Phase 1b Study to Evaluate Safety, Tolerability, and Maximum Tolerated Dose of PF-05230907 for Intracerebral Hemorrhage

Background and Purpose: This study aimed to determine the maximum tolerated dose and to evaluate the overall safety and tolerability of single doses of PF-05230907 in subjects with acute intracerebral hemorrhage. Methods: Individuals presenting with intracerebral hemorrhage were enrolled in a phase 1, multicenter, open-label clinical trial. A Bayesian modified continual reassessment method design based on treatment-emergent thromboembolic or ischemic events was adopted. Sequential dosing, an external data monitoring committee, and prespecified stopping rules were incorporated as safeguards. Results: Twenty-one subjects received PF-05230907. The mean (+/- SD) age in years and intracerebral hemorrhage volume in mL at baseline were 62 (+/- 9) and 18 (+/- 11), respectively. Two treatment-emergent thromboembolic or ischemic events occurred (deep vein thrombosis and cerebral ischemia), in the 30 mu g/kg dose group. There were no other clear drug-related toxicities at dose levels ranging from 5 to 30 mu g/kg. At the time of study termination, the maximum tolerated dose was estimated to be 24 mu g/kg, with a mean fitted dose-toxicity estimate of 11.9% (95% CI, 1.2%-27.4%). Conclusions: Single doses of PF-05230907 appeared to be tolerated across a range of doses in the intracerebral hemorrhage population, with thrombotic events observed only at the highest dose level tested. Recruitment within the recommended therapeutic window of opportunity remains a challenge. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02687191.

Automated summary

This study identified the maximum tolerated dose of PF-05230907 in subjects with acute intracerebral hemorrhage and evaluated its overall safety and tolerability. Thrombotic events were only observed at the highest dose level tested, with the maximum tolerated dose estimated to be 24 µg/kg.