Safety and Efficacy of Tipifarnib in Head and Neck Cancer With HRAS Mutations and Impact of HRAS on Response to Therapy

KO-TIP-007 is an international, multicenter, open-label, 2 cohort, non-comparative, pivotal
study evaluating the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN) and the impact of
HRAS mutations on response to first line systemic therapies for HNSCC (SEQ-HN). KO-TIP-007
has 2 study cohorts. The first study cohort, named AIM-HN, includes HNSCC subjects with HRAS
mutations. AIM-HN subjects will receive treatment with tipifarnib and the outcome of this
cohort will be evaluated for ORR by an independent review facility.

The second study cohort, SEQ-HN, is an observational sub-study and includes 2 types of
patients: (1) the historical record of first line therapy in AIM-HN (HRAS mutant HNSCC)
subjects in whom first line outcome data are available and (2) matched control HNSCC patients
in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consent to provide
first line outcome data and additional follow up.

HNSCC patients in whom HRAS mutations are identified and who meet eligibility criteria will
be offered participation in AIM-HN. HNSCC patients in whom HRAS mutations are not identified
may participate in SEQ-HN only. These patients will be followed and the comparison of
outcomes of HRAS mutant and HRAS wild type HNSCC will address the exploratory objective to
determine the effect of HRAS mutation on the ORR of first line systemic therapy in patients
with recurrent/metastatic HNSCC. Outcome data from subsequent lines of therapy will be
collected.

Inclusion Criteria:

AIM-HN

1. At least 18 years of age.

2. 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).

3. Documented tumor progression or recurrence from at least one prior platinum-containing
regimen in the primary, neoadjuvant, adjuvant, advanced, recurrent or metastatic
setting.

4. Known tumor missense HRAS mutation.

5. Measurable disease by RECIST v1.1.

6. ECOG performance status of 0-2.

7. Acceptable liver, renal and hematological function

Exclusion Criteria:

1. Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or
nonsquamous histologies (e.g. mucosal melanoma).

2. 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.

3. Non-tolerable Grade 2 or ≥ Grade 3 neuropathy or evidence of unstable neurological
symptoms within 4 weeks of Cycle 1 Day 1.

4. Active, uncontrolled bacterial, viral or fungal infections requiring systemic therapy.
Known history of infection with human immunodeficiency virus or an active infection
with hepatitis B or hepatitis C.

5. Received treatment for non-cancer related liver disease within prior year.

Inclusion Criteria: SEQ-HN

1. At least 18 years of age.

2. Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx,
sinonasal, nasopharyngeal, or unknown primary) of squamous histology.

3. Will or has received at least one systemic anti-cancer therapy for recurrent or
metastatic HNSCC.

Exclusion Criteria: SEQ-HN

1. Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or
nonsquamous histologies (e.g. mucosal melanoma).