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.
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