This Phase II study consists of 2 parts: 1) pre-screening phase and 2) treatment phase.
The pre-screening phase will investigate the presence of HRAS mutations in subjects with a
histologically or cytologically confirmed diagnosis of squamous non-small cell lung cancer
(SQ-NSCLC). Subjects may participate in the pre-screening phase at initial diagnosis or
following prior lines of therapy for SQ-NSCLC.
The treatment phase will investigate the antitumor activity in terms of ORR of tipifarnib in
subjects with locally advanced squamous non-small cell lung cancer (SQ-NSCLC) with HRAS
mutations and for whom there is no curative therapy available.
Subject enrolment may proceed with information available on tumor HRAS status previously
generated during the pre-screening phase, but all subjects must consent to provide tumor
slides (or tumor tissue block) from a prior diagnostic biopsy for a retrospective testing of
RAS gene status, including T81C polymorphism, and other potential biomarkers at a central
Tipifarnib will be administered at a starting dose of 900 mg, po, bid daily on days 1-7 and
15-21 of 28-day treatment cycles. In the absence of unmanageable toxicities, subjects may
continue to receive tipifarnib treatment for up to 24 months in the absence of disease
progression and unmanageable toxicity. Treatment may continue beyond 24 months if there is
documented evidence of continued clinical benefit. At the judgement of the investigator, the
dose of tipifarnib may be increased to 1,200 mg.
Tumor assessments will be performed at screening and approximately every 8 weeks for the
first 6 months (cycles 2, 4, 6) and then every 12 weeks (cycles 9, 12, 15, etc.) until
disease progression, starting at the end of Cycle 2. Additional tumor assessments may be
conducted if deemed necessary by the Investigator or for a confirmation of an objective
response. Subjects who discontinue tipifarnib treatment for reasons other than disease
progression must continue tumor assessments until disease progression, withdrawal of
subject's consent to study procedures or initiation of another anticancer therapy.
Determination of objective tumor response will be performed by the Investigator according to
the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Electronic copies of tumor
images may be de-identified of subject's personal information at the clinical sites and
collected by the Sponsor to undergo an external independent radiological review if the
sponsor deems it necessary for the final assessment of treatment efficacy. Subjects with a
solitary site of disease who have experienced a response may be considered for surgical
resection. Subjects with a best response of a partial response and residual disease after
salvage surgery will be eligible to continue on study therapy. Information on the duration of
response to the last prior therapy will be collected.
Upon disease progression, subjects will be followed approximately every 12 weeks for survival
until either death or 24 months after accrual in the subject's study cohort has been
completed, whichever occurs first. Information on subsequent anticancer therapy will be
All subjects will be followed-up for safety during treatment and for approximately 30
additional days after treatment discontinuation (or until immediately before the
administration of another anticancer treatment). Additional safety follow up may be conducted
if unresolved toxicity is present at the End of Treatment visit.
1. Subject has a histologically or cytologically confirmed diagnosis of squamous
non-small cell lung cancer (SQ-NSCLC) for which there is no curative therapy
2. Subject has relapsed (progressive disease) or is refractory to one or more prior
therapies. In the case of therapy received in the adjuvant or neo-adjuvant setting,
relapse must have occurred within 12 months to be considered prior therapy. Subject
may have received prior immunotherapy.
3. Subject has a tumor that carries a missense HRAS mutation. HRAS status may have been
assessed either in blood, primary tumor tissue, recurrent or metastatic disease.
4. Subject has consented to provide tumor slides (or tumor tissue blocks) for biomarker
evaluation. If enrolment in the treatment portion of the study has taken place based
on HRAS mutant status as assessed using a blood sample, tumor tissue will be used in
part for confirmation of HRAS mutant tumor status. Confirmation of HRAS mutant status
in tumor tissue is required for continuation of treatment. All treated subjects will
be evaluated for safety.
5. Subject has measurable disease according to RECIST v1.1.
6. 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.
7. 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. Subjects may be on a daily dose of corticosteroids (≤ 20mg prednisone or
equivalent), as part of their management from prior radiotherapy.
8. ECOG (Eastern cooperative oncology group) performance status of 0 or 1.
9. Acceptable liver function:
1. Bilirubin less than 1.5 times upper limit of normal (x ULN); does not apply to
subjects with Gilbert's syndrome diagnosed as per institutional guidelines.
2. AST Aspartate Amino-transferasa (SGOT) and ALT Aspartate-Alanina-transferasa
(SGPT) less than 3 x ULN; if liver metastases are present, then ≥ 5 x ULN is
10. Acceptable renal function with serum creatinine less than 1.5 x ULN or a calculated
creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault formula.
11. Acceptable hematologic status:
1. ANC (absolut neuthophil count) ≥ 1500 cells/μL.
2. Platelet count ≥ 100,000/μL.
3. Hemoglobin ≥ 9.0 g/dL.
12. Female subjects must be either:
1. Of non-child-bearing potential (surgically sterilized or at least 2 years
2. If of child-bearing potential, subject must use an adequate method of
contraception consisting of two-barrier method or one barrier method with a
spermicide or intrauterine device. Both females and male subjects with female
partners of child-bearing potential must agree to use an adequate method of
contraception for 2 weeks prior to screening, during, and at least 4 weeks after
last dose of trial medication. Female subjects must have a negative serum or
urine pregnancy test within 72 hours prior to start of trial medication.
3. Not breast feeding at any time during the study.
13. Written and voluntary informed consent for the treatment phase understood, signed and
1. Ongoing treatment with an anticancer agent not contemplated in this protocol.
2. Prior treatment (at least 1 full treatment cycle) with an FTase inhibitor.
3. 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.
4. Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and
well controlled for at least 4 weeks prior to Cycle 1 Day 1).
5. 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 patient is not able to
endure for the conduct of instrumental activities of daily life or that persists ≥ 7
6. Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1,
without complete recovery.
7. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy. Known infection with HIV, or an active infection with hepatitis B or
8. 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. Patients with hypersensitivity to these agents will be
excluded from enrolment.
9. 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.
10. The subject has legal incapacity or limited legal capacity.
11. 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.