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Safety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: a phase

Zachary W Veitch1, David W Cescon1,2, Trisha Denny2

  • 1Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

British Journal of Cancer
|July 16, 2019
PubMed
Abstract

Insights

CFI-400945, a novel polo-like kinase 4 inhibitor, demonstrated acceptable safety and tolerability in a phase 1 trial for advanced solid tumors. The recommended phase 2 dose is 64 mg daily, with neutropenia as a key adverse event.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • CFI-400945 is a first-in-class oral inhibitor targeting polo-like kinase 4 (PLK4), an enzyme crucial for centriole duplication.
  • This study represents the first-in-human phase 1 clinical trial of CFI-400945 in patients with advanced solid tumors.

Purpose of the Study:

  • To determine the safety and tolerability of CFI-400945 in patients with advanced solid tumors.
  • To establish the recommended phase 2 dose (RP2D) and evaluate pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy of CFI-400945.

Main Methods:

  • A 3+3 dose escalation design was employed to evaluate continuous daily oral dosing of CFI-400945.
  • Safety was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0, and efficacy was evaluated by Objective Response Rate (ORR) and Clinical Benefit Rate (CBR) per RECIST v1.1.

Main Results:

  • A total of 43 patients received escalating doses from 3 to 96 mg/day, with 9 patients in the 64 mg dose expansion cohort.
  • The recommended phase 2 dose (RP2D) was established at 64 mg/day after dose-limiting toxicities were observed at higher doses.
  • Neutropenia was the most common high-grade treatment-related adverse event (19%) at doses ≥64 mg. The drug exhibited a half-life of 9 hours.
  • Limited efficacy was observed, with an ORR of 2% and CBR of 6%, including one partial response and two cases of stable disease ≥6 months.

Conclusions:

  • CFI-400945 at 64 mg/day is well-tolerated, with dose-dependent neutropenia as a primary toxicity.
  • Favorable pharmacokinetic profiles were achieved with daily oral administration.
  • Low response rates were observed in this unselected patient population, suggesting the need for biomarker-guided or combination studies.

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