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

Abstract

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 μg/kg dose group. There were no other clear drug-related toxicities at dose levels ranging from 5 to 30 μg/kg. At the time of study termination, the maximum tolerated dose was estimated to be 24 μg/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.

• Authors: Yolanda Silva Blas, Michael N Diringer, Benjamin Lo, Jaime Masjuan, Natalia Pérez de la Ossa, Matthew Cardinal, Florence Yong, Tong Zhu, Gang Li, Steven Arkin
• Journal: Stroke (Stroke) Vol. 52 Issue 1 Pg. 294-298 (01 2021) ISSN: 1524-4628 [Electronic] United States
• PMID: 33272131 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Hemostatics
• Recombinant Proteins
• Factor X
• PF-05230907

Topics

• Aged
• Bayes Theorem
• Cerebral Hemorrhage (diagnostic imaging, drug therapy, mortality)
• Factor X (administration & dosage, adverse effects)
• Female
• Hemostatics (therapeutic use, toxicity)
• Humans
• Ischemic Stroke (drug therapy)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Recombinant Proteins (administration & dosage, adverse effects)
• Thromboembolism (drug therapy)
• Treatment Outcome