A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors

Our plain-English summary of A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors, by J.C. Soria, H.K. Gan, S.P. Blagden, et al (Annals of Oncology, 2016).

The study

• Authors: J.C. Soria, H.K. Gan, S.P. Blagden, R. Plummer, H.T. Arkenau, M. Ranson, T.R. Evans, G. Zalcman, R. Bahleda, A. Hollebecque, C. Lemech, E. Dean, J. Brown, D. Gibson, V. Peddareddigari, S. Murray, N. Nebot, J. Mazumdar, L. Swartz, K.R. Auger, R.A. Fleming, R. Singh, M. Millward
• Journal: Annals of Oncology
• Published: 2016;27(12):2268-2274
• Cited by: 131 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients.

Patients And Methods: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined.

Results: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6).

Conclusions: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.

© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

In plain English

This phase I trial tested GSK2256098, which blocks focal adhesion kinase (FAK). Sixty-two patients with advanced solid tumors unresponsive to standard therapy took it orally twice daily at 80 to 1500 mg. Mesothelioma was the commonest tumor (29 patients). The maximum tolerated dose was 1000 mg twice daily. Most adverse events, counted regardless of cause, were grade 1 to 2. The most frequent were nausea (76%), diarrhea (65%), vomiting (58%) and decreased appetite (47%). Paired tumor biopsies from six patients showed phosphorylated FAK, relative to total FAK, fell 80% or more in five. Stable disease was the best response in 28 patients (45%). In malignant pleural mesothelioma, median progression-free survival was 12 weeks (95% CI 9.1 to 23.4). By merlin status it was 23.4 weeks (95% CI 6.0 to 28.1) for merlin-negative (14 patients), 11.4 weeks (4.3 to 22.6) for merlin-positive (9) and 10.9 weeks (9.1 to not determined) for unknown (6). The authors concluded the drug had clinical activity in mesothelioma, particularly with merlin loss. They could not determine whether merlin status is prognostic or predictive.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Three-part phase I clinical trial of an oral drug (dose escalation, safety expansion, pharmacodynamics)
• Who was studied: 62 adult patients with histologically confirmed advanced solid tumors that had not responded to standard therapy, including 29 with mesothelioma. Study centers were in France, the UK and Australia. The article does not give study dates.
• Exposure: The FAK inhibitor GSK2256098, taken orally twice daily at doses from 80 to 1500 mg. The study did not examine asbestos exposure.
• Main results:
  • The maximum tolerated dose was 1000 mg twice daily.
  • Among all 62 patients, the most frequent adverse events, recorded regardless of whether the drug caused them, were nausea (76%), diarrhea (65%), vomiting (58%) and decreased appetite (47%).
  • Six patients at 750, 1000 and 1500 mg twice daily gave paired tumor biopsies. In five of the six, phosphorylated FAK (Y397) relative to total FAK decreased by 80% or more.
  • A best response of stable disease occurred in 28 patients (45%).
  • In patients with malignant pleural mesothelioma, the overall median progression-free survival was 12 weeks (95% CI 9.1, 23.4).
  • Median progression-free survival in mesothelioma patients, by merlin status: merlin-negative (n = 14), 23.4 weeks (95% CI 6.0, 28.1); merlin-positive (n = 9), 11.4 weeks (95% CI 4.3, 22.6); unknown (n = 6), 10.9 weeks (95% CI 9.1, not determined).
  • Of the mesothelioma patients, 14 (48%) had tumor tissue that stained negative for merlin.
• The authors' conclusion: The authors concluded that GSK2256098 has an acceptable safety profile, shows evidence of target engagement, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.
• Limitations the authors state:
  • The study could not determine whether merlin negativity is a prognostic or predictive biomarker. The authors said prospective studies are needed.
  • The analyses of toxicity, dose-limiting toxicities and maximum tolerated dose were primarily descriptive or exploratory.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Progression-Free Survival, Merlin.

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