Abstract CT066: First-in-human phase I trial of the oral PLK4 inhibitor CFI-400945 in patients with advanced solid tumors
Authors: Bedard Philippe L. , Cescon David W. , Fletcher Graham , Denny Trish , Brokx Richard , Sampson Peter , Bray Mark R. , Slamon Dennis J. , Mak Tak W. , Wainberg Zev A. 
Published: July 2016

Abstract
Background: CFI-400945 is a first-in-class, potent, selective, orally active inhibitor of Polo-like kinase 4 (PLK4) (Ki = 0.26 nM), a conserved master regulator of centriole duplication that is important for maintenance of genomic integrity. In preclinical studies, CFI-400945 demonstrated robust anti-tumor activity, including durable complete tumor regression, in a large number of patient-derived xenograft models from multiple tumor types (breast, ovarian, pancreas, prostate carcinomas; some derived from heavily pre-treated patients). The objectives of this first-in-human phase I trial are to establish safety, tolerability, pharmacokinetics, and recommended phase II dose (RP2D) of CFI-400945.
Methods: Patients with advanced solid tumors age &gt;18 years, with ECOG performance status of 0-1, adequate organ function and RECIST-measurable disease progressing on standard treatments are eligible. Dose escalation follows a standard 3+3 design, with a starting dose of 3mg once daily continuous oral dosing based upon preclinical data and a severely toxic dose to 10 percent (STD10) in rats of 3 mg/kg. The primary endpoint is the incidence of dose limiting toxicities (DLTs) during the first cycle. Safety assessments using CTCAE version 4.03 criteria are performed weekly during the first three cycles and then every two weeks. Response assessments are performed every two cycles.
Results: From April/14 to December/15, 31 patients were enrolled across eight pre-defined dose levels (3, 6, 11, 16, 24, 32, 48 and 72 mg). No DLT events have been observed. Dose escalation at 96mg is currently ongoing. The most frequent treatment-related adverse events (trAEs) include fatigue (24%), diarrhea (17.2%), nausea (17.2%), decreased appetite (13.8%) and vomiting (6.9%). All trAEs were grade 1 or grade 2. Fifteen serious adverse events (SAEs) have occurred in 9 patients, all considered unrelated to CFI-400945 treatment. Preliminary PK results estimate a half-life of about 10 hours, with Cmax and AUC showing dose proportionality. Two patients enrolled at the 48 mg dose level have completed &gt;6 cycles, including a patient with KRAS mutant colorectal cancer who achieved 24% reduction in target lesions and &gt;50% reduction in serum CEA levels.
Conclusions: CFI-400945 is well tolerated at doses up to 72mg with a favorable PK profile. Preliminary evidence of anti-tumor activity has been observed. Exploration of 96mg daily dosing is ongoing and once the RP2D has been established exploration of anti-tumor activity in biomarker-driven expansion arms of CFI-400945 in indications including advanced breast cancer is planned. Updated results of this ongoing trial will be presented at the meeting.
Citation Format: Philippe L. Bedard, David W. Cescon, Graham Fletcher, Trish Denny, Richard Brokx, Peter Sampson, Mark R. Bray, Dennis J. Slamon, Tak W. Mak, Zev A. Wainberg. First-in-human phase I trial of the oral PLK4 inhibitor CFI-400945 in patients with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT066.