Safety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: a phase 1 dose-escalation trial

Br J Cancer. 2019 Aug;121(4):318-324. doi: 10.1038/s41416-019-0517-3. Epub 2019 Jul 15.


Background: CFI-400945 is a first-in-class oral inhibitor of polo-like kinase 4 (PLK4) that regulates centriole duplication. Primary objectives of this first-in-human phase 1 trial were to establish the safety and tolerability of CFI-400945 in patients with advanced solid tumours. Secondary objectives included pharmacokinetics, pharmacodynamics, efficacy, and recommended phase 2 dose (RP2D).

Methods: Continuous daily oral dosing of CFI-400945 was evaluated using a 3+3 design guided by incidence of dose-limiting toxicities (DLTs) in the first 28-day cycle. Safety was assessed by CTCAE v4.0. ORR and CBR were evaluated using RECIST v1.1.

Results: Forty-three patients were treated in dose escalation from 3 to 96 mg/day, and 9 were treated in 64 mg dose expansion. After DLT occurred at 96 and 72 mg, 64 mg was established as the RP2D. Neutropenia was a common high-grade (19%) treatment-related adverse event at ≥ 64 mg. Half-life of CFI-400945 was 9 h, with Cmax achieved 2-4 h following dosing. One PR (45 cycles, ongoing) and two SD ≥ 6 months were observed (ORR = 2%; CBR = 6%).

Conclusions: CFI-400945 is well tolerated at 64 mg with dose-dependent neutropenia. Favourable pharmacokinetic profiles were achieved with daily dosing. Response rates were low without biomarker pre-selection. Disease-specific and combination studies are ongoing.

Trial registration: Clinical Trials Registration Number - NCT01954316 (Oct 1st, 2013).

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / adverse effects*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Indazoles / adverse effects*
  • Indazoles / pharmacokinetics
  • Indoles / adverse effects*
  • Indoles / pharmacokinetics
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neutropenia / chemically induced
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*


  • 2-(3-(4-((2,6-dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5'-methoxyspiro(cyclopropane-1,3'-indolin)-2'-one
  • Antineoplastic Agents
  • Indazoles
  • Indoles
  • PLK4 protein, human
  • Protein Serine-Threonine Kinases

Associated data