elisib than the effect of gastricpH value.
Coadministration of the H2 receptor antagonist ranitidine in combination with a single 300 mg oral dose ofalpelisib decreased the absorption and overall exposure of alpelisib. In the presence of a low-fat low-caloriemeal, AUC was decreased on average by 21% and Cmax by 36% with ranitidine. Under the fasted state, AUC
was decreased on average by 30% and Cmax by 51% with ranitidine.
CYP3A4 Substrates: No clinically significant differences in pharmacokinetics of everolimus (a substrate ofCYP3A4 and P-gp) were observed when coadministered with alpelisib.
In Vitro Studies
Effect of Alpelisib on CYP Enzymes: Alpelisib inhibits CYP3A4 in a time-dependent manner and inducesCYP2B6, CYP2C9 and CYP3A4.
Effect of Transporter on Alpelisib: Alpelisib is a substrate of BCRP.
Effect of Alpelisib on Transporters: Alpelisib is an inhibitor of P-gp. Alpelisib has a low potential to inhibit
BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, OCT2, MATE1, and MATE2K at
clinically relevant concentrations.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with alpelisib.
Alpelisib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay, or aneugenic or clastogenicin human cell micronucleus and chromosome aberration tests in vitro. Alpelisib was not genotoxic in an in vivorat micronucleus test.
Fertility studies in animals have not been conducted. In repeated-dose toxicity studies up to 13 weeks duration,adverse effects were observed in reproductive organs including vaginal atrophy and estrous cycle variations inrats at doses ≥ 6 mg/kg/day (approximately 0.6 times the exposure in humans at the recommended dose of 300
mg/day based on AUC), and prostate atrophy in dogs at doses ≥ 15 mg/kg/day (approximately 2.6 times theexposure in humans at the recommended dose of 300 mg/day based on AUC).
14 CLINICAL STUDIES
SOLAR-1 (NCT02437318) was a randomized, double-blind, placebo-controlled trial of PIQRAY plusfulvestrant versus placebo plus fulvestrant in 572 patients with HR-positive, HER2-negative, advanced ormetastatic breast cancer whose disease had progressed or recurred on or after an aromatase inhibitor-basedtreatment (with or without CDK4/6 combination). Patients were excluded if they had inflammatory breastcancer, diabetes mellitus Type 1 or uncontrolled Type 2, or pneumonitis. Randomization was stratified bypresence of lung and/or liver metastasis and previous treatment with CDK4/6 inhibitor(s). Overall, 60% ofenrolled patients had tumors with one or more PIK3CA mutations in tissue, 50% had liver/lung metastases, and6% had previously been treated with a CDK4/6 inhibitor.
There were 341 patients enrolled by tumor tissue in the cohort with a PIK3CA mutation and 231 enrolled in thecohort without a PIK3CA mutation. Of the 341 patients in the cohort with a PIK3CA mutation, 336 (99%)patients had one or more PIK3CA mutations confirmed in tumor tissue using the FDA-approved therascreen®PIK3CA RGQ PCR Kit. Out of the 336 patients with PIK3CA mutations confirmed in tumor tissue, 19 patientshad no plasma specimen available for testing with the FDA-approved therascreen® PIK3CA RGQ PCR Kit. Ofthe remaining 317 patients with PIK3CA mutations confirmed in tumor tissue, 177 patients (56%) had PIK3CAmutations identified in plasma specimen, and 140 patients (44%) did no |
