Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations

This Phase II study will investigate the antitumor activity in terms of ORR of tipifarnib in
subjects with locally advanced, unresectable or metastatic, relapsed and/or refractory tumors
that carry HRAS mutations and for whom there is no curative therapy available. Subject with
information available on tumor HRAS status previously generated are eligible. All subjects
must consent to provide at least 10 tumor slides from a prior diagnostic biopsy for a
retrospective testing of RAS gene status at a central facility.

Subjects will be enrolled into two nonrandomized cohorts:

- Cohort 1: Malignant thyroid tumors with HRAS mutations.

- Cohort 2: Squamous Head and Neck Cancer with HRAS mutations.

Inclusion Criteria:

- histologically or cytologically confirmed diagnosis of thyroid cancer (cohort 1) or
squamous head and neck cancer (cohort 2) for which there is no curative therapy
available.

- tumor that carries a missense HRAS mutation

- Subject consents to provide at least 10 unstained tumor slides for retrospective
testing of HRAS gene tumor status

- Subject has measurable disease according to RECIST v1.1 and has relapsed or is
refractory to prior therapy.

- At least 2 weeks since the last systemic therapy or radiotherapy regimen prior to
enrolment

- ECOG PS 0 or 1

- Acceptable liver function

- Acceptable renal function

- Acceptable hematologic status

Exclusion Criteria:

- Prior treatment with an FTase inhibitor

- History of relevant coronary heart disease or myocardial infarction within last 3
years, NYHA Grade III or greater congestive heart failure, cerebro-vascular attack
within the prior year, or 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 unstable neurological symptoms
within 4 weeks first dose

- Major surgery, other than diagnostic surgery, within 4 weeks prior to first dose,
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