(ChemotherapyAdvisor) – The next-generation, investigational oral PI3 kinase inhibitor GDC-0032 exhibits a favorable safety profile and early signs of “promising” activity against PI3 kinase alpha-mutation hormone receptor-positive breast tumors, according to a first-in-human phase 1a dose escalation study presented at the American Association for Cancer Research (AACR) Annual Meeting 2013, in Washington, DC.

“We’ve shown that this novel agent is well tolerated,” said Dejan Juric, MD, of the Massachusetts General Hospital Cancer Center, in Boston, MA, and his coauthors. “Early results show that the drug has very promising activity, particularly in tumors that have activating mutations in PI3 kinase alpha.”

About 40% of hormone receptor–positive breast cancers harbor PI3 kinase alpha mutations. GDC-0032 has been shown in preclinical studies to be active against this mutation.


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“We currently have no approved therapies that directly target this critically important component of cancer cells,” Dr. Juric noted.

The multicenter, open-label phase 1a study enrolled 34 patients who had been diagnosed with locally advanced or metastatic solid tumors. Participants were assigned to five dose cohorts that received 3 mg, 5 mg, 8 mg, 12 mg, or 16 mg GDC-0032 once per day.

Adverse events affecting 10% or more of participants were “very common and predictable,” Dr. Juric noted, and included hyperglycemia, diarrhea, fatigue, nausea, vomiting, and decreased appetite.

Hyperglycemia is an “on-target” adverse event, Dr. Juric said; PI3 kinase alpha “plays an important role in glucose metabolism,” he explained. “All agents that effectively block PI3 kinase alpha lead to some level of glucose elevation.”

Dose-limiting toxicities were seen in two patients assigned to the 16-mg dose cohort: one patient experienced a grade 4 hyperglycemia; the other, grade 3 fatigue.

The study yielded early clinical evidence of GDC-0032 inhibition of the PI3K pathway, Dr. Juric noted.

“Paired pretreatment 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,” they reported. Among 13 participants whose breast cancers were driven by PI3 kinase alpha mutation and whose tumor responses were assessed with Fluorodeoxyglucose(18F) positron emission tomography (FDG-PET).

“Metabolic partial responses via FDG-PET (≥20% decrease in maximum standardized uptake value) were observed in seven out of 13 patients assessed (54%),” Dr. Juric and colleagues reported. “Clinical partial responses were observed in five patients treated at doses of GDC-0032 ranging from 3-12 mg [administered every day].”

Three of those patients had PIK3CA mutant breast tumors and one had HER2-positive PIK3CA wild-type breast cancer. One patient with non-small cell lung cancer (NSCLC) driven by PI3 kinase alpha mutation experienced clinical partial response, Dr. Juric and his coauthors noted.

GDC-0032 is under development by Genetech.

Abstract (#LB-64)