GDC-0032, a beta isoform-sparing PI3K inhibitor: Results of a first-in-human phase Ia dose escalation study

  • Dejan Juric, Ian Krop, Ramesh K. Ramanathan, Jim Xiao, Sandra Sanabria E
  • 4

    Readers

    Mendeley users who have this article in their library.
  • N/A

    Citations

    Citations of this article.

Abstract

Background: GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3Kα, , and isoforms, with 30 fold less inhibition of the PI3K β isoform relative to the PI3Kα isoform. Preclinical data show that GDC-0032 has increased activity against PI3Kα isoform (PIK3CA) mutant and HER2-amplified cancer cell lines. Methods: A Phase Ia, multicenter, open-label study was conducted to evaluate the safety and pharmacokinetics (PK) of GDC-0032 administered once daily in patients with locally advanced or metastatic solid tumors. Preliminary assessment of the anti-tumor activity of GDC-0032 was also performed. The study consisted of 3+3 dose-escalation cohorts with a 35-day window to evaluate dose-limiting toxicity (DLT). Results: As of August 1, 2012, 34 patients were enrolled in this study. Five dosing cohorts ranging from 3 to 16 mg QD were tested (3, 5, 8, 12, and 16 mg), and dose escalation has been completed. Two DLTs (Grade 4 hyperglycemia and Grade 3 fatigue) were observed in two patients from the 16 mg cohort. Adverse events (AEs) assessed by the investigator as related to GDC-0032 in 10% of patients, were diarrhea, hyperglycemia, fatigue, nausea, decreased appetite, and vomiting. The only Grade 4 treatment-related AE (hyperglycemia) occurred in the 16 mg cohort. GDC-0032 PK was approximately dose proportional and time independent with a mean t1/2 of 40 hours. Paired pre-treatment and on-treatment tumor biopsies of a patient in the 3 mg cohort showed pharmacodynamic inhibition of the PI3K pathway as assessed by reverse phase protein array. Metabolic partial responses via FDG-PET ( 20% decrease in mSUVmax) were observed in 7 out of 13 patients assessed (54%). Clinical partial responses (PRs) were observed in 5 patients treated at doses of GDC-0032 ranging from 3-12 mg QD. Consistent with GDC-0032 preclinical data, 3 PRs (2 confirmed) were observed out of 5 patients with PIK3CA mutant breast cancer (RECIST -30% to -70%). One cPR has been observed in a patient with PIK3CA mutant NSCLC, and 1 uPR in a patient with HER2-positive, PIK3CA wildtype, breast cancer. Conclusion: GDC-0032 is a PI3K inhibitor with dose-linear PK and expected in-class toxicities. Pharmacodynamic inhibition of the PI3K pathway has been observed in tumor biopsies and FDG-PET imaging. Clinical partial responses observed in patients with PIK3CA mutant and HER2+ tumors suggest that GDC-0032 may have increased anti-tumor activity in diagnostically defined subpopulations.

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Authors

  • et al. Dejan Juric, Ian Krop, Ramesh K. Ramanathan, Jim Xiao, Sandra Sanabria

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free