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|Ref Type||Journal Article|
|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|
|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).|
|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|