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

• Published in: British journal of cancer Vol. 120; no. 10; pp. 975 - 981
• Main Authors: Mak, Gabriel, Soria, Jean-Charles, Blagden, Sarah P., Plummer, Ruth, Fleming, Ronald A., Nebot, Noelia, Zhang, Jianping, Mazumdar, Jolly, Rogan, Debra, Gazzah, Anas, Rizzuto, Ivana, Greystoke, Alastair, Yan, Li, Tolson, Jerry, Auger, Kurt R., Arkenau, Hendrik-Tobias
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.05.2019; Nature Publishing Group
• Subjects: 692/4028; 692/4028/67/1641; Aged; Aminopyridines - administration & dosage; Aminopyridines - adverse effects; Aminopyridines - pharmacokinetics; Appetite loss; Biomedical and Life Sciences; Biomedicine; Cancer Research; Diarrhea; Dose-Response Relationship, Drug; Drug Resistance; Drug-Related Side Effects and Adverse Reactions - classification; Drug-Related Side Effects and Adverse Reactions - pathology; Enzyme inhibitors; Epidemiology; Female; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors; Focal Adhesion Protein-Tyrosine Kinases - genetics; Humans; Hydroxamic Acids - administration & dosage; Hydroxamic Acids - adverse effects; Hydroxamic Acids - pharmacokinetics; Inhibitor drugs; Kinases; Male; Mesothelioma; Mesothelioma - drug therapy; Mesothelioma - genetics; Mesothelioma - pathology; Middle Aged; Molecular Medicine; Nausea; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Oncology; Pharmacodynamics; Pharmacokinetics; Progression-Free Survival; Protein kinase; Pruritus; Pyridones - administration & dosage; Pyridones - adverse effects; Pyridones - pharmacokinetics; Pyrimidinones - administration & dosage; Pyrimidinones - adverse effects; Pyrimidinones - pharmacokinetics; Solid tumors; Targeted cancer therapy; Tumors
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-019-0452-3

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.