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

TitleSafety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: a phase 1 dose-escalation trial
Authors
Issue Date2019
Citation
British Journal of Cancer, 2019, v. 121, n. 4, p. 318-324 How to Cite?
AbstractBackground: 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).
Persistent Identifierhttp://hdl.handle.net/10722/292119
ISSN
2023 Impact Factor: 6.4
2023 SCImago Journal Rankings: 3.000
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorVeitch, Zachary W.-
dc.contributor.authorCescon, David W.-
dc.contributor.authorDenny, Trisha-
dc.contributor.authorYonemoto, Lisa Maria-
dc.contributor.authorFletcher, Graham-
dc.contributor.authorBrokx, Richard-
dc.contributor.authorSampson, Peter-
dc.contributor.authorLi, Sze Wan-
dc.contributor.authorPugh, Trevor J.-
dc.contributor.authorBruce, Jeffrey-
dc.contributor.authorBray, Mark R.-
dc.contributor.authorSlamon, Dennis J.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorWainberg, Zev A.-
dc.contributor.authorBedard, Philippe L.-
dc.date.accessioned2020-11-17T14:55:48Z-
dc.date.available2020-11-17T14:55:48Z-
dc.date.issued2019-
dc.identifier.citationBritish Journal of Cancer, 2019, v. 121, n. 4, p. 318-324-
dc.identifier.issn0007-0920-
dc.identifier.urihttp://hdl.handle.net/10722/292119-
dc.description.abstractBackground: 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).-
dc.languageeng-
dc.relation.ispartofBritish Journal of Cancer-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleSafety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: a phase 1 dose-escalation trial-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41416-019-0517-3-
dc.identifier.pmid31303643-
dc.identifier.pmcidPMC6738068-
dc.identifier.scopuseid_2-s2.0-85069052540-
dc.identifier.volume121-
dc.identifier.issue4-
dc.identifier.spage318-
dc.identifier.epage324-
dc.identifier.eissn1532-1827-
dc.identifier.isiWOS:000480675100005-
dc.identifier.issnl0007-0920-

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