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A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with
Joaquin Mateo1, Gopinath Ganji2, Charlotte Lemech3
1Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
Abstract:
Background: The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on- and off-target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ.Methods: We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended phase II dose (RP2D). During the dose-selection and dose-escalation stages (parts 1 and 2), patients with PTEN-deficient advanced solid tumors received escalating doses of GSK2636771 (25-500 mg once daily) using a modified 3+3 design to determine the RP2D; tumor type-specific expansion cohorts (part 3) were implemented to further assess tumor responses at the RP2D.Results: A total of 65 patients were enrolled; dose-limiting toxicities were hypophosphatemia and hypocalcemia. Adverse events included diarrhea (48%), nausea (40%), and vomiting (31%). Single- and repeat-dose exposure increased generally dose proportionally. GSK2636771 400 mg once daily was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate-resistant prostate cancer (CRPC) patient harboring PIK3CB amplification had a partial response for over a year; an additional 10 patients derived durable (≥24 weeks) clinical benefit, including two other patients with CRPC with PIK3CB alterations (≥34 weeks). GSK2636771 400 mg once daily orally induced sufficient exposure and target inhibition with a manageable safety profile.Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); 5981-92. ©2017 AACR.
Insights
The PI3K/AKT pathway inhibitor GSK2636771 shows promise for treating advanced solid tumors. A recommended Phase II dose of 400 mg daily was established, with some patients experiencing durable clinical benefit, particularly those with PIK3CB alterations.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway is frequently activated in various cancers.
- Selective inhibition of PI3Kβ may offer a targeted approach to pathway modulation, potentially mitigating side effects associated with pan-PI3K inhibitors.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of GSK2636771, a selective PI3Kβ inhibitor.
- To determine the recommended Phase II dose (RP2D) for GSK2636771 in patients with advanced solid tumors.
Main Methods:
- A modified 3+3 dose-escalation study was conducted, enrolling patients with PTEN-deficient advanced solid tumors.
- GSK2636771 doses ranged from 25-500 mg once daily, with subsequent expansion cohorts at the RP2D to assess tumor responses.
Main Results:
- The RP2D was determined to be 400 mg once daily, with dose-limiting toxicities including hypophosphatemia and hypocalcemia.
- GSK2636771 demonstrated dose-proportional pharmacokinetics and target engagement, evidenced by decreased phospho/total AKT ratios.
- A notable partial response exceeding one year was observed in a castrate-resistant prostate cancer patient with PIK3CB amplification; 10 additional patients achieved durable clinical benefit.
Conclusions:
- GSK2636771 exhibits a manageable safety profile and achieves sufficient target inhibition at the RP2D of 400 mg daily.
- Genomic alterations in PIK3CB may predict clinical benefit from GSK2636771 treatment in advanced solid tumors.
