Inclusion Criteria: - AIM-HN

• Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).
• Documented treatment failure from most recent prior therapy (e.g. tumor progression, clinical deterioration, or recurrence), and from at least one prior platinum-containing regimen in any treatment setting.
• Known tumor missense HRAS mutation.
• Measurable disease by RECIST v1.1.
• ECOG performance status of 0-1.
• Acceptable liver, renal and hematological function.

Exclusion Criteria: - AIM-HN

• Has disease that is suitable for local therapy administered with curative intent.
• Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g., mucosal melanoma).
• Known additional malignancy that is progressing or requires active treatment (excluding non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
• Ongoing treatment with an anticancer agent not contemplated in this protocol (excluding adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
• Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor (FTI).
• Any use of investigational therapy within 2 weeks of Cycle 1 Day 1 (C1D1) or 5 half-lives (whichever is longer).
• Received treatment for unstable angina within prior year, myocardial infarction within the prior year, cerebro-vascular attack within the prior year, history of New York Heart Association grade III or greater congestive heart failure, or current serious cardiac arrhythmia requiring medication except atrial fibrillation.
• 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, including known history of infection with human immunodeficiency virus or an active infection with hepatitis B or hepatitis C.
• Subjects who have exhibited allergic reactions to tipifarnib or structural compounds similar to tipifarnib or to its excipients.
• Required use of concomitant medications classified as strong inhibitors or inducers of cytochrome P450 3A4 or UDP-glucuronosyltransferase (UGT).
• Concomitant disease or condition that could interfere with the conduct of the study or that would, in the opinion of the investigator, pose an unacceptable risk to the subjects in this study.
• Female subjects who are pregnant or lactating

Inclusion Criteria: SEQ-HN

• Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology.
• HRAS wildtype determined by a test
• Will or has received at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC.

Exclusion Criteria: SEQ-HN

• Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g., mucosal melanoma).
• Concomitant disease or condition that could interefere with the conduct of the study or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.