Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin pathway due to alterations in PIK3CA (encoding PI3Kα) frequently occurs in aST. We report safety findings from an ongoing, phase Ib dose-escalation study of ALP (PI3Kα inhibitor) + PTX (NCT02051751).
Patients (pts) aged ≥18 years with aST (not amenable to resection/progressed on standard therapy), ECOG performance status ≤2, adequate bone marrow/organ function, and no prior treatment with PI3K or AKT inhibitors were recruited. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose of ALP + PTX based on dose-limiting toxicities (DLTs) in Cycle 1. Dose escalation of ALP was guided by an adaptive Bayesian logistic regression model with escalation with overdose control principle.
As of Dec 7, 2015, 19 pts received oral ALP (300 mg [n = 6], 250 mg [n = 4], or 150 mg [n = 9] once daily [QD]) and IV PTX (80 mg/m2 once weekly [QW]). The most common primary sites of cancer were breast (n = 5) and rectum (n = 3). Treatment was discontinued in 18/19 pts due to disease progression (n = 12, 63%), pt decision (n = 3, 16%), adverse events (AEs; n = 2, 11%; 1 pt for grade [G]3 dehydration, G3 hyperglycemia, and G3 acute kidney injury; 1 pt for G4 neutropenia and G4 ɣ-glutamyltransferase increase), and physician decision (n = 1, 5%). DLTs occurred in 5/12 pts in the dose-determining set: 1/1 (100%) pt at 300 mg QD, 2/3 (67%) pts at 250 mg QD, and 2/8 (25%) pts at 150 mg QD. Six DLTs were reported: G2 hyperglycemia (n = 3), G4 hyperglycemia, G4 leukopenia, and G3 acute kidney injury (each n = 1). The MTD of ALP + PTX (80 mg/m2 QW) was declared as 150 mg QD. All 19 pts had ≥1 treatment-emergent AE. Grade 3/4 AEs occurred in 11 (58%) pts, the most frequent being hyperglycemia (n = 6, 32%), diarrhea, anemia, lymphopenia, neutropenia, and leukopenia (each n = 2, 11%).
In pts with aST, the MTD of ALP + PTX (80 mg/m2 QW) was 150 mg QD. Due to the challenging safety profile of the combination and lack of available data confirming the pharmacodynamics and/or clinical activity of ALP at 150 mg QD, planned dose expansion in pts with breast cancer and head and neck squamous cell carcinoma will not go forward.
Clinical trial identification
Legal entity responsible for the study
J. Rodón: Advisory board for Novartis, Lily, Servier, Leti, Oncompass, Orion Pharma. V. Donnet: Novartis Full-time Employee. Y. Han: I am an employee at Novartis and receive a salary from Novartis. L. Blumenstein: I hereby confirm to be a Novartis Pharma AG employee with stock ownership. C. Wilke: Employee of Novartis AG, sponsor of the study. All other authors have declared no conflicts of interest.