Inclusion Criteria:  At least 18 years of age. Histologically confirmed head and neck cancer of squamous histology not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy). Documented treatment failure from at least 1 prior systemic therapy in the R/M setting, unless determined not appropriate. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Has a tumor that is dependent upon HRAS and/or PIK3CA. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Acceptable liver, renal, endocrine, and hematologic function. Must be able to swallow alpelisib whole tablet or oral suspension containing crushed tablets. Feeding tube may not be used for alpelisib administration. Other protocol defined inclusion criteria may apply.  Exclusion Criteria:  Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (eg, mucosal melanoma). Ongoing treatment with certain anticancer agents. Prior treatment (at least 1 full treatment cycle) with an FTI or PI3K, mTOR, or AKT inhibitor. Received treatment for unstable angina, myocardial infarction, and/or cerebro-vascular attack within the prior 6 months. Non-tolerable Grade 2, or ≥ Grade 3 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery. Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy. Participant with an established diagnosis of diabetes mellitus Type 1 or not controlled Type 2. Participant has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the trial drugs based on Investigator discretion. Participant has currently documented pneumonitis/interstitial lung disease. Participant has a history of severe cutaneous reaction, such as Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Other protocol defined exclusion criteria may apply.