A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours.

Authors:
Gabriel Mak
Gabriel Mak
Australia bSarah Cannon Research UK and University College London
United Kingdom
Jean-Charles Soria
Jean-Charles Soria
University Paris Sud
France
Sarah P Blagden
Sarah P Blagden
Imperial College
United Kingdom
Ruth Plummer
Ruth Plummer
Northern Institute for Cancer Research
Ronald A Fleming
Ronald A Fleming
Wake Forest University School of Medicine
Noelia Nebot
Noelia Nebot
University of Sydney
Australia
Jianping Zhang
Jianping Zhang
Nanjing Medical University
China
Jolly Mazumdar
Jolly Mazumdar
University of Pennsylvania School of Medicine
United States

Br J Cancer 2019 May 17;120(10):975-981. Epub 2019 Apr 17.

Sarah Cannon Research Institute, London, UK.

Background: Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy.

Methods: This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed.

Results: Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks).

Conclusions: Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.

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http://dx.doi.org/10.1038/s41416-019-0452-3DOI Listing
May 2019
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