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Ref Type Journal Article
PMID (31303643)
Authors Veitch ZW, Cescon DW, Denny T, Yonemoto LM, Fletcher G, Brokx R, Sampson P, Li SW, Pugh TJ, Bruce J, Bray MR, Slamon DJ, Mak TW, Wainberg ZA, Bedard PL
Title Safety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: a phase 1 dose-escalation trial.
Journal British journal of cancer
Vol 121
Issue 4
Date 2019 08
URL
Abstract Text 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).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.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%).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.Clinical Trials Registration Number - NCT01954316 (Oct 1st, 2013).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
CFI-400945 CFI-400945 is a selective Polo-like kinase 4 (PLK4) inhibitor that inhibits cell division and induces apoptosis in tumor cells (PMID: 25043604, PMID: 31303643).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable CFI-400945 Phase I Actionable In a Phase I trial, treatment with CFI-400945 was tolerable and resulted in a clinical benefit rate of 6% (3/49; 1 partial response and 2 stable disease) in patients with advanced solid tumors, with 1 partial response in a patient with adenoid cystic carcinoma, and stable disease in 1 patient with KRAS-mutant microsatellite stable (MSS) colorectal cancer lasting 12 cycles with a 24% reduction in target lesions, and 1 patient with MSS ovarian cancer lasting 8 cycles (PMID: 31303643; NCT01954316) 31303643