Inclusion Criteria:

• Subject is at least 18 years of age.
• Subject has a histologically or cytologically confirmed diagnosis of non-hematological malignancy for which there is no curative therapy available. In addition, in France and Korea, Republic of, subject must have a malignancy that has relapsed or is considered treatment failure to standard of care therapy in a multidisciplinary clinical staff meeting.
  • Cohort 1 will enroll subjects with malignant thyroid tumors with HRAS mutations, independently of thyroid histology.
  • Subjects with non-hematological HRAS mutant tumors (except malignant thyroid tumors) who met eligibility criteria were enrolled in the first stage of Cohort 2 (completed).  Subjects must have HNSCC with HRAS mutations in order to be enrolled in the second stage of Cohort 2 and its extension.
  • Cohort 3 will enroll subjects with SCCs with HRAS mutations other than HNSCC, independently of tissue origin. Subjects with mucosal HNSCC with skin involvement will be enrolled in cohort 2 whereas subjects with primary skin SCC in the head and neck will be enrolled in cohort 3.
• Subject has a tumor that carries a missense HRAS mutation with a variant allele frequency (VAF) ≥ 20% according to Next Generation Sequencing or any other methodology approved by the Sponsor. HRAS status may have been assessed either in primary tumor tissue, recurrent or metastatic disease.
• Subject has consented to provide at least 10 unstained tumor slides (or equivalent tumor tissue blocks) for retrospective testing of HRAS gene tumor status, including T81C polymorphism, except in cases of anaplastic thyroid cancer. Provision of tumor slides is not required for cases of anaplastic thyroid cancer.
• Subject has measurable disease according to RECIST v1.1 and has relapsed (progressive disease) or is refractory to prior therapy.
• At least 2 weeks since the last systemic therapy regimen prior to enrolment. Subjects must have recovered to NCI CTCAE v. 4.03 < Grade 2 from all acute toxicities (excluding Grade 2 toxicities that are not considered a safety risk by the Sponsor and Investigator) or toxicity must be deemed irreversible by the Investigator.
• At least 2 weeks since last radiotherapy. If radiation was localized to the only site of measurable disease, there must be documentation of disease progression of the irradiated site. Subjects must have recovered from all acute toxicities from radiotherapy.
• ECOG performance status of 0 or 1.
• Acceptable liver function:
  • Bilirubin ≤ 1.5 times upper limit of normal (x ULN).
  • AST (SGOT) and ALT (SGPT) ≤ 1.5 x ULN.
• Acceptable renal function with serum creatinine ≤ 1.5 x ULN or a calculated creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault, CKD-EPI or MDRD formulas.
• Acceptable hematologic status:
  • ANC ≥ 1000 cells/μ.
  • Platelet count ≥ 75,000/μ.
  • Hemoglobin ≥ 8.0 g/dL.
• Serum albumin ≥ 3.5 g/dL. Subjects with tumors potentially highly sensitive to tipifarnib (HRAS mutant VAF ≥35%) may be enrolled despite a serum albumin < 3.5 g/dL.
• Female subjects must be:
  • Of non-child-bearing potential (surgically sterilized or at least 2 years post-menopausal); or
  • If of child-bearing potential, subject must use a highly effective method of contraception, such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence. Both females and male subjects with female partners of child-bearing potential must agree to use a highly effective method of contraception for 2 weeks prior to screening, during, and at least 28 days after last dose of trial medication for females and 90 days for males. Female subjects must have a negative serum or urine pregnancy test within 72 hours prior to start of trial medication;
  • Not breast feeding at any time during the study.
• Written and voluntary informed consent understood, signed and dated.

Exclusion Criteria:

• Ongoing treatment with an anticancer agent not contemplated in this protocol.
• Prior treatment (at least 1 full treatment cycle) with an FTase inhibitor.
• Any history of clinically relevant coronary artery disease or myocardial infarction within the last 3 years, New York Heart Association (NYHA) grade III or greater congestive heart failure, cerebro-vascular attack within the prior year, or current serious cardiac arrhythmia requiring medication except atrial fibrillation.
• Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 4 weeks prior to Cycle 1 Day 1). Controlled brain metastases that require continuous high dose corticosteroid use within 4 weeks of Day 1.
• Non-tolerable > Grade 2 neuropathy or evidence of emerging or rapidly progressing neurological symptoms within 4 weeks of Cycle 1 Day 1. Non-tolerable grade 2 toxicities are defined as those with moderate symptoms that the subject is not able to endure for the conduct of instrumental activities of daily life or that persists ≥ 7 days.
• Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1, without complete recovery.
• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. Known infection with HIV, or an active infection with hepatitis B or hepatitis C.
• Received treatment for non-cancer related liver disease (excluding cholelithiasis) within prior year.
• Subjects who have exhibited allergic reactions to tipifarnib or structural compounds similar to tipifarnib or to the drug product excipients. This includes hypersensitivity to imidazoles, such as clotrimazole, ketoconazole, miconazole and others in this drug class. Subjects with hypersensitivity to these agents will be excluded from enrolment.
• Required use of concomitant medications classified as strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4, Table 4) 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 subject in this study.
• The subject has legal incapacity or limited legal capacity.
• Significantly altered mental status that would limit the understanding or rendering of informed consent and compliance with the requirements of this protocol. Unwillingness or inability to comply with the study protocol for any reason.