Background: HRAS mutations define a unique molecular subset of ~ 5% of HNSCC. Evidence suggests that these tumors respond poorly to standard systemic therapy but the impact of HRAS missense mutations on clinical outcomes has not been formally characterized. Tipifarnib is a potent and selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity. Phase 2 Proof of concept for tipifarnib in HRAS mutant HNSCC was recently achieved in study KO-TIP-001 (NCT02383927, Ho et. al. ESMO 2018). Methods: The AIM-HN and SEQ-HN Study (KO-TIP-007, NCT03719690) is an ongoing international, multicenter, open-label, 2 cohort (AIM-HN and SEQ-HN), pivotal trial designed to determine the Overall Response Rate (ORR) of tipifarnib in patients (pts) with HRAS mutant HNSCC (AIM-HN). SEQ-HN will retrospectively investigate how the ORR to first line treatment compares between the accrued HRAS mutant pts to matched-case control HRAS wild type (wt) HNSCC pts. Information on subsequent lines of therapy for HRAS mutant and wt pts will also be collected. AIM-HN will enroll at least 59 pts (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) who are refractory or have relapsed from at least one prior line of systemic platinum-based therapy and have measurable disease by RECIST 1.1. AIM-HN pts must have tumors with >35% HRAS mutant variant allele frequency (VAF) or >20% VAF if serum albumin is >3.5 g/l. AIM-HN pts will receive treatment with tipifarnib at 600 mg bid on days 1-7 and 14-21 of 28-day cycles. Using Simon's Two-Stage Minimax design, if true ORR is > 30%, the study will have 80% power to detect ORR > 15% at 0.025 significance level. Both interim (after first 31 pts) and final analysis, 2-sided 95% CI on ORR, will be performed on the modified intent to treat population. The SEQ-HN observational cohort will enroll ~225 control pts who will receive standard of care treatment. A subset of SEQ-HN pts will be matched to the HRAS mutant AIM-HN pts according to defined patient characteristics and compared for responses to therapy. Clinical trial information: NCT02383927.