The AIM-HN and SEQ-HN Study: A 2 Cohort, Non-comparative, Pivotal Study Evaluating the Efficacy of Tipifarnib in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS Mutations (AIM-HN) and the Impact of HRAS Mutations on Response to First Line Systemic Therapies for HNSCC (SEQ-HN)

Inclusion criteria: AIM-HN
For inclusion of a subject in the tipifarnib treatment portion of the study
(AIM-HN), all of the following inclusion criteria must be fulfilled. If a
subject does initially not meet any inclusion criteria, the subject may be
re-screened at a later time:
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). Enrollment may proceed with local diagnosis but
all subjects must consent to provide tumor tissue for a central pathology
review.
3. 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. The most recent
prior and platinum-based therapy may be the same regimen. Those subjects who,
at the judgment of the investigator, are considered clinically unsuitable to
receive standard platinum-containing regimen, may also be enrolled and the
reason for clinical unsuitability recorded. There is no limit on the number of
prior lines of therapy.
4. Known tumor missense HRAS mutation detected by Next Generation Sequencing
(NGS) or any other methodology approved by the Sponsor. Variant allele
frequency (VAF) needs to be determined and must be available. HRAS status
should be assessed on tumor tissue obtained subsequent to the most recent prior
therapy so that the most accurate tumor biology is evaluated. If tumor tissue
that does not meet this criterion must be used (e.g. risk of new biopsy is too
high, patient refuses new biopsy), the investigator should document the reason.
Enrollment may proceed with the identification of a missense HRAS mutation
using a test preferred by the investigator and approved by the Sponsor during
pre-screening, but all subjects must consent to provide tumor tissue for
central HRAS confirmation.
a) At least 59 per protocol subjects must have a VAF >=20%
b) No more than approximately 21 per protocol subjects may have a VAF of <20%
5. Measurable disease by RECIST v1.1 (Appendix I) that meets the criteria for
selection as a target lesion according to RECIST v1.1. The presence of at
least one measurable target lesion per RECIST v1.1 must be confirmed by local
radiology prior to subject entry.
6. At least 2 weeks or 5 half-lives, whichever is longer, since the last
systemic therapy regimen prior to Cycle 1 Day 1. Last dose of any prior
checkpoint inhibitor therapy must have been administered at least 2 weeks prior
to C1D1. Subjects must have recovered to NCI CTCAE v5.0 < 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.
7. At least 2 weeks since last radiotherapy. Subjects must have recovered from
all acute toxicities from radiotherapy.
8. ECOG performance status of 0-1.
9. Acceptable liver function:
a) Bilirubin < 1.5 times upper limit of normal (x ULN).
b) AST (SGOT) and ALT (SGPT) < 1.5 x ULN.
The subject must meet/continue to meet these criteria at the time of first
dosing, as confirmed by analysis within 72 hours of C1D1.
10. Acceptable renal function with either serum creatinine < 1.5 x ULN or a
calculated creatinine clearance >= 60 mL/min using the Cockcroft-Gault or
Modification of Diet in Renal Disease (MDRD) formulas.
The subject must meet/continue to meet these criteria at the time of first
dosing, as confirmed by review of analysis performed within 72 hours of C1D1.
11. Acceptable hematologic status:
a) ANC > 1000 cells/µL.
b) Platelet count > 75,000/µL.
c) Hemoglobin > 8.0 g/dL.
The subject must meet/continue to meet these criteria at the time of first
dosing, as confirmed by review of analysis performed within 72 hours of C1D1.
12. Female subjects must be:
a) Of non-child-bearing potential (surgically sterilized or at least 2 years
post-menopausal); or
b) 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 from the first dose of tipifarnib, during tipifarnib
treatment, and at least 28 days after last dose of tipifarnib 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.
c) Not breast feeding at any time during the study.
13. Written and voluntary informed consent understood, signed and dated.

Inclusion Criteria: SEQ-HN
For inclusion of a subject in the noninterventional portion of the study
(SEQ-HN), all of the following inclusion criteria must be fulfilled:
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. HRAS wildtype (i.e. have no identified tumor missense HRAS mutation)
determined by a test preferred by the investigator and approved by the Sponsor
or through central HRAS testing.
4. Will or has received at least one systemic anti-cancer therapy for recurrent
or metastatic HNSCC for which there is available outcome information in terms
of ORR, or can be determined based on the subject*s records. Subjects who have
not yet received or completed at least one systemic anti-cancer therapy for
recurrent or metastatic HNSCC must consent to the collection of treatment
outcome information and additional follow up contact in order to participate in
the SEQ-HN portion of the study.
5. Written and voluntary informed consent understood, signed and dated.

Inclusiecriteria: AIM-HN
If a subject initially meets any exclusion criteria, the subject may be
re-screened at a later time.
1. Has disease that is suitable for local therapy administered with curative
intent.
2. Histologically confirmed salivary gland, thyroid, (primary) cutaneous
squamous or nonsquamous histologies (e.g. mucosal melanoma).
3. 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).
4. 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).
5. Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase
inhibitor (FTI).
6. Any use of investigational therapy within 2 weeks of Cycle 1 Day 1 (C1D1) or
5 half-lives (whichever is longer). Last dose of any prior checkpoint inhibitor
therapy must have been administered at least 2 weeks prior to C1D1.
7. 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.
8. Non-tolerable Grade 2 or >= Grade 3 neuropathy or evidence of unstable
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.
9. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle
1 Day 1, without complete recovery.
10. 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.
11. Subjects who have exhibited allergic reactions to tipifarnib or structural
compounds similar to tipifarnib or to its 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 enrollment.
12. Required use of concomitant medications classified as strong inhibitors or
inducers of cytochrome P450 3A4 (CYP3A4) or UDP-glucuronosyltransferase (UGT).
13. 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.
14. Female subjects who are pregnant or lactating.
15. Unwillingness or inability to comply with the study protocol for any reason.

Exclusion Criteria: SEQ-HN
1. Histologically confirmed salivary gland, thyroid, (primary) cutaneous
squamous or nonsquamous histologies (e.g. mucosal melanoma).
2. 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.
3. The subject has legal incapacity or limited legal capacity.