Novel FAK Inhibitor Merits Further Investigation in Advanced Solid Tumors

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(ChemotherapyAdvisor) – The first-in-class study of a novel compound that selectively targets focal adhesion kinase (FAK) and proline-rich tyrosine kinase (Pyk2) in patients with advanced malignancies supports “further clinical investigation of FAK inhibitors, either alone or in combination, as novel targeted strategies for cancer treatment,” investigators concluded in the Journal of Clinical Oncology published online March 26.

The objectives of the Phase 1 study were to identify the recommended Phase 2 dose and assess safety and tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of PF-00562271. The study was conducted in two parts: part 1 evaluated dose escalation in 12 fasting and 3 fed cohorts and part 2 enrolled 99 patients (median age, 60 years) with specific tumor types at the recommended Phase 2 dose (125mg twice daily) with food and assessed effect on single-dose midazolam pharmacokinetics.

The majority of patients (75%) had three or more prior chemotherapy regimens; primary tumor types included colorectal (23%) squamous cell carcinoma of the head and neck (16%), pancreatic (14%), prostate (6%), non-small-cell lung cancer (5%), ductal breast cancer (5%), and other (30%). Of 14 patients evaluable by [18F]fluorodeoxyglucose positron emission tomography, 7 metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans; 15 remained stable for 6 or more cycles.

Investigators found grade 3 dose-limiting toxicities to be headache, nausea/vomiting, dehydration, and edema. Nausea was observed in 60% of patients at the recommended Phase 2 dose; all were grades 1 or 2. “Food did not seem to affect the exposure profile, but it clearly improved tolerability and mitigated some of the GI treatment-related AEs,” they wrote.

PF-00562271 displayed time- and dose-dependent nonlinear PK. A preliminary drug interaction study with midazolam suggests the agent is most likely a potent inhibitor of CYP 3A, they found. Results of a recently completed Phase 1 clinical trial of PF-04554878, a second-generation compound with a more favorable PK profile, are awaited.


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