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
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.