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

Zachary W Veitch, David W Cescon, Trisha Denny, Lisa-Maria Yonemoto, Graham Fletcher, Richard Brokx, Peter Sampson, Sze-Wan Li, Trevor J Pugh, Jeffrey Bruce, Mark R Bray, Dennis J Slamon, Tak W Mak, Zev A Wainberg, Philippe L Bedard, Zachary W Veitch, David W Cescon, Trisha Denny, Lisa-Maria Yonemoto, Graham Fletcher, Richard Brokx, Peter Sampson, Sze-Wan Li, Trevor J Pugh, Jeffrey Bruce, Mark R Bray, Dennis J Slamon, Tak W Mak, Zev A Wainberg, Philippe L Bedard

Abstract

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).

Conflict of interest statement

CFI-400945 is a proprietary compound developed at the Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre/University Health Network, with which Z.W.V., D.W.C., S.-W.L., T.D., G.F., R.B., P.S., T.J.P., J.B., M.R.B., T.W.M., and P.L.B. are affiliated. D.W.C. has provided a consulting or advisory role for Pfizer, AstraZeneca, Novartis, GlaxoSmithKline, Merck, Roche/Genentech, Agendia, and Puma Biotechnology. He has also received research funding from Merck, GlaxoSmithKline, and Pfizer. In addition, he has a patent pending for Biomarkers of TTK inhibitors. P.L.B. has received research funding from Bristol-Myers Squibb, Sanofi, AstraZeneca, Genentech/Roche, SERVIER, GlaxoSmithKline, Novartis, SignalChem, PTC Therapeutics, Nektar, Merck, Seattle Genetics, Mersana, Immunomedics, and Eli-Lilly. Z.A.W. has performed consulting services for Merck, Lilly, BMS, Five Prime, and Novartis. D.J.S. currently holds board membership for Biomarin and is compensated for travel and accommodation expenses. He also holds stock in Pfizer and is provided research funding and compensated for travel and accommodations. He also receives honoraria from Novartis in addition to providing consulting/advisory services, receiving research funding, and is compensated for travel and accommodations. He also provides a general consulting and advisory role for Eli Lily Pharmaceuticals. M.R.B. and T.W.M. are shareholders in a company that has an option agreement for CFI-400945. T.W.M. has performed consulting services for Symphogen, CASI, Sanofi, and Agios. He is also a stockholder in Agios. L.-M.Y. declares no competing interests.

Figures

Fig. 1
Fig. 1
Pharmacokinetics of CFI-400945. Plasma concentration of CFI-400945 as a function of time and dose level following dosing on Cycle 1 day 1 (a). Cmax (b) and AUC (c) as a function of dose level following dosing on day 1 are also shown. Shapes represented in black (b/c) indicate patients experiencing grade 3 or 4 neutropenia at various dose levels Cmax concentration maximum. AUC area under the curve
Fig. 2
Fig. 2
Waterfall plot (a) of individual patient target lesion best response, swimmers plot (b) of time on study by tissue type, and select patient oncoprint heatmap (c) by whole-exome sequencing. NSCLC non-small cell lung carcinoma, NET neuroendocrine tumour, SCLC small cell lung carcinoma, EHE epithelioid hemangioepithelioma, ID study identification number. *a (waterfall)—Of the 49 efficacy-evaluable patients, 3 patients had progressive disease (described in the section “Efficacy evaluation”) but no target lesion measurement (not included in waterfall plot)

References

    1. Schoffski P. Polo-like kinase (plk) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009;14:559–570. doi: 10.1634/theoncologist.2009-0010.
    1. Archambault V, Glover DM. Polo-like kinases: conservation and divergence in their functions and regulation. Nat. Rev. Mol. Cell. Biol. 2009;10:265–275. doi: 10.1038/nrm2653.
    1. Lens SMA, Voest EE, Medema RH. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat. Rev. Cancer. 2010;10:825–841. doi: 10.1038/nrc2964.
    1. Bettencourt-Dias M, Glover DM. Centrosome biogenesis and function: centrosomics brings new understanding. Nat. Rev. Mol. Cell. Biol. 2007;8:451–463. doi: 10.1038/nrm2180.
    1. Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics. 2006;7:96. doi: 10.1186/1471-2164-7-96.
    1. Schreiber GJ, He YD, Atsma D, Glas A, van’t Veer LJ, Friend SH, et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 2002;347:1999–2009. doi: 10.1056/NEJMoa021967.
    1. Macmillan JC. Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer. Ann. Surg. Oncol. 2001;8:729–740. doi: 10.1007/s10434-001-0729-6.
    1. He Y, Wang H, Yan M, Yang X, Shen R, Ni X, et al. High LIN28A and PLK4 co‑expression is associated with poor prognosis in epithelial ovarian cancer. Mol. Med. Rep. 2018;18:5327–5336.
    1. Salvatore G, Nappi TC, Salerno P, Jiang Y, Garbi C, Ugolini C, et al. A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma. Cancer Res. 2007;67:10148–10158. doi: 10.1158/0008-5472.CAN-07-1887.
    1. Chng WJ, Braggio E, Mulligan G, Bryant B, Remstein E, Valdez R, et al. The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition. Blood. 2007;111:1603–1609. doi: 10.1182/blood-2007-06-097774.
    1. Mason JM, Lin DC-C, Wei X, Che Y, Yao Y, Kiarash R, et al. Functional characterization of CFI-400945, a polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell. 2014;26:163–176. doi: 10.1016/j.ccr.2014.05.006.
    1. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a cancer dependency map. Cell. 2017;170:564–576.e16. doi: 10.1016/j.cell.2017.06.010.
    1. Hart T, Chandrashekhar M, Aregger M, Steinhart Z, Brown KR, MacLeod G, et al. High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities. Cell. 2015;163:1515–1526. doi: 10.1016/j.cell.2015.11.015.
    1. Marcotte R, Sayad A, Brown KR, Sanchez-Garcia F, Reimand J, Haider M, et al. Functional genomic landscape of human breast cancer drivers, vulnerabilities, and resistance. Cell. 2016;164:293–309. doi: 10.1016/j.cell.2015.11.062.
    1. Lohse I, Mason J, Cao PM, Pintilie M, Bray M, Hedley DW. Activity of the novel polo-like kinase 4 inhibitor CFI-400945 in pancreatic cancer patient-derived xenografts. Oncotarget. 2017;8:3064–3071. doi: 10.18632/oncotarget.13619.
    1. Kawakami M, Mustachio LM, Zheng L, Chen Y, Rodriguez-Canales J, Mino B, et al. Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers. Proc. Natl Acad. Sci. 2018;115:1913–1918. doi: 10.1073/pnas.1719760115.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur. J. Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Cescon, D. W. A multicenter phase Ib/II study of a polo-kinase 4 inhibitor CFI-400945+the PD-L1 inhibitor durvalumab in patients with triple negative breast cancer (TNBC). Canadian Cancer Trials Group (CCTG) IND Website (2019).

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner