/kg is currently being evaluated. Plasma concentrations of PTC596 increased in a dose-proportional manner. Though no objective responses have been observed to date, plasma concentrations at doses ≥2.6 mg/kg biw exceed those demonstrated to be efficacious in mouse xenograft models.


PTC596, a first-in-class oral small molecule that lowers the levels of BMI1, is generally well tolerated as a monotherapy at doses that achieve preclinical target plasma concentrations. Doses

Clinical trial identification

ClinicalTrials.gov, Identifier NCT02404480.

Legal entity responsible for the study

Dana Farber Cancer Institute, Sarah Cannon, & Research Institute Princess Margaret Cancer Centre


PTC Therapeutics


O. Laskin, M. Weetall, J. Baird, R. Spiegel: Financially compensated as an employee of PTC Therapeutics. All other authors have declared no conflicts of interest.