Safety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: a phase 1 dose-escalation trial
| Autor: | David Cescon, Jeffrey Bruce, Lisa-Maria Yonemoto, Philippe L. Bedard, Trisha Denny, Dennis J. Slamon, Mark R. Bray, Tak W. Mak, Zev A. Wainberg, Sze-Wan Li, Graham C. Fletcher, Peter Brent Sampson, Zachary William Neil Veitch, Trevor J. Pugh, Richard Brokx |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Oncology
Adult Male Cancer Research medicine.medical_specialty Indazoles Indoles Neutropenia Clinical Trials and Supportive Activities Oncology and Carcinogenesis Cmax Drug development Antineoplastic Agents Protein Serine-Threonine Kinases Article Dose-Response Relationship 03 medical and health sciences 0302 clinical medicine Targeted therapies Pharmacokinetics Clinical Research Internal medicine Neoplasms medicine Humans Dosing Oncology & Carcinogenesis Adverse effect Aged Dose-Response Relationship Drug business.industry Evaluation of treatments and therapeutic interventions Middle Aged medicine.disease Clinical trial Tolerability 030220 oncology & carcinogenesis Pharmacodynamics 6.1 Pharmaceuticals Public Health and Health Services Female Drug business |
| Zdroj: | British Journal of Cancer British journal of cancer, vol 121, iss 4 |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | 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) |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink