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

Background
CFI-400945 is a first-in-class oral inhibitor of polo-like kinase 4 (PLK4), a key regulator of centriole duplication. This first-in-human Phase 1 trial aimed primarily to assess the safety and tolerability of CFI-400945 in patients with advanced solid tumors. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, preliminary efficacy, and determination of the recommended Phase 2 dose (RP2D).

Methods
A standard 3+3 dose-escalation design was used to evaluate continuous daily oral dosing of CFI-400945, with dose-limiting toxicities (DLTs) monitored during the initial 28-day treatment cycle. Safety assessments were conducted in accordance with CTCAE v4.0. Objective response rate (ORR) and clinical benefit rate (CBR) were measured using RECIST v1.1 criteria.

Results
A total of 43 patients were enrolled in the dose-escalation phase across dose levels ranging from 3 to 96 mg/day, and an additional 9 patients were treated in a 64 mg/day dose-expansion cohort. DLTs observed at the 96 mg and 72 mg dose levels led to the selection of 64 mg/day as the RP2D. Neutropenia emerged as a common grade ≥3 treatment-related adverse event, particularly at doses ≥64 mg (incidence: 19%). CFI-400945 exhibited a half-life of approximately 9 hours, with peak plasma concentrations (Cmax) reached within 2–4 hours post-dose. Among evaluable patients, one partial response (ongoing for 45 cycles) and two cases of stable disease lasting ≥6 months were observed, resulting in an ORR of 2% and a CBR of 6%.

Conclusions
CFI-400945 demonstrated an acceptable safety profile at the RP2D of 64 mg/day, with dose-dependent neutropenia as the primary toxicity. The drug displayed favorable pharmacokinetic properties with daily oral administration. Although response rates were modest in an unselected patient population, further investigations are underway in biomarker-enriched and combination therapy settings.