Background: Understanding connections between key cellular pathways is particularly important when selecting combinatorial cancer therapies. HRAS preferentially activates PI3K 5-fold more efficiently than KRAS, while KRAS is a more efficient activator of RAF (Yan et al. 1998). Further, mutant HRAS is insufficient for oncogenic transformation if it is unable to recruit PI3K in preclinical models (Gupta et al. 2007). Conversely, mutant PI3K requires RAS to drive tumor growth (Zhao and Vogt 2008). HRAS mutation/overexpression and PIK3CA mutations/amplifications account for up to 50% of head and neck squamous cell carcinoma (HNSCC). Recognition of these interdependencies was the basis for the evaluation of HNSCC PDX models which demonstrated additive or synergistic anti-tumor effects that confirmed the codependency of these pathways, thus providing robust rationale for investigating combined pathway inhibition in the clinic. The KURRENT trial is enrolling patients with HRAS and/or PIK3CA-dependent tumors who will receive combination treatment with tipifarnib (a potent and selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity) and alpelisib, a PI3K inhibitor. Methods: The KURRENT trial (KO-TIP-013, NCT04809233) is an ongoing multicenter, open-label, 2-cohort, phase 1/2 trial designed to evaluate the safety of the combination of tipifarnib and alpelisib, determine the recommended combination dose(s) regimen, and evaluate preliminary anti-tumor activity in patients with recurrent/metastatic (R/M) HNSCC whose tumors are dependent upon HRAS and/or PIK3CA signaling. The trial will enroll 40 HNSCC patients; 20 each into two biomarker defined cohorts (Cohort 1; PIK3CA; Cohort 2; HRAS). Participants must have documented treatment failure from at least one prior therapy in the R/M setting and have measurable disease by RECIST v1.1. At the starting dose level, participants will receive tipifarnib at 300 mg twice daily on days 1-7 and 15-21 and alpelisib 200 mg each morning continuously during a 28-day cycle. The trial will use an adaptive dose escalation design (based on a Bayesian logistic regression model) to characterize safety, tolerability, and clinical activity of the combination to identify the Optimal Biologically Active Dose (OBAD) while maintaining a dose limiting toxicity (DLT) rate < 33%. No formal interim analysis is planned as the model-based dose escalation process requires decisions based on real-time evaluation of aggregate toxicity and efficacy data. All observed/available data among each cohort will be evaluated before choosing the combination dose for a subsequent cohort. Enrollment into the PIK3CA cohort began in October 2021. Clinical trial information: NCT04809233.