Abstract CT156: Characterization of PEN-866, a Heat Shock Protein 90 (HSP90) binding conjugate of SN-38, in patient plasma and tumors from the first in human study
Authors: Thomas Anish , Kriksciukaite Kristina , Falchook Gerald , Bendel Johanna , Ulahannan Susanna , Redon Christophe , Mei Laura , Whalen Kerry , Bloss Jeffrey , Bilodeau Mark T. 
Published: September 2020

Abstract
Background: Heat Shock Protein 90 (HSP90) is a molecular chaperone that aids in folding and trafficking of proteins and is upregulated in cells under stress. HSP90 is overexpressed in cancer cells and exists in the activated configuration within the tumor microenvironment. PEN-866 is a novel small molecule drug conjugate containing a HSP90 targeting moiety that accumulates in tumors and releases its payload SN-38 through a cleavable linker within the tumor cells. The first in human phase 1/2a PEN-866 study was designed to assess safety, pharmacokinetics (PK), and exploratory biomarkers of PEN-866 related to its mechanism of action. Here we describe the evaluation of PEN-866 and the payload SN-38 in plasma and tumors. Methods: Patients with advanced solid malignancies were enrolled in dose escalation cohorts and received PEN-866 IV on days 1, 8, and 15 in 28-days cycles, over a dose range of 16-228 mg/m2. Plasma samples were collected up to 8 days after the first dose and up to 24 hours after the third dose. Non-compartmental analysis was performed to obtain PK parameters. Optional tumor biopsies were collected from two patients and analyzed for PEN-866 and SN-38 concentrations. Results: PEN-866 plasma concentration profile was biphasic with a rapid concentration decline after end of infusion resulting in an average half-life (t½) of approximately 10 hours across all dose cohorts. PEN-866 maximum plasma concentrations (Cmax) ranged from 0.69 to 54 µg/mL and area under the concentration curve (AUC) from 0.80 to 88 h·µg/mL. The Cmax and AUC increased higher than dose proportionally at the lower dose levels which resulted in higher clearance (CL) and volume of distribution (Vd) variability. Free SN-38 AUC's were generally low demonstrating linker stability in circulation and low systemic exposure. PEN-866 and SN-38 levels in patient tumors confirmed accumulation and retention of the conjugate up to 6 days after PEN-866 dose and the targeted release of SN-38. Conclusion: PEN-866 has an extended plasma half-life in patients with advanced solid malignancies and showed good stability in circulation with limited plasma exposure of the payload SN-38. Analysis of tumor biopsies up to 6 days after dosing demonstrated significant accumulation and extended exposures of PEN-866 and SN-38 within the tumor tissue that exceed plasma exposures.
Citation Format: Anish Thomas, Kristina Kriksciukaite, Gerald Falchook, Johanna Bendel, Susanna Ulahannan, Christophe Redon, Laura Mei, Kerry Whalen, Jeffrey Bloss, Mark T. Bilodeau. Characterization of PEN-866, a Heat Shock Protein 90 (HSP90) binding conjugate of SN-38, in patient plasma and tumors from the first in human study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT156.