A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors

Toshio Shimizu, Kazuya Fukuoka, Masayuki Takeda, Tutomu Iwasa, Takeshi Yoshida, Joanna Horobin, Mitchell Keegan, Lou Vaickus, Ajit Chavan, Mahesh Padval, Kazuhiko Nakagawa, Toshio Shimizu, Kazuya Fukuoka, Masayuki Takeda, Tutomu Iwasa, Takeshi Yoshida, Joanna Horobin, Mitchell Keegan, Lou Vaickus, Ajit Chavan, Mahesh Padval, Kazuhiko Nakagawa

Abstract

Purpose: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting.

Methods: VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response.

Results: Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer).

Conclusions: VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

Trial registration: ClinicalTrials.gov NCT01951690.

Keywords: Defactinib; First-in-Asian phase 1 study; Focal adhesion kinase; Proline-rich tyrosine kinase-2; VS-6063.

Figures

Fig. 1
Fig. 1
Steady-state serum VS-6063 concentration–time profiles over the 12-h dose interval (VS-6063 doses 200–600 mg twice daily). PK analysis of previous first-in-human phase 1 study revealed that VS-6063 dose of 163 mg twice daily (per 70-kg person) is projected to achieve a steady-state average plasma concentration equivalent to the predicted efficacious free (non-protein-bound) plasma concentration of 13.3 ng/mL required to produce 50 % inhibition of tumor pFAK activity in humans

References

    1. Siesser PM, Hanks SK. The signaling and biological implications of FAK overexpression in cancer. Clin Cancer Res. 2006;12(11 Pt 1):3233–3237. doi: 10.1158/1078-0432.CCR-06-0456.
    1. Schwock J, Dhani N, Hedley DW. Targeting focal adhesion kinase signaling in tumor growth and metastasis. Expert Opin Ther Targets. 2010;14:77–94. doi: 10.1517/14728220903460340.
    1. Schultze A, Fiedler W. Therapeutic potential and limitations of new FAK inhibitors in the treatment of cancer. Expert Opin Investig Drugs. 2010;19:777–788. doi: 10.1517/13543784.2010.489548.
    1. Schlaepfer DD, Mitra SK, Ilic D. Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochim Biophys Acta. 2004;1692:77–102. doi: 10.1016/j.bbamcr.2004.04.008.
    1. Hao H, Naomoto Y, Bao X, et al. Focal adhesion kinase as potential target for cancer therapy (Review) Oncol Rep. 2009;22:973–979. doi: 10.3892/or_00000573.
    1. Tilghman RW, Parsons JT. Focal adhesion kinase as a regulator of cell tension in the progression of cancer. Semin Cancer Biol. 2008;18:45–52. doi: 10.1016/j.semcancer.2007.08.002.
    1. Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells—perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res. 2006;66(19):9339–9344. doi: 10.1158/0008-5472.CAN-06-3126.
    1. Shibue T, Brooks MW, Fatih Inan M, et al. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discov. 2012;2(8):706–721. doi: 10.1158/-11-0239.
    1. Jones SF, Siu LL, Shapiro GI, et al. A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2015;33(5):1100–1107. doi: 10.1007/s10637-015-0282-y.
    1. Infante JR, Camidge DR, Mileshkin LR, et al. Safety, pharmacokinetic, and pharmacodynamic phase I dose-escalation trial of PF-00562271, an inhibitor of focal adhesion kinase, in advanced solid tumors. J Clin Oncol. 2012;30:1527–1533. doi: 10.1200/JCO.2011.38.9346.
    1. Zer A, Verheijen RB, De Vos F et al (2015) A phase I study of BI 853520, a potent and selective inhibitor of focal adhesion kinase (FAK), in patients with advanced or metastatic solid tumors. J Clin Oncol 33 (suppl; abstr 2541)
    1. Doi T, Lin CC, Ohtsu A et al (2014) A phase I dose-finding study of BI 853520, a potent and selective inhibitor of focal adhesion kinase (FAK), in Japanese and Taiwanese patients with advanced or metastatic solid tumors. Eur J Cancer 50 (suppl 6; abstr 213)
    1. Jemnitz K, Lengyel G, Vereczkey L. In vitro induction of bilirubin conjugation in primary rat hepatocyte culture. Biochem Biophys Res Commun. 2002;291:29–33. doi: 10.1006/bbrc.2002.6400.
    1. Zucker SD, Qin X, Rouster SD, et al. Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl Acad Sci USA. 2001;98:12671–12676. doi: 10.1073/pnas.231140698.
    1. Soria JC, Gan HK, Arkenau HT et al (2012) Phase I clinical and pharmacologic study of the focal adhesion kinase (FAK) inhibitor GSK2256098 in pts with advanced solid tumors. J Clin Oncol 30 (Suppl) Abst. 3000
    1. Konstantinidou G, Ramadori G, Torti F, et al. RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. Cancer Discov. 2013;3:444–457. doi: 10.1158/-12-0388.
    1. Serrels A, Lund T, Serrels B, et al. Nuclear FAK controls chemokine transcription, tregs, and evasion of anti-tumor immunity. Cell. 2015;163:160–173. doi: 10.1016/j.cell.2015.09.001.
    1. Poulikakos PI, Xiao GH, Gallagher R, et al. Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Oncogene. 2006;25:5960–5968. doi: 10.1038/sj.onc.1209587.
    1. Thurneysen C, Opitz I, Kurtz S, et al. Functional inactivation of NF2/merlin in human mesothelioma. Lung Cancer. 2009;64:140–147. doi: 10.1016/j.lungcan.2008.08.014.
    1. Shapiro IM, Kolev VN, Vidal CM, et al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Transl Med. 2014;6:237–268.
    1. Soria JC, Plummer R, Ranson M, et al. Loss of the tumor suppressor Merlin as a potential predictive biomarker of clinical activity for the oral, focal adhesion kinase (FAK) inhibitor GSK2256098 in pts with recurrent mesothelioma. Eur J Cancer. 2012;48(Suppl 6):188. doi: 10.1016/S0959-8049(12)72407-3.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi