Conditions: Thyroid Cancer Squamous Cell Carcinoma Head and Neck Cancer (HNSCC) HRAS Mutant Tumor Other Squamous Cell Carcinoma (SCC) With HRAS Mutant Tumor
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 63
Healthy volunteers: no

Brief summary:
Phase II study to investigate the antitumor activity in terms of objective response rate (ORR) of tipifarnib in subjects with advanced tumors that carry HRAS mutations and for whom there is no standard curative therapy available.

Detailed description:
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. Subjects 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 HRAS gene status at a central facility.

Subjects will be enrolled into three nonrandomized cohorts:

* Cohort 1: Malignant thyroid tumors with HRAS mutations.
* Cohort 2: Squamous Cell Carcinoma Head and Neck Cancer with HRAS mutations.
* Cohort 3: Squamous Cell Carcinoma (SCC) with HRAS mutations other than HNSCC.

Arms:
arm 1: Thyroid Cancer arm 2: Squamous Head and Neck Cancer

Interventions: intervention 1: Tipifarnib
Intervention descriptions: intervention 1: FTase inhibitor

Protocol document:
Prot_000.pdf: 
Protocol Number: KO-TIP-001 
Official Title: An Open Label Phase II Study of Tipifarnib in Advanced Non-Hematological 
Malignancies with HRAS Mutations 
NCT Number: NCT02383927 
Document Date: 01 November 2018 


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CLINICAL TRIAL PROTOCOL 
 
An Open Label Phase II Study of Tipifarnib in Advanced Non-Hematological 
Malignancies with HRAS Mutations 
 
CTP ID Number: KO-TIP-001 
Investigational Product: Tipifarnib (R115777; Zarnestra™) 
US IND Number: 127,209 
EudraCT Number: 2015-004535-12 
Indication: Advanced Non-Hematological Malignancies 
Development Phase: Phase II 
 
Sponsor: Kura Oncology, Inc. 
3033 Science Park Road, Suite 220 
San Diego, CA 92121 (USA) 
Phone: +1 858 500 8800  
 
Protocol Author: 
 
 
Medical Responsible Officer: 
  
Version and Date: Protocol AMENDMENT version 5.0 of 01 November 2018 
CONFIDENTIAL 
This is a Kura Oncology, Inc. document that contains confidential information. It is intended solely for the 
recipient clinical Investigator(s) and must not be disclosed to any other party. This material may be used only 
for evaluating or conducting clinical investigations; any other proposed use requires written consent from Kura 
Oncology, Inc. 
 




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2 
SYNOPSIS 
 
TITLE: An Open Label Phase II Study of Tipifarnib in Advanced Non-Hematological 
Malignancies with HRAS mutations 
SPONSOR: Kura Oncology, Inc. 
PROTOCOL NUMBER: KO-TIP-001 
STUDY SITES: Multiple centers in the United States (U.S.), European Union (E.U.) and Korea.  
PHASE OF DEVELOPMENT: Phase II 
STUDY PERIOD: This trial is planned to initiate enrollment in the first half of 2015. It is 
estimated that it may require approximately 5 years to complete all its study objectives. 
OBJECTIVES: 
Primary Objective: To determine the antitumor activity in terms of objective response rate 
(ORR) of tipifarnib in subjects with locally advanced unresectable or metastatic, relapsed and/or 
refractory, non-hematological malignancies with HRAS mutations.   
Secondary Objective:  Safety and tolerability of tipifarnib in subjects with locally advanced 
unresectable or metastatic, relapsed and/or refractory, non-hematological malignancies with 
HRAS mutations. 
Exploratory Objective 1:  To explore the antitumor activity in terms of progression free 
survival (PFS) and duration of response (DOR) of tipifarnib in subjects with locally advanced 
unresectable or metastatic, relapsed and/or refractory, non-hematological malignancies with 
HRAS mutations. 
Exploratory Objective 2: To explore the feasibility of collecting archival biopsies and 
analyzing these biopsies for the detection of tissue biomarkers potentially related to tipifarnib 
activity. 
STUDY DESIGN: 
This Phase II study will investigate the antitumor activity in terms of ORR of tipifarnib in 
subjects with locally advanced tumors that carry HRAS mutations and for whom there is no 
curative therapy available. Subject enrolment may proceed with information available on tumor 
HRAS status previously generated at the clinical study sites, but all subjects, except those with 
anaplastic thyroid tumors, must consent to provide at least 10 tumor slides (or equivalent tumor 
tissue block) from a prior diagnostic biopsy for a retrospective testing of RAS gene status, 
including T81C polymorphism, at a central facility. 
Subjects will be enrolled into three nonrandomized cohorts: 
 Cohort 1: Malignant thyroid tumors with HRAS mutations. 


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 Cohort 2: Non-hematological malignancies with HRAS mutations in stage 1.  Head and 
neck squamous cell carcinomas (HNSCC) with HRAS mutations in stage 2. 
 Cohort 3: Squamous cell carcinoma (SCC) with HRAS mutations other than HNSCC  
Study Schema: 
 
Cohort 1 will enroll subjects with malignant thyroid tumors with HRAS mutations, 
independently of thyroid histology. Any subject with a non-hematological HRAS mutant tumor 
who meets eligibility criteria may be enrolled in the first stage of Cohort 2. Subjects with 
HNSCC, salivary malignancies and urothelial carcinomas may be more frequently enrolled in 
Cohort 2 due to the relatively high rate of HRAS mutations in these indications; however, 
enrolment is not limited to these tumor types. Subjects with malignant thyroid tumors with 
HRAS mutations will only be enrolled in cohort 1. Based on the anti-tumor activity observed 
during stage 1 of cohort 2, the protocol was amended (Amendment 3) to restrict enrollment in 
stage 2 of Cohort 2 to subjects with HNSCC with HRAS mutations only.  
Cohort 3 will enroll subjects (N=20 evaluable) who have SCC with HRAS mutations.   The 
purpose of this cohort is to explore tipifarinib’s anti-tumor activity in HRAS mutation positive 
SCCs independent of tissue origin.  
Tipifarnib will be administered at a starting dose of 600 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 12 months in the absence of disease progression and 
unmanageable toxicity. Treatment may continue beyond 12 months upon agreement of the 
Investigator and Sponsor.  
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 


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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 12 months after accrual in the subject’s study cohort has been completed, 
whichever occurs first. Information on subsequent anticancer therapy will be collected.  
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. 
NUMBER OF SUBJECTS PLANNED: Up to 75 evaluable study subjects: 18 subjects in 
Cohort 1, 37 subjects in Cohort 2 (30 HNSCC, 7 other HRAS mutant solid tumor enrolled in 
Stage 1) and 20 subjects in Cohort 3.   
SUBJECT SELECTION:  
Inclusion Criteria 
For inclusion of a subject in the study, all of the following inclusion criteria must be fulfilled: 
1. Subject is at least 18 years of age. 
2. 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.  
a. Cohort 1 will enroll subjects with malignant thyroid tumors with HRAS mutations, 
independently of thyroid histology.  
b. Subjects with non-hematological HRAS mutant tumors (except malignant thyroid 
tumors) who met eligibility criteria were enrolled in the first stage of Cohort 2 


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(completed). Subjects must have HNSCC with HRAS mutations in order to be enrolled in 
the second stage of Cohort 2 and its extension.   
c. 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. 
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. 
4. 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.  
5. Subject has measurable disease according to RECIST v1.1 and has relapsed (progressive 
disease) or is refractory to prior therapy. 
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.  
8. ECOG performance status of 0 or 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. 
10. 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. 
11. Acceptable hematologic status: 
a. ANC  1000 cells/μL. 
b. Platelet count  75,000/μL. 
c. Hemoglobin  8.0 g/dL. 


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12. 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. 
13. 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 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. 
c. Not breast feeding at any time during the study. 
14. Written and voluntary informed consent understood, signed and dated. 
Exclusion Criteria 
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). Controlled brain metastases that 
require continuous high dose corticosteroid use within 4 weeks of 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 subject is not able to endure for the 
conduct of instrumental activities of daily life or that persists ≥ 7 days. 
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 hepatitis C. 


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8. Received treatment for non-cancer related liver disease (excluding cholelithiasis) within prior 
year. 
9. 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. 
10. Required use of concomitant medications classified as strong inhibitors or inducers of 
cytochrome P450 3A4 (CYP3A4, 
) or UDP-glucuronosyltransferase (UGT).   
11. 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.  
12. The subject has legal incapacity or limited legal capacity. 
13. 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. 
STATISTICAL METHODS: 
For Cohorts 1 and 2 
Up to 18 subjects will be enrolled in a treatment cohort. A two-stage design will be 
independently employed at each cohort. Eleven initial study subjects will be enrolled in the 
cohort; if two or more responses are observed, 7 additional study subjects will be enrolled. At the 
completion of the study cohort, treatment will be considered of further interest if the true ORR is 
higher than 10%. To determine the total trial size, a response of interest of 30% is assumed. This 
design provides 80% power to detect a difference between 10% and 30% ORR at one-sided 
significance level of 0.087. Using this design, the probability of terminating the study at the end 
of stage 1 if the true ORR is 10% is 0.697 while the probability of terminating the study at the 
end of stage 1 if the true ORR is 30% is 0.113.   
In Cohort 2, upon observation of 4 confirmed responses, enrollment of HRAS mutant HNSCC 
subjects will continue up to 30 subjects with HRAS mutant HNSCC (10 enrolled in Stage 1 and 
2 combined, plus 20 additional subjects). 
For Cohort 3 (HRAS mutant SCC) 
Twenty subjects will be enrolled, treated and followed in the same manner as the two cohorts 
above. The choice of 20 subjects is empirical for this exploratory cohort due to the rarity of 
HRAS mutations in SCC other than HNSCC.  
STUDY ASSESSMENTS: 
The evaluations to be performed during the study are summarized in Table 1.  
 


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Table 1: Schedule of Activities 
1. 
Assessed throughout the course of the treatment and approximately 30 days after treatment discontinuation. Additional 
assessments may be performed until AE resolution or the adverse event is deemed irreversible by the Investigator. Collect 
AE (only) on Day 7. 
2. 
12- Lead ECG is performed during screening within 14 days of first administration of study drug. Additional ECGs may be 
performed if deemed necessary by the Investigator.  
3. 
Fasting for chemistry testing is not required. Laboratory tests may need to be conducted on additional time points if deemed 
necessary by the Investigator. Samples will be analyzed locally at the clinical site or its reference laboratory. Laboratory 
assessments may be repeated if values are borderline to inclusion level or may change due to best supportive care measures. 
4. 
Assessment must be done within 14 days prior to first administration of study drug on Day 1 of Cycle 1.   
5. 
Laboratory tests do not need to be repeated on Cycle 1 Day 1 if they were conducted within 72 hours prior to the first dose 
of tipifarnib. Dehydration, creatinine elevations and hypokalemia have been described with tipifarnib treatment. A serum 
Activity 
Screening 
Day 
116 
Day 717  
(± 2 days) 
Day 22 
(± 5 days) 
End of 
Treatment 
Visit12 
Follow 
Up 
Visit14 
Follow 
Up 
Contact15 
ICF, Inclusion/exclusion 
criteria evaluation, 
Collection of HRAS 
mutation information 
X 
 
 
 
 
 
 
Demographics and 
medical history, 
including HPV status 
and information on prior 
anti-cancer therapy(ies)  
X 
 
 
 
 
 
 
Concomitant meds and 
AE assessment1 
X 
X 
X 
X 
X 
X18 
 
12-Lead ECG2 
X 
 
 
 
 
 
 
ECOG performance 
status 
X4 
X 
 
 
X 
 
 
Physical Exam13 
X4 
X 
 
 
X 
 
 
Weight 
X4 
X 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
Vital Signs (temperature, 
blood pressure heart 
rate) 
X4 
X 
X 
 
X 
 
 
Hematology3 
X4 
X5 
X5 
 
X 
 
 
Blood chemistry3 
X4 
X5 
X5 
 
X 
 
 
Coagulation3 
X4 
 
 
 
 
 
 
Urinalysis3, 6 
X4 
 
 
 
 
 
 
Tumor blocks or slides 
for HRAS7 
X 
 
 
 
 
 
 
Pregnancy test8 
X19 
X20 
 
 
X 
 
 
Tumor assessment (CT 
scan or MRI)9 
X 
 
 
X 
X 
X 
 
Tipifarnib 
administration10 
  
X 
 
 
 
 
 
Buccal swab11 
X 
 
 
 
 
 
 
Collection of survival 
and anticancer treatment 
information 
 
 
 
 
 
X 
X 


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chemistry test will be conducted at Day 7 ± 2 days and hydration and electrolyte imbalances, if observed, corrected 
according to institutional guidelines. Additional follow up tests may be conducted at the discretion of the investigator. 
6. 
Macroscopic assessment of the amount of protein, glucose, white blood cells and blood will be conducted in the urine 
samples. If abnormalities are noted, these will be recorded and a microscopic urinalysis conducted and recorded. If at any 
time, the subject’s serum creatinine is ≥ Grade 2, then a serum chemistry, microscopic urinalysis including the measurement 
of protein, glucose, blood, and white blood cells will be conducted. If abnormalities are noted, then spot urine sodium, 
protein and creatinine should be performed to assess fractional sodium excretion (plasma creatinine x urine sodium / plasma 
sodium x urine creatinine) and urine protein/creatinine ratio (urine protein mg/urine creatinine mg ratio).  
7. 
Collection of available archival tumor tissues in paraffin embedded blocks or a minimum of 10 unstained slides except in 
cases of anaplastic thyroid cancer. Provision of tumor slides is not required for cases of anaplastic thyroid cancer. The 
archival tumor tissue(s) can be gathered anytime within Cycles 1-3 if additional time is needed to locate the tissue 
blocks/slides, but time of actual tissue biopsies are always to be prior to any dosing of tipifarnib. Efforts should be made to 
collect these materials as early as possible. HRAS status, including T81C genetic polymorphism, will be assessed 
retrospectively. The result of this assessment is not required for subject enrollment. Enrollment may proceed with the 
information on tumor HRAS status already available at the study sites.  
8. 
Pregnancy tests (urine or serum) will be conducted at screening within 72 hours of first administration of study drug, on Day 
1 at each treatment cycle starting at Cycle 2 and at the End of Treatment visit. 
9. 
Tumor assessments: Appropriate spiral CT with contrast (preferred method) or MRI scans will be conducted at screening 
and Day 22 ± 5 days of every even cycle for the first 6 months (Cycles 2, 4, 6) and then every 12 weeks (Cycles 9, 12, 15, 
etc.) until disease progression or subject’s End of Treatment visit. Scans at the End of Treatment visit will be performed if 
not done within the prior 8 weeks unless additional anticancer therapy has been initiated or if a tumor assessment is required 
for the confirmation of response. Subjects who discontinue treatment for reasons other than disease progression should 
continue tumor assessments until disease progression, withdrawal of subject’s consent or initiation of another anticancer 
therapy. If subject is allergic to IV contrast, MRI scans or non-contrast CT may be used. The imaging schedule (every 8-12 
weeks) should be maintained regardless of dosing delays or additional imaging assessments performed. Tumor scans will be 
reviewed by the clinical sites. Tumor assessments may be conducted locally for convenience; however, efforts should be 
made to decrease the variability of the assessments. An independent review of tumor scans may be conducted if deemed 
necessary by the Sponsor for the assessment of the efficacy of tipifarnib. Copies of tumor images must be de-identified of 
subject’s personal information at the clinical sites and provided to the Sponsor or its designee if an independent review is 
requested by the Sponsor. 
10. Subjects will receive tipifarnib starting at 600 mg orally bid with food on days 1-7 and 15-21 of 28 day treatment cycles. 
11. Buccal swabs will be collected at screening for CXCL12 SNP testing and as a control sample for the analysis of tumor 
mutations using kits provided by the Sponsor. If swabs are not collected during screening for any reason, collection can be 
conducted at any time during the study. Detailed buccal swab collection, storage and shipping procedures will be provided 
in a separate lab manual. 
12. An End of Treatment visit will be conducted within 30 days (+/- 7 days) from the last dose of tipifarnib or immediately 
before the initiation of any other anticancer therapy. 
13. Complete physical exam will be performed at screening within 14 days of first administration of study drug and at the End 
of Treatment visit. A symptom-based physical exam will be conducted on Day 1 of every treatment cycle.  
14. On-site visits every 2-3 months will be required only if tumor assessments are conducted.  
15. Information on subject’s survival and use of subsequent anticancer therapy may be collected by phone. Upon disease 
progression, all subjects will be followed approximately every 12 weeks for survival and the use of subsequent therapy until 
either death or 12 months after accrual in the subject’s study cohort has been completed, whichever occurs first. Information 
on survival and subsequent anticancer therapy may be collected by phone. 
16. The visit at Day 1 of Cycle 2 and beyond can take place +/- 2 days if deemed necessary due to scheduling conflicts. The ± 2 
day window is instituted to facilitate the scheduling of the visit, but should not affect dosing schedule. Subjects will be 
dosed using the 1-week on, 1-week off schedule independent of the visit.  
17. Visit to be performed during Cycle 1 only. 
18. Assessment of AEs and concomitant medications may also be conducted at the Follow Up Visit if not resolved at the End of 
Treatment Visit. 
19. Assessment must be done within 72 hrs prior to first administration of study drug on Day 1 of Cycle 1.   
20. Assessment to begin at Day 1 of Cycle 2. 


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3 
TABLE OF CONTENTS 
Section 
 
1 
PROTOCOL APPROVAL PAGE ........................................................2 
2 
SYNOPSIS ...........................................................................................3 
3 
TABLE OF CONTENTS ...................................................................11 
4 
ABBREVIATIONS ............................................................................15 
5 
INTRODUCTION ..............................................................................17 
5.1 
Mechanism of Action .........................................................................17 
5.1.1 
Clinical Pharmacology ........................................................................19 
5.2 
Clinical Development .........................................................................20 
5.3 
Rationale for the Study .......................................................................21 
6 
OBJECTIVES .....................................................................................23 
6.1 
Primary Objectives and Endpoints .....................................................23 
6.2 
Secondary Objectives and Endpoints .................................................23 
6.3 
Exploratory Objective and Endpoints .................................................23 
7 
SUBJECT SELECTION .....................................................................24 
7.1 
Inclusion Criteria ................................................................................24 
7.2 
Exclusion Criteria ...............................................................................25 
8 
TRIAL DESIGN .................................................................................26 
8.1 
Study Design .......................................................................................26 
8.2 
Subject Identification and Replacement of Subjects ..........................30 
8.3 
Assignment to Treatment Groups .......................................................30 
8.4 
Removal of Subjects from Treatment or Assessment .........................30 
8.5 
Premature Discontinuation of the Trial ..............................................31 
8.6 
Definition of End of Study .................................................................32 
9 
TREATMENTS ..................................................................................32 
9.1 
Investigational Product (IP) ................................................................32 
9.1.1 
Product Characteristics .......................................................................32 
9.1.2 
Storage and Labeling ..........................................................................33 
9.2 
Treatment Administration ...................................................................33 
9.3 
Treatment Assignment ........................................................................34 


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9.4 
Dose Selection ....................................................................................34 
9.5 
Dose Modification and Management of Toxicity ...............................35 
9.6 
Treatment of Overdose .......................................................................38 
9.7 
Blinding ..............................................................................................38 
9.8 
Treatment Compliance ........................................................................38 
9.9 
Investigational Product Accountability ..............................................39 
9.10 
Return and Disposition of Clinical Supplies ......................................39 
9.11 
Prior and Concomitant Medications ...................................................39 
9.12 
Non-permitted Treatments ..................................................................40 
9.13 
Dietary or Other Protocol Restrictions ...............................................41 
9.14 
Potential Effects on Reproduction and Development .........................41 
9.15 
Medical Care of Subjects after End of Trial .......................................42 
10 
EFFICACY AND SAFETY VARIABLES ........................................42 
10.1 
Efficacy Variables ..............................................................................42 
10.2 
Assessment of Safety ..........................................................................43 
10.3 
Adverse Events ...................................................................................43 
10.4 
Abnormal Laboratory Findings and Other Abnormal 
Investigational Findings ......................................................................45 
10.5 
Serious Adverse Event ........................................................................45 
10.6 
Events that Do Not Meet the Definition of an SAE ...........................46 
10.7 
Events Not to Be Considered as AEs/SAEs .......................................46 
10.8 
Methods of Recording and Assessing Adverse Events ......................46 
10.9 
Adverse Event Reporting Period ........................................................46 
10.10 
Procedure for Reporting Serious Adverse Events ..............................47 
10.11 
Safety Reporting to Health Authorities, Institutional Review 
Boards and Investigators .....................................................................47 
10.12 
Monitoring of Subjects with Adverse Events .....................................48 
10.13 
Pregnancy and In Utero Drug Exposure .............................................48 
10.14 
Laboratory Assessments .....................................................................48 
10.14.1 
Blood Sample Collection for General Clinical Laboratory 
Assessments ........................................................................................49 
10.14.2 
Urinalysis ............................................................................................49 
10.15 
Additional Variables ...........................................................................49 


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11 
STUDY PROCEDURES ....................................................................49 
11.1 
Screening and Baseline Assessments .................................................49 
11.2 
Day 1 of Cycle 1 .................................................................................51 
11.3 
Day 7 (+/- 2 days) of Cycle 1 .............................................................51 
11.4 
Day 1 (+/- 2 days) of Cycle 2 and Beyond .........................................52 
11.5 
Day 22 (±5 days) of Cycles 2, 4, 6 and Cycles 9, 12, 15, etc.) ...........52 
11.6 
End of Treatment Visit .......................................................................53 
11.7 
Post Treatment Follow up ...................................................................53 
11.7.1 
Follow Up after Disease Progression .................................................54 
12 
STATISTICAL METHODS ...............................................................54 
12.1 
Populations .........................................................................................54 
12.1.1 
Efficacy Analysis ................................................................................54 
12.1.2 
Safety Analysis ...................................................................................55 
12.2 
Endpoints ............................................................................................55 
12.2.1 
Efficacy ...............................................................................................55 
12.2.2 
Safety and Tolerability .......................................................................56 
12.3 
Biomarkers ..........................................................................................57 
12.4 
Sample Size Determination ................................................................57 
12.5 
Changes in the Conduct of the Study or Planned Analyses ................58 
13 
ETHICAL AND REGULATORY ASPECTS ...................................58 
13.1 
Responsibilities of the Investigator ....................................................58 
13.2 
Subject Information and Informed Consent .......................................59 
13.3 
Subject Identification and Privacy ......................................................60 
13.4 
Emergency Medical Support and Subject Card ..................................60 
13.5 
Clinical Trial Insurance and Compensation to Subjects .....................60 
13.6 
Institutional Review Board/Independent Ethnic Committee ..............61 
13.7 
Communication to Health Authorities ................................................61 
14 
TRIAL MANAGEMENT ...................................................................61 
14.1 
Case Report Form Management .........................................................61 
14.2 
Source Data and Subject Files ............................................................61 
14.3 
Investigator Site File and Archiving ...................................................63 
14.4 
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................63 


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14.5 
Changes to the Clinical Trial Protocol ................................................63 
14.6 
Clinical Trial Report ...........................................................................64 
14.7 
Publication ..........................................................................................64 
15 
REFERENCES ...................................................................................64 
 
 
 
 
 
 
 
 
 
 
 
 
Tables 
Table 1: Schedule of Activities ............................................................................................9 
Table 2: Tipifarnib dose levels ..........................................................................................36 
Table 3: Summary of  Dose Modifications for Treatment Related Toxicities ................37 
 
 
Figures 
Figure 1: Tipifarnib activity in HRAS-mutant HNSCC PDX models ...............................18 
Figure 2: Tipifarnib activity in cetuximab-resistant HRAS-mutant HNSCC PDX 
models .................................................................................................18 
Figure 3: Tipifarnib activity in HRAS-mutant LSCC PDX models ..................................19 
Figure 4: KO-TIP-001 Study Schema................................................................................28 
 
 
 


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4 
ABBREVIATIONS 
 
AE 
Adverse event 
AKT 
Serine/Threonine kinase AKT 
ALT 
Alanine Aminotransferase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
ASaT 
All subjects as treated 
AST 
Aspartate Aminotransferase 
AUC 
Area under the curve 
bid 
Twice a day 
BSC 
Best supportive care 
BUN 
Blood urea nitrogen 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
CBC 
Complete blood count 
CEA 
Carcinoembryonic antigen 
CFR 
Code of federal regulations 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical study report 
CT 
Computer tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
DOR 
Duration of response 
DPA 
Data protection act 
DTC 
Differentiated thyroid cancer 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
ERK 
Extracellular signal-regulated kinase 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed, paraffin-embedded 
FTase 
Farnesyl transferase 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HNSCC 
Head and neck squamous cell carcinoma 
HRAS 
Harvey rat sarcoma virus gene homolog 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 


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INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
IV 
Intravenous 
KRAS 
Kirsten rat sarcoma virus gene homolog 
MDRD 
Modification of the diet in renal disease 
MDS 
Myelodysplastic syndromes  
MeDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTC 
Medullary thyroid cancer 
NCI 
National Cancer Institute  
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
PD 
Progressive disease 
PE 
Physical examination 
PFS 
Progression free survival 
PI 
Principal Investigator 
PIC 
Patient informed consent 
PK 
Pharmacokinetic 
PR 
Partial response 
PT/INR 
Prothrombin time/international normalized ratio 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCC 
Squamous cell carcinoma 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase  
SGPT 
Serum glutamic pyruvic transaminase 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum concentration 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
v 
Version 
VAF 
Variant Allele Frequency 
 
 
 


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5 
INTRODUCTION 
Brief information on tipifarnib is presented in this section; more extensive information is 
provided in the Investigator’s Brochure (Tipifarnib Investigator’s Brochure, Edition 14, 06 
February 2018 
5.1 
Mechanism of Action 
Tipifarnib is a potent and selective inhibitor of farnesyltransferase (FTase), an enzyme 
responsible for adding a farnesyl group to proteins.  Although FTase inhibitors (FTIs) prevent 
more than 140 potential proteins from getting farnesylated, the function of many of these 
proteins is kept intact due to the compensative prenylation through type 1 geranylgeranyl 
transferase (GGTase-1) (Baines 2011; Berndt 2011; Takashima 2013).   Among RAS isoforms, 
inhibition of the farnesylation of KRAS and NRAS leads to their geranylgeranylation and 
unchanged membrane localization (Whyte 1997).   HRAS cannot be geranylgerantylated and its 
membrane localization and cellular function is suppressed by tipifarnib (Berndt 2011). 
Tipifarnib has consistently shown high activity in HRAS mutated tumor cell lines.  Early 
characterization of tipifarnib demonstrated that it caused de-farnesylation and loss of membrane 
localization of HRAS, but not KRAS or NRAS (Lerner 1997; Mahgoub 1999).  Tipifarnib 
inhibited cell proliferation of HRAS transformed NIH3T3 cells with an IC50 of 1.7 nM but did 
not inhibit parental NIH3T3 cells up to a concentration of 500 nM (End et al, 2001).  Consistent 
with a specific activity against HRAS, tipifarnib was found to potently inhibit the only two 
HRAS mutant cell lines from a 53 human tumor cell panel with IC50 of 1.7 nM and 5.2 nM, 
whereas cell lines with KRAS and NRAS mutations displayed a wide range sensitivity (~ 10 nM 
to > 500 nM) (End 2001).   
In preclinical animal models of HRAS driven cancer, tipifarnib has consistently shown potent 
activity.  In mouse cell line xenograft models, tipifarnib inhibited 86% tumor growth at 25mg/kg 
BID dose in HRAS mutated model while inhibiting only 10% tumor growth at the same dose in 
KRAS mutated model (End 2001).  FTIs have also shown strong efficacy in several HRAS 
driven transgenic mouse models (Kohl 1995; Barrington 1998; Trempus, 2000; Chen 2014).  
Further, in a methylnitrosourea induced rat mammary tumor model, 90% of tumors with HRAS 
mutation showed complete regression upon tipifarnib treatment, whereas the non-HRAS mutant 
tumors showed variable responses (Yao 2006).  
Tipifarnib has been tested in several clinically-relevant tumor types using patient derived 
xenograft (PDX) models. PDX models are thought to be more predictive of clinical activity 
because they are transplanted directly from the patient into host animals without in vitro culture 
and hence retain the properties of the original tumor more faithfully. As shown in Figure 1, 
tipifarnib dosed orally at 80mg/kg BID was highly active in PDX models of several HRAS-
mutant head and neck squamous cell carcinomas (HNSCCs) inducing tumor stasis, partial 
responses and some complete regressions of established tumors. Importantly, the robust 


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antitumor activity with tipifarnib was achieved in models that were resistant to both cetuximab 
(1mg/kg QW) and methotrexate (10mg/kg BIW) (Figure 2). 
Figure 1: Tipifarnib activity in HRAS-mutant HNSCC PDX models 
 
 
Figure 2: Tipifarnib activity in cetuximab-resistant HRAS-mutant HNSCC PDX models 
 
Head and neck tumors with HRAS mutations have previously been reported to be resistant to 
cetuximab and erlotinib in vitro and in vivo (Rampias 2014, Hah 2014, Wang 2014).  An 
intriguing study recently reported employed serial liquid biopsies from HNSCC patients to reveal 
that acquired resistance to cetuximab in the clinic is in some cases associated with the early 
appearance of de novo HRAS mutations (Braig 2016).   
Recent reports of gene expression patterns among squamous cell carcinomas have revealed that 
HNSCC and lung squamous cell carcinoma (LSCC) are closely related (Wilkerson 2010, Keck 
2014); indeed, LSCC biology is now thought to more closely resemble HNSCC than lung 
adenocarcinoma, so additional preclinical studies were carried out in a panel of LSCC PDX 
models. Encouragingly, six of seven HRAS-mutant lung squamous PDX models tested were 
highly sensitive to tipifarnib therapy, exhibiting response that ranged from full stasis to partial 
and complete regressions, as shown in Figure 3. As in the HNSCC models, activity was observed 
in tumors mutated at the G12, G13 and Q61 loci, and in models that were resistant to cetuximab 
(not shown) and cisplatin/gemcitabine (Figure 3). 




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instructed to use antacids (magnesium or aluminum containing products) at least 2 hours before 
or after intake of oral study drug. 
Tipifarnib is a substrate for cytochrome P450 (CYP450) enzymes and glucuronosyltransferase. 
Inhibitors of CYP450 enzymes, including azole antifungals and omeprazole, did not reduce the 
clearance of tipifarnib in humans. However, antiepileptic drugs that are potent inducers of 
CYP450 enzymes (e.g. phenytoin, phenobarbital and carbamazepine) reduce plasma 
concentrations of tipifarnib and caution is warranted if concomitant administration of such agents 
is necessary.  Therefore, it is recommended that subjects use non-enzyme-inducing anti-
convulsants (e.g., gabapentin, topiramate, valproate) if necessary while taking tipifarnib.  
In addition, population pharmacokinetic analyses evaluated the influence of various concomitant 
medications on the pharmacokinetics of tipifarnib in clinical studies. Amphotericin, antiemetics, 
5HT3 antagonists (dolasetron, granisetron, ondansetron, and tropisetron), antifungal azoles 
(econazole, fluconazole, itraconazole, ketoconazole, and miconazole), benzodiazepines, 
ciprofloxacin, and corticosteroids appeared to have no discernible impact on the plasma 
concentrations of tipifarnib.  
5.2 
Clinical Development 
Tipifarnib was the first specific inhibitor of FTase to enter clinical studies. The clinical 
development of tipifarnib began in 1997 and consisted of over 70 clinical oncology and 
hematology studies.  
Several efficacy trials of tipifarnib in subjects with nonhematological malignancies have been 
reported, including those in subjects with advanced breast cancer, metastatic pancreatic cancer, 
melanoma, small cell lung cancer (SCLC), myelodysplastic syndromes (MDS), multiple 
myeloma, urothelial tract transitional cell carcinoma, colorectal cancer and non-small cell lung 
cancer (NSCLC) (Adjei 2003; Cohen 2003; Johnston 2003; Alsina 2004; Heymach 2004; 
Kurzrock 2004; Rao2004; Rosenberg 2005; Hong, 2011; Gajewski 2012). In the study in 76 
subjects with advanced breast cancer, 9 partial responses and 9 cases of stable disease (of at least 
24 weeks’ duration) were observed. In a phase II study of tipifarnib in subjects with metastatic 
transitional cell carcinoma of the urothelial tract (n=34), two responses were observed (6%) in 
subjects with no prior chemotherapy treatment and a total of 13 study subjects achieved disease 
stabilization. Objective responses were also observed in subjects with differentiated thyroid 
(DTC, including follicular thyroid cancer) and medullary thyroid cancer (MTC) in combination 
with the multi-kinase inhibitor sorafenib. MTC partial response rate was 38% (five of 13) 
whereas the DTC partial response rate was 4.5% (one of 22). Median progression-free survival 
for all 35 subjects in the study was 18 months (Hong 2011). Of note, a high prevalence of HRAS 
mutations have been reported in RET-negative sporadic medullary thyroid carcinomas. Somatic 
H-RAS mutations were detected in 14 of 25 (56.0%) of RET-negative sporadic MTC whereas 
only 1 of 40 (2.5%) RET-positive sporadic MTC had an HRAS mutation (Moura 2011). 


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However, a high frequency of HRAS mutation in RET-negative MTC has not been observed in 
other studies (Schulten 2011). 
Promising activity of tipifarnib in an unselected patient population was reported in poor-risk 
acute myeloid leukemia or MDS, in which a 33% response rate (eight complete responses, two 
partial responses) was initially seen. Patients were dosed at 600 mg twice daily for 21 days. In a 
second phase II trial in subjects with MDS, tipifarnib showed activity in 3 of 27 patients, 
resulting in two complete remissions and one partial remission. The drug was administered at a 
dose of 600 mg twice daily for 4 weeks, followed by 2 weeks of rest. Subsequent phase III 
studies in acute myeloid leukemia and MDS failed to confirm a clinical benefit derived from 
tipifarnib treatment in these indications. 
5.3 
Rationale for the Study 
Initial studies of tipifarnib were conducted without a selection of treatment subjects based on 
their tumor molecular characteristics. Preclinical data indicate that tumor models carrying HRAS 
mutations are highly sensitive to FTase inhibitor. The reason for this selectivity is potentially the 
fact that, contrary to KRAS and NRAS, HRAS protein does not undergo geranylgenarylation. 
Geranylgenarylation allows membrane localization and signal transduction of KRAS and NRAS 
in a setting of FTase inhibition, overcoming the effect of FTase inhibitors. In HRASG12V +/+, p53 -
/- mouse cells, incubation with tipifarnib at concentrations of 25 nM for 48 hours resulted in 
complete loss of pERK and pMEK (Kura Oncology Inc., data on file). Likewise, HRASG12V +/+, 
p53 -/- anaplastic thyroid tumors in mice treated with tipifarnib 80 mg/kg bid for 14 days, 
underwent 5 regressions out of 9 animals with no significant loss in body weight noted (Dr. 
James Fagin, MSKCC). Similar results were observed in other HRAS mutant tumor models. For 
example, in a patient HRASQ61R adeno-squamous lung cancer-derived mouse xenograft model, a 
4-week tipifarnib treatment of 80 mg/kg, bid resulted in regression or complete tumor growth 
inhibition in 2 out of 3 animals (Kura Oncology Inc. data on file).  These experiments strongly 
suggested that tipifarnib may be particularly active against tumors carrying HRAS mutations. 
Consistent with this hypothesis, the present study will include only subjects with tumors that 
carry missense HRAS mutations. Indications in which a relatively high incidence of HRAS 
mutations have been detected include thyroid cancer as well as HNSCC, urothelial carcinomas 
and salivary gland malignancies (cBIO Portal and COSMIC).  
Preliminary antitumor activity in Stage 1 of Cohort 2 at a pre-specified interim analysis showed 
that of the 11 evaluable subjects with HRAS mutant tumors, 2 subjects had a confirmed partial 
response (PR) by RECIST v.1.1 and 4 subjects had stable disease > 6 months.  
Three subjects with HRAS mutant HNSCC were enrolled in Stage 1 of Cohort 2: 
 The first subject was an elderly male with metastatic HNSCC (primary tracheal tumor 
and prior history of nasal SCC) who received prior treatment with 2 cycles of paclitaxel, 
carboplatin and cetuximab. Further treatment consisted of paclitaxel and cetuximab 


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followed by cetuximab and radiation. This subject did not reach an objective response 
and his outcome from standard therapy is qualified by investigator as a “mixed response”. 
Approximately 8 months later, upon evidence of disease progression, the subject was 
enrolled in the tipifarnib study, experienced a PR at his first on study tumor assessment 
(cycle 2) and remained on single agent tipifarnib treatment for approximately a year and a 
half, at which time, he experienced disease progression.  
 An additional PR of >1 year duration was observed in a subject who experienced a best 
response of disease progression on his prior regimen of cetuximab in combination with 
paclitaxel. This partial response was observed at the first on study tumor assessment on 
cycle 2. This patient continues on study treatment. 
 A disease stabilization of 7 months duration was observed in a subject who experienced a 
best response of progressive disease in his prior cetuximab treatment. This subject left the 
tipifarnib study without imaging evidence of disease progression.   
Based on the antitumor activity observed during stage 1 of cohort 2, the protocol was amended to 
restrict enrollment in stage 2 of cohort 2 to subjects with HNSCC with HRAS mutations only. 
Four additional subjects with HNSCC had been enrolled at the time of the preparation of 
Amendment 4: 
 A PR was observed in a subject who had a best response of progressive disease (PD) to 
her prior pembrolizumab treatment. The PR was observed at her first on study tumor 
assessment on cycle 2 experienced and was confirmed on cycle 4. This subject continues 
on study treatment. 
 The second subject of Cohort 2 Stage 2 had a short lived partial response (3 months 
duration) on prior platinum-based therapy and experienced disease stabilization on his 
first on study evaluation. This subject continues on study treatment. 
 The third subject experienced a PR in Cycle 1 with confirmation of the response in Cycle 
3.  Prior to enrolling in KO-TIP-001, this subject was treated as part of a clinical trial 
investigating nivolumab in combination with an undisclosed investigational agent.  After 
2 weeks of treatment on the nivolumab combination, this patient was experiencing hyper 
progression of disease, was removed from the study and subsequently enrolled into KO-
TIP-001.  Prior to the nivolumab combination, this subject had a best response of stable 
disease on a platinum based therapy.   
 The fourth subject of Cohort 2, Stage 2 was ongoing in Cycle 1 and has not reached the 
first response assessment visit. 
Upon on the observation of 4 confirmed responses in Cohort 2 (Stages 1 and 2), the primary 
objective of rejection of the null hypothesis of 10% ORR was met in this cohort, and the study 
was amended (Amendment 4) to continue enrollment of HRAS mutant HNSCC subjects to up to 


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a total of 30 (10 enrolled in Stage 1 and 2 combined, plus 20 additional subjects) to further 
explore the antitumor activity of tipifarnib in this tumor type. 
In addition, based on the similarities of other SCC tumors with HNSCC, a new cohort, Cohort 3, 
was included in amendment 4 with an increase in the target enrollment to up to 20 subjects added 
as part of amendment 5. These subjects will be treated and followed in the same manner as the 
two cohorts described above. The choice of 20 subjects is empirical due to the rarity of HRAS 
mutations in SCC other than HNSCC. 
The rationale for the selection of the dose and treatment regimen is provided in section 9.4. 
6 
OBJECTIVES 
6.1 
Primary Objectives and Endpoints 
Primary Objective: To determine the antitumor activity in terms of ORR of tipifarnib in subjects 
with locally advanced unresectable or metastatic, relapsed and/or refractory, HRAS mutant non 
hematological malignancies.   
Primary endpoint: Response assessments according to RECIST 1.1.   
6.2 
Secondary Objectives and Endpoints 
Secondary Objective: Safety and tolerability of tipifarnib in subjects with locally advanced 
unresectable or metastatic, relapsed and/or refractory, HRAS mutant non hematological 
malignancies. 
Secondary Endpoint: Treatment-emergent adverse events (TEAE) and SAEs evaluated 
according to NCI CTCAE v.4.03.   
6.3 
Exploratory Objective and Endpoints 
Exploratory Objective 1:  To determine the antitumor activity in terms of PFS and DOR of 
tipifarnib in subjects with locally advanced unresectable or metastatic, relapsed and/or refractory, 
HRAS mutant non hematological malignancies. 
Exploratory Endpoints 1: PFS and DOR according to RECIST 1.1. 
Exploratory Objective 2: To explore the feasibility of collecting archival biopsies and analyzing 
these biopsies for the detection of tissue biomarkers potentially related to tipifarnib activity. 
Exploratory Endpoints 2: Molecular analyses of archival tissue samples. 


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7 
SUBJECT SELECTION 
7.1 
Inclusion Criteria 
For inclusion of a subject in the study, all of the following inclusion criteria must be fulfilled: 
1. Subject is at least 18 years of age. 
2. 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.   
a. Cohort 1 will enroll subjects with malignant thyroid tumors with HRAS mutations, 
independently of thyroid histology.  
b. 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.   
c. 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 located in the head and 
neck will be enrolled in cohort 3. 
3. Subject has a tumor that carries a missense HRAS mutation with a 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. 
4. 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. 
5. Subject has measurable disease according to RECIST v1.1 and has relapsed or is refractory 
to prior therapy. 
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 toxicity 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.  


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8. ECOG performance status of 0 or 1 
 
9. Acceptable liver function:  
a. Bilirubin  1.5 x ULN. 
b. AST (SGOT) and ALT (SGPT)  1.5 x ULN. 
10. 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. 
11. Acceptable hematologic status: 
a. ANC  1000 cells/μL. 
b. Platelet count  75,000/μL. 
c. Hemoglobin  8.0 g/dL. 
12. 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. 
13. Female subjects must be: 
a. Of non-child-bearing potential (surgically sterilized or at least 2 years post-menopausal);  
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 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. 
c. Not breast feeding at any time during the study. 
14. Written and voluntary informed consent understood, signed and dated. 
7.2 
Exclusion Criteria 
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. 


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4. 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.  
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 subject is not able to endure for the 
conduct of instrumental activities of daily life or that persists ≥ 7 days. 
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 hepatitis C. 
8. Received treatment for non-cancer related liver disease (excluding cholelithiasis) within prior 
year. 
9. 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. 
10. Required use of concomitant medications classified as strong inhibitors or inducers of 
cytochrome P450 3A4 (CYP3A4, 
) or UDP-glucuronosyltransferase (UGT).   
11. 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.  
12. The subject has legal incapacity or limited legal capacity. 
13. Dementia or 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. 
8 
TRIAL DESIGN 
8.1 
Study Design 
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 standard curative therapy available. Enrollment 
may proceed using available known HRAS tumor status information previously generated at the 
clinical study sites; however, all subjects, except those with anaplastic thyroid tumors, must 
consent to provide at least 10 slides from a prior diagnostic biopsy for a retrospective testing of 


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HRAS status, including T81C polymorphism, at a central facility. Exploratory analyses of 
additional biomarkers potentially related to tipifarnib’s mechanism of action may also be 
conducted in these archival samples. The Sponsor is planning to develop a methodology for the 
detection of HRAS mutations in parallel to the conduct of the study, but subjects enrolled in the 
study will not undergo any additional procedures (e.g. tissue biopsy), beyond those previously 
conducted as part of their standard of care, in support of the development of this test.  
Subjects will be enrolled into three nonrandomized cohorts: 
 Cohort 1: Malignant thyroid tumors with HRAS mutations. 
 Cohort 2: Non-hematological malignancies with HRAS mutations in stage 1.  Head and 
neck squamous cell carcinomas (HNSCC) with HRAS mutations in stage 2. 
 Cohort 3: Squamous cell carcinoma (SCC) with HRAS mutations (excluding thyroid and 
mucosal head and neck tumors). 
Cohort 1 will enroll subjects with malignant thyroid tumors with HRAS mutations, 
independently of thyroid histology. Any subject with a non-hematological HRAS mutant tumor 
who meets eligibility criteria may be enrolled in the first stage of Cohort 2. Subjects with 
HNSCC, salivary malignancies and urothelial carcinomas may be more frequently enrolled in 
Cohort 2 due to the relatively high rate of HRAS mutations in these indications; however, 
enrolment is not limited to these tumor types. Subjects with malignant thyroid tumors with 
HRAS mutations will only be enrolled in cohort 1. Based on the anti-tumor activity observed 
during stage 1 of cohort 2, the protocol was amended (Amendment 3) to restrict enrollment in 
stage 2 of Cohort 2 to subjects with HNSCC with HRAS mutations only.  
Cohort 3 was added as part of amendment 4 to the protocol and enrollment expanded to a target 
20 subjects as part of amendment 5. Subjects (N=20) planned for enrollment are those who have 
SCC with HRAS mutations with a VAF >20%.   The purpose of this cohort is to explore 
tipifarinib’s anti-tumor activity in HRAS mutation positive SCCs independent of tissue origin. 
The study design is shown in Figure 4. 


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Figure 4: KO-TIP-001 Study Schema 
 
 
Only consented subjects who meet all the eligibility criteria will be enrolled in the study. All 
screening evaluations will be completed within 4 weeks (28 days) of Cycle 1 Day 1. Any 
screening evaluation, including disease status, will need to be repeated if performed more than 4 
weeks from Cycle 1 Day 1. Efforts will be made to collect information on the response and 
duration of response of the subject’s last prior therapy. 
Up to 75 evaluable subjects may be enrolled in the study. A two-stage study design will be used 
in Cohort 1 and Cohort 2 in order to minimize the number of study subjects treated if tipifarnib 
were considered not sufficiently efficacious to grant further development in this subject 
population. This design is intended to allow the termination of accrual in a particular study 
cohort in case of unacceptably low efficacy after objective responses in the first 11 evaluable 
subjects (stage 1) in the cohort are assessed in a Full Analysis Set (FAS) basis. If no objective 
responses are observed in a cohort after the first 11 evaluable subjects, the cohort will be closed 
to further enrolment. If two or more responses are observed in the cohort, 7 additional subjects 
will be enrolled (stage 2). Treatment will be considered of further interest if at least 4 responses 
are observed in a cohort (out of 18 subjects). Tumor response assessments will be conducted 
according to RECIST v1.1 criteria (confirmation of response is required), but in order to expedite 
the response assessment of the initial 11 evaluable subjects, tipifarnib will be considered not 
sufficiently efficacious if no confirmed objective tumor responses are observed in the study 
cohort prior to 6 months from the time of enrolment of the last of the 11 evaluable subjects.   
In Cohort 2, upon observation of 4 confirmed responses, enrollment of HRAS mutant HNSCC 
subjects will continue up to 30 subjects with HRAS mutant HNSCC (10 enrolled in Stage 1 and 
2 combined, plus 20 additional subjects) to further explore the antitumor activity of tipifarnib in 
this tumor type. 


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In Cohort 3, 20 subjects will be enrolled, treated and followed in the same manner as the two 
cohorts above. The choice of 20 subjects is empirical due to the rarity of HRAS mutations in 
SCC other than HNSCC.  
Tipifarnib will be administered at a starting dose of 600 mg, po, bid daily for 7 days in 
alternating weeks (Days 1-7 and 15-21) in 28-day cycles. Tipifarnib will be given with food.  
Stepwise 300 mg dose reductions to control treatment-related, treatment-emergent toxicities are 
described in Section 9.5. Unless otherwise contraindicated, subjects should be advised to be 
appropriately hydrated during the course of the study (e.g. drinking at least 8 glasses of 
water/day). 
In the absence of emerging unmanageable toxicity, subjects may continue tipifarnib treatment in 
the absence of disease progression and unmanageable toxicity. Treatment may continue beyond 
12 months upon agreement by the Investigator and Sponsor. 
Tumor assessments will be performed at screening and approximately every 8 weeks starting at 
the end of cycle 2 for the first 6 months (cycles 2, 4, 6) and then every 12 weeks (cycles 9, 12, 
15, etc.), or sooner if deemed necessary by the Investigator, and will continue until disease 
progression. A tumor assessment will be performed upon treatment discontinuation (End of 
Treatment visit) if the reason for discontinuation is other than disease progression and no tumor 
assessment was performed in the prior 8 weeks, or a tumor assessment is required for the 
confirmation of response to treatment. Subjects who discontinue treatment for reasons other than 
disease progression must continue tumor assessments until disease progression, withdrawal of 
subject’s consent or initiation of another anticancer therapy. Determination of objective tumor 
response will be performed by the Investigator. However, tumor images may be de-identified of 
subject’s personal information at the clinical sites and collected by the Sponsor or designee to 
undergo an external independent radiological review if the sponsor deems it necessary for the 
final assessment of the efficacy of the treatment. If an independent radiological review were to 
be conducted, reviewers would be blinded to Investigator’s tumor response assessments. An 
independent review committee charter would be generated to provide the specific procedures that 
would be filed with IRB/ECs and regulatory authorities. 
Subjects with a solitary site of disease who have experienced a response may be considered for 
surgical resection. Subjects with a Partial Response (PR) and residual disease after salvage 
surgery are eligible to continue on study therapy.  
Upon disease progression, all subjects in the study cohort will be followed approximately every 
12 weeks for survival and the use of subsequent therapy until either death or 12 months after 
accrual in the subject’s study cohort has been completed, whichever occurs first. Information on 
survival and subsequent anticancer therapy may be collected by phone.  
All subjects will be followed-up for safety during treatment and up to approximately 30 days (30 
+/- 7 days) after treatment discontinuation or until immediately before the initiation of another 
anti-cancer therapy, whichever occurs first. Additional follow up may be implemented until the 


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subject recovers from any emergent treatment related toxicity or the adverse event is considered 
irreversible by the Investigator. Target organ toxicities will be monitored via clinical and 
laboratory assessments using the National Cancer Institute Common Terminology Criteria for 
Adverse Events version 4.03 (CTCAE v 4.03). 
8.2 
Subject Identification and Replacement of Subjects 
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
eCRF pages. Subjects who do not receive at least one dose of tipifarnib will be replaced. 
Subjects who do not have post-baseline endpoint data subsequent to at least 1 dose of study drug 
may be replaced. 
8.3 
Assignment to Treatment Groups 
This is a nonrandomized study. Each treatment cohort will be conducted as single arm trial. 
Subjects will be assigned sequentially to the available dose cohort according to tumor histology.  
8.4 
Removal of Subjects from Treatment or Assessment 
Subjects may withdraw their consent to participate in this study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. A 
subject’s participation in the study may also be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. Every effort should be made to 
complete, whenever possible, the tests and evaluations listed for the End of Treatment visit. The 
Sponsor must be notified of all subject withdrawals as soon as possible. The Sponsor also 
reserves the right to discontinue the study at any time for either clinical research or 
administrative reasons and to discontinue participation by an individual Investigator or site for 
poor enrolment or noncompliance. 
Overall, the reasons for which the Investigator or Kura Oncology may withdraw a subject from 
study treatment include, but are not limited to, the following: 
 Subject experiences disease progression 
 Subject experiences unacceptable toxicity 
 Subject experiences toxicity that is deemed by the Investigator to be no longer safe for 
the subject to continue therapy 
 Subject requests to withdraw from the study treatment 
 Subject requires or has taken medication prohibited by the protocol 
 Subject is unwilling or unable to comply with the study requirements 
 Subject withdraws consent to collect health information 
 Subject was erroneously admitted into the study or does not meet entry criteria 


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 Subject is lost to follow-up 
 Subject becomes pregnant 
Subjects will return for an End of Treatment visit within approximately 30 days after the last 
administration of the study drug (or sooner if another anticancer therapy is to be initiated). If a 
subject fails to return for scheduled visits, a documented effort must be made to determine the 
reason. If the subject cannot be reached by telephone after 2 attempts, a certified letter should be 
sent to the subject (or the subject’s legally authorized representative, if appropriate) requesting 
contact with the Investigator. This information should be recorded in the study records.  
Prior to enrolment into the study, the Investigator or designee must explain to each subject, that 
the subject’s protected health information obtained during the study may be shared with the 
study Sponsor, regulatory agencies, and IRB/IEC in order to analyze and evaluate study results. 
It is the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as HIPAA in the US, from each subject, 
or if appropriate, the subject’s legally authorized representative. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written request, 
to ensure that no further data will be collected from the subject and the subject will be removed 
from the study. 
8.5 
Premature Discontinuation of the Trial 
This trial may be discontinued prematurely in the event of any of the following: 
 New information leading to a judgment of unfavorable risk-benefit of tipifarnib becomes 
available, e.g. due to evidence of inefficacy of tipifarnib in HRAS mutant tumors, 
occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of previously known adverse reactions, or other unfavorable safety 
findings in the HRAS mutant tumor subject population. Evidence of inefficacy may arise 
from this trial or from other trials and unfavorable safety findings may arise from clinical 
or non-clinical examinations, e.g. toxicology. 
 Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical 
reasons. 
 Poor enrollment of subjects making completion of the trial within an acceptable time 
frame unlikely.  
 Discontinuation of development of tipifarnib by the Sponsor.  
 Request by a Health Authority. 
Health Authorities and IRBs/IECs will be informed about the discontinuation of the trial in 
accordance with applicable regulations. In the case of premature discontinuation of the study, the 


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investigations scheduled for the End of Treatment assessment should be performed and the 
appropriate eCRF section completed. 
8.6 
Definition of End of Study 
For administrative and safety reporting purposes, the end of this clinical study is defined as 12 
months from enrollment of the last enrolled study subject.  If the last enrolled study subject 
discontinues treatment within 12 months of study enrollment, the End of Study will occur no 
earlier than the date of the last enrolled subject’s safety follow-up assessment performed 
approximately 30 days after treatment discontinuation (or until initiation of another anti-cancer 
therapy).  At the time of End of Study, provisions will be made to transition all remaining study 
subjects who demonstrate sustained clinical benefit beyond the end of the study to other means 
of continued treatment with tipifarnib, including appropriate safety monitoring, e.g. single 
patient treatment protocol.  For subjects enrolled in France and who have evidence of clinical 
benefit, continuation of treatment with tipifarnib may only take place in the setting of a separate 
study protocol. For subjects enrolled in Germany and who have evidence of clinical benefit, 
continuation of treatment with tipifarnib may only take place in the setting of a clinical trial or 
hardship program (“compassionate use”) per German Drug Law (AMG). 
9 
TREATMENTS 
Subjects will receive tipifarnib as monotherapy in this study. In the absence of unacceptable 
tipifarnib related emergent toxicity or disease progression, subjects may receive treatment with 
tipifarnib for up to 12 months at the discretion of the Investigator. Treatment beyond 12 months 
may continue upon agreement of the Investigator and the Sponsor. Kura Oncology, Inc. or its 
designee will provide the study site with a supply of tipifarnib sufficient for the completion of 
the study. 
All study subjects will be also eligible to receive best supportive care (BSC) defined as any 
standard supportive measures that are not considered a primary treatment of the disease under 
study, including the use of growth factors (i.e. GCSF) or blood transfusions for 
myelosuppression. BSC will be provided by the study sites. 
9.1 
Investigational Product (IP) 
Tipifarnib is a small molecule being developed as a potent, selective inhibitor of FTase for the 
treatment of cancer and other malignancies. 
9.1.1 
Product Characteristics 
Tipifarnib film-coated tablets for oral administration are supplied in HDPE bottles. Two 
strengths (100 mg and 300 mg) of tablets are provided containing either 100 or 300 mg of 
tipifarnib active substance, respectively. In addition to the active substance, the tablets contain 


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the following inactive ingredients: lactose monohydrate, maize starch, hypromellose, 
microcrystalline cellulose, crospovidone, colloidal anhydrous silica, and magnesium stearate. 
The nonfunctional, taste-masking film coatings contain hypromellose, titanium dioxide, lactose 
monohydrate, polyethylene glycol, and triacetin. Each strength of tablet has the same excipients 
but the quantitative composition is slightly different. Further information can be obtained from 
the current version of the Investigator’s Brochure.  
9.1.2 
Storage and Labeling 
At a minimum, the label of each bottle of tipifarnib tablets shipped to the study sites will provide 
the following information: batch number/lot number, study identification, required storage 
conditions, directions for use, and country specific required caution statements (including “New 
Drug – Limited by United States federal law to investigational use” language). 
Tipifarnib accountability records will be maintained by the pharmacy or designated drug 
preparation area at the study sites. Upon receipt of tipifarnib supplies, the pharmacist or 
designated study site investigational drug handler will inventory tipifarnib (separately for each 
strength, if applicable) and complete the designated section of the shipping form. The 
shipping/inventory form must be sent to Kura Oncology, Inc. or its designee, as instructed. 
Tipifarnib should be stored at controlled room temperature 15 to 30 C (59 to 86 F). All study 
supplies must be kept in a restricted access area. 
9.2 
Treatment Administration 
Tipifarnib will be administered with food at a starting dose of 600 mg, po, bid daily on days 1-7 
and 15-21 of 28-day treatment cycles.  
The first study dosing (Cycle 1 Day 1) will take place in the study clinic. Tipifarnib will be 
administered orally with a meal in the morning and again approximately 12 hours later at 
approximately the same times each treatment day. Tablets should be swallowed whole with 
water (~8 oz. or 250 mL) but may be chewed or crushed if the Investigator deems it necessary. 
Use of percutaneous endoscopic gastrostomy tubes is allowed at the judgment of the 
Investigator. If a dose is vomited or partially vomited, it should not be replaced with a new dose. 
Subjects may use proton pump inhibitors or H2 antagonists during the treatment portion of this 
study. However, subjects should be instructed to use antacids (magnesium or aluminum 
containing products) at least 2 hours before or after intake of oral study drug. 
On Cycle 1 Day 1, the site will provide tipifarnib to the subject from bulk supplies. Subjects will 
be provided with diaries with instructions to record the date and time of each dose and asked to 
bring the diaries and tablet bottles to each clinic visit for subject compliance and drug 
accountability review by the site staff.   


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9.3 
Treatment Assignment 
Treatment at each study cohort will be conducted in an open label manner.  Kura Oncology, Inc. 
or its designee will assign a subject number identifier and treatment cohort for each subject that 
is enrolled into the study. Study sites cannot enroll or start dosing the subject without receiving 
the assigned subject number.  
9.4 
Dose Selection 
In the majority of its phase II program, tipifarnib was given orally at a dose of 300 mg bid daily 
for 21 days, followed by 1 week of rest, in 28-day treatment cycles (21-day schedule). This 
regimen was employed in a prior version of this protocol. Under that protocol, a first subject was 
enrolled who presented with an advanced metastatic salivary gland tumor with a single HRAS 
mutation (Cheng 2015). The lack of effectiveness of the 21-day schedule in this subject and the 
hematological toxicity observed (grade 4 thrombocytopenia) prompted a review of the data 
generated with other tipifarnib dosing regimens as follows.  
The effect of higher dose levels given at intermittent schedules was tested in several phase 1 
studies, including a 5-day bid dosing followed by 9-day rest (5-day schedule; Zujewski 2000) 
and two trials investigating a 7-day bid dosing followed by 7-day rest (7-day schedule; Lara 
2005; Kirschbaum 2011). In the 5-day schedule phase 1 trial in patients with non-hematological 
malignancies, doses from 25 to 1300 mg bid were explored. No MTD was identified. Dose-
limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue in 4 of 6 
patients treated with 1300 mg bid. Fatigue, that was not dose-limiting, was observed at the prior 
dose level (800 mg bid). Of note, myelosuppression which was the most common toxicity in the 
21-day schedule (45% at 300 mg bid, Tipifarnib Investigator’s Brochure 2017), was limited with 
the 5-day schedule and included a grade 3 neutropenia in a patient with a prior history of 
myelosuppression treated with 50 mg bid and a grade 2 thrombocytopenia in a patient treated at 
the 1300 mg bid dose level. No objective responses were noted. 
In the first of the 7-day schedule studies (Lara 2005), the starting dose was 300 mg bid with 300 
mg dose escalations to a maximum planned dose of 1800 mg bid. Two of 6 patients with non-
hematological tumors in dose level 3 (900 mg bid) developed grade 3 fatigue attributable to 
study drug, and 600 mg bid on alternate weeks was identified as the recommended phase II dose. 
There were no objective responses but 4 out of 21 patients, 3 of whom had NSCLC, remained on 
study for at least 1 year with stable disease (12, 13, 16 and 17 months). Five grade 3 events of 
myelosuppression (out of 21 patients) were described by the authors (doses not indicated) that 
were not considered DLTs and hematological toxicity was described as moderate and 
manageable. 
The second 7-day schedule study was conducted in patients with relapsed/refractory AML 
(Kirschbaum 2011). Tipifarnib was administered bid on days 1–7 and days 15–21 of 28-day 
cycles at doses up to 1600 mg bid (Kirschbaum 2011). At the 400 mg bid dose level, a grade 5 


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hepatorenal failure occurred, potentially related to the study drug. There were no additional 
DLTs reported at 600, 800 or 1000 mg bid dose levels. At the 1200 mg bid dose level, a grade 3 
creatinine elevation was seen in one patient out of 6 treated. At the 1400 mg bid dose level, one 
patient experienced a grade 4 hypotension and a rising grade 2 creatinine that were dose limiting, 
and a second patient had a rising grade 2 creatinine that resulted in treatment discontinuation and 
was therefore considered dose limiting. At the 1600 mg dose level, grade 3 liver function tests 
and a rising grade 2 creatinine were dose limiting, and in a second patient, a rapidly rising 
creatinine was seen and treatment stopped. As a result, the 1200 mg bid dose was established as 
the MTD and 7 additional patients treated. Sixteen patients were treated at the 1000 and 1200 mg 
dosing levels, with 3 of them experiencing complete responses. No formal responses were seen 
among patients treated at the lower dose levels. 
Based on these data, the tipifarnib regimen to be investigated in the current study was modified 
to a starting dose of 900 mg, po, bid on days 1-7 and 15-21 of 28-day treatment cycles. 
Preliminary data from KO-TIP-001 indicate a tolerability that is broadly similar to the safety 
profile observed of other tipifarnib regimens in prior clinical studies which administered 
tipifarnib daily in a 21-day on, 7 days off treatment cycle schedule. The most common AES of 
tipifarnib including hematological events, gastrointestinal disturbances (nausea, vomiting and 
diarrhea) and fatigue have been monitorable and manageable with protocol defined assessments 
and management of toxicity guidance.  Dose reduction to 600 mg has been able to reduce 
tipifarnib-related toxicity and several subjects have maintained their response and continued on 
treatment for over 1 year.    
Given these preliminary observations and in discussion with study investigators, the starting dose 
has been reduced to 600 mg, po, bid on days 1-7 and 15-21 of 28-day treatment cycles as part of 
amendment 5 to the study protocol. In the absence of unmanageable toxicities, subjects may 
continue to receive tipifarnib treatment for up to 12 months in the absence of disease progression 
and unmanageable toxicity. Stepwise 300 mg dose reductions to control treatment-related, 
treatment-emergent toxicities are also included in this protocol amendment. Treatment may 
continue beyond 12 months upon agreement of the Investigator and Sponsor. 
Ongoing subjects receiving the 21-day schedule will be allowed to switch to the 7-day schedule 
at the discretion of the investigator.  Similarly, ongoing subjects receiving 900 mg bid will be 
allowed to maintain that dose or switch to 600 mg bid at the discretion of the investigator. 
9.5 
Dose Modification and Management of Toxicity 
All subjects will begin treatment with tipifarnib at a starting dose of 600 mg bid in alternating 
weeks.  If treatment-related, treatment-emergent AEs are observed meeting criteria for dose 
modification detailed further in this section, the dose level reductions summarized in Table 2 will 
be used. 


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Table 2: Tipifarnib dose levels 
Dose Level 
Alternate Week Schedule 
Doses in mg (am + pm) 
Starting Dose 
600 + 600 
-1 
300 + 600* 
-2 
300 + 300 
*Depending on subject preference, the 600 mg dose may be taken in the morning or in the evening, as long as the 
total daily dose is 900 mg, i.e. 600 mg can be taken in the morning or evening with 300 mg taken for the other 
scheduled dose time.  Tipifarnib should always be taken with a meal. 
If treatment-related treatment-emerging CTCAE grade 4 non-hematological toxicity is observed, 
treatment with tipifarnib will be permanently discontinued.  
If treatment-related treatment-emerging CTCAE > grade 3 hematological or grade 3 non-
hematological toxicity is observed that cannot be managed with supportive care measures, 
treatment with tipifarnib will be interrupted until recovery to < grade 2. If recovery requires more 
than 4 weeks, treatment is to be discontinued. Upon recovery, tipifarnib may be restarted at the 
original dose or at the next lower dose level (see Table 2) at the discretion of the investigator.  If 
grade 3 or 4 toxicity recurs, subsequent dose reductions may be conducted according to Table 2. 
If treatment-related treatment-emerging CTCAE grade 2 renal toxicity is observed that cannot be 
managed with supportive care measures (including hydration and correction of electrolyte 
abnormalities, if appropriate), treatment with tipifarnib will be interrupted until recovery to < 
grade 1.  Upon recovery to < grade 1, the subject may restart tipifarnib at their current dose level. 
If treatment-related treatment-emerging CTCAE grade 2 renal toxicity recurs or if grade 3 renal 
toxicity is observed that cannot be managed with supportive care measures, treatment with 
tipifarnib will be interrupted until recovery to < grade 1. Additional treatment may be given at 
the next lower dose level (see Table 2) upon subject’s recovery from toxicity. If grade 2 or 3 
renal toxicity recurs, a subsequent dose reduction may be conducted. Reduced doses due to renal 
toxicity will not be re-escalated.   
Treatment with tipifarnib should also be interrupted until recovery to grade 2 tolerable or better 
if treatment-related treatment-emergent CTCAE grade 2 intolerable neurological toxicity is 
observed. Additional treatment may be given at the next lower dose level (see Table 2) upon 
subject’s recovery from toxicity. If grade 2 intolerable neurological toxicity recurs, a subsequent 
dose reduction may be conducted. Reduced doses due to neurological toxicity will not be re-
escalated.  The occurrence of grade 3 neurological toxicity will result in permanent 
discontinuation of treatment.  
Unless otherwise indicated (e.g. dosing discontinuation), reduced doses may be re-escalated to 
the original dose at the judgement of the investigator. However, subjects who experience serious 
adverse events or a recurrence of ≥ grade 3 toxicity deemed to be related to tipifarnib will not 


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have their dose re-escalated following dose reduction.  In addition, subjects experiencing more 
than one dose delay of ≥ 14 days will not have their dose re-escalated.   
Asymptomatic laboratory findings will not be considered dose limiting unless otherwise 
determined by the Investigator. A summary of dose modifications is presented in Table 3. 
Table 3: Summary of  Dose Modifications for Treatment Related Toxicities 
Adverse Event 
Management 
Tipifarnib Dosing 
Grade 4 Non-Hematological 
Discontinue tipifarnib permanently 
> Grade 3  Hematological or 
Grade 3 Non-Hematological 
Manage with BSC, including RBC 
or platelet transfusion. If not 
manageable, interrupt tipifarnib 
treatment until recovery to grade 2 
or better.  
If recovery requires more than 4 
weeks, treatment is to be 
discontinued.  
Upon recovery to < grade 2, re-
start tipifarnib at current dose or 
at the next lower dose level (see 
Table 2) at the judgement of the 
investigator.  
If the same toxicity recurs, upon 
recovery to < grade 2, re-start 
tipifarnib at the next lower dose 
level (see Table 2). If grade 3 
thrombocytopenia recurs, consider 
additional cycles at original dose 
at the judgement of the 
investigator 
Grade 2 Renal 
Manage with BSC, including 
hydration and correction of 
electrolyte abnormalities, if 
appropriate.  
Upon recovery to < grade 1, re-
start tipifarnib at current dose. 
Grade 2 Recurrent or Grade 3 
Renal 
Manage with BSC, including 
hydration and correction of 
electrolyte abnormalities, if 
appropriate. If not manageable, 
interrupt tipifarnib treatment until 
recovery to grade 1 or better 
Upon recovery to < grade 1, re-
start tipifarnib at the next lower 
dose level (see Table 2).  
If grade 2 or 3 renal toxicity 
recurs, upon recovery to < grade 
1, re-start tipifarnib at the next 
lower dose level (see Table 2). 
Grade 2 non-tolerable 
Neurological  
Manage with BSC. If not 
tolerable, interrupt tipifarnib 
treatment until recovery to grade 2 
tolerable or better 
Upon recovery to grade 2 
tolerable or better, re-start 
tipifarnib at the next lower dose 
level (see Table 2).  
If grade 2 intolerable neurological 
toxicity recurs, upon recovery to 
grade 2 tolerable or better, re-start 
tipifarnib at the next lower dose 
level (see Table 2). 
Grade 3 Neurological  
Discontinue tipifarnib permanently 


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In exceptional circumstances, dosing delays or skipping of dosing for reasons other than the 
management of toxicity will be allowed at the judgement of the investigator as long as 50% of 
the total dose is maintained in a given cycle. 
Upon restarting tipifarnib following a treatment interruption, the cycle and dosing day are to be 
defined by the following:  
 If a dose delay/interruption occurs and resolves within a cycle, dosing picks up where it 
left off.   
o For example, if a subject’s treatment is held on Day 3, subject recovers 14 days 
later (nominal Day 17 in the cycle) and resumes tipifarnib treatment, the subject is 
considered to be dosing on Day 3 of the same cycle. 
 If the delay goes beyond the cycle (> nominal day 28 of that cycle), upon recovery, the 
subject should be started at Day 1 of the next cycle.   
o For example, if a subject’s treatment is held on Day 3, subject recovers 30 days 
later (nominal Day 33 in the cycle) and resumes tipifarnib treatment, the subject is 
considered to be dosing on Day 1 of the next cycle. 
 
Radiographic imaging for tumor response must maintain the fixed time schedule and is 
invariant to the drug exposure of the subject. Radiographic imaging will be performed at least 
once approximately every 8 weeks for 6 months, thereafter once approximately every 12 weeks. 
All other procedures/visits can follow the cycle’s drug administration. 
9.6 
Treatment of Overdose 
An overdose is defined as any dose greater than 20% over the daily tipifarnib dose. Any 
overdose must be recorded in the trial medication and adverse event sections of the eCRF. There 
is no known antidote for tipifarnib. In the event of overdose of tipifarnib, subjects should receive 
appropriate advice and supportive medical care by the Investigator or his/her designee and be 
followed-up accordingly. 
For monitoring purposes, any case of overdose – whether or not associated with an AE (serious 
or non-serious) – must be reported to the Sponsor in an expedited manner. 
9.7 
Blinding 
This is an open label study with no placebo or comparators. 
9.8 
Treatment Compliance 
The importance of treatment compliance should be emphasized to the subject. Subjects will be 
given study drug and detailed instructions on how to take medications at home. Subjects will be 
instructed to return all used and unused study drug containers at each study visit. Subject 
compliance with the dosing schedule will be assessed by reconciliation of the used and unused 


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study drug at each clinic visit and review of the dosing diaries. The quantity dispensed, returned, 
used, lost, etc. must be recorded on the dispensing log provided.  
Compliance will be monitored and documented by site personnel on the appropriate form. The 
site personnel will question the subject regarding adherence to the dosing schedule by reviewing 
the dosing diaries, recording the number of tablets (and strengths, if applicable) returned, the 
date returned, and determining treatment compliance (at least 80% of the total assigned dose) 
before dispensing new medication to the study subject. 
9.9 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates and 
quantities) of IP received, subjects to whom IP is dispensed (subject by subject specific 
accounting), and IP lost or accidentally or deliberately destroyed.  
9.10 
Return and Disposition of Clinical Supplies 
Unused tablets returned by the subject from a prior cycle of treatment may be re-dispensed to the 
subject. Study drug must be kept in a secure location for accountability and reconciliation by the 
Sponsor’s designated clinical trial monitor. The Investigator or designee must provide an 
explanation for any destroyed or missing study drug or study materials. 
Study drug may be destroyed on site, per the site’s standard operating procedures, but only after 
the Sponsor or its designee has been notified and granted approval for drug destruction. All study 
drug destroyed on site must be documented. 
Documentation must be provided to the Sponsor or its designee and retained in the Investigator’s 
study files. If a site is unable to destroy study drug appropriately, the site can return unused study 
drug to the Sponsor or its designee upon request. The return of study drug or study drug 
materials must be accounted for on a form provided by the Sponsor or its designee. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed or 
returned according to applicable state and federal regulations and study procedures. 
9.11 
Prior and Concomitant Medications 
All prescription and over-the-counter medications taken by a subject within 28 days before the 
first study drug administration will be recorded in the eCRF.  In particular, subjects will be asked 
about the use of agents that may affect the mevalonate pathway including statins (e.g. 
atorvastatin, simvastatin, rosuvastatin, pravastatin), bisphosphonates (e.g. pamidronate, 
risedronate, ibandronate, etidronate, alendronate) and nutritional agents (e.g. coenzyme Q₁₀, 
ubiquinone). 
Supportive care medications considered necessary for the subject’s safety and well-being may be 
given at the discretion of the Investigator. Any additional concomitant therapy that becomes 


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necessary during the trial and any change to concomitant drugs must be recorded in the 
corresponding section of the eCRF, noting the name, dose, duration and indication of each drug. 
BSC will be provided by the clinical study sites according to local guidelines and standard 
practices. 
Furthermore, the following treatments are allowed during the trial: 
 Correction of electrolyte deficiency. 
 Radiotherapy for pain control against non-target lesions as long as it does not influence 
bone marrow function. 
 Total tumor resection in responding subjects who have become candidates for curative 
resection. 
 Hematopoietic growth factors and transfusions of blood or blood products in subjects 
who are experiencing hematological toxicity in accordance with standard institutional 
practice. However, such supportive care should not be used prior to hematological 
findings unless absolutely clinically necessary and after discussion with the Sponsor or 
designee’s medical monitor.  
 Antiemetic therapy in a subject experiencing gastrointestinal symptoms in accordance 
with standard clinical practice.  If a subject experiences vomiting or nausea, prophylactic 
antiemetic medications may be administered with subsequent treatment in accordance 
with standard clinical practice. 
 Concurrent use of bisphosphonates as well as Thyroid-Stimulating Hormone (TSH) 
suppressive therapy.  
9.12 
Non-permitted Treatments 
Use of the following medications and therapies is not allowed during the trial: 
 Investigational agents other than tipifarnib. 
 Any other anticancer therapy, including radiation or surgery, for the primary disease 
under study with the exceptions of palliative treatment of non-target lesions and treatment 
of residual disease in study subjects who have experienced a partial response during the 
study. 
 High dose systemic corticosteroids or any other immunosuppressive drugs except: 
o Glucocorticosteroid treatment administered with a daily dose of ≤ 20 mg 
prednisone or equivalent,  
o Single doses for the management of treatment-related AEs or for premedication of 
BSC agents. 


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o Short course (≤ 7 days, including tapering) high dose systemic steroids for the 
treatment of upper airway obstruction associated with HNSCC 
 Strong inhibitors or inducers of CYP3A4 or UGT beginning at least 14 days prior to 
Cycle 1 Day 1 and during the subject’s participation in the tipifarnib treatment portion of 
this study.  
 
  If continued concomitant therapy is needed, subjects should be transitioned 
to a medicine that is not a strong inhibitor or inducer of CYP3A4 or UGT. 
 Sensitive substrates of CYP3A4 beginning Cycle 1 Day 1 and during the subject’s 
participation in the tipifarnib treatment portion of this study.  
 
 If continued concomitant therapy 
is needed, subjects should be transitioned to a medicine that is not a sensitive substrate of 
CYP3A4. 
 Subjects should not use enzyme-inducing anti-convulsants (e.g. phenytoin, phenobarbital, 
and carbamazepine) while taking tipifarnib. If needed, subjects may use non-enzyme-
inducing anti-convulsants (e.g. gabapentin, topiramate, valproate) while taking tipifarnib.  
If the administration of a non-permitted concomitant drug becomes necessary during the trial, 
e.g., because of AEs or disease progression, the subject in question will be withdrawn from the 
trial, and the subject’s data which will have been obtained before the withdrawal may be used for 
safety and efficacy evaluations. 
9.13 
Dietary or Other Protocol Restrictions 
No dietary restrictions related to tipifarnib are required. Subjects will be instructed to administer 
their dose of tipifarnib with a meal as the presence of food has been shown to improve the 
absorption of tipifarnib, as well as to reduce variability in the pharmacokinetic profile.   
Tablets should be swallowed whole with water (~8 oz. or 250 mL). Tablets may be chewed or 
crushed if the Investigator deems it necessary. Use of a percutaneous endoscopic gastrostomy 
tube or nasogastric tube is allowed at the judgment of the Investigator.  
Unless otherwise contraindicated, subjects should be advised to be appropriately hydrated during 
the course of the study (e.g. drinking at least 8 glasses of water/day). 
9.14 
Potential Effects on Reproduction and Development 
Male and female fertility and reproductive capacity has been shown to be impaired in rats and 
additional details can be found in the Tipifarnib Investigator’s Brochure.  
In light of the observations in nonclinical testing, both female subjects 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 4 weeks after last dose of trial 


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medication.  Female subjects of child-bearing potential must have a negative serum or urine 
pregnancy test within 72 hours prior to start of trial medication. 
Additionally, since tipifarnib could induce toxicity of male reproductive organs and cause 
impairment of fertility, sperm cryopreservation should be recommended for male subjects 
wishing to preserve their fertility following tipifarnib treatment.  Additionally, if the participant 
in the study is male, then the following items will be discussed with the subject: 
 Prevention of pregnancy in a female partner 
 Prevention of exposure of a partner to semen by any means (not just intercourse) 
 Prevention of the possible exposure of a pregnant female to the study drug from semen. 
 Informing their partner of the potential for harm to an unborn baby. The partner should 
know that if pregnancy occurs, she should promptly notify her personal doctor. 
 Acceptable methods of birth control for male subjects while participating in this study 
and for 4 weeks after the last dose of the study drug: 
o Abstinence (no sex) 
o Condom plus spermicidal agent (foam gel/cream/film/suppository) 
9.15 
Medical Care of Subjects after End of Trial 
After a subject has completed the trial or has withdrawn from the study, standard treatment will 
be administered, if required, in accordance with the trial site’s standard of care and generally 
accepted medical practice and according to the subject’s individual medical needs. 
10 
EFFICACY AND SAFETY VARIABLES 
Table 1 summarizes the study required evaluations. 
10.1 
Efficacy Variables 
Radiological and/or physical assessments of the tumor lesions, and evaluations of relevant tumor 
markers (e.g. CA125, PSA, CA19-9, CA27.29, thyroglobulin, anti-thyroglobulin antibodies, 
calcitonin and CEA, to be assessed at the judgment of the Investigator) will be made at screening 
(4 weeks before the first study drug administration), at the end of cycle 2 and at approximately 8 
week intervals thereafter until disease progression. Additional tumor assessments may be 
conducted at the judgment of the Investigator. Subjects who discontinue treatment for reasons 
other than disease progression must continue tumor assessments until disease progression, 
withdrawal of their consent to study procedures or initiation of another anticancer therapy. 
Efficacy assessments may also be conducted at treatment discontinuation (End of Treatment 
visit) if the reason for the treatment termination is other than disease progression and a tumor 
assessment was not done within 8 weeks before treatment discontinuation (assessment must be 


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conducted before additional anti-tumor therapy is started). Scans at the End of Treatment visit 
will be also conducted if required to confirm response to treatment. 
Lesions to be included in the tumor assessments should follow RECIST v1.1. Spiral CT scan 
with a contrast agent is the preferred imaging method. Tumor assessment with spiral CT scans 
should be performed as appropriate. Subjects with contrast allergy may use non-contrast CT or 
MRI, whichever is required to adequately assess all disease.  
Objective response (complete response and partial response) as determined by the subject’s best 
tumor response, duration of response, and time to progression will be assessed using RECIST 
v1.1. Confirmation of response is required. 
In addition to Investigator’s tumor response assessment, a central independent review tumor 
response assessment may be performed if the sponsor deems it necessary for the final assessment 
of the efficacy of the treatment. If an independent radiological review were to be conducted, 
reviewers will be blinded to the Investigator’s efficacy assessments. The sponsor, in consultation 
with the investigators, may initiate this independent review at any time during the trial. In that 
case, an independent review committee charter would be generated to provide the specific 
procedures that would be filed with IRBs/IECs and regulatory authorities prior to their initiation. 
Upon disease progression, all subjects will be followed approximately every 12 weeks for 
survival and the use of subsequent therapy until either death or 12 months after accrual in the 
subject’s study cohort has been completed, whichever occurs first. Information on survival and 
subsequent anticancer therapy may be collected by phone.  
10.2 
Assessment of Safety 
Adverse events will be graded according to the NCI CTCAE v 4.03. Adverse events will be 
summarized by relationship to trial drug, severity and grade. The safety profile of the IPs will be 
assessed through the recording, reporting and analyzing of baseline medical conditions, adverse 
events, physical examination findings including vital signs and laboratory tests. Comprehensive 
assessment of any apparent toxicity experienced by the subject will be performed throughout the 
course of the trial, from the time of the subject’s signature of informed consent. Trial site 
personnel will report any adverse event (AE), whether observed by the Investigator or reported 
by the subject. 
A safety monitoring committee comprised of the Investigators and Sponsor clinicians or 
designees will review all relevant safety data on a regular basis. 
10.3 
Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 


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medicinal product, whether or not considered related to the medicinal product. In cases of 
surgical or diagnostic procedures, the condition/illness leading to such a procedure is considered 
as the AE rather than the procedure itself. In case of a fatality, the cause of death is considered as 
the AE, and the death is considered as its outcome. 
The Investigator is required to grade the severity/intensity of each adverse event. Investigators 
will reference the NCI-CTCAE v 4.03. This is a descriptive terminology that can be used for 
adverse event reporting. A general grading (severity/intensity) scale is provided at the beginning 
of the referenced document, and specific event grades are also provided. If a particular AE’s 
severity/intensity is not specifically graded by the guidance document, the Investigator is to 
revert to the general definitions of Grade 1 through Grade 5 and use his or her best medical 
judgment. 
The 5 general grades are: 
 Grade 1: Mild 
 Grade 2: Moderate 
 Grade 3: Severe 
 Grade 4: Life-threatening or disabling 
 Grade 5: Death related to AE. Note: Death (Grade 5 as defined by NCI-CTCAE version 
4.03) is mainly regarded as an outcome, to be documented as described below. 
According to the Sponsor’s convention, if a severity/intensity of Grade 4 or 5 is applied to an 
AE, then the Investigator must also report the event as a serious adverse event (SAE; see 
definition below) as per Section 10.5. However, a laboratory abnormality with a 
severity/intensity of Grade 4, such as anemia or neutropenia, is considered serious only if the 
condition meets one of the serious criteria described below. 
In the case of death, the primary cause of death (the event leading to death) should be recorded 
and reported as an SAE. “Fatal” will be recorded as the outcome of this respective event; death 
will not be recorded as separate event. Only if no cause of death can be reported (e.g., sudden 
death, unexplained death), the death per se might be reported as an SAE. 
Investigators must also systematically assess the causal relationship of AEs to the IPs, other 
medicinal products using the following definitions. Decisive factors for the assessment of causal 
relationship of an AE to the trial treatments include, but may not be limited to, temporal 
relationship between the AE and the trial treatments, known side effects of the trial treatments, 
medical history, concomitant medications and procedures, course of the underlying disease, trial 
procedures. 
Relatedness of an AE will be evaluated as follows: 


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 Not related: Not suspected to be reasonably related to the IPs. AE could not medically 
(pharmacologically/clinically) be attributed to the IPs under trial in this clinical trial 
protocol. A reasonable alternative explanation must be available. 
 Related: Suspected to be reasonably related to the IPs. AE could medically 
(pharmacologically/clinically) be attributed to the IPs under trial in this clinical trial 
protocol. 
10.4 
Abnormal Laboratory Findings and Other Abnormal 
Investigational Findings 
Abnormal laboratory findings and other abnormal investigational findings (e.g. on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead 
to treatment discontinuation or are considered otherwise medically important by the Investigator. 
If an abnormality fulfills these criteria, the identified medical condition (e.g. anemia, increased 
ALT) must be reported as the AE rather than the abnormal value itself. 
10.5 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death. 
 Is life-threatening. NOTE: The term “life-threatening” in this definition refers to an event 
in which the subject is at risk of death at the time of the event; it does not refer to an 
event that hypothetically might cause death if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly/birth defect. 
 Is otherwise considered as medically important. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in subject hospitalization, or the development of drug dependency or drug 
abuse. 
For the purposes of reporting, any suspected transmission of an infectious agent via an IP is also 
considered a serious adverse reaction and all such cases should be reported in an expedited 
manner. 


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10.6 
Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (e.g. an 
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered as SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (e.g., undesirable effects of any administered 
treatment) must be documented and reported as SAEs. 
10.7 
Events Not to Be Considered as AEs/SAEs 
Medical conditions are present at the initial trial visit that do not worsen in severity or frequency 
during the trial are defined as Baseline Medical Conditions, and are NOT to be considered AEs. 
Progression of underlying disease is not an AE and therefore not an SAE per se, rather an 
efficacy end-point, unless deemed to be causally related to administration of IPs. However, if 
adverse signs or symptoms occur in association with disease progression then these should be 
recorded as AEs and reported as SAEs if meeting any seriousness criteria. 
10.8 
Methods of Recording and Assessing Adverse Events 
At each trial visit, the subject will be queried on changes in his/her condition. During the 
reporting period of the trial any unfavorable changes in the subject’s condition will be recorded 
as AEs, whether reported by the subject or observed by the Investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the 
eCRF. Among these AEs, all serious AEs must be additionally documented and reported using 
an Adverse Event Report Form. It is important that each AE report include a description of the 
event, its duration (onset and resolution dates (/times “/times” to be completed when it is 
important to assess the time of AE onset relative to the recorded treatment administration time)), 
its severity, its relationship with the trial treatment, any other potential causal factors, any 
treatment given or other action taken (including dose modification or discontinuation of the IPs) 
and its outcome. In addition, serious cases should be identified and the appropriate seriousness 
criteria documented. Specific guidance can be found in the eCRF completion and monitoring 
conventions provided by the Sponsor. 
10.9 
Adverse Event Reporting Period 
The adverse event reporting period for safety surveillance begins when the subject is included 
into the trial (date of first signature of informed consent) and continues through the trial’s post-
treatment follow-up period, defined as 30 days from the final administration of the trial treatment 
or immediately before initiation of any other anticancer therapy, whichever comes first. 


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10.10 
Procedure for Reporting Serious Adverse Events 
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (i.e. within a maximum 24 HOURS after becoming aware of the event) inform the 
person (s) identified in the Serious Adverse Event Report Form by telephone, by fax or by email. 
When an event (or follow-up information) is reported by telephone, a written report must be sent 
immediately thereafter by fax or e-mail. Reporting procedures and timelines are the same for any 
new information on a previously reported SAE. For names, addresses, telephone and fax 
numbers for SAE reporting, see information included in the Adverse Event Report Form. All 
written reports should be transmitted using the Adverse Event Report Form, which must be 
completed by the Investigator following specific completion instructions. 
The AE section of the eCRF must be completed and a copy of the information transmitted with 
the Adverse Event Report Form. Other relevant pages from the eCRF may also be provided (e.g., 
medical history, concomitant drugs). The Investigator/Reporter must respond to any request for 
follow-up information (e.g. additional information, outcome and final evaluation, specific 
records where needed) or to any question the Sponsor may have on the AE within the same 
timelines as described for initial reports. This is necessary to permit a prompt assessment of the 
event by the Sponsor to allow for strict regulatory timelines associated with expedited safety 
reporting obligations. 
10.11 
Safety Reporting to Health Authorities, Institutional Review 
Boards and Investigators 
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. The Investigator must comply with any applicable site-specific 
requirements related to the reporting of SAEs (and in particular deaths) involving his/her 
subjects to the IRB/IEC that approved the trial. 
In accordance with ICH GCP guidelines, the Sponsor will inform the Investigator of “findings 
that could adversely affect the safety of subjects, impact the conduct of the trial or alter the 
IRB/IEC’s approval/favorable opinion to continue the trial.” In particular and in line with 
respective regulations, the Sponsor will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (“suspected unexpected 
serious adverse reactions”, SUSARs). The Sponsor will also provide SUSAR information to the 
Competent Authorities in all Member States concerned and Ethics Committees in compliance 
with SUSAR reporting outlined in the European Directive 2001/20/EC.  The Investigator should 
place copies of Safety reports in the Investigator Site File. National regulations with regards to 
safety reporting notifications to investigators will be taken into account. When specifically 
required by regulations and guidelines, the Sponsor will provide appropriate safety reports 
directly to the concerned lead IRB/IEC and to the Competent Authorities in all Member States 
concerned and will maintain records of these notifications. When direct reporting by the Sponsor 


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is not clearly defined by national or site specific regulations, the Investigator will be responsible 
for promptly notifying the concerned 
IRB/IEC of any Safety reports provided by the Sponsor and of filing copies of all related 
correspondence in the Investigator Site File. 
10.12 
Monitoring of Subjects with Adverse Events 
Any AE that occurs during the course of a clinical trial and is considered to be possibly related to 
the IP must be monitored and followed up by the Investigator until stabilization or until the 
outcome is known, unless the subject is documented as “lost to follow-up”. Reasonable attempts 
to obtain this information must be made and documented. It is also the responsibility of the 
Investigator to ensure that any necessary additional therapeutic measures and follow-up 
procedures are performed. The Sponsor will actively follow-up and collect information on any 
AE that occurs during the course of a clinical trial, however while this activity will continue for 
any serious AEs until stabilization or until the outcome is known, it will be discontinued at the 
time of database lock for non-serious AEs. 
10.13 
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator as related to trial treatment (e.g., resulting from 
a drug interaction with a contraceptive medication) are considered as adverse events. However, 
all pregnancies with an estimated conception date during the study safety period must be 
recorded by convention in the AE page/section of the e-CRF. The same rule applies to 
pregnancies in female subjects and in female partners of male subjects. The Investigator must 
notify the Sponsor in an expedited manner of any pregnancy using the Pregnancy Report Form, 
which must be transmitted according to the same process as described for SAE reporting. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial. The Investigator must notify the 
Sponsor of these outcomes using the Pregnancy Report Form, and in case of abnormal outcome, 
the Adverse Event Report Form when the subject sustains an event and the Parent-Child/Fetus 
Report Form when the child/fetus sustains an event. 
Any abnormal outcome must be reported in an expedited manner, while normal outcomes must 
be reported within 45 days from delivery. 
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor must be notified without delay 
and the subject must be followed as mentioned above. 
10.14 
Laboratory Assessments 
All clinical safety laboratory tests listed in the section below will be performed at local 
laboratories. Subject eligibility will be determined based on the baseline laboratory results. 


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Clinically significant laboratory test abnormalities will be followed until resolution or 
stabilization and the overall clinical outcome has been ascertained (See Section 10.4). 
10.14.1 
Blood Sample Collection for General Clinical Laboratory 
Assessments 
Blood samples will be collected for the following clinical laboratory tests: 
 Serum Chemistry: Glucose, Blood Urea Nitrogen (or Uric Acid), Creatinine, Sodium, 
Potassium, Chloride, Calcium, Magnesium, Phosphorus, Total Protein, Albumin, Total 
Bilirubin, Alkaline Phosphatase, ALT, AST, Gamma-Glutamyltransferase, Lactate 
Dehydrogenase, Bicarbonate (or total CO2). 
 Hematology: White Blood Cell Count, Red Blood Cell Count, Hemoglobin, Hematocrit, 
Platelet Count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils 
 Coagulation profile: APTT, PT/INR 
10.14.2 
Urinalysis 
Macroscopic assessment of the amount of protein, glucose, white blood cells and blood will be 
conducted. If abnormalities are noted, these will be recorded and a microscopic analysis 
conducted and recorded. If at any time, the subject’s serum creatinine is ≥ Grade 2, then a serum 
chemistry, microscopic urinalysis including the measurement of protein, glucose, blood, white 
blood cells will be conducted. If abnormalities are noted, then spot urine sodium, protein and 
creatinine should be performed to assess fractional sodium excretion (plasma creatinine x urine 
sodium / plasma sodium x urine creatinine) and urine protein/creatinine ratio (urine protein 
mg/urine creatinine mg ratio).  
10.15 
Additional Variables 
Additional variables to be examined as a part of this study include somatic mutations in archival 
tumor tissue. These biomarkers include but are not limited to members of the RAS family.  
11 
STUDY PROCEDURES 
11.1 
Screening and Baseline Assessments 
A signed ICF must be obtained before any study-specific screening evaluations are performed 
and should be documented in the subject’s medical chart. 
The following evaluations and procedures will be performed within 28 days prior to the first 
study drug administration (Cycle 1 Day 1): 


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 Signed informed consent form (ICF)/ patient informed consent (PIC) and form for the 
Health Insurance of Portability and Accountability Act (HIPAA)/Data Protection Act 
(DPA) 
 Demographics and medical history, including HPV status and information on prior anti-
cancer therapy(ies), outcome and duration of response 
 Collection of HRAS mutation data (Nominal HRAS mutation, VAF, methodology)  
 Adverse event assessment 
 Concomitant medications 
 12-lead ECG 
 Record subject height 
 Radiological assessments:  
o CT scan with a contrast agent is the preferred imaging method and the same 
technique should be used at baseline and post-treatment assessments.  
o In subjects with HNSCC, CT scan coverage at screening should encompass scans 
of the neck (including the skull base), chest and abdomen (including the liver and 
adrenals).  Any other areas of disease involvement should be scanned based on 
the subject’s signs and symptoms. 
o In subjects with other solid tumors, scan coverage should be appropriate to ensure 
that all areas of disease involvement are scanned. 
 Collection of available archival tumor tissue in paraffin embedded blocks or a minimum 
of 10 unstained slides except in cases of anaplastic thyroid cancer. Provision of tumor 
slides is not required for cases of anaplastic thyroid cancer. The archival tumor tissue 
may be collected at any time during Cycles 1-3 if additional time is needed to locate the 
samples. Efforts should be made to collect these materials as early as possible.  
 Buccal swab 
The following evaluations and procedures will be performed within 14 days prior to the first 
administration of study drug (Cycle 1 Day 1): 
 Physical examination 
 Record subject weight and vital signs (blood pressure, pulse, temperature) 
 ECOG performance status 
 Hematology 
 Chemistry (fasting not required) 
 Coagulation 


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 Urinalysis   
The following evaluations and procedures will be performed within 72 hours prior to the first 
administration of study drug (Cycle 1 Day 1): 
 Serum/urine pregnancy test for females of child-bearing potential only 
If the subject meets all eligibility criteria after the screening visit(s), the study site will request an 
assigned subject number using the Sponsor or designee.  
11.2 
Day 1 of Cycle 1 
Assessments prior dosing (Cycle 1 Day 1 only): The following assessments will be conducted 
before the first dose of tipifarnib on Day 1 of Cycle 1. Laboratory tests will not need to be 
repeated in Cycle 1 Day 1 if they were previously conducted at screening within 72 hr prior to 
tipifarnib administration on Day 1: 
 Record subject weight and vital signs (blood pressure, pulse, temperature) 
 ECOG performance status  
 Physical examination 
 Hematology  
 Chemistry (fasting not required) 
 Concomitant medications 
 Assessment of adverse events 
Subjects will be administered the first dose of tipifarnib (600 mg) with food. 
Subjects will continue to self-administer tipifarnib twice a day (approximately every 12 hours, 
same time every morning and evening) with food on days 1 – 7 and days 15 – 21 in 28-day 
treatment cycles (i.e. alternating week schedule). The interval between dosing should not be less 
than 8 hours. 
11.3 
Day 7 (+/- 2 days) of Cycle 1 
Assessments will include: 
 Record subject vital signs (blood pressure, pulse, temperature) 
 Hematology  
 Chemistry (fasting not required) 
 Assessment of adverse events 


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11.4 
Day 1 (+/- 2 days) of Cycle 2 and Beyond 
The following procedures will be performed at this visit: 
 Record subject weight and vital signs (blood pressure, pulse, temperature) 
 ECOG performance status  
 Physical examination 
o For subjects enrolled in France, physical examinations will include questioning 
about potential visual changes. If clinically indicated, a visual acuity test will be 
performed. If abnormal results are observed, subjects will be referred to an 
ophthalmological consultation. Additional physical examinations will be 
conducted as clinically indicated. 
 Hematology  
 Chemistry (fasting not required)  
 Serum/urine pregnancy test for females of child-bearing potential only 
 Concomitant medications 
 Assessment of adverse events  
In addition to the above procedures, the clinical site will conduct a drug accountability on the 
returned empty bottles and unused medications. 
11.5 
Day 22 (±5 days) of Cycles 2, 4, 6 and Cycles 9, 12, 15, etc.)  
Tumor response assessment should occur approximately every 8 weeks for the first 6 months of 
a subject’s participation; thereafter, tumor response assessment should occur approximately 
every 12 weeks until disease progression. The tumor response assessment schedule (every 8-12 
weeks) should be maintained regardless of dosing delays or additional imaging assessments 
performed. 
The following procedures will be performed at this visit: 
 Tumor radiological assessments: CT scan with a contrast agent is the preferred imaging 
method and the same technique should be used at baseline and post-treatment 
assessments.  
o In subjects with HNSCC, CT scan coverage at screening should encompass scans 
of the neck (including the skull base), chest and abdomen (including the liver and 
adrenals).  Any other areas of disease involvement should be scanned based on 
the subject’s signs and symptoms. 
o In subjects with other solid tumors, scan coverage should be appropriate to ensure 
that all areas of disease involvement are scanned. 


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o For the purposes of tumor assessment recording, the nomenclature Cycle 2 Day 
22, Cycle 4 Day 22, Cycle 6 Day 22, Cycle 9 Day 22, Cycle 12 Day 22, etc. is 
used to name the tumor assessment visits.  However, due to treatment delays or 
interruptions, it may happen that the tumor assessment visit will not coincide with 
the current treatment cycle for a given subject.  
11.6 
End of Treatment Visit 
The following assessments will occur approximately 30 days (+/- 7 days) after the last 
administration of study drug or immediately before the administration of another anti-cancer 
drug, whichever takes place first: 
 Physical examination 
 Record subject weight and vital signs (blood pressure, pulse, temperature) 
 ECOG performance status. 
 Hematology 
 Chemistry (fasting not required) 
 Serum/urine pregnancy test for females of child-bearing potential only 
 Tumor radiological assessments for subjects who have not previously demonstrated 
disease progression in the study unless completed within the previous 4 weeks.  Tumor 
assessments may also be undertaken for a confirmation of objective response. 
o CT scan with a contrast agent is the preferred imaging method and the same 
technique should be used at baseline and post-treatment assessments.  
o In subjects with HNSCC, CT scan coverage at screening should encompass scans 
of the neck (including the skull base), chest and abdomen (including the liver and 
adrenals).  Any other areas of disease involvement should be scanned based on 
the subject’s signs and symptoms. 
o In subjects with other solid tumors, scan coverage should be appropriate to ensure 
that all areas of disease involvement are scanned. 
 Assessments of adverse event and concomitant medications. 
 Conduct drug accountability on the returned empty bottles and unused medications. 
11.7 
Post Treatment Follow up 
Follow up visit(s) are required only for subjects who terminated treatment for reasons other than 
death or disease progression and should occur approximately every 8-12 weeks until disease 
progression or death, whichever occurs first.  If the subject initiates a new anticancer therapy 
without evidence of disease progression by RECIST v1.1, tumor assessments should continue 


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until there is evidence of disease progression unless withdrawal of subject’s consent to study 
procedures. 
The assessments to be conducted at these visits are: 
 Radiographic Imaging: to be performed if not done within the prior 8 weeks or if a tumor 
assessment is required for the confirmation of response. 
o CT scan with a contrast agent is the preferred imaging method and the same 
technique should be used at baseline and post-treatment assessments.  
o In subjects with HNSCC, CT scan coverage at screening should encompass scans 
of the neck (including the skull base), chest and abdomen (including the liver and 
adrenals).  Any other areas of disease involvement should be scanned based on 
the subject’s signs and symptoms. 
o In subjects with other solid tumors, scan coverage should be appropriate to ensure 
that all areas of disease involvement are scanned. 
 Assessments of AEs and concomitant medications may also be conducted if AEs were not 
resolved at the time of the End of Treatment visit. 
11.7.1 
Follow Up after Disease Progression 
Upon disease progression, all subjects will be followed approximately every 12 weeks for 
survival and the use of subsequent therapy until either death or 12 months after accrual in the 
subject’s study cohort has been completed, whichever occurs first. Information on survival and 
subsequent anticancer therapy may be collected by phone.  
12 
STATISTICAL METHODS  
This section outlines the statistical analysis strategy and procedures for the study. Specific details 
of the primary and key secondary analyses will be provided in the Statistical Analysis Plan 
(SAP). If, after the study has begun, but prior to the final analysis, important changes are made to 
the protocol that affect principal features of the primary or key secondary analyses, then the 
protocol and/or SAP will be amended, as appropriate. Any other changes made to the planned 
analyses after the protocol and SAP have been finalized, along with an explanation as to when 
and why they occurred, will be listed in the Clinical Study Report (CSR) for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR. 
12.1 
Populations 
12.1.1 
Efficacy Analysis 
The FAS population will serve as the primary population for the analysis of tumor response and 
other efficacy-related data. Subjects will be excluded for FAS for the following reasons: 


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 No baseline data 
 Failure to receive at least one dose of tipifarnib 
 No post-baseline endpoint data subsequent to at least 1 dose of study drug 
Subjects will be grouped in the FAS population according to cohort and tumor histology. A 
supportive analysis using the Per-Protocol population will be performed for the tumor response 
analysis. The Per-Protocol population excludes subjects due to important deviations from the 
protocol that may substantially affect the results of the primary analysis, such as not taking at 
least 80% of the intended dose in cycle 1. The final determination on protocol violations, and 
thereby the composition of the Per-Protocol population, will be made prior to locking the clinical 
database and final analysis and will be documented in a separate memorandum.  
12.1.2 
Safety Analysis 
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data. The 
ASaT population consists of all enrolled subjects who receive at least one dose of tipifarnib. At 
least one laboratory or vital sign measurement obtained subsequent to at least one dose of study 
drug is required for inclusion in the analysis of a specific safety parameter. To assess change 
from baseline, a baseline measurement is also required. 
12.2 
Endpoints 
12.2.1 
Efficacy 
The objective response rate will be estimated for each tumor histology type evaluated.  The 
estimate of the objective response rate will be calculated based on the maximum likelihood 
estimator (i.e., crude proportion of subjects whose best overall response is Complete Response 
(CR) or PR. The estimate of the objective response rate will be accompanied by 2-sided 95% 
exact binomial confidence intervals. 
The duration of objective response will be calculated for subjects who achieve CR or PR. For 
such subjects, the duration of objective response is defined as the number of days from the start 
date of PR or CR (whichever response is achieved first) to the first date that progressive disease 
is objectively documented. Disease progression will be determined by the Investigator using 
RECIST (version 1.1). The duration of objective response will be right-censored for subjects 
who achieve CR or PR and meet 1 of the following conditions: 1) non-protocol anticancer 
treatment started before documentation of disease progression, 2) death or documented disease 
progression after more than 1 missed disease assessment visit, or 3) alive and does not have 
documentation of disease progression before a data analysis cutoff date.  
The duration of objective response will be summarized descriptively using the Kaplan-Meier 
method. The 50th percentile of the Kaplan-Meier distribution will be used to estimate the median 
response duration. 


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Progression free survival will be defined as the time (in months) from enrollment to either first 
observation of progressive disease or occurrence of death due to any cause within 126 days 
(approximately 2 time intervals for tumor assessments) of either first administration of tipifarnib 
or the last tumor assessment. In subjects without a progression date or with a death date more 
than 126 days after the first administration of study drugs or the last tumor assessment, the PFS 
time should be censored on the date of last tumor assessment or date of first administration of 
study tipifarnib. Progression free survival analyses should consider tumor assessments after 
treatment discontinuation or metastatic surgery. Sensitivity analyses for PFS will be performed 
according to the FDA Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics (May 2007). 
The PFS will be summarized descriptively using the Kaplan-Meier method. The 50th percentile 
of the Kaplan-Meier distribution will be used to estimate the median PFS of each cohort of 
subjects. 
12.2.2 
Safety and Tolerability  
Safety and tolerability of tipifarnib will be assessed based on the following: 
 Incidence, duration, and severity of treatment-emergent adverse events, serious adverse 
events, adverse events resulting in permanent discontinuation of study drug, and deaths 
within approximately 30 days from the last dose of study drug (or immediately before the 
administration of another anti-cancer treatment) 
 Changes in laboratory test results 
 Changes in vital signs including blood pressure, pulse, and temperature 
 Changes in electrocardiogram results 
Adverse events will be coded using the latest available version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Treatment-emergent adverse events are defined as adverse 
events that start on or after the first dose of study drug and within approximately 30 days of the 
last administration of study drug. Adverse events will be summarized by the number and 
percentage of subjects who experienced the event, according to system organ class and preferred 
term. A subject reporting multiple cases of the same adverse event will be counted once within 
each system organ class and similarly counted once within each preferred term. 
Unless specified otherwise, the denominator for these calculations will be based on the number 
of subjects in each cohort who received at least one administration of tipifarnib, irrespective of 
the total number of doses or treatment cycles administered. These conventions will be 
appropriately modified to calculate AE incidence rates separately for each cycle that study 
therapy is administered. AE incidence rates may also be calculated based on other measures of 
subject exposure (e.g., total number of treatment cycles administered). AEs will also be 
summarized by NCI-CTCAE version 4.03 severity grade and by relationship to each study drug. 


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Additional summaries may also be provided for SAEs, and events resulting in the permanent 
discontinuation of therapy. All AEs will be included in individual subject listings. 
The incidence of grade 3 and 4 hematological toxicities (including neutropenia, 
thrombocytopenia, and anemia) will be provided by treatment cycle and across all treatment 
cycles. The toxicity grades for laboratory tests will be based on NCI-CTCAE version 4.03 
criteria. The use of blood transfusions (platelets, red blood cells) and/or growth factor support 
will be reported.  
Vital sign results (blood pressure, pulse, respirations, and temperature) will be summarized 
descriptively for each scheduled and unscheduled protocol time point. Changes will be 
calculated relative to the assessments at baseline and on the first day of each cycle of therapy. 
12.3 
Biomarkers 
Descriptive statistics will be primarily used to summarize the biomarker and other laboratory 
data generated in this study. For continuous variables, the number of subjects with non-missing 
data, mean, either the standard error or standard deviation, median, 25th percentile (first 
quartile), 75th percentile (third quartile), minimum, and maximum will be presented. For discrete 
data, the frequency and percent distribution will be presented. 
The Wilcoxon signed rank test may be used to identify any statistically significant (p<0.05) 
changes in biomarker or laboratory levels. Additionally, correlations may be assessed by 
calculating Spearman’s correlation coefficient between pairs of biomarkers or other parameters. 
12.4 
Sample Size Determination 
In Cohort 1 and Cohort 2, a two-stage design will be independently employed for each of these 
two cohorts.  Eleven study subjects will be enrolled for the first stage of study for each cohort; 
the study will be terminated if one or less response was observed at end of first stage. A two-
stage study design will be used in order to minimize the number of study subjects treated if 
tipifarnib is not efficacious. This design is intended to allow the termination of accrual earlier in 
case of unacceptably low efficacy observed during the study.  
An additional seven subjects will be enrolled for the second stage.  At the completion of two-
stage study, the study is considered as failure if there will be three or less responses out of 18 
evaluable subjects, indicating the true ORR is 10% or less.  If there are four or more responses, 
the treatment will be considered of further interest indicating the true ORR is higher than 10%.   
 For this two-stage study design, a null response rate of 10% and alternative response rate of 30% 
are assumed. It provides 80% power to detect a difference between 10% and 30% ORR at one-
sided significance level of 0.087.  Using this design, the probability of terminating the study at 
the end of first stage is 0.697 if the true ORR is 10% or less while the probability of terminating 
the study at the end of first stage is 0.113 if the true ORR is 30%.  


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In order to reject the null hypothesis, 4 confirmed response are required in Cohort 1 or Cohort 2. 
In Cohort 2, upon observation of 4 confirmed responses, enrollment of HRAS mutant HNSCC 
subjects will continue up to 30 subjects with HRAS mutant HNSCC (10 enrolled in Cohort 2 
Stage 1 and 2 combined, plus 20 additional subjects) to further explore the antitumor activity of 
tipifarnib in this tumor type. No statistical hypotheses will be tested in this extension. 
Cohort 3, consisting of SCC subjects (other than HNSCC) regardless of organ, will enroll 20 
subjects. This cohort is added as an amendment to the protocol and its size is empiric due to 
constraints resulting from the rarity of HRAS mutations in SCC other than HNSCC.  
Thus, up to approximately 75 evaluable subjects (Cohorts 1, 2 and 3) may be enrolled in the 
study. 
12.5 
Changes in the Conduct of the Study or Planned Analyses 
Only the Sponsor, upon consultation with the principal Investigator may modify the protocol. 
The Sponsor will issue a formal protocol amendment to implement any changes. The only 
exception is when an Investigator considers that a subject’s safety is compromised without 
immediate action. In these circumstances, immediate approval of the chairman of the IRB/IEC 
must be sought, and the Investigator should inform the Sponsor and the full IRB/IEC within 2 
working days after the emergency has occurred. 
The IRBI/EC must review and approve all protocol amendments. Protocol amendments that have 
an impact on subject risk or the study objectives, or require revision of the ICF, must receive 
approval from the IRB/IEC prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to subjects, the ICF will be amended and approved by the Sponsor and the IRB/IEC, and all 
active subjects must again provide informed consent.  The approval of the substantial 
amendment from the Competent Regulatory Authority will be sought before implementation. 
13 
ETHICAL AND REGULATORY ASPECTS 
13.1 
Responsibilities of the Investigator 
The Investigator is responsible for the conduct of the trial at his/her site. He/she will ensure that 
the trial is performed in accordance with the clinical trial protocol and with the ethical principles 
that have their origin in the Declaration of Helsinki, as well as with the ICH Note for Guidance 
on Good Clinical Practice (ICH Topic E6, 1996) and applicable regulatory requirements. In 
particular, the Investigator must ensure that only subjects who have given their informed consent 
are included into the trial. 


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13.2 
Subject Information and Informed Consent 
An unconditional prerequisite for a subject’s participation in the trial is his/her written informed 
consent. The subject’s written informed consent to participate in the trial must be given before 
any trial-related activities are carried out.  
Adequate information must therefore be given to the subject by the Investigator before informed 
consent is obtained (a person designated by the Investigator may give the information, if 
permitted by local regulations). 
With the cooperation of the Sponsor, and in accordance with the Note for Guidance on Good 
Clinical Practice (ICH Topic E6, 1996), and the ethical principles that have their origin in the 
Declaration of Helsinki, the Investigator will prepare the informed consent form and other 
written information to be used in obtaining informed consent from the trial subjects. The 
Investigator should cooperate with the sponsor for preparation of aforementioned written 
information. 
Before the consent may be obtained, the potential subject (or the potential subject’ legally 
acceptable representative) should be provided with sufficient time and opportunity to be accessed 
to the details of clinical trial and to decide if they would participate in the trial. All the queries 
related to the trial from the potential subject or legally acceptable representative should be 
answered by the Investigator or collaborators. 
In addition to providing this written information to a potential subject, the Investigator or his/her 
designate will inform the subject verbally of all pertinent aspects of the trial. The language used 
in doing so must be chosen so that the information can be fully and readily understood by lay 
persons. 
Depending on local regulations, a person other than the Investigator may inform the subject and 
sign the Informed Consent Form. Where the information is provided by the Investigator, the 
Informed Consent Form must be signed and personally dated by the subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived by the Investigator so that the forms can be retrieved at any time for 
monitoring, auditing and inspection purposes. A copy of the signed and dated information and 
Informed Consent Form should be provided to the subject prior to participation. 
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor and be submitted again to the IRB/IEC for review and 
favorable opinion. The agreed, revised information will be provided to each subject in the trial 
for signing and dating. The Investigator will explain the changes to the previous version. 


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13.3 
Subject Identification and Privacy 
A unique subject number will be assigned to each subject at inclusion, immediately after 
informed consent has been obtained. This number will serve as the subject’s identifier in the trial 
as well as in the clinical trial database. 
The subject’s data collected in the trial will be stored under this number. Only the Investigator 
will be able to link the subject’s trial data to the subject via an identification list kept at the site. 
The subject’s original medical data that are reviewed at the site during source data verification 
by the Monitor, audits and Health Authority inspections will be kept strictly confidential. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing subject data. Subjects will be informed accordingly, and will be requested to give 
their consent on data handling procedures in accordance with national regulations. 
13.4 
Emergency Medical Support and Subject Card 
Subjects enrolled in this clinical trial will be provided with Emergency Medical Support cards 
during their trial participation, which will be provided by the Sponsor or designee. The 
Emergency Medical Support card is based on the need to provide clinical trial subjects with a 
way of identifying themselves as participating in a clinical trial, and subsequently to give health 
care providers access to the information about this participation that may be needed to determine 
the course of the subject’s medical treatment. 
This service is designed to provide information to health care providers who are not part of the 
clinical trial. Clinical trial investigators, who are already aware of the clinical trial protocol and 
treatment, have other means of accessing the necessary medical information for the management 
of emergencies occurring in their subjects. 
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, s/he will answer 
any questions. Any subsequent action will follow the standard processes established for the 
Investigators. 
In cases where the Investigator is not available, the Sponsor or designee will provide a 24 hour 
contact number whereby health care providers will be given access to the appropriate Sponsor’s 
physician or designee to assist with any information regarding tipifarnib in case of a medical 
emergency. 
13.5 
Clinical Trial Insurance and Compensation to Subjects 
The Sponsor is entirely responsible for AEs that are associated with this trial and cause damage 
to the health of the subjects, except for AEs caused by an intentional and/or significant deviation 
on the part of the Investigator, the trial site, and/or the subject. Insurance coverage shall be 


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provided for participating to the trial. Insurance conditions shall meet good local standards, as 
applicable. 
13.6 
Institutional Review Board/Independent Ethnic Committee 
Prior to commencement of the trial at a given site, the clinical trial protocol will be submitted 
together with its associated documents (Investigator’s brochure, Subject Information and 
Informed Consent Forms) to the responsible IRB/IEC for its favorable opinion/approval. The 
written favorable opinion/approval of the IRB/IEC will be filed in the Investigator Site File, and 
a copy will be filed in the Trial Master File at the Sponsor. 
The trial must not start at a site before the Sponsor has obtained written confirmation of 
favorable opinion/approval from the concerned IRB/IEC. The IRB/IEC will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the trial, the clinical trial protocol version and the Subject 
Information and Informed Consent Form version reviewed should be provided. Where possible, 
copies of the meeting minutes should be obtained. 
Amendments to the clinical trial will also be submitted to the concerned IRB/IEC, before 
implementation in case of substantial changes. Relevant safety information will be submitted to 
the IRB/IEC during the course of the trial in accordance with national regulations and 
requirements. 
13.7 
Communication to Health Authorities 
The clinical trial protocol and its amendments and any applicable documentation (e.g. 
Investigator’s Brochure, Subject Information and Informed Consent Form) will be submitted or 
notified to the Health Authorities. 
14 
TRIAL MANAGEMENT 
14.1 
Case Report Form Management 
The Investigator or designee will be responsible for entering trial data in the eCRFs that will be 
provided by the Sponsor or its designee. It is the Investigator’s responsibility to ensure the 
accuracy of the data entered in the eCRFs. Database lock will occur once quality control and 
quality assurance procedures (if applicable) have been completed.  
14.2 
Source Data and Subject Files 
The Investigator must keep a subject file (medical file, original medical records) on paper or 
electronically for every subject included in the trial. This file will contain the available 
demographic and medical information for the subject, and should be as complete as possible.  


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In particular, the following data should be available in this file: 
 Subject’s full name 
 Date of birth 
 Gender 
 Height 
 Weight 
 Relevant medical history and concomitant diseases 
 Prior and concomitant therapies (including changes during the trial) 
 Trial identification  
 Date of subject’s inclusion into the trial (i.e. date of informed consent) 
 Subject identifier in the trial 
 Dates of the subject’s visits to the site 
 Any medical examinations and clinical findings predefined in the clinical trial protocol 
 All adverse events observed in the subject 
 Date of subject’s end of trial, and 
 Date of and reason for early withdrawal of the subject from the trial or from treatment, if 
applicable. 
It must be possible to identify each subject by using this subject file. Additionally, any other 
documents containing source data must be filed. This includes original printouts of data recorded 
or generated by automated instruments, CT scan images, ECG recordings, laboratory value 
listings, etc. Such documents must bear at least the subject identifier and the date when the 
procedure was performed. Information should be printed by the instrument used to perform the 
assessment or measurement, if possible. Information that cannot be printed by an automated 
instrument will be entered manually. Medical evaluation of such records should be documented 
as necessary and the documentation signed and dated by the Investigator. 
The following information described in the eCRFs is regarded as the source data: 
 Any Investigator’s comments 
 Subject identifier 
 Information on AE (e.g. seriousness, severity, outcome, and causality to the IP) 
 Reason for providing concomitant medications and procedures (if applicable) 
 Assessment of antitumor effect including tumor measurements 


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 Description about trial discontinuation 
14.3 
Investigator Site File and Archiving 
The Investigator will be provided with an Investigator Site File upon initiation of the trial. This 
file will contain all documents necessary for the conduct of the trial and will be updated and 
completed throughout the trial. It must be available for review by the Monitor, and must be ready 
for audit by the Sponsor as well as for inspection by Health Authorities during and after the trial, 
and must be safely archived for at least 15 years (or per local requirements or as otherwise 
notified by the Sponsor) after the end of the trial. The documents to be thus archived include the 
Subject Identification List and the signed subject Informed Consent Forms. If archiving of the 
Investigator Site File is no longer possible at the site, the Investigator must notify the Sponsor. 
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per 
ICH GCP guidelines or ordinance of GCP, whichever is longer. In any case, the Investigator 
should ensure that no destruction of medical records is performed without the written approval of 
the Sponsor. 
14.4 
Monitoring, Quality Assurance and Inspection by Health 
Authorities 
This trial will be monitored in accordance with the ICH Note for Guidance on Good Clinical 
Practice (ICH Topic E6, 1996). The site Monitor will perform visits to the trial site at regular 
intervals. 
The Sponsor, as well as Health Authorities, must be permitted to inspect all trial-related 
documents and other materials at the site, including the Investigator Site File, the completed 
CRFs, the IP(s), and the subjects’ original medical records/files. 
The clinical trial protocol, each step of the data captures procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance 
activities. Audits may be conducted at any time during or after the trial to ensure the validity and 
integrity of the trial data. 
14.5 
Changes to the Clinical Trial Protocol 
Changes to the clinical trial protocol will be documented in written protocol amendments. Major 
(substantial, significant) amendments will usually require submission to the Health Authorities 
and to the relevant IRB/IEC for approval or favorable opinion. In such cases, the amendment 
will be implemented only after approval or favorable opinion has been obtained. 


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Minor (non-substantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and by the Investigator at the clinical study site. They will be submitted to the 
relevant IRB/IEC or to Health Authorities only where requested by pertinent regulations. 
Any amendment that could have an impact on the subject’s agreement to participate in the trial 
requires the renewal of the subject’s informed consent prior to implementation. 
14.6 
Clinical Trial Report 
After completion of the trial, a clinical trial report according to ICH E3 will be generated by the 
Sponsor in consultation with the Principal Investigator. 
14.7 
Publication 
The first publication will be either a publication of the results of the analysis of the primary 
endpoint, that will include data from all trial sites, or a publication of data from one of the study 
cohorts. Lead investigators will be identified for each of the study cohorts based on accrual and 
Good Publication Practices and the decision to publish or present the initial data from all the trial 
sites, or a subset of the data based on the results of one of the study cohorts, will reside in the 
Sponsor in consultation with the lead investigators. Publications or presentations prior to the 
generation of a final clinical study report will be clearly marked as preliminary reports. 
Investigators will inform the Sponsor in advance about any subsequent plans to publish or 
present data from any portion of the trial. Any publications and presentations of the results 
(abstracts in journals or newspapers, oral presentations, etc.), either in whole or in part, by 
investigators or their representatives will require a pre-submission review by the Sponsor. The 
Sponsor will not suppress or veto publications, but maintains the right to a reasonable delay of a 
publication in order to protect intellectual property rights. 
15 
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SAP_001.pdf: 
Protocol Number: KO-TIP-001 
 
Official Title: An Open Label Phase II Study of Tipifarnib in Advanced Non-Hematological 
Malignancies with HRAS Mutations 
 
NCT Number: NCT02383927 
 
Document Date: 05 January 2021 


 
 
STATISTICAL ANALYSIS PLAN 
Protocol Title:  
An Open Label Phase II Study of Tipifarnib in Advanced Non-
Hematological Malignancies with HRAS Mutations 
 
 
SAP Version:   
Version 4.0 
 
 
SAP Date:   
05 JAN 2021  
 
 
Study Drug: 
Tipifarnib (R115777; Zarnestra™) 
 
 
Phase of Study:    
Phase 2 
 
 
Protocol Number:   
KO-TIP-001 
 
 
Protocol Version: 
Protocol Amendment Version 5.0 
 
 
Protocol Date:  
01 November 2018 
 
 
Sponsor:    
Kura Oncology, Inc.  
3033 Science Park Road, Suite 220   
San Diego, CA 92121 (USA)  
Phone: +1 858.500.8800 
 
(Note: effective 12 June 2020, Kura has a new address) 
12730 High Bluff Drive, Suite 400  
San Diego, CA 92130 
Phone: +1 858.500.8803 
CRO Preparing SAP:  
 
 
 




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SYNOPSIS 
Sponsor:  Kura Oncology, Inc. 
 
Product:   
Tipifarnib (R115777; Zarnestra™) 
Phase of development:   
Phase 2 
Protocol title: An Open Label Phase II Study of Tipifarnib in Advanced Non-Hematological 
Malignancies with HRAS Mutations 
SAP date: 
05 JAN 2021 
SAP version:  4.0 
Investigators and study centers: 
Multiple centers 
Objectives: 
 
Primary: 
To determine the antitumor activity in terms of objective response rate (ORR) of tipifarnib in subjects 
with locally advanced unresectable or metastatic, relapsed and/or refractory, non-hematological 
malignancies with HRAS mutations.  
 
Secondary: 
To determine the safety and tolerability of tipifarnib in subjects with locally advanced unresectable or 
metastatic, relapsed and/or refractory, non-hematological malignancies with HRAS mutations. 
 
Exploratory:  
To explore the antitumor activity in terms of progression free survival (PFS and duration of response 
(DOR) of tipifarnib in subjects with locally advanced unresectable or metastatic, relapsed and/or 
refractory, non-hematological malignancies with HRAS mutations. 
To explore the feasibility of collecting archival biopsies and analyzing these biopsies for the detection 
of tissue biomarkers potentially related to tipifarnib activity. 
Methodology:   
This Phase II study will investigate the antitumor activity in terms of ORR of tipifarnib in subjects with 
locally advanced tumors that carry HRAS mutations and for whom there is no curative therapy 
available.  
Subjects will be enrolled into three nonrandomized cohorts: 
 
• 
Cohort 1: Malignant thyroid tumors with HRAS mutations. 
• 
Cohort 2: Non-hematological malignancies with HRAS mutations in stage 1.  Head and 
neck squamous cell carcinomas (HNSCC) with HRAS mutations in stage 2. 
• 
Cohort 3: Squamous cell carcinoma (SCC) with HRAS mutations other than HNSCC  
 


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Investigational product:   
Treatment:  Tipifarnib will be administered at a starting dose of 600 mg, po, bid daily for 7 days in 
alternating weeks (Days 1-7 and 15-21) in 28-day cycles. 
Mode of Administration: Oral.  
Duration of Treatment:  In the absence of unacceptable tipifarnib related emergent toxicity or disease 
progression, subjects may receive treatment with tipifarnib for up to 12 months at the discretion of the 
Investigator. Treatment beyond 12 months may continue upon agreement of the Investigator and the 
Sponsor. 
Comparator product:  None 
Criteria for evaluation:  
Efficacy: 
Determination of objective tumor response will be performed by the Investigator according to the 
Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 
.    
 
Safety: 
Adverse events will be graded according to the NCI CTCAE v 4.03. Adverse events will be 
summarized by relationship to trial drug, severity and grade. The safety profile of the IP will be 
assessed through the recording, reporting and analyzing of baseline medical conditions, adverse events, 
physical examination findings including vital signs and laboratory tests. 
 
Comprehensive assessment of any apparent toxicity experienced by the subject will be performed 
throughout the course of the trial, from the time of the subject’s signature of informed consent. Trial 
site personnel will report any adverse event (AE), whether observed by the Investigator or reported by 
the subject.  
 
 


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
 
SYNOPSIS ......................................................................................................................................5 
1. 
LIST OF ABBREVIATIONS.......................................................................................9 
2. 
INTRODUCTION ......................................................................................................11 
3. 
STUDY OBJECTIVES ..............................................................................................11 
3.1. 
Primary Objectives and EndPoints .............................................................................11 
3.2. 
Secondary Objectives and ENDPOINTS ...................................................................11 
3.3. 
Exploratory Objective and Endpoints .........................................................................11 
4. 
STUDY DESIGN .......................................................................................................12 
4.1. 
General Study Design and Plan ..................................................................................12 
4.2. 
Study Population .........................................................................................................14 
4.2.1. 
Selection of Study Population ....................................................................................14 
4.2.2. 
Removal of Subjects from Treatment or Assessment .................................................15 
4.3. 
Premature Discontinuation of the Trial ......................................................................15 
4.4. 
Definition of End of Study .........................................................................................15 
4.5. 
Randomization and Blinding ......................................................................................15 
4.6. 
Study Assessments......................................................................................................15 
5. 
SAMPLE SIZE DETERMINATION .........................................................................15 
6. 
ANALYSIS POPULATIONS ....................................................................................16 
7. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................17 
7.1. 
Data Handling Conventions ........................................................................................17 
7.2. 
Interim Analyses and Data Monitoring ......................................................................18 
7.3. 
Multi-Center Studies ...................................................................................................19 
7.4. 
Multiple Comparisons / Multiplicity ..........................................................................19 
7.5. 
Examination of Subgroups .........................................................................................19 
7.6. 
Handling of Dropouts or Missing Data ......................................................................19 
7.7. 
Outlier Handling .........................................................................................................19 
7.8. 
Adustments for Covariates .........................................................................................20 


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8. 
SUMMARY OF STUDY POPULATION DATA .....................................................20 
8.1. 
Subject Disposition .....................................................................................................20 
8.2. 
Protocol Deviations ....................................................................................................20 
8.3. 
Demographics and Baseline Characteristics ...............................................................20 
8.4. 
Dosing and Extent of Exposure ..................................................................................21 
8.5. 
Prior and Concomitant Medications ...........................................................................21 
9. 
EFFICACY ANALYSES ...........................................................................................21 
9.1. 
Primary Efficacy Analyses .........................................................................................21 
9.2. 
Exploratory Efficacy Analyses ...................................................................................22 
9.3. 
Other Efficacy Analyses .............................................................................................23 
10. 
SAFETY ANALYSES ...............................................................................................23 
10.1. 
Adverse Events ...........................................................................................................24 
10.2. 
Clinical Laboratory Evaluations .................................................................................25 
10.3. 
Transfusion .................................................................................................................25 
10.4. 
Vital Signs ..................................................................................................................25 
10.5. 
ECGs ...........................................................................................................................25 
10.6. 
Other Safety Measures ................................................................................................25 
11. 
CLINICAL PHARMACOLOGY ANALYSES .........................................................26 
12. 
OTHER ANALYSES .................................................................................................26 
13. 
REPORTING CONVENTIONS ................................................................................26 
14. 
CHANGES IN THE STATISTICAL METHODS FROM THOSE STATED 
IN THE PROTOCOL .................................................................................................26 
15. 
TABLES, FIGURES, LISTINGS ...............................................................................26 
16. 
REFERENCES ...........................................................................................................26 
 
 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
ASaT 
all subjects as treated 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
BID 
bis in die, twice a day 
CR 
complete response 
CSR 
clinical study report 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
FAS 
full analysis set 
FTase 
farnesyl transferase 
HNSCC 
head and neck squamous cell carcinomas 
HRAS 
Harvey Rat Sarcoma Virus Gene Homolog 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse Events 
ORR 
objective response rate 
OS 
overall survival 
PFS 
progression free survival 
PP 
per-protocol  
PR 
partial response 
PT 
preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 
VAF 
variant allele frequency 


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WHO 
World Health Organization 
 
 


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2. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to describe the planned analysis and 
reporting for Kura Oncology’s Protocol KO-TIP-001, entitled ‘An Open Label Phase II Study of 
Tipifarnib in Advanced Non-Hematological Malignancies with HRAS Mutations”.  Tipifarnib is 
a selective nonpeptide inhibitor of farnesyl transferase (FTase) which could interfere with RAS 
function.  More information on Tipifarnib and its mechanism of action can be found in the 
Protocol. 
This SAP describes the analyses of the protocol endpoints to be completed by 
, as well as 
the presentation of study data to be included in the clinical study report (CSR).  A discussion of 
the steps taken to prepare the data for analysis, such as study milestones, data partitioning, and 
derived data, is provided.  Examples of tables and figures that will be used to summarize the data 
are included in the companion document KO-TIP-001 Tables, Listings, and Figures Shells 
(TLF).  The results of the analysis described in this SAP will be included in the clinical study 
report (CSR).   
This SAP has been developed according to 
 
 
, and accordingly, this plan and any deviations from this plan must be 
finalized, approved, and placed on file before the study database is frozen.  After completion of 
the final CSR, all applicable datasets, outputs, programs, and specifications documents will be 
transferred to the study sponsor for archiving. 
3. 
STUDY OBJECTIVES 
3.1. 
Primary Objectives and EndPoints 
Primary Objective: To determine the antitumor activity in terms of ORR of tipifarnib in 
subjects with locally advanced unresectable or metastatic, relapsed and/or refractory, HRAS 
mutant non hematological malignancies. 
Primary Endpoint: Response assessments according to RECIST 1.1. 
 
 
3.2. 
Secondary Objectives and ENDPOINTS 
Secondary Objective:  To determine the safety and tolerability of tipifarnib in subjects with 
locally advanced unresectable or metastatic, relapsed and/or refractory, HRAS mutant non 
hematological malignancies.  
Secondary Endpoint: Treatment-emergent adverse events (TEAE) and SAEs evaluated 
according to NCI CTCAE v.4.03. 
3.3. 
Exploratory Objective and Endpoints 
Exploratory Objective 1: To determine the antitumor activity in terms of progression free 
survival (PFS), and duration of response (DOR) of tipifarnib in subjects with locally advanced 


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unresectable or metastatic, relapsed and/or refractory, HRAS mutant non hematological 
malignancies. 
Exploratory Endpoints 1: PFS, and DOR according to RECIST 1.1. 
Exploratory Objective 2: To explore the feasibility of collecting archival biopsies and 
analyzing these biopsies for the detection of tissue biomarkers potentially related to tipifarnib 
activity. 
Exploratory Endpoints 2: Molecular analyses of archival tissue samples. 
4. 
STUDY DESIGN 
4.1. 
General Study Design and Plan 
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 standard curative therapy available.  Enrollment 
may proceed using available known HRAS tumor status information previously generated at the 
clinical study sites; however, all subjects, except those with anaplastic thyroid tumors, must 
consent to provide at least 10 slides from a prior diagnostic biopsy for a retrospective testing of 
HRAS status including T81C polymorphism at a central facility.  Exploratory analyses of 
additional biomarkers potentially related to tipifarnib’s mechanism of action may also be 
conducted in these archival samples.  The Sponsor is planning to develop a methodology for the 
detection of HRAS mutations in parallel to the conduct of the study, but subjects enrolled in the 
study will not undergo any additional procedures (e.g. tissue biopsy), beyond those previously 
conducted as part of their standard of care, in support of the development of this test. 
Subjects will be enrolled into three nonrandomized cohorts: 
• Cohort 1: Malignant thyroid tumors with HRAS mutations.  
• Cohort 2: Non-hematological malignancies with HRAS mutations in stage 1, and  
head and neck squamous cell carcinomas (HNSCC) with HRAS mutations in stage 2.  
• Cohort 3: Squamous cell carcinoma (SCC) with HRAS mutations (excluding thyroid 
and mucosal head and neck tumors). 
Cohort 1 will enroll subjects with malignant thyroid tumors with HRAS mutations, 
independently of thyroid histology.  Any subject with a non-hematological HRAS mutant tumor 
who meets eligibility criteria may be enrolled in the first stage of Cohort 2.  Subjects with 
HNSCC, salivary malignancies and urothelial carcinomas may be more frequently enrolled in 
Cohort 2 due to the relatively high rate of HRAS mutations in these indications; however, 
enrollment is not limited to these tumor types.  Subjects with malignant thyroid tumors with 
HRAS mutations will only be enrolled in Cohort 1.  Based on the anti-tumor activity observed 
during Stage 1 of Cohort 2, the protocol was amended (Amendment 3) to restrict enrollment in 
Stage 2 of Cohort 2 to subjects with HNSCC with HRAS mutations only. 


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Cohort 3 is added as part of Amendment 4 to the protocol to include subjects who have SCC 
with HRAS mutations.  The purpose of this cohort is to explore tipifarinib’s anti-tumor activity 
in HRAS mutation positive SCCs independent of tissue origin. 
Only consented subjects who meet all the eligibility criteria will be enrolled in the study.  All 
screening evaluations will be completed within 4 weeks (28 days) of Cycle 1 Day 1.  Any 
screening evaluation, including disease status, will need to be repeated if performed more than 4 
weeks from Cycle 1 Day 1.  Efforts will be made to collect information on the response and 
duration of response of the subject’s last prior therapy. 
Up to 75 evaluable subjects may be enrolled in the study.  A two-stage study design will be used 
separately in Cohort 1 and in Cohort 2 in order to minimize the number of study subjects treated 
if tipifarnib were considered not sufficiently efficacious to grant further development in this 
subject population.  This design is intended to allow the termination of accrual in a particular 
study cohort in case of unacceptably low efficacy after objective responses in the first 11 
evaluable subjects (Stage 1) in the cohort are assessed in a Full Analysis Set (FAS) basis.  If no 
objective responses are observed in a cohort after the first 11 evaluable subjects, the cohort will 
be closed to further enrollment.  If two or more responses are observed in the cohort, 7 additional 
subjects will be enrolled (Stage 2).  Treatment will be considered of further interest if at least 4 
responses are observed in a cohort (out of 18 subjects).  Tumor response assessments will be 
conducted according to RECIST v1.1 criteria (confirmation of response is required), but in order 
to expedite the response assessment of the initial 11 evaluable subjects, tipifarnib will be 
considered not sufficiently efficacious if no confirmed objective tumor responses are observed in 
the study cohort prior to 6 months from the time of enrollment of the last of the 11 evaluable 
subjects. 
In Cohort 2, upon observation of 4 confirmed responses, enrollment of HRAS mutant HNSCC 
subjects will continue up to 30 subjects with HRAS mutant HNSCC (10 enrolled in Stage 1 and 
2 combined, plus 20 additional subjects) to further explore the antitumor activity of tipifarnib in 
this tumor type. 
In Cohort 3, 20 subjects will be enrolled, treated and followed in the same manner as the two 
cohorts above.  The choice of 20 subjects is empirical due to the rarity of HRAS mutations in 
SCC other than HNSCC. 
Tipifarnib will be administered at a starting dose of 600 mg, PO, twice a day(BID) daily for 7 
days in alternating weeks (Days 1 - 7 and 15 - 21) in 28-day cycles.  Tipifarnib will be given 
with food.  Subjects may use proton pump inhibitors or H2 antagonists during the treatment 
portion of this study.  However, subjects should be instructed to use antacids (magnesium or 
aluminum containing products) at least 2 hours before or after intake of oral study drug.  Also, 
potent inducers of the cytochrome P450 enzymes such as enzyme-inducing antiepileptic drugs 
may reduce plasma concentrations of tipifarnib and concurrent administration of tipifarnib with 
these agents should be avoided whenever possible. 
In the absence of emerging unmanageable toxicity, subjects may continue tipifarnib treatment in 
the absence of disease progression and unmanageable toxicity.  Treatment may continue beyond 
12 months upon agreement by the Investigator and Sponsor. 


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Tumor assessments will be performed at screening and approximately every 8 weeks starting at 
the end of cycle 2 for the first 6 months (Cycles 2, 4, 6) and then every 12 weeks (Cycles 9, 12, 
15, etc.), or sooner if deemed necessary by the Investigator, and will continue until disease 
progression.  A tumor assessment will be performed upon treatment discontinuation (End of 
Treatment visit) if the reason for discontinuation is other than disease progression and no tumor 
assessment was performed in the prior 8 weeks, or a tumor assessment is required for the 
confirmation of response to treatment.  Subjects who discontinue treatment for reasons other than 
disease progression must continue tumor assessments until disease progression, withdrawal of 
subject’s consent or initiation of another anticancer therapy.  Determination of objective tumor 
response will be performed by the Investigator.  However, tumor images may be de-identified of 
subject’s personal information at the clinical sites and collected by the Sponsor or designee to 
undergo an external independent radiological review if the sponsor deems it necessary for the 
final assessment of the efficacy of the treatment.  If an independent radiological review were to 
be conducted, reviewers would be blinded to Investigator’s tumor response assessments.  An 
independent review committee charter would be generated to provide the specific procedures that 
would be filed with Institutional Review Board (IRB) and regulatory authorities.  
Subjects with a solitary site of disease who have experienced a response may be considered for 
surgical resection.  Subjects with a Partial Response (PR) and residual disease after salvage 
surgery are eligible to continue on study therapy. 
Upon disease progression, all subjects in the study cohort will be followed approximately every 
12 weeks for survival and the use of subsequent therapy until either death or 12 months after 
accrual in the subject’s study cohort has been completed, whichever occurs first.  Information on 
survival and subsequent anticancer therapy may be collected by phone. 
All subjects will be followed-up for safety during treatment and up to approximately 30 days (30 
± 7 days) after treatment discontinuation or until immediately before the initiation of another 
anti-cancer therapy, whichever occurs first.  Additional follow up may be implemented until the 
subject recovers from any emergent treatment related toxicity or the adverse event is considered 
irreversible by the Investigator.  Target organ toxicities will be monitored via clinical and 
laboratory assessments using the National Cancer Institute Common Terminology Criteria for 
Adverse Events version 4.03 (CTCAE v 4.03). 
4.2. 
Study Population  
4.2.1. 
Selection of Study Population 
Up to 75 male and female adult subjects at least 18 years old who meet the inclusion and 
exclusion criteria as outlined in Protocol Section 7 will be enrolled in the study.  Subjects will be 
further enrolled into three nonrandomized cohorts: Cohort 1: Malignant thyroid tumors with 
HRAS mutations; Cohort 2/Stage 1: Non-hematological malignancies with HRAS mutations, 
Cohort 2/Stage 2: Head and neck squamous cell carcinomas with HRAS mutations; Cohort 3: 
Squamous cell carcinoma with HRAS mutations (excluding thyroid and mucosal head and neck 
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4.2.2. 
Removal of Subjects from Treatment or Assessment 
Subjects may withdraw their consent to participate in this study at any time without prejudice.  
The Investigator must withdraw from the study any subject who requests to be withdrawn.  A 
subject’s participation in the study may also be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment.  Every effort should be made to 
complete, whenever possible, the tests and evaluations listed for the End of Treatment visit. 
More details are available in Protocol Section 8.4. 
4.3. 
 Premature Discontinuation of the Trial 
This trial may be discontinued prematurely in the event of any of the reasons listed in Protocol 
Section 8.5. 
4.4. 
Definition of End of Study 
For administrative and safety reporting purposes, the end of this clinical study is defined as 12 
months from enrollment of the last enrolled study subject.  If the last enrolled study subject 
discontinues treatment within 12 months of study enrollment, the End of Study will occur no 
earlier than the date of the last enrolled subject’s safety follow-up assessment performed 
approximately 30 days after treatment discontinuation (or until initiation of another anti-cancer 
therapy).  At the time of End of Study, provisions will be made to transition all remaining study 
subjects who demonstrate sustained clinical benefit beyond the end of the study to other means 
of continued treatment with tipifarnib, including appropriate safety monitoring, e.g. single 
patient treatment protocol.  For subjects enrolled in France and who have evidence of clinical 
benefit, continuation of treatment with tipifarnib may only take place in the setting of a separate 
study protocol.  For subjects enrolled in Germany and who have evidence of clinical benefit, 
continuation of treatment with tipifarnib may only take place in the setting of a clinical trial or 
hardship program (“compassionate use”) per German Drug Law (AMG).  
4.5. 
Randomization and Blinding 
There is no randomization and blinding involved in this study. 
4.6. 
Study Assessments 
Details of scheduled assessments are displayed in Table 1 of the Protocol. 
5. 
SAMPLE SIZE DETERMINATION 
In Cohort 1 and Cohort 2, a two-stage design will be independently employed for each of these 
two cohorts. Eleven study subjects will be enrolled for the first stage of study for each cohort; the 
study will be terminated if one or less response was observed at end of first stage.  A two- stage 
study design will be used in order to minimize the number of study subjects treated if tipifarnib 
is not efficacious.  This design is intended to allow the termination of accrual earlier in case of 
unacceptably low efficacy observed during the study. 


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An additional seven subjects will be enrolled for the second stage.  At the completion of two- 
stage study, the study is considered as failure if there will be three or less responses out of 18 
evaluable subjects, indicating the true ORR is 10% or less.  If there are four or more responses, 
the treatment will be considered of further interest indicating the true ORR is higher than 10%. 
For this two-stage study design, a null response rate of 10% and alternative response rate of 30% 
are assumed.  It provides 80% power to detect a difference between 10% and 30% ORR at one- 
sided significance level of 0.087.  Using this design, the probability of terminating the study at 
the end of first stage is 0.697 if the true ORR is 10% or less while the probability of terminating 
the study at the end of first stage is 0.113 if the true ORR is 30%. 
In order to reject the null hypothesis, 4 confirmed response are required in Cohort 1 or Cohort 2. 
In Cohort 2, upon observation of 4 confirmed responses, enrollment of HRAS mutant HNSCC 
subjects will continue up to 30 subjects with HRAS mutant HNSCC (10 enrolled in Cohort 2 
Stage 1 and 2 combined, plus 20 additional subjects) to further explore the antitumor activity of 
tipifarnib in this tumor type.  No statistical hypotheses will be tested in this extension. 
In addition, to allow for the compassionate treatment of a subject with an HRAS mutant salivary 
gland tumor, Stage 1 of Cohort 2 was expanded to 12 total subjects in Amendment 4.2.  The 
primary hypothesis of the study was met at the time of this amendment and the addition of this 
subject will not be taken into consideration for the analyses of the primary or interim analyses of 
the trial. 
Cohort 3, consisting of SCC subjects (other than HNSCC) regardless of organ, will enroll 20 
subjects.  This cohort is added as an amendment to the protocol and its size is empiric due to 
constraints resulting from the rarity of HRAS mutations in SCC other than HNSCC. 
Thus, up to approximately 75 evaluable subjects (Cohorts 1, 2 and 3) may be enrolled in the 
study. 
6. 
ANALYSIS POPULATIONS 
Enrolled subjects are those that signed informed consent and either met all inclusion and 
exclusion criteria or were authorized by Sponsor to receive study drug treatment.   
 
Full analysis set (FAS) 
The FAS population will serve as the primary population for the analysis of tumor response and 
other efficacy-related data.  Subjects will be excluded from FAS for the following reasons:  
• No baseline data  
• Failure to receive at least one dose of tipifarnib  
• No evaluable post-baseline endpoint data subsequent to at least 1 dose of study drug 
• If the only post-baseline assessment is Stable Disease and it occurred prior to 6 weeks 
from first dose.  


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Subjects will be grouped in the FAS population according to cohort as described in Section 4.1.  
Per-Protocol (PP) Population  
A supportive analysis using the PP population will be performed for the tumor response analysis.  
The PP population excludes subjects due to major deviations from the protocol that may 
substantially affect the results of the primary analysis.  The final determination on protocol 
violations, and thereby the composition of the PP population, will be made prior to locking the 
clinical database and final analysis and will be documented in a separate memorandum. 
All Subjects as Treated (ASaT) population 
The ASaT population will be used for the analysis of safety data.  The ASaT population consists 
of all enrolled subjects who receive at least one dose of tipifarnib.  At least one laboratory or 
vital sign measurement obtained subsequent to at least one dose of study drug is required for 
inclusion in the analysis of a specific safety parameter.  To assess change from baseline, a 
baseline measurement is also required. 
7. 
GENERAL STATISTICAL CONSIDERATIONS 
7.1. 
Data Handling Conventions 
Analyses will be performed using SAS® [SAS Institute 2011] Version 9.3 or higher. 
• Summary tables for continuous variables will contain the following statistics: N 
(number of subjects in the population); n (number of subjects with data); mean; 
standard deviation; median; minimum; and maximum.  Selected statistics may also 
include a 2-sided 95% normal approximation confidence intervals (CIs) on the mean.  
• Summary tables for categorical variables will include: N (number of subjects in the 
denominator, X); n (number of subjects in the numerator, xx); and percent and will be 
presented in the format XX (XX.X%), where the percentage is in parentheses. 
Selected statistics also may include 2-sided 95% CIs for the percent.  
• Date variables are formatted as yyyy-MM-dd for presentation.  
• The baseline value for a given parameter is the last non-missing value prior to the 
first dose.  A value is considered post-baseline if it is obtained after the first study 
drug administration. 
• Change from baseline is calculated as (post-baseline result – baseline result).  Percent 
change from baseline is calculated as (change from baseline/baseline results * 100).  
If either the baseline or post-baseline result is missing, the change from baseline and 
percent change from baseline is set to missing as well.  
• If days should be converted to months, the divisor of 30.4375 will be used (i.e., 
Months = Days / 30.4375)  
• Data from all study centers will be pooled for all analyses.  


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• Study day is defined as calendar date – date of first treatment + 1 if the calendar date 
is on or after the date of first treatment, and calendar date – date of first treatment if 
the calendar date is before the date of first treatment  
• Measurements from unscheduled visits will be included in listings, but not summary 
tables, including laboratory tests performed at the site.  
• Listings will be provided of all data collected in the electronic case report forms 
(eCRF).  
• Wherever possible, data will be decimal aligned.  
• For continuous variables, the following conventions will be made for significant 
digits: 
− Mean (xx.xx) 
− Standard deviation (x.xxx) 
− Median (x.xx) 
− Minimum and maximum (xx.x)  
7.2. 
Interim Analyses and Data Monitoring 
One or more interim analyses may be conducted.  The first interim analysis will be conducted to 
assess preliminary anti tumor activity in Cohort 2 Stage 1 patients (N = 11).  At this interim 
analysis the decision to terminate the study can be made if one or fewer responses are observed.  
Further interim analyses may be conducted to present the current data without requiring the 
application of  predefined stopping rules. 
Interim Analyses to present data will  include all events, including but not limited to adverse 
events, response assessments, and study drug administration, that are recorded in the database 
(data cut of Sept 30, 2020 and April 10, 2020). 
• Adverse Events 
− If stop date is past the cut off date 
 Remove stop date and change to ‘Ongoing’ 
 Have Action and Outcome = ‘Not Recovered/Not Resolved’ 
 Duration will be censored at the data cut off of date, death, or end of 
study, whichever is first 
• Con Med Data 
− If stop date is past cut off date, remove stop date and change to ‘Ongoing’ 
• Study Drug Data 
− Remove stop date if past cut off date.  ‘Last treatment’ will be the last treatment 
prior to or on cut off date. 


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• Any other dates past cut off 
− Remove stop date and change to ‘Ongoing’ 
− Blank out any information not attainable until completion of record 
7.3. 
Multi-Center Studies 
This is a multi-center study. Given the small sample size of the study, no site effect will be 
considered in any statistical analysis.   
7.4. 
Multiple Comparisons / Multiplicity 
No adjustment for multiple comparisons will be conducted.  The P values will not be adjusted 
for multiple comparisons and be reported/interpreted according to the nominal levels of 
significance.  
7.5. 
Examination of Subgroups 
Analysis will be performed for each histological type cohort, with Cohort 2 described as Stage 1 
or Stage 2.  An adverse event incidence table will be presented with subjects grouped by starting 
dose – 600 mg BID or 900 mg BID.  In addition, efficacy data will be grouped and presented 
with the following subgroups:  
• All HNSCCs 
• All HNSCCs with HRAS VAF ≥ 20% and serum albumin ≥ 3.5 g/dL or HRAS VAF 
≥ 35%. (“High VAF”) 
• SCC Other (Cohort 3) 
• SCC Other (Cohort 3) with HRAS VAF ≥ 20% and serum albumin ≥ 3.5 g/dL or 
HRAS VAF ≥ 35%. (“High VAF”) 
• All SCCs including HN (Cohorts 2/Stage 2 and 3 combined) 
• All SCCs including HN (Cohorts 2/Stage 2 and 3 combined) with HRAS VAF ≥ 20% 
and serum albumin ≥ 3.5 g/dL or HRAS VAF ≥35%.  (“High VAF”) 
7.6. 
Handling of Dropouts or Missing Data 
Where individual data points are missing because of insufficient samples, dropouts, or other 
reasons, the data will be analyzed based on reduced denominators.  For survival analysis, 
dropouts without confirming events will be treated as censored. 
7.7. 
Outlier Handling 
Potential data entry errors manifested as outliers will be handled in the data management process 
through edit checks. 


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7.8. 
Adustments for Covariates 
Not applicable. 
8. 
SUMMARY OF STUDY POPULATION DATA 
All data will be summarized by cohort.  A subgroup analysis will further summarize data 
according to HRAS status and albumin levels at baseline (see Section 7.5).  A single safety table 
will be presented by starting dose (600 mg or 900 mg). 
8.1. 
Subject Disposition 
Subject disposition will be provided for all subjects screened.  A summary table will present the 
total number of subjects screened, total number enrolled, and total number in each analysis 
population.  Among subjects who received any study drug, this summary will also present the 
frequency and percentage of subjects who discontinued treatment and came off study.  The 
primary reasons for discontinuation of treatment, and for end of study will be tabulated. 
Detailed subject disposition information, as well as eligibility and analysis population 
assignment will be provided in listings. 
8.2. 
Protocol Deviations 
A detailed listing of all protocol deviations will be included. 
8.3. 
Demographics and Baseline Characteristics 
Descriptive statistics of demographic measurements at screening such as age, sex, ethnicity, race, 
measurements of height and weight, and ECOG performance status score at screening will be 
summarized for the ASaT and FAS populations.  
Medical and surgical history / physical findings will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) version 19.0 and summarized by system organ class (SOC)/ 
preferred term (PT) for enrolled subjects. 
Summaries of cancer history at screening by cancer diagnosis and stage will be provided for 
enrolled subjects.  Thyroid cancer subtype at screening will be summarized for enrolled subjects. 
Prior anti-cancer therapy, cancer surgery and radiation therapy will be summarized for both the 
ASaT and FAS populations.  For prior anti-cancer therapy, descriptive statistics on the number of 
regimens per subject, best overall response on last prior therapy, and last therapy progression 
free survival will be presented.  Progression free survival on last prior therapy will be calculated 
as follows: 
((Progression Date – Earliest Treatment Initiation Date of Most Recent Prior Cancer 
Therapy) + 1)/30.4375.  If date of progression is not available for the last prior therapy, then the 
start date of Tipifarnib will be used to calculate PFS.  
Kaplan Meier curves will present PFS on last prior therapy for the FAS population by cohort and 
PFS of last prior cancer therapy for the subgroups.   


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Descriptive statistics will be presented for the number of cancer surgery procedures per subject, 
the number of prior radiation therapies per subject, and the radiation intent (adjuvant, salvage, 
palliative, unknown). 
Data on individual subject demographics; baseline medical, surgical history/physical findings; 
HRAS status at screening; cancer history at screening; and prior anti-cancer therapy, prior cancer 
surgery, and prior radiation therapy will be displayed in listings. 
8.4. 
Dosing and Extent of Exposure 
Number of treatment cycles and average dose intensity per cycle will be summarized for the 
ASaT and PP populations.  Dose intensity is defined as the mean % compliance per treatment 
cycle, where compliance = (actual dose/planned dose)*100.  A summary will also be presented 
for the frequency and incidence of drug modification (dose reduction, dose interruption, dose 
increase, or drug withdrawn), which will include summary statistics for the number of dose 
modifications if any per subject.  
Data for study drug dispensing and dosing will be presented in listings. 
8.5. 
Prior and Concomitant Medications 
Prior cancer therapies, and prior and concomitant medications (other than cancer treatment) will 
be coded by WHO Drug Dictionary (WHODD version Dec 2014 B2) and summarized by 
preferred ATC Level 4 text and preferred drug name.  For drugs not having ATC Level 4, ATC 
Level 3 text will be used.   
Data for prior cancer therapies  prior and concomitant medication (other than cancer treatment), 
and for non-drug treatments or procedures will be presented in listings.  
9. 
EFFICACY ANALYSES 
Summaries for efficacy data will be presented by cohort and by subgroup. 
9.1. 
Primary Efficacy Analyses 
The objective response rate (ORR) of tipifarnib in subjects with locally advanced unresectable or 
metastatic, relapsed and/or refractory, HRAS mutant non hematological malignancies will be 
estimated.  The primary endpoint will be response assessments according to RECIST 1.1 
. 
The estimate of the objective response rate will be calculated based on the maximum likelihood 
estimator (i.e., crude proportion of subjects whose best overall response is Complete Response 
(CR) or Partial Response (PR)).  The estimate of the objective response rate will be accompanied 
by 2-sided 95% Confidence Interval (CI).  When 𝑁𝑁𝑝𝑝̂ > 5 , where 𝑁𝑁 is number of subjects, the 
95% CI can be estimated using the Wilson, score test based, method.  


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A summary of the ORR will be presented for the FAS population.  A corresponding summary for 
the PP population will be presented as a sensitivity analysis.  In addition, the data will be 
presented for the subgroups as described in Section 7.5. 
Data on tumor assessment information, target tumor assessment, non-target tumor assessment, 
new lesion assessment and overall response assessment will be displayed in listings. 
9.2. 
Exploratory Efficacy Analyses 
The duration of objective response (DOR) will be calculated for subjects who achieve CR or PR.  
For such subjects, the DOR is defined as the number of days from the start date of PR or CR 
(whichever response is achieved first) to the first date that progressive disease is objectively 
documented.  Disease progression will be determined by the Investigator using RECIST (version 
1.1).  The DOR will be right-censored at the date for subjects who achieve CR or PR and meet 1 
of the following conditions: 1) when non-protocol anticancer treatment started before 
documentation of disease progression, 2) when death prior to documented disease progression or 
documented disease progression after more than 1 missed disease assessment visit, or 3) when 
alive and does not have documentation of disease progression before a data analysis cutoff date.  
(Therefore, analysis cutoff date will be used as the censoring date). 
Progression free survival (PFS) will be defined as the time (in months) from first dose (Cycle 1 
Day 1) to either first observation of progressive disease or occurrence of death due to any cause 
within 126 days (approximately 2 time intervals for tumor assessments) of either first 
administration of tipifarnib or the last tumor assessment.  Observation of progressive disease can 
be by either documented radiographic progression (i.e., scan results) or documentation of 
symptomatic or clinical progression agreed upon and documented by investigators.  In subjects 
without a progression date or with a death date more than 126 days after the first administration 
of study drugs or the last tumor assessment, the PFS time should be censored on the date of last 
tumor assessment or date of first administration of study tipifarnib.  PFS analyses should 
consider tumor assessments after treatment discontinuation or metastatic surgery.  
The DOR and PFS, will be summarized descriptively using the Kaplan-Meier (KM) method.  
The 25th, 50th, and 75th percentiles of the Kaplan-Meier distribution will be used to describe the 
median response duration and median PFS. 
The median DOR and PFS and corresponding pointwise 95% confidence interval will be 
displayed by cohort for the FAS population and for the PP population, and for the subgroups.   
The KM curves of DOR and PFS by each cohort will be displayed for the FAS population, the 
PP Population, and for the subgroups in figures.  A per subject summary of DOR, such as 
treatment initiation date, progression date, first response date, durations, censoring status, best 
overall response, and analysis population inclusion, will be provided.  Similarly, a per subject 
summary of PFS, including enrollment date, treatment initiation date, progression date, duration, 
censoring status, best overall response, and analysis population inclusion, will also be provided. 
Subgroup analysis may be conducted to estimate PFS and DOR in the subset of subjects with 
partial response. Sensitivity analysis may be conducted to assess the impact of the median 
survival estimation method.  Interpolation based estimates can be used to estimate the median 


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survival whenever the sample size is small or there is not sufficient information (events) to 
robustly estimate the median survival based on KM function.   
Further analysis may include the comparison of the PFS between tipifarnib and prior therapies.  
A P value comparing the two PFS profiles (prior therapy and the current using tipifarnib) will be 
obtained using Wei-Lin (Cox regression based) robust estimator.  
If biomarkers including somatic mutations in archival tumor tissue have been successfully 
obtained for enough subjects, the relationship of the detection of tissue biomarkers potentially 
related to tipifarnib activity will be investigated as described in the protocol. 
9.3. 
Other Efficacy Analyses 
Per subject data on detail of tumor burden marker, and on subsequent therapy and survival status 
will be displayed in listings.   
Waterfall figures and spider plots will illustrate best overall percent change in tumor burden 
(defined as sum of diameters) for the FAS population, the PP population and by subgroup.   
An analysis of overall survival to estimate median overall survival time and corresponding 95% 
confidence interval and provide per subject summary of overall survival will be conducted.  
Overall survival will be defined as the time (in months) from first dose (Cycle 1 Day 1) to the 
occurrence of death due to any cause.  In subjects without a death date, the OS will be censored 
on 1) the last date of survival status if alive, 2) a data analysis cutoff date for subjects with no 
survival status documentation, or 3) the date a subject withdraws consent or is lost to follow-up, 
if there is no additional information. 
10. 
SAFETY ANALYSES 
Safety and tolerability of tipifarnib will be assessed based on the following:  
• Adverse events 
• Hematology and chemistry toxicities reported as adverse events 
• Changes in vital signs including blood pressure, pulse, and temperature  
• Changes in electrocardiogram results  
Unless explicitly indicated otherwise, all analyses for safety will be based on the ASaT 
population. 
The toxicity grades for laboratory tests will be based on NCI-CTCAE version 4.03 criteria.  The 
use of blood transfusions (platelets, red blood cells) will be reported.  Similar analyses will be 
done for selected chemistry tests: glucose, blood urea nitrogen (or uric acid), creatinine, sodium, 
potassium, chloride, calcium, magnesium, phosphorus, total protein, albumin, total bilirubin, 
alkaline phosphatase, alt, ast, gamma-glutamyl transferase, lactate dehydrogenase, bicarbonate 
(or total CO2).  


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Vital sign results (weight, blood pressure, pulse, respiration, and temperature) will be 
summarized descriptively for each scheduled protocol time point.  Changes will be calculated 
relative to the assessments at baseline and on the first day of each cycle of therapy.  Unscheduled 
results will be displayed in a listing. 
10.1. 
Adverse Events 
Adverse events will be coded using the latest available version of the Medical Dictionary for 
Regulatory Activities (MedDRA) Version 19.0.  Treatment-emergent adverse events are defined 
as adverse events that start on or after the first dose of study drug and within approximately 30 
days of the last administration of study drug.  Adverse events will be summarized by the number 
and percentage of subjects who experienced the event, according to system organ class and 
preferred term.  A subject reporting multiple cases of the same adverse event will be counted 
once within each system organ class and similarly counted once within each preferred term. 
Unless specified otherwise, the denominator for these calculations will be the number of subjects  
who received at least one administration of tipifarnib, irrespective of the total number of doses or 
treatment cycles administered.  These conventions will be appropriately modified to calculate 
AE incidence rates separately for each cycle that study therapy is administered.  AE incidence 
rates may also be calculated based on other measures of subject exposure (e.g., total number of 
treatment cycles administered).  
AE durations will be calculated using all TEAEs.  For AEs that are still ongoing at the end of 
study, we will use either death or the last contact date as the end of AE stop date for calculation 
the duration of AEs.  Median, minimum and maximum of AE durations will be reported. 
AEs will also be summarized by NCI-CTCAE version 4.03 severity grade and by relationship to 
study drug.  Additional summaries may also be provided for SAEs, and events resulting in the 
permanent discontinuation of therapy. All AEs will be included in individual subject listings. 
An overall view of TEAEs will be provided, which will include the total number of TEAEs, 
number of subjects with TEAEs, study drug-related TEAEs, Serious TEAEs, study drug-related 
Serious TEAEs, Grade 3 or higher study drug-related TEAEs, deaths within 30-days of 
administration of study-drug, and AEs leading to permanent discontinuation of study drug. 
Additionally, a corresponding overall view of exposure-adjusted AE incidence will be provided, 
which will present exposure-adjusted incidence rates (calculated as the mean number of events 
per treatment cycle) with corresponding 95% confidence intervals. 
Summary tables will be provided which present the incidence of TEAEs by SOC and PT; and the 
incidence of TEAEs by SOC/PT by maximum severity (NCI-CTCAE Grades 1 through 5), 
overall and by cohort. Corresponding summaries for laboratory-related AEs will also be 
provided. 
A summary of the AE durations for all TEAEs by SOC/PT will be provided. 
Summary tables will be provided which present the incidence of study-drug related TEAEs and 
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Summary tables will be provided which present the incidence of SAEs, the incidence of study 
drug-related SAEs, the incidence of TEAEs leading to permanent discontinuation of drug, and 
the incidence of TEAEs by starting dose (600 mg BID versus 900 mg BID), all by SOC/PT. 
Summary tables will be provided which present Grade 3 or above chemistry and hematology 
toxicities by treatment cycle, fatigue (preferred term) by treatment cycle, and gastrointestinal 
events (SOC) by treatment cycle.   
Data on adverse events will be presented in listings. 
10.2. 
Clinical Laboratory Evaluations 
As noted above, hematological adverse events Grade 3 or above based on NCI CTCAE version 
4.03 criteria will be summarized by treatment cycle and across all cohorts.  A similar summary 
will be provided for selected chemistry toxicities, including: glucose, blood urea nitrogen (or uric 
acid), creatinine, sodium, potassium, chloride, calcium, magnesium, phosphorus, total protein, 
albumin, total bilirubin, alkaline phosphatase, alt, ast, gamma-glutamyltransferase, lactate 
dehydrogenase, bicarbonate (or total CO2). 
The data for clinical chemistry and hematology laboratory evaluations will be presented in 
listings.  In addition to the results, these listings will present the normal range, toxicity grade, and 
clinical assessment (Normal; Abnormal, but not clinically significant; Abnormal, clinically 
significant) associated with evaluations. 
Per subject laboratory comments for hematology, clinical chemistry, coagulation, urinalysis, 
serum tumor burden biomarker, and serum or urine pregnancy will also be displayed in listings.  
10.3. 
Transfusion  
The incidence of blood transfusion (platelets, red blood cells) will be summarized by treatment 
cycle and across all cohorts.  
10.4. 
Vital Signs 
Vital sign results (weight, blood pressure, pulse rate, respiratory rate, and temperature) will be 
summarized descriptively for each scheduled protocol time point.  Changes will be calculated 
relative to the assessments at baseline. 
Data on vital signs will be presented in listings. 
10.5. 
ECGs 
A summary of ECG overall category and shifts from screening will be provided for tests 
performed at Cycle 1 Day 1, Cycle 1 Day 7, end of treatment. 
Data for all ECG overall assessments will be displayed in a listing. 
10.6. 
Other Safety Measures 
ECOG performance status per subject during the trial will be displayed in a listing. 


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11. 
CLINICAL PHARMACOLOGY ANALYSES 
None. 
12. 
OTHER ANALYSES 
Not applicable.  
13. 
REPORTING CONVENTIONS 
The table, listing and figure reporting layout will be detailed in the companion document 
KO-TIP-001 Table, Listing and Figure Shells. 
14. 
CHANGES IN THE STATISTICAL METHODS FROM THOSE 
STATED IN THE PROTOCOL 
Overall survival was added as an additional analysis.  
Included sensitivity analysis for PFS and DOR on a subset of subjects. 
15. 
TABLES, FIGURES, LISTINGS 
Tables, listings and, if applicable, figures will be generated according to the companion 
document which details the layout of the output.  Minor style deviation from specification 
defined in the shell document in the final production is permissible.   
16. 
REFERENCES 
A. Agresti and B.A. Coull, Approximate is better than "exact" for interval 
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