Effect of Alpelisib in Healthy Volunteers

The goal of this clinical trial is to test a single dose of the phosphoinositide-3-kinase (PI3K) inhibitor alpelisib versus placebo in healthy volunteers. The main questions it aims to answer are the impact of acute alpelisib-induced insulin resistance on parameters of glucose and lipid metabolism (how healthy people respond to temporary insulin resistance so that the investigators can see what happens to how the liver handles fat and sugar).Participants will:Consume their total calculated daily caloric needs in nutritional supplements, divided in three meals, and otherwise fast for 24 hoursTake a dose of alpelisib 300 mg or placebo at bedtimeWear a continuous glucose monitor for 24 hoursParticipate in an oral glucose tolerance test (OGTT)Researchers will compare blood tests before and during OGTT in participants randomized (like the flip of a coin) to alpelisib versus placebo to see how the drug treatment affects plasma glucose, serum insulin, and serum lipid parameters (triglycerides, free fatty acids, and apolipoprotein B).

Inclusion Criteria:Adults aged 18-65 years, using highly effective contraception if of childbearing potentialAble to understand written and spoken English and/or SpanishBody mass index of 18.0-26.9 kg/m2Healthy, as determined by screening assessments and Principal Investigator's (PI's) clinical/scientific judgment. "Healthy" status is defined by the absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead EKG, and laboratory tests on blood and urine.Exclusion Criteria:Inability to provide informed consent in English or SpanishConcerns arising at screening visit (any of the following):i. Unwillingness to fast (except water) for up to 15 hoursii. Documented weight change of ≥ 3.0% of baseline within the previous 6 monthsiii. Abnormal blood pressureSystolic blood pressure < 90 mm Hg or > 160 mm Hg, and/orDiastolic blood pressure < 60 mm Hg or > 100 mm Hgiv. Abnormal resting heart rate ≤ 60 bpm or ≥ 100 bpmSinus tachycardia that has been extensively worked up and considered benign by the recruit's personal physician may be permitted at the PI's discretionv. Abnormal screening electrocardiogram (or if on file, performed within previous 90 d)Non-sinus rhythmSignificant QTc prolongation (≥ 480 ms)New or previously unknown ischaemic changes that persist on repeat EKG:ST elevationsT-wave inversionsvi. Abnormal screening serum electrolytes and/or liver function testsvii. Fasting serum insulin level ≥ 15 µIU/mLviii. Laboratory evidence of prediabetic state or diabetes mellitus:Hemoglobin A1c ≥ 5.7%, and/orFasting plasma glucose ≥ 100 mg/dLix. Abnormal fasting lipids at screening (either of the following)Triglycerides ≥ 150 mg/dLLDL-cholesterol ≥ 160 mg/dLx. Abnormal screening thyroid-stimulating hormone (TSH) levelExempt from TSH screening if previously obtained value within 2 months of screening is availablexi. Positive qualitative human chorionic gonadotropin beta subunit (β-hCG) (i.e., pregnancy test) in women of childbearing potentialCOVID-19 precautionsi. Not fully vaccinated against COVID-19 (4 doses if ages 50-65, 3 doses if ages 18-49)ii. Unwillingness to comply with masking requirements per hospital policyiii. Active, documented COVID-19 at any time after screening through study completionReproductive concernsi. Women of childbearing potential not using highly effective contraception, defined as:Surgical sterilization (e.g., bilateral tubal occlusion, bilateral oophorectomy and/or salpingectomy, hysterectomy)Combined oral contraceptive pills taken daily, including during the studyIntrauterine device (levonorgestrel-eluting or copper) active at the time of the studyMedroxyprogesterone acetate (Depo-Provera®) injection active at the time of the studyEtonogestrel implants (e.g., Implanon®, etc.) active at the time of the studyNorelgestromin/ethinyl estradiol transdermal system (e.g., Ortho-Evra®) active at the time of the studyii. Women currently pregnantiii. Women currently breastfeedingAny clinically relevant history or the presence of any active or chronic disease, including respiratory, renal, hepatic, gastrointestinal, hematological, lymphatic, neurological, cardiovascular, psychiatric, etc. disease or diseases except for:Osteoarthritis, not using chronic anti-inflammatory medicationsNon-melanoma skin cancer, localized and not receiving systemic therapyN.B. Minor chronic health problems that do not impair overall health/functional status and are judged unlikely to interfere with study conduct or data analysis may be permitted at the discretion of the PICurrently taking any prescription medications other than vitamins or other nutritional supplements, subject to review by the PIo Any participant using biotin (vitamin B7) at >1000 international units per day must not take it for 3 d prior to any study blood draw due to interference with laboratory assaysDermatologic concernsHistory of cutaneous and/or mucosal eruptive reactions to food or drugs, including, but not limited to, rash or urticariaActive skin conditions requiring ongoing care by a dermatologist except for localized non-melanoma skin cancer (not receiving systemic therapy)Clinical concern for alcohol overuse, including phosphatidylethanol ≥ 0.05 µmol/L at screening and/or by participant's report of consuming more than 14 standard drinks per week for males or more than 7 standard drinks per week for femalesPositive urine drug screenTobacco smoking currently or within the previous 6 monthsHistory of or ongoing febrile illness within 30 days of screeningAny other disease or condition or laboratory value that, in the opinion of the investigator, would place the participant at an unacceptable risk and/or interfere with the analysis of study data.Known allergy/hypersensitivity to any component of the medicinal product formulations (including soy or cow dairy), other biologics, venipuncture materials, plastics, adhesive or silicone, or ongoing clinically important allergy/hypersensitivity as judged by the investigator.Dietary restrictions (e.g.., vegan, kosher, halal) on gelatin present in overencapsulationConcurrent enrollment in another clinical study of any investigational drug therapy or use of any biologicals within 6 months prior to screening or within 5 half-lives of an investigational agent or biologic, whichever is longer.