Purpose We report the first-in-human phase Ia study to our knowledge ( 
ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated 
dose and assessing safety and preliminary efficacy of single-agent alpelisib 
(BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. 
Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered 
advanced solid tumors received once-daily or twice-daily oral alpelisib on a 
continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered 
solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal 
growth factor receptor 2-negative breast cancer received alpelisib 400 mg once 
daily. Results One hundred thirty-four patients received treatment. Alpelisib 
maximum tolerated doses were established as 400 mg once daily and 150 mg twice 
daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting 
toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and 
hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events 
included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), 
diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; 
half-life was 7.6 hours at 400 mg once daily with minimal accumulation. 
Objective tumor responses were observed at doses ≥ 270 mg once daily; overall 
response rate was 6.0% (n = 8; one patient with endometrial cancer had a 
complete response, and seven patients with cervical, breast, endometrial, colon, 
and rectal cancers had partial responses). Stable disease was achieved in 70 
(52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease 
control rate (complete and partial responses and stable disease) was 58.2%. In 
patients with estrogen receptor-positive/human epidermal growth factor receptor 
2-negative breast cancer, median progression-free survival was 5.5 months. 
Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS 
(22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a 
tolerable safety profile and encouraging preliminary activity in patients with 
PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα 
inhibition in combination with other agents for the treatment of PIK3CA-mutant 
tumors.