Clinical trial NCT03719690
Conditions: HRAS Gene Mutation HNSCC
Keywords: TIPIFARNIB HEAD AND NECK CANCER
Sponsor: Kura Oncology, Inc.
Start date: 2019-03-15; Completion date: 2023-05-02
Enrollment: 296 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
An international, multicenter, open-label, 2 cohort, non-comparative, pivotal study evaluating the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN). The first cohort will assess the objective response rate (ORR) of tipifarnib in subjects with HNSCC with HRAS mutations. The second study cohort, SEQ-HN, is an observational sub-study including HNSCC patients in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consent to provide first line outcome data and additional follow up.

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

The second study cohort, SEQ-HN, is an observational sub-study including HNSCC patients in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consent to provide first line outcome data and additional follow up.

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

Arms: arm 1: Tipifarnib, Oral Tablet. Dose Level 1 orally, bid on days 1-7 and 15-21 of 28-day treatment cycles arm 2: HNSCC patients in whom HRAS mutations were not identified (wild type HRAS HNSCC) and who consent to provide first line outcome data and additional follow up.
Interventions: intervention 1: Tipifarnib intervention 2: HRAS Detection Assay
Intervention descriptions: intervention 1: Tablet for oral administration intervention 2: In Vitro Assay to detect HRAS mutations

Protocol documents:
Prot_000.pdf: 
Protocol Number: KO-TIP-007 
 
Official Title: The AIM-HN and SEQ-HN Study: A Multi-national, Single Arm Pivotal Study Evaluating 
the Efficacy of Tipifarnib in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC) with 
HRAS Mutations (AIM-HN) and an Observational Study to Evaluate the Impact of HRAS Mutational 
Status on Response to First Line Systemic Therapies for HNSCC (SEQ-HN) 
NCT Number: NCT03719690 
 
Document Date: 09 June 2020 


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CLINICAL TRIAL PROTOCOL 
Protocol Number: KO-TIP-007 
Title: The AIM-HN and SEQ-HN Study: A 2 Cohort, Non-comparative, Pivotal Study 
Evaluating the Efficacy of Tipifarnib in Patients with Head and Neck Squamous Cell Carcinoma 
(HNSCC) with HRAS Mutations (AIM-HN) and the Impact of HRAS Mutations on Response to 
First Line Systemic Therapies for HNSCC (SEQ-HN). 
US IND Number: 127,209 
EudraCT Number: 2018-001437-40 
Version:  Final:  14 June 2018 
 Amendment 1:  25 July 2018 
 Amendment 2:  15 November 2018 
 Amendment 3:   9 June 2020 
 
Sponsor: Kura Oncology, Inc. 
3033 Science Park Road, Suite 220 
San Diego, CA 92121 (USA) 
Phone: +1 858.500.8803  
(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   
 
Protocol Author: 
  
 
CONFIDENTIAL 
This document contains proprietary and confidential information of Kura Oncology, Inc. Acceptance of this 
document constitutes agreement by the recipient that no previously unpublished information contained herein will 
be published or disclosed without the prior written approval of Kura Oncology, Inc. with the exception that this 
document may be disclosed to study personnel under your supervision who need to know the contents for 
conducting the study and appropriate Institutional Review Boards (IRBs)/Ethics Committees (EC) under the 
condition that the personnel have agreed to keep this information confidential. The foregoing shall not apply to 
disclosure required by governmental regulations or laws, however, Kura Oncology, Inc. shall be promptly notified 
of any such disclosure. 
 




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1 
TABLE OF CONTENTS 
Section 
 
1 
TABLE OF CONTENTS .....................................................................3 
2 
STUDY SYNOPSIS .............................................................................9 
3 
LIST OF ABBREVIATIONS .............................................................26 
4 
BACKGROUND ................................................................................28 
4.1 
Investigational Agent ..........................................................................28 
4.2 
Study Rationale ...................................................................................28 
4.2.1 
Head and Neck Squamous Cell Carcinoma ........................................28 
4.2.2 
Mechanism of Action .........................................................................29 
4.2.3 
Clinical Development .........................................................................30 
4.3 
Risk/Benefits .......................................................................................31 
4.4 
Dose Rationale ....................................................................................32 
4.5 
Trial Conduct ......................................................................................33 
4.6 
Population ...........................................................................................34 
5 
TRIAL OBJECTIVES ........................................................................35 
6 
TRIAL DESIGN .................................................................................36 
6.1 
Study Endpoints ..................................................................................36 
6.1.1 
Primary Endpoint ................................................................................36 
6.1.2 
Key Secondary Endpoints ...................................................................36 
6.1.3 
Other Secondary Endpoints ................................................................37 
 
 
 
6.2 
Study Design .......................................................................................37 
6.2.1 
AIM-HN Design .................................................................................38 
6.2.2 
SEQ-HN Design .................................................................................40 
6.3 
Randomization ....................................................................................40 
6.4 
Maintenance ........................................................................................40 
6.5 
Trial Treatment ...................................................................................41 
6.5.1 
Investigational Product (IP) ................................................................41 
6.5.2 
Product Characteristics .......................................................................41 
6.5.3 
Storage and Labeling ..........................................................................41 
6.5.4 
Emergency Medical Support and Subject Card ..................................42 


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6.6 
Duration ..............................................................................................42 
6.7 
Discontinuation ...................................................................................43 
6.7.1 
Definition of End of Study .................................................................43 
6.7.2 
Premature Discontinuation of the Trial ..............................................43 
6.8 
Product Accountability .......................................................................44 
6.9 
Data Identification ..............................................................................44 
6.9.1 
Subject Identification and Privacy ......................................................44 
6.9.2 
Case Report Form Management .........................................................45 
6.9.3 
Source Data and Subject Files ............................................................45 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS ......................46 
7.1 
Inclusion Criteria ................................................................................46 
7.1.1 
Inclusion Criteria: AIM-HN ...............................................................46 
7.1.2 
Inclusion Criteria: SEQ-HN ...............................................................48 
7.2 
Exclusion Criteria ...............................................................................49 
7.2.1 
Exclusion Criteria: AIM-HN ..............................................................49 
7.2.2 
Exclusion Criteria: SEQ-HN ..............................................................50 
7.3 
Subject Withdrawal ............................................................................50 
7.3.1 
Removal of Subjects from Treatment or Assessment .........................50 
7.3.2 
Medical Care of Subjects after End of Trial .......................................51 
7.3.3 
Replacement of Subjects .....................................................................51 
8 
TREATMENT OF SUBJECTS ..........................................................52 
8.1 
Medication ..........................................................................................52 
8.1.1 
Tipifarnib Administration ...................................................................52 
 
 
8.1.3 
Treatment of Tipifarnib Overdose ......................................................57 
8.1.4 
Prior and Concomitant Medications ...................................................57 
8.1.5 
Non-permitted Treatments ..................................................................58 
8.1.6 
Dietary or Other Protocol Restrictions ...............................................59 
8.2 
Monitoring of Subject Compliance ....................................................60 
9 
STUDY PROCEDURES ....................................................................60 
9.1 
Pre-screening for HRAS Mutation .....................................................60 
9.1.1 
Subjects With Known HRAS Mutation ..............................................61 


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9.1.2 
Subjects Without Known HRAS Mutational Status: Testing for 
HRAS mutation at a Sponsor Designated Laboratory ........................62 
9.1.3 
Subjects Without Known HRAS Mutational Status: Local testing 
for HRAS mutation using a Sponsor approved test: ...........................62 
9.1.4 
Subjects who have HNSCC without HRAS mutation ........................63 
9.2 
AIM-HN .............................................................................................63 
9.2.1 
Screening Procedures ..........................................................................63 
9.2.2 
Day 1 of Cycle 1 .................................................................................66 
9.2.3 
Day 7 of Cycle 1 .................................................................................67 
9.2.4 
Day 1 (± 2 days) of Cycle 2 ................................................................67 
9.2.5 
Day 1 (± 2 days) of Cycle 3 and Beyond ............................................68 
9.2.6 
Tumor Response Assessment Visits ...................................................68 
9.2.7 
End of Treatment Visit .......................................................................69 
9.2.8 
Follow up Visit ...................................................................................70 
9.2.9 
Follow Up Contact ..............................................................................71 
9.3 
SEQ-HN ..............................................................................................71 
9.3.1 
Screening Procedures ..........................................................................71 
9.3.2 
Study Enrollment ................................................................................71 
9.3.3 
On Study Visit ....................................................................................72 
9.3.4 
Follow Up Contact ..............................................................................73 
10 
ASSESSMENT OF EFFICACY ........................................................73 
10.1 
Efficacy Parameters ............................................................................73 
10.1.1 
Efficacy Variables...............................................................................73 
10.1.2 
Method and Timing ............................................................................73 
10.2 
Additional Variables ...........................................................................74 
10.2.1 
Population Pharmacokinetics ..............................................................74 
10.2.2 
Biomarkers ..........................................................................................75 
11 
ASSESSMENT OF SAFETY .............................................................76 
11.1 
Safety Parameters ...............................................................................76 
11.2 
Method and Timing ............................................................................76 
11.2.1 
Monitoring of Subjects with Adverse Events .....................................76 
11.2.2 
Pregnancy and In Utero Drug Exposure .............................................77 
11.2.3 
Laboratory Assessments .....................................................................77 


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11.3 
Adverse Event Reporting ....................................................................78 
11.3.1 
Procedure for Reporting Adverse Events ...........................................78 
11.3.2 
Procedure for Reporting Serious Adverse Events ..............................79 
11.3.3 
Safety Reporting to Health Authorities, Institutional Review 
Boards and Investigators .....................................................................80 
11.4 
Definitions ..........................................................................................80 
11.4.1 
Adverse Events ...................................................................................80 
11.4.2 
Serious Adverse Event ........................................................................81 
11.4.3 
Events that Do Not Meet the Definition of an SAE ...........................81 
11.4.4 
Events Not to Be Considered as AEs/SAEs .......................................81 
11.4.5 
Abnormal Laboratory Findings and Other Abnormal 
Investigational Findings ......................................................................82 
11.5 
Adverse Event Follow-up ...................................................................82 
12 
STATISTICAL CONSIDERATIONS ...............................................82 
12.1 
Statistical Methods ..............................................................................82 
12.1.1 
Efficacy ...............................................................................................82 
12.1.2 
Safety and Tolerability .......................................................................86 
12.1.3 
Population Pharmacokinetics ..............................................................87 
12.2 
Subject Population(s) for Analysis .....................................................87 
12.2.1 
Efficacy Analysis ................................................................................87 
12.2.2 
Safety Analysis ...................................................................................87 
 
 
12.3 
Significance ........................................................................................88 
12.4 
Termination Criteria ...........................................................................89 
12.5 
Accountability Procedure ...................................................................89 
12.6 
Deviation Reporting ............................................................................89 
13 
Regulatory, Ethical, and Study Oversight Considerations .................89 
13.1 
Regulatory and Ethical Considerations ..............................................89 
13.2 
Financial Disclosure ...........................................................................90 
13.3 
Informed Consent Process ..................................................................90 
13.4 
Data Protection ...................................................................................90 
13.5 
Dissemination of Clinical Study Data ................................................91 
13.6 
Data Quality Assurance ......................................................................91 


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13.6.1 
Data Quality and Integrity Monitoring ...............................................91 
13.7 
Source Documents ..............................................................................92 
13.8 
Study and Site Closure ........................................................................92 
13.9 
Publication Policy ...............................................................................92 
14 
Guidelines To Be Applied During Infectious Disease Outbreak – 
COVID-19 ..........................................................................................92 
14.1 
Ensuring Continuity of Safety Reporting ...........................................93 
14.2 
Maintaining Protocol Requirements, Including Schedule of 
Activities .............................................................................................93 
14.2.1 
Clinic Visits ........................................................................................93 
14.2.2 
Clinical Laboratory Testing ................................................................94 
14.2.3 
Disruptions for Shipping to Central Laboratories ..............................94 
14.3 
Informed Consent Process ..................................................................94 
14.4 
Ensuring Continuity of Drug Supply to Subjects ...............................95 
14.5 
Managing Restrictions to Site Monitoring by CRAs ..........................95 
14.6 
Documentation of COVID-19 Related Guidelines or Other 
Measures. ............................................................................................95 
15 
LITERATURE ....................................................................................95 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Tables 
Table 1: Schedule of Events: Pre-screening for for HRAS Mutations ..............................21 
Table 2: Schedule of Events: AIM-HN .............................................................................22 
Table 3: Schedule of Events: SEQ-HN ..............................................................................25 
 
 
 
 
 
 
 
 
 
Figures 
Figure 1: KO-TIP-007 Study Design .................................................................................11 
Figure 2: AIM-HN Design .................................................................................................13 
Figure 3: SEQ-HN Design .................................................................................................14 
Figure 4: Tipifarnib Activity in HRAS-Mutant HNSCC PDX Models .............................30 
Figure 5: Tipifarnib Activity in Cetuximab-Resistant HRAS-Mutant HNSCC PDX 
Models ................................................................................................30 
 
 
 


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2 
STUDY SYNOPSIS 
TITLE: The AIM-HN and SEQ-HN Study: A 2 Cohort, Non-comparative, Pivotal Study 
Evaluating the Efficacy of Tipifarnib in Patients with Head and Neck Squamous Cell Carcinoma 
(HNSCC) with HRAS Mutations (AIM-HN) and the Impact of HRAS Mutations on Response to 
First Line Systemic Therapies for HNSCC (SEQ-HN). 
SPONSOR: Kura Oncology, Inc. 
PROTOCOL NUMBER: KO-TIP-007 
PHASE OF DEVELOPMENT: Pivotal 
OBJECTIVES: 
Primary Objective:  
• To determine the objective response rate (ORR) of tipifarnib in subjects with Head and 
Neck Squamous Cell Carcinoma (HNSCC) with HRAS mutations with a VAF≥20% 
(High VAF population), as assessed by Independent Review Facility (IRF).   
Key Secondary Objectives: 
• To determine the objective response rate (ORR) of tipifarnib in subjects with Head and 
Neck Squamous Cell Carcinoma (HNSCC) with HRAS mutations of any VAF (All VAF 
population), as assessed by IRF. 
• To determine the Duration of Response (DOR) of tipifarnib in subjects with Head and 
Neck Squamous Cell Carcinoma (HNSCC) with HRAS mutations with a VAF≥20% 
(High VAF population), as assessed by IRF. 
• To determine the Duration of Response (DOR) of tipifarnib in subjects with Head and 
Neck Squamous Cell Carcinoma (HNSCC) with HRAS mutations of any VAF (All VAF 
population), as assessed by IRF. 
Other Secondary Objectives for AIM-HN: 
• To determine the anti-tumor activity of tipifarnib in terms of progression free survival, 
and rate of progression free survival at 6 and 9 months in both the high VAF and all VAF 
populations 
• To determine the anti-tumor activity of tipifarnib in terms of overall survival, and rate of 
overall survival at 12 months in both the high VAF and all VAF populations 
• To determine the anti-tumor activity of tipifarnib in terms of time to response in both the 
high and all VAF populations  
• To determine the anti-tumor activity of tipifarnib in terms of time to progression (TTP) in 
both the high and all VAF populations  


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• To investigate the safety and tolerability of tipifarnib according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE 
v5.0).  
• To investigate the effects of tipifarnib treatment on quality of life measures, including 
EORTC QLQ-H&N35 and EQ-5D-5L. 
• To assess population pharmacokinetics (PK) of tipifarnib in subjects with HNSCC with 
HRAS mutations.   
STUDY DESIGN: 
KO-TIP-007 is an international, multicenter, open-label single- arm pivotal study. There are two 
sub-studies, not intended for comparison (1) an interventional open label, single arm, pivotal 
study evaluating the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN) and (2) an 
observational study to evaluate the impact of HRAS mutations on response to first line systemic 
therapies for HNSCC (SEQ-HN).  
AIM-HN, includes HNSCC subjects with HRAS mutations. AIM-HN subjects will receive 
treatment with tipifarnib and the outcome will address the primary objective of the KO-TIP-007 
study. SEQ-HN, is an observational sub-study and includes wild type HRAS HNSCC subjects 
who consent to provide first line outcome data and additional follow up. HNSCC patients in 
whom HRAS mutations are identified and who meet eligibility criteria will be offered 
participation in AIM-HN. HNSCC patients in whom HRAS mutations are not identified may 
participate in SEQ-HN only. These patients will be followed and the comparison of outcomes of 
HRAS mutant and HRAS wild type HNSCC 
 
 
 


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KO-TIP-007 will enroll a total of at least 305 subjects. AIM-HN, the tipifarnib treatment sub-
study of KO-TIP-007, will investigate the efficacy of tipifarnib in at least 80 subjects with head 
and neck tumors of confirmed squamous histology with HRAS mutations.  SEQ-HN, the non-
interventional observational sub-study, will enroll an additional, at least 225 subjects with HRAS 
wildtype HNSCC tumors. Additional HRAS mutant subjects that consent to pre-screening, but 
do not enroll in AIM-HN may have first line treatment data collected as well. 
The study design is shown in Figure 1. 
Figure 1: KO-TIP-007 Study Design 
   
• AIM-HN 
AIM-HN will enroll patients with head and neck tumors of confirmed squamous histology with 
HRAS mutations. Subjects must have failed (e.g. tumor progression, clinical deterioration, or 
recurrence) their most recent prior therapy, and at least one prior line of systemic platinum-based 
therapy (the most recent prior and platinum-based therapy may be the same regimen). However, 
subjects who, at the judgment of the investigator, are considered not to be candidates to receive 
standard therapy with a platinum-containing regimen may also be enrolled (further detailed in 
Section 4.6).  The primary objective of AIM-HN is to determine the ORR of tipifarnib in 
subjects with HNSCC with HRAS mutations and a VAF≥20%, as assessed by IRF.     


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To participate in AIM-HN, all subjects must have measurable disease that meets the criteria for 
selection as a target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1. The presence of at least one measurable target lesion per RECIST v1.1 must be confirmed 
by local radiology prior to enrollment. Subjects without at least one measurable target lesion 
confirmed by local radiology will not be enrolled into AIM-HN.  
HNSCC diagnosis by local site pathology laboratory will be used; however, all subjects must 
provide pathology material for central pathology review.  Central confirmation of pathological 
diagnosis of HNSCC will be required for inclusion of subjects in the per-protocol analysis set.  
Subjects in whom a diagnosis of HNSCC is not confirmed by central review may continue to 
receive study treatment and will be included in the modified intent-to-treat (mITT) analysis set.  
All AIM-HN enrolled subjects must have a known missense HRAS tumor mutation based on 
centralized testing or other HRAS test used by the trial site that has been approved by the 
Sponsor. HRAS status should be assessed on tumor obtained subsequent to the most recent prior 
therapy in order to obtain the most recent tumor biology; if tumor tissue that does not meet this 
criterion must be used (e.g. risk of biopsy is too high, patient refuses new biopsy), the 
investigator should document the reason. If several samples are available, HRAS testing should 
be performed in the most recently obtained tumor sample. To facilitate development of 
appropriate diagnostic testing, all subjects must provide enough tumor material for confirmation 
of HRAS status by central lab. This tissue should be from the same source as that used for pre-
screening, or the reason that is not possible documented.  Subjects who were enrolled in the 
study based on HRAS mutation using a Sponsor approved test, but in whom a missense HRAS 
mutation is not confirmed by central laboratory, may continue to receive study treatment. SEQ-
HN subjects who were initially identified as wild type HRAS but in whom an HRAS mutation is 
later detected during the course of their standard therapy, will become eligible to screen for 
AIM-HN.   
AIM-HN enrolled subjects will receive tipifarnib administered at a dose of 600 mg, orally with a 
meal twice a day (bid) for 7 days in alternating weeks (Days 1-7 and 15-21) in 28-day cycles.  
Stepwise 300 mg dose reductions to control treatment-related, treatment-emergent toxicities are 
described in Section 8.1.2.  In the absence of unmanageable toxicities, subjects may continue to 
receive tipifarnib treatment until disease progression.  If a complete response is observed, and 
subject continues to tolerate therapy, therapy with tipifarnib will be maintained for at least 6 
months beyond the start of response. 
Tumor assessment for the primary analysis will be performed by the IRF according to RECIST 
v1.1 and assessed by an Independent Data Monitoring Board (IDMB).  Investigator assessment 
of tumor response will also be collected and reported as a supportive analysis. Assessments will 
be performed at screening and approximately every 8 weeks for the first 12 months of a subject’s 
participation in AIM-HN; thereafter, tumor response assessment should occur approximately 
every 12 weeks until disease progression.  Radiological assessments will be discontinued at the 
time of tumor progression.  If the subject initiates a new anticancer therapy without evidence of 


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disease progression by RECIST v1.1, tumor scans should continue until there is evidence of 
disease progression unless withdrawal of subject’s consent to study procedures.  Local 
investigator evaluation of tumor assessment will guide on-study treatment decisions, including 
decisions to stop study treatment due to progressive disease.   
Upon disease progression, all subjects will be followed approximately every 12 weeks for 
survival and the use of subsequent therapy until either death or End of Study (up to 2 years after 
the enrollment of the last study subject in AIM-HN, see Section 6.7.1), whichever occurs first. 
All subjects will be followed-up for safety through the End of Treatment visit which occurs 
approximately 30 days after treatment discontinuation or immediately before the administration 
of another anticancer treatment, whichever occurs first. Additional safety follow-up may be 
conducted if unresolved toxicity is present at this End of Treatment visit. The IDMB will provide 
periodic evaluations of safety and other data to ensure adequate benefit/risk as well as the 
validity and scientific merit of the study. 
An overview of the AIM-HN sub-study design is shown in Figure 2. 
Figure 2: AIM-HN Design 
   
• SEQ-HN 
SEQ-HN is an observational sub-study 
 
  Demographics, 
disease history, information on prior anti-cancer treatments and outcomes to prior treatments for 
HNSCC will be collected from all enrolled subjects. At least approximately 225 control patients 


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with HNSCC without known HRAS mutations, will be enrolled into SEQ-HN.  As part of their 
participation in SEQ-HN, patients will be followed up through initiation of second line therapies, 
death or consent withdraw, whichever occurs first. A subset of the approximate 225 control 
patients will be matched to the HRAS mutant subjects to the greatest extent possible according to 
pre-defined patient characteristics. If necessary, additional follow up of the matched HRAS 
wildtype HNSCC patients enrolled into SEQ-HN may continue until all AIM-HN objectives are 
completed and KO-TIP-007 end of study is reached. Control patients with HNSCC with wildtype 
HRAS will not receive tipifarnib treatment as part of their participation in SEQ-HN; however, 
they may be compensated for their participation in data collection, blood sampling, screening 
and follow up procedures according to institutional guidelines. 
An overview of the SEQ-HN design is shown in Figure 3. 
Figure 3: SEQ-HN Design  
  
NUMBER OF SUBJECTS PLANNED:  
In AIM-HN, at least 80 subjects meeting all criteria for inclusion in the per-protocol analysis set 
will be enrolled.  
Subject criteria for inclusion in the per-protocol analysis set include: received at least one dose of 
tipifarnib, confirmed measurable disease at baseline per RECIST v1.1 by IRF, confirmed 
diagnosis of HNSCC by central pathology review, and at least one post baseline disease 
assessment (e.g. tumor assessment visit). In SEQ-HN, approximately an additional 225 patients 
with HNSCC but without detected HRAS mutations will also be enrolled. A subset of the 
wildtype HRAS subjects will be selected as a matched-control subset to those subjects with: 
• HRAS mutant tumors enrolled as part of AIM-HN,   


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• HRAS mutant tumors that do not enroll in AIM-HN, but have 1L data collected 
during the pre-screening period 
SUBJECT SELECTION:  
Inclusion Criteria: AIM-HN 
For inclusion of a subject in the tipifarnib treatment portion of the study (AIM-HN), all of the 
following inclusion criteria must be fulfilled. If a subject does initially not meet any inclusion 
criteria, the subject may be re-screened at a later time:  
1. 
At least 18 years of age. 
2. Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, 
nasopharyngeal, or unknown primary) of squamous histology not amenable to local therapy 
with curative intent (surgery or radiation therapy with or without chemotherapy). Enrollment 
may proceed with local diagnosis but all subjects must consent to provide tumor tissue for a 
central pathology review. 
3. Documented treatment failure from most recent prior therapy (e.g. tumor progression, 
clinical deterioration, or recurrence), and from at least one prior platinum-containing 
regimen, in any treatment setting. The most recent prior and platinum-based therapy may be 
the same regimen. Those subjects who, at the judgment of the investigator, are considered 
clinically unsuitable to receive standard platinum-containing regimen, may also be enrolled 
and the reason for clinical unsuitability recorded. There is no limit on the number of prior 
lines of therapy.  
4. 
Known tumor missense HRAS mutation detected by Next Generation Sequencing (NGS) or 
any other methodology approved by the Sponsor. Variant allele frequency (VAF) needs to be 
determined and must be available.  HRAS status should be assessed on tumor tissue obtained 
subsequent to the most recent prior therapy so that the most accurate tumor biology is 
evaluated. If tumor tissue that does not meet this criterion must be used (e.g. risk of new 
biopsy is too high, patient refuses new biopsy), the investigator should document the reason. 
Enrollment may proceed with the identification of a missense HRAS mutation using a test 
preferred by the investigator and approved by the Sponsor during pre-screening, but all 
subjects must consent to provide tumor tissue for central HRAS confirmation.  
 
 
5. 
Measurable disease by RECIST v1.1 (Appendix I) that meets the criteria for selection as a 
target lesion according to RECIST v1.1.  The presence of at least one measurable target 
lesion per RECIST v1.1 must be confirmed by local radiology prior to subject entry. 
6. 
At least 2 weeks or 5 half-lives, whichever is longer, since the last systemic therapy regimen 
prior to Cycle 1 Day 1. Last dose of any prior checkpoint inhibitor therapy must have been 


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administered at least 2 weeks prior to C1D1. Subjects must have recovered to NCI CTCAE 
v5.0 < Grade 2 from all acute toxicities (excluding Grade 2 toxicities that are not considered 
a safety risk by the Sponsor and Investigator) or toxicity must be deemed irreversible by the 
Investigator. 
7. 
At least 2 weeks since last radiotherapy. Subjects must have recovered from all acute 
toxicities from radiotherapy.  
8. 
ECOG performance status of 0-1 (Appendix II). 
9. 
Acceptable liver function: 
a) Bilirubin  1.5 times upper limit of normal (x ULN). 
b) AST (SGOT) and ALT (SGPT)  1.5 x ULN. 
The subject must meet/continue to meet these criteria at the time of first dosing, as 
confirmed by analysis within 72 hours of C1D1. 
10. Acceptable renal function with either serum creatinine  1.5 x ULN or a calculated creatinine 
clearance ≥ 60 mL/min using the Cockcroft-Gault or Modification of Diet in Renal Disease 
(MDRD) formulas. 
The subject must meet/continue to meet these criteria at the time of first dosing, as 
confirmed by review of analysis performed within 72 hours of C1D1. 
11. Acceptable hematologic status: 
a) ANC  1000 cells/μL. 
b) Platelet count  75,000/μL. 
c) Hemoglobin  8.0 g/dL. 
The subject must meet/continue to meet these criteria at the time of first dosing, as 
confirmed by review of analysis performed within 72 hours of C1D1. 
12. Female subjects must be:  
a) Of non-child-bearing potential (surgically sterilized or at least 2 years post-
menopausal); or 
b) If of child-bearing potential, subject must use a highly effective method of 
contraception, such as combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation, progestogen-only hormonal 
contraception associated with inhibition of ovulation, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised 
partner or sexual abstinence.  Both females and male subjects with female 
partners of child-bearing potential must agree to use a highly effective method of 
contraception from the first dose of tipifarnib, during tipifarnib treatment, and at 


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least 28 days after last dose of tipifarnib for females and 90 days for males. 
Female subjects must have a negative serum or urine pregnancy test within 72 
hours prior to start of trial medication. 
c) Not breast feeding at any time during the study. 
13. Written and voluntary informed consent understood, signed and dated. 
Exclusion Criteria: AIM-HN  
If a subject initially meets any exclusion criteria, the subject may be re-screened at a later time. 
1. Has disease that is suitable for local therapy administered with curative intent. 
2. Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or 
nonsquamous histologies (e.g. mucosal melanoma).  
3. Known additional malignancy that is progressing or requires active treatment (excluding 
non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and hormonal 
treatment for castration sensitive prostate cancer). 
4. Ongoing treatment with an anticancer agent not contemplated in this protocol (excluding 
adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive 
prostate cancer). 
5. Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor (FTI). 
6. Any use of investigational therapy within 2 weeks of Cycle 1 Day 1 (C1D1) or 5 half-lives 
(whichever is longer). Last dose of any prior checkpoint inhibitor therapy must have been 
administered at least 2 weeks prior to C1D1. 
7. Received treatment for unstable angina within prior year, myocardial infarction within the 
prior year, cerebro-vascular attack within the prior year, history of New York Heart 
Association grade III or greater congestive heart failure, or current serious cardiac arrhythmia 
requiring medication except atrial fibrillation. 
8. Non-tolerable Grade 2 or ≥ Grade 3 neuropathy or evidence of unstable neurological 
symptoms within 4 weeks of Cycle 1 Day 1. Non-tolerable Grade 2 toxicities are defined as 
those with moderate symptoms that the subject is not able to endure for the conduct of 
instrumental activities of daily life or that persists ≥ 7 days. 
9. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without 
complete recovery. 
10. Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy, 
including known history of infection with human immunodeficiency virus or an active 
infection with hepatitis B or hepatitis C. 


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11. Subjects who have exhibited allergic reactions to tipifarnib or structural compounds similar 
to tipifarnib or to its excipients. This includes hypersensitivity to imidazoles, such as 
clotrimazole, ketoconazole, miconazole and others in this drug class. Subjects with 
hypersensitivity to these agents will be excluded from enrollment. 
12. Required use of concomitant medications classified as strong inhibitors or inducers of 
cytochrome P450 3A4 (CYP3A4, Table 11) or UDP-glucuronosyltransferase (UGT).   
13. Concomitant disease or condition that could interfere with the conduct of the study or that 
would, in the opinion of the investigator, pose an unacceptable risk to the subject in this 
study.  
14. Female subjects who are pregnant or lactating. 
15. Unwillingness or inability to comply with the study protocol for any reason. 
Inclusion Criteria: SEQ-HN  
For inclusion of a subject in the noninterventional portion of the study (SEQ-HN), all of the 
following inclusion criteria must be fulfilled:  
1. At least 18 years of age. 
2. Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, 
nasopharyngeal, or unknown primary) of squamous histology.   
3. HRAS wildtype (i.e. have no identified tumor missense HRAS mutation) determined by a 
test preferred by the investigator and approved by the Sponsor or through central HRAS 
testing.  
4. Will or has received at least one systemic anti-cancer therapy for recurrent or metastatic 
HNSCC for which there is available outcome information in terms of ORR, or can be 
determined based on the subject’s records. Subjects who have not yet received or completed 
at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC must consent to 
the collection of treatment outcome information and additional follow up contact in order to 
participate in the SEQ-HN portion of the study.  
5. Written and voluntary informed consent understood, signed and dated. 
Exclusion Criteria: SEQ-HN 
1. Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or 
nonsquamous histologies (e.g. mucosal melanoma).  
2. Concomitant disease or condition that could interfere with the conduct of the study or that 
would, in the opinion of the investigator, pose an unacceptable risk to the subject in this 
study.  
3. The subject has legal incapacity or limited legal capacity. 


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STATISTICAL METHODS: 
AIM-HN: 
AIM-HN is based on a two-stage minimax design with a hypothesized ORR of p1=30% for 
tipifarnib and a minimal or uninteresting ORR of p0=15%.  The primary efficacy analysis, based 
on the evaluation of a 2-sided 95% confidence interval around the ORR, will be performed on 
the mITT population comprised of all enrolled subjects who have received at least one dose of 
tipifarnib through their participation in AIM-HN. The mITT will also be used for all safety 
analyses. 
AIM-HN plans to enroll at least 80 subjects with HRAS mutations 
 
 
meeting all criteria for inclusion in the per-protocol analysis set.  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
The final analysis will be conducted on all subjects in the mITT analysis population set as well 
as the planned 80 subjects in the per-protocol analysis set.   


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STUDY ASSESSMENTS: 
Table 1: Schedule of Events: Pre-screening for HRAS Mutations 
Upon determination of HRAS mutational status, subject will proceed to cohort-specific screening 
procedures for participation in AIM-HN (HRAS mutant HNSCC subjects, refer to Table 2) or SEQ-
HN (HRAS wildtype HNSCC subjects, refer to Table 3) 
 
1. 
Pre-screening for HRAS mutation procedures can be done at any time prior to enrollment in AIM-HN or SEQ-HN. 
2. 
Required for subjects with unknown HRAS mutational status. Tumor tissue for HRAS testing should be on a biopsy taken 
subsequent to the most recent prior therapy so that the most current tumor biology is assessed; if a biopsy meeting this 
criterion is not possible, the reason must be documented. Detailed tumor sample collection, storage and shipping procedures 
will be provided in a separate lab manual. Results must be obtained prior to enrolment in either cohort. Further collection of 
tissue may be requested from wildtype patients. 
 
 
4. 
Information to be collected from all subjects: anatomical biopsy site, date of sampling and setting (e.g. primary, locally 
advanced, metastatic lesion), HRAS mutation in sample including variant allele frequency or HRAS wildtype status.  
Additionally, the test platform (e.g. NGS gene panels, PCR, other) will be collected if performed at the clinical site or 
reference laboratory employed by the clinical site using a Sponsor approved test. 
5. 
Demographics and disease history including primary diagnosis (date of initial diagnosis, stage of disease at diagnosis, 
anatomical disease site(s) at diagnosis), current stage of disease, smoking and betel nut exposure history, alcohol use, HPV 
status and other relevant medical history.Prior anti-cancer therapy for HNSCC including name, dates (start, end), treatment 
outcome (response and response criteria), duration of response, date of progression. Additionally, information will be 
collected specific to first line systemic treatment for recurrent or metastatic HNSCC. Information will also be collected on 
prior cancer surgery for HNSCC including date(s) of surgery. Information will be collected on prior/current radiological 
treatments for HNSCC including anatomical site(s) and date(s) of radiation treatment. In subjects who have not yet received 
or completed first line systemic treatment for recurrent or metastatic HNSCC, first line systemic treatment information 
(anatomical disease site, performance status, names and dates of treatment, treatment outcome, duration of response and date 
of progression) will be collected through follow-up contact.  
 
 
 
 
 
 
 
 
 
 
Activity 
Pre-Screening1 
ICF for Pre-screening for HRAS mutations  
X  
Tumor tissue for HRAS mutational testing2 
X 
HRAS mutation information4 
X 
Collection of first line efficacy/response data and demographics5 
X 


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Table 2: Schedule of Events: AIM-HN 
Activity 
Screenin
g1 
Day 1 
(± 2d) of 
every 
Cycle 
Day 7 
(± 2d) of 
Cycle 118 
Tumor 
Response 
Assessme
nt 
Visit2 
End of 
Treatme
nt Visit3 
Follo
w Up 
Visit4  
Follo
w Up 
Conta
ct 
AIM-HN ICF/PIC, forms 
X 
 
 
 
 
 
 
Completion of inclusion/ 
exclusion criteria 
evaluation and submission 
of enrollment form to 
Sponsor or their designee 
X 
 
 
 
 
 
 
Confirmation of 
measurable disease per 
RECIST v1.1 by local 
radiology 
X 
 
 
 
 
 
 
Demographics and Disease 
History5  
X 
 
 
 
 
 
 
Prior anti-cancer therapy 
for HNSCC6 
X 
 
 
 
 
 
 
Buccal swab7 
X 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
X 
X 
X8 
 
AE assessment9 
X 
X 
 
X 
X 
X8 
 
Complete physical 
examination 
X10 
 
 
 
X 
 
 
Symptom based physical 
exam 
 
X11 
 
 
 
 
 
Height 
X10 
 
 
 
 
 
 
Weight 
X10 
X11 
 
 
X 
 
 
Vital signs12 
X10 
X11 
 
 
X 
 
 
Electrocardiogram 
X10 
 
 
 
 
 
 
ECOG performance status 
X10 
X11 
 
 
X 
 
 
Pregnancy test14 
X15 
X16 
 
 
X 
 
 
Serum chemistry17 
X10 
X11 
X18 
 
X 
 
 
Hematology17 
X10 
X11 
X18 
 
X 
 
 
Coagulation17 
X10 
 
 
 
 
 
 
Urinalysis19 
X10 
 
 
 
 
 
 
Radiographic Imaging, 
transfer of tumor scans and 
related clinical data to 
IRF20 
X13 
 
 
X21 
X22 
X23 
 
Tumor tissue for HRAS 
mutational testing and 
pathology confirmation at a 
central lab31, 32 
X 
 
 
 
 
 
 


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1. 
Screening evaluations will be completed within 4 weeks (28 days) of Cycle 1 Day 1. Evaluations performed as part of the 
standard of care within 28 days of dosing (prior to study specific consent signature) do not need to be repeated.  
2. 
Tumor response assessment should occur approximately every 8 weeks (± 5 days) for the first 12 months of a subject’s 
participation in AIM-HN; thereafter, tumor response assessment should occur approximately every 12 weeks (± 5 days) 
until disease progression. 
3. 
An End of Treatment visit will be conducted approximately 30 days (± 7 days) from the last dose of tipifarnib or 
immediately before the initiation of any other anticancer therapy, whichever occurs first. 
4. 
Follow up visit required only for subjects who terminated treatment for reasons other than disease progression and should 
occur approximately every 8 or 12 weeks (± 5 days) until disease progression. 
5. 
Demographics and disease history including primary diagnosis (date of initial diagnosis, stage of disease at diagnosis, 
anatomical disease site(s) at diagnosis), current stage of disease, smoking and betel nut exposure history, alcohol use, HPV 
status and other relevant medical history. 
6. 
Prior anti-cancer therapy for HNSCC including name, dates (start, end), treatment outcome (response and response criteria), 
duration of response, date of progression. Additionally, information will be collected specific to first line systemic treatment 
for recurrent or metastatic HNSCC.  Information will also be collected on prior cancer surgery for HNSCC including date(s) 
of surgery.  Information will be collected on prior/current radiological treatments for HNSCC including anatomical site(s) 
and date(s) of radiation treatment. 
7. 
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. 
8. 
Assessments of adverse events and concomitant medications may also be conducted if adverse events were not resolved at 
the time of the End of Treatment visit. 
9. 
Assessed from signing the AIM-HN ICF through approximately 30 days after treatment discontinuation. Additional 
assessments may be performed until AE resolution or the AE is deemed irreversible by the Investigator. 
10. Evaluation should be performed within 14 days prior to the first administration of study drug. Lab investigations 
(hematology and serum chemistry) should be repeated and reviewed within 72 hours of first dosing and continued eligibility 
for dosing confirmation. 
11. Assessment on Cycle 1 Day 1 is to occur prior to tipifarnib dosing. Labs drawn within 72 hours of dosing may be used for 
C1D1. Labs must be reviewed prior to dosing to confirm subject remains eligible. 
12. Vital signs to include: heart rate, blood pressure and temperature. 
13. In addition to baseline tumor scans that are to be obtained within 28 days prior to Cycle 1 Day 1, efforts should be made to 
obtain historical scans to document tumor progression on prior line of therapy for transfer to the IRF. All efforts to submit 
these scans by the first tumor response assessment (approximately 8 weeks following Cycle 1 Day 1) should be made.  
These historical scans should include the scans that demonstrate progression that occurred on the prior regimen and a prior 
scan demonstrating the nadir prior to the progression.   
14. Pregnancy testing will be performed in females of child-bearing potential and testing may be performed on urine or serum.  
If a positive urine pregnancy test is obtained, a confirmatory serum pregnancy test should be conducted.  If confirmatory test 
is positive, subject must terminate tipifarnib treatment immediately and follow pregnancy reporting guidelines outlined in 
the protocol. Pregnancy testing will be performed locally at the clinical site or its reference laboratory. 
15. Female subjects of child-bearing potential must have a negative serum or urine pregnancy test within 72 hours prior to start 
of study medication (Cycle 1 Day 1).     
16. Assessment to begin starting at Cycle 2. 
17. Fasting for laboratory testing is not required. Laboratory tests may be conducted at 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.  
Serum chemistry should include: Glucose, Blood Urea Nitrogen (or Urea), Creatinine, Sodium, Potassium, Chloride, 
Calcium, Magnesium, Phosphorus, Total Protein, Albumin, Total Bilirubin, Alkaline Phosphatase, ALT, AST, Gamma-
Glutamyltransferase, Lactate Dehydrogenase, Bicarbonate or total CO2 (optional, as clinically indicated). Hematology 
Tipifarnib administration28 
  
X 
 
 
 
 
 
Drug accountability and 
diary review 
 
X16 
 
 
X 
 
 
Collection of survival and 
anticancer treatment 
information29 
 
 
 
 
 
 
X 
QoL questionaires34 
X 
X 
 
 
X 
 
 


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should include: White Blood Cell Count, Red Blood Cell Count, Hemoglobin, Hematocrit, Platelet Count, Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, Basophils. Coagulation should include: APTT, PT/INR.   
18. Laboratory tests for C1D7 are required for Denmark, and are optional/should be performed based upon clinical judgment for 
all other regions. 
19. 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). Samples will be 
analyzed locally at the clinical site or its reference laboratory. 
20. CT scan with a contrast agent is the preferred imaging method and the same technique should be used at baseline and post-
treatment assessments. 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. If subjects are allergic to IV contrast, MRI scans or non-contrast CT may be used. Subjects 
with contrast allergy or renal insufficiency may use non-contrast CT or MRI, whichever is required to adequately assess all 
disease. The one exception where MRI would not be recommended is for the evaluation of parenchymal lung metastases.  In 
this instance, CT would be preferred.  If imaging of the brain is indicated, MRI of the brain with and without gadolinium 
should be performed for optimal evaluation of the brain.  If MRI is medically contraindicated, CT of the brain with and 
without contrast would be suggested.  Guidelines for imaging and instructions for transmission of the images to the IRF will 
be provided to each study site. 
21. CT scans will be performed at least once approximately every 8 weeks (± 5 days) for 12 months, thereafter once 
approximately every 12 weeks (± 5 days) until disease progression. The imaging schedule (every 8 weeks or every 12 
weeks) should be maintained regardless of dosing delays or additional imaging assessments performed. 
22. Scans at the End of Treatment visit: Applies only for subjects who terminated treatment for reasons other than disease 
progression.  In these subjects, imaging should be performed at the End of Treatment visit if not done within the prior 8 
weeks or if a tumor assessment is required for the confirmation of response. 
23. Subjects who discontinue treatment for reasons other than disease progression should continue tumor assessments until 
disease progression. Tumor assessments may continue upon initiation of another anticancer therapy unless withdrawal of 
subject’s consent to study procedures.   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
28. Subjects will receive tipifarnib starting at 600 mg orally bid with food on days 1-7 and 15-21 of 28-day treatment cycles. 
29. Upon disease progression, follow up contact with the subject and/or caregiver(s) (e.g. electronic technology-based, 
telephone or in person) is to occur approximately every 12 weeks (± 1 week) for survival and the use of subsequent therapy 
until either death or End of Study (up to 2 years since the enrollment of the last study subject in AIM-HN, see Section 
6.7.1), whichever occurs first. Information on survival and subsequent anticancer therapy for HNSCC will be collected 
including name, dates (start, end), treatment outcome (response and response criteria), duration of response, date of 
progression. Information will also be collected on subsequent cancer surgery(ies) for HNSCC including date of surgery.  
Information will be collected on subsequent radiological treatments for HNSCC including anatomical site(s) and date(s) of 
radiation treatment. 
 
 
   
31. Tumor tissue for central review/confirmation, preferably from the same tissue sample used for Pre-screening HRAS 
mutational testing, must be confirmed as available prior to Cycle 1 Day 1 of AIM-HN. Whenever possible, sample should be 
sent to Sponsor (or designee) prior to Cycle 1 Day 1. 
32. Detailed tumor sample collection, storage and shipping procedures will be provided in a separate lab manual. 
 
 
   
34. EORTC QLQ-H and N35 and EQ-5D-5L (Appendix III) quality of life questionnaires will be completed at baseline, 
monthly on treatment, and at the End of Treatment visit. 
 


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Table 3: Schedule of Events: SEQ-HN 
 
1. 
Screening and study enrollment may occur during the same visit. 
2. 
On study visit is to occur between weeks 16 – 24 from the subject’s enrollment in SEQ-HN.  If a subject experiences disease 
progression or initiates second line therapy prior to weeks 16 - 24, the blood sample for HRAS mutational analysis should 
be collected at that time.     
3. 
Follow up contact with the subject and/or caregiver(s) (e.g. electronic technology-based, telephone or in person) is to occur 
approximately every 12 weeks (± 1 week) from the time of study enrollment through initiation of second line therapy 
consent withdraw, or completion of AIM-HN, whichever occurs first. Regimen and start date of second line therapy initiated 
will be recorded. Additional follow up of the matched HRAS wildtype HNSCC patients enrolled into SEQ-HN may 
continue until all AIM-HN objectives are completed and KO-TIP-007 end of study is reached. 
4. 
Demographics and disease history including primary diagnosis (date of initial diagnosis, stage of disease at diagnosis, 
anatomical disease site(s) at diagnosis), current stage of disease, smoking and betel nut exposure history, alcohol use, HPV 
status and other relevant medical history. 
5. 
Prior anti-cancer therapy for HNSCC including name, dates (start, end), treatment outcome (response and response criteria), 
duration of response, date of progression. Additionally, information will be collected specific to first line systemic treatment 
for recurrent or metastatic HNSCC. Information will also be collected on prior cancer surgery for HNSCC including date(s) 
of surgery. Information will be collected on prior/current radiological treatments for HNSCC including anatomical site(s) 
and date(s) of radiation treatment. In subjects who have not yet received or completed first line systemic treatment for 
recurrent or metastatic HNSCC, first line systemic treatment information (anatomical disease site, performance status, 
names and dates of treatment, treatment outcome, duration of response and date of progression) will be collected through 
follow-up contact.  
 
 
 
 
 
 
 
Activity 
Screening1 
Study 
Enrollment1 
On Study Visit: 16 – 24 weeks since 
enrollment in SEQ-HN or at disease 
progression, whichever occurs first2 
Follow Up 
Contact3 
ICF for participation in 
SEQ-HN 
X 
 
 
 
Inclusion/ exclusion 
criteria evaluation  
X 
 
 
 
Demographics and disease 
history4  
 
X 
 
 
Prior anti-cancer therapy 
for HNSCC5 
 
X 
 
X 


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3 
LIST OF ABBREVIATIONS 
 
ALCOA+ 
Data integrity principles of attributable, legible, contemporaneous, original, accurate, 
complete, consistent, enduring and available. 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
bid 
twice a day 
BIW 
twice weekly 
BSC 
best supportive care 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CSR 
clinical study report 
CT 
computer tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose limiting toxicity 
DOR 
duration of response 
DPA 
Data Protection Act 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
FTase 
farnesyltransferase 
FTI 
farnesyltransferase inhibitor 
GCP 
Good Clinical Practice 
HDPE 
high density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV/AIDS 
human immunodeficiency virus infection and acquired immune deficiency syndrome 
HPV 
human papilloma virus 
HNSCC 
head and neck squamous cell carcinoma 
HRAS 
Harvey rat sarcoma virus gene homolog 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IDMB 
Independent Data Monitoring Board 
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
IRF 
Independent Review Facility 
KRAS 
Kirsten rat sarcoma virus gene homolog 
MDRD 
modification of diet in renal disease 
MDS 
myelodysplastic syndromes  
MeDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute  
NGS 
next generation sequencing 
NRAS 
neuroblastoma RAS viral oncogene homolog 


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NSCLC 
non-small cell lung cancer 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PDX 
patient derived xenograft 
PFS 
progression free survival 
PIC 
patient informed consent 
PK 
pharmacokinetic 
PR 
partial response 
PT/INR 
prothrombin time/international normalized ratio 
QW 
once weekly 
RECIST 
response evaluation criteria in solid tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCLC 
small cell lung cancer 
SGOT 
serum glutamic oxaloacetic transaminase  
SGPT 
serum glutamic pyruvic transaminase 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TTP 
time to progression 
UGT 
UDP-glucuronosyltransferase 
ULN 
upper limit of normal 
US 
United States 
v 
version 
VAF 
variant allele frequency 
 
 
 
 


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4 
BACKGROUND 
Brief information on tipifarnib is presented in this section; more extensive information is 
provided in the Tipifarnib Investigator’s Brochure. 
4.1 
Investigational Agent 
Tipifarnib (R115777; Zarnestra™) 
4.2 
Study Rationale 
4.2.1 
Head and Neck Squamous Cell Carcinoma 
Head and neck squamous cell carcinoma accounts for more than 550,000 cases annually, 
worldwide (Leemans 2011) with incidence rates of certain subtypes (oropharyngeal) on the rise 
(Chaturvedi 2011). Carcinogen (tobacco, alcohol) exposure and infection with the human 
papillomavirus (HPV) are described as the two major etiological causes of HNSCC. Differences 
in prognoses have been reported for HPV-negative and HPV-positive HNSCC, with HPV 
negativity being associated with worse clinical outcome (Leemans 2011). 
Genomic structural alterations are commonly seen in HNSCC. Both HPV-positive and HPV-
negative tumors harbor amplifications of 1q, 3q, 5p and 8q and deletions of 3p, 5q, and 11q. The 
amplification of 3q26/28 region containing the squamous lineage transcription factors TP63 and 
SOX2, and the PIK3CA oncogene is seen in both HPV-positive and HPV-negative tumors, but 
more frequently in the HPV-positive subtype. In HPV-positive tumors, recurrent deletions in 
TRAF3 and 11q, including the ATM1 region, and focal amplification of E2F1 are also seen, but 
9p21.3, containing CDKN2A, is usually intact. In contrast, in HPV-negative tumors 9p21.3 is 
commonly deleted while 11q13, containing ANO1, CCND1 and FADD, and 11q22, containing 
BIRC2 and YAP1 are amplified (Aung 2016).  
From a biological perspective, the recurrent CDKN2A deletions and CCND1 amplification seen 
in HPV-negative tumors and E2F1 amplifications in HPV-positive tumors indicate that loss of 
cell cycle regulation is a fundamental event in HNSCC carcinogenesis. Also, the importance of 
the RAS/MAPK and PI3K/AKT pathways, particularly in HPV-negative HNSCC, is highlighted 
by EGFR amplification, HRAS mutation and PIK3CA related alterations (Aung 2016). Of note, 
it has been suggested that HRAS signals almost exclusively through PI3K-AKT and not through 
MAPK in HNSCC (Endhardt 2014). TP53 is also frequently mutated in HPV-negative cases 
whereas TP53 alterations are infrequent in HPV-positive tumors. However, a small subset of 
HPV-negative, frequently oral cavity, carcinomas do not have TP53 mutations and harbor 
activating HRAS mutations with or without inactivating CASP8 mutations, constituting a distinct 
subset of HNSCC (TCGA 2015).  
The relevance of HRAS mutations is highlighted by the availability of farnesyltransferase 
inhibitors (FTIs).  Although FTIs prevent more than 140 potential proteins from getting 


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farnesylated, the function of many of these proteins is kept intact due to the compensative 
prenylation through type 1 geranylgeranyl transferase (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.  HRAS cannot be 
geranylgeranylated and its membrane localization and cellular function is suppressed by FTIs 
(Whyte 1997).  Consequently, HRAS driven tumors are very sensitive to FTIs. 
4.2.2 
Mechanism of Action 
Tipifarnib is a potent and selective inhibitor of farnesyltransferase (FTase), an enzyme 
responsible for adding a farnesyl group to proteins.   
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 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 4, 
tipifarnib dosed orally at 80mg/kg bid was highly active in PDX models of several HRAS-
mutant HNSCCs inducing tumor stasis, partial responses and some complete regressions of 
established tumors. Importantly, the robust antitumor activity with tipifarnib was achieved in 
models that were resistant to both cetuximab (1mg/kg once weekly, QW) and methotrexate 
(10mg/kg twice weekly, BIW) (Figure 5). 


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Figure 4: Tipifarnib Activity in HRAS-Mutant HNSCC PDX Models 
 
 
Figure 5: 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).   
4.2.3 
Clinical Development 
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, Rao 2004, Rosenberg 2005, Hong, 2011, Gajewski 2012). While sporadic tumor 
responses were observed in some of these studies, the level of activity in the absence of a 
molecular selection strategy did not support further development of tipifarnib as a single agent. 
Preclinical data indicated that tumor models carrying HRAS mutations are highly sensitive to 
FTIs. The reason for this selectivity is potentially the fact that, contrary to KRAS and NRAS, 


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HRAS protein does not undergo geranylgeranylation. Consistent with this hypothesis, Kura 
Oncology initiated a Phase 2 clinical study in HRAS mutant solid tumors (KO-TIP-001).  
Tipifarnib was given at a starting dose of 900 mg orally twice daily on days 1-7 and 15-21 of 28-
day cycles. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Preliminary data indicate that 5 of 6 evaluable 
HNSCC subjects enrolled in Study KO-TIP-001 have experienced objective responses (Ho 
2017).  
Tipifarnib was generally well tolerated with hematological events, gastrointestinal disturbances 
(nausea, vomiting and diarrhea) and fatigue constituting the most common adverse events (AEs). 
Additional information on KO-TIP-001 is available in the current version of the Investigator’s 
Brochure.  
4.3 
Risk/Benefits  
Standard therapy for HNSCC is multimodal consisting of radiation, chemotherapy and surgery. 
For recurrent and metastatic disease, platinum-based chemotherapy (cisplatin or carboplatin plus 
5-fluorouracil) with and without cetuximab, remains an important therapy (Vermorken 2008). 
Other approved systemic therapies include immunotherapy with pembroluzimab and nivolumab, 
and their use as single agents and in combination in the front-line setting continue to increase 
(KEYNOTE-048; Ferris, 2016). Overall response rates to systemic therapy in this indication are 
<20% with a median overall survival of 5-8 months in the 2nd line setting (Seiwert 2016, Ferris 
2016) emphasizing the significant unmet need for effective therapies for the treatment of 
HNSCC.  
HNSCC with HRAS mutations have been shown to be resistant to EGFR inhibition with 
cetuximab and erlotinib in vitro and in vivo (Rampias 2014, Hah 2014, Wang 2014).  
Furthermore, a recent study employing serial liquid biopsies from HNSCC patients prior to and 
at progression on cetuximab treatment demonstrated that acquired resistance to cetuximab is 
commonly associated with the early appearance of HRAS mutations (Braig 2016). This last 


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observation also suggests that additional cases of HRAS-driven HNSCC may arise as a result of 
treatment with anti-EGFR therapy. Additionally, in a comparison of TTP between patients with 
no HRAS mutation (N=48) and HRAS mutants (n=7), a statistically significant better prognosis 
for patients with no HRAS mutation (P=0.04) and a trend toward improved overall survival was 
demonstrated (Rampias 2014).  These published data compliment preliminary data from study 
KO-TIP-001 which indicate that patients with HRAS mutant HNSCC may be particularly 
refractory to multiple standard treatments of HNSCC.   
Initial data from the ongoing KO-TIP-001 in which tipifarnib is given at a starting dose of 
600mg (900mg at study start) orally twice daily on days 1-7 and 15-21 of 28-day cycles, 
suggests a tolerability that is broadly similar to the well characterized safety profile observed in 
prior clinical studies which administered tipifarnib at doses up to 600 mg bid 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 
are monitorable and manageable with protocol defined assessments and management of toxicity 
guidance.    
Based on the unmet medical need of the HRAS mutant HNSCC population and the favorable 
efficacy and safety results observed in study KO-TIP-001, Kura Oncology has planned KO-TIP-
007 as an international, multicenter, open-label, 2 cohort, non-comparative pivotal study 
evaluating the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN) and the impact of 
HRAS mutations on response to first line systemic therapies for HNSCC (SEQ-HN). 
4.4 
Dose Rationale 
The effect of intermittent schedules of tipifarnib 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 2018), 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 weekly 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 2 dose. 
There were no objective responses but 4 out of 21 patients, 3 of whom had NSCLC, remained on 


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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 dose limiting toxicities (DLTs) and hematological toxicity was described as 
moderate and manageable. 
The second weekly 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. At the 400 mg bid dose level, a grade 5 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 investigated in KO-TIP-001, a phase 2 study of 
tipifarnib in nonhematological malignancies that carry HRAS mutations was set with a starting 
dose of 900 mg, orally, 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.    
Based on these data, the tipifarnib regimen to be investigated in AIM-HN is a starting dose of 
600 mg, orally, bid 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 until disease 
progression or unmanageable toxicity. Stepwise 300 mg dose reductions to control treatment-
related, treatment-emergent toxicities are further detailed in Section 8.1.2.  
4.5 
Trial Conduct  
This clinical trial will be conducted in compliance with the clinical protocol, current Good 
Clinical Practice (ICH Topic E6, GCP) and applicable regulatory requirements. 
Only the Sponsor, upon consultation with the principal Investigator and IDMB may modify the 
protocol. The Sponsor will issue a formal protocol amendment to implement any changes. The 


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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 
Institutional Review Board/Independent Ethics Committee (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 IRB/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 informed consent form 
(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. 
4.6 
Population 
AIM-HN will enroll at least 80 patients with head and neck tumors of confirmed squamous 
histology with HRAS mutations who have failed prior platinum therapy (e.g. tumor progression, 
clinical deterioration, or disease recurrence)); however, subjects who, at the judgment of the 
investigator, are not considered to be candidates to receive standard therapy with a platinum-
containing regimen may be also enrolled.  Platinum based therapy does not have to be the most 
recent prior therapy, however the patient must have failed their most recent prior therapy. HRAS 
mutations of any variant allele frequency will be enrolled, 
 
 
Platinum regimens are contraindicated in patients with poor performance status (ECOG > 3), 
renal dysfunction (creatinine clearance < 50/mL), otologic disorders, neuropathy > grade 2, 
known hypersensitivity to platinum-based therapy, pregnant or lactating, or have HIV/AIDS 
(CD4 counts <350/μL) (Ahn 2016). Of note, poor performance, renal dysfunction, neuropathy, 
pregnancy and lactation, and lymphopenia can also be considered potential risk factors for 
tipifarnib therapy and therefore the totality of inclusion/exclusion criteria must be considered 
when determining eligibility. However, subjects with hearing loss (CTCAE 4.03 hearing 
impaired grade >2), known hypersensitivity to platinum based therapy (prior evidence of allergic 
reaction to platinum or mannitol manifested by skin rash, flushing, cardiovascular or respiratory 
symptoms), or other clinically relevant criteria per investigator judgement that makes platinum 
based therapy inappropriate for a subject’s treatment may be enrolled in KO-TIP-007, without a 
requirement of prior platinum based therapy. 
Additionally, approximately 225 control patients with HNSCC without detected HRAS 
mutations will be also enrolled as part of the observational SEQ-HN sub-study, and a subset of 
those will be matched to the HRAS mutant patients who provide data through pre-screening 
collection, patients enrolled into SEQ without enrolment into AIM-HN, and the AIM-HN study 


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population to the greatest extent possible according to defined patient characteristics. Patients 
will not receive tipifarnib treatment as part of their participation in SEQ-HN.  
5 
TRIAL OBJECTIVES 
Primary Objective:  
• To determine the objective response rate (ORR) of tipifarnib in subjects with Head and 
Neck Squamous Cell Carcinoma (HNSCC) with HRAS mutations with a VAF≥20% 
(High VAF population), as assessed by Independent Review Facility (IRF).   
Key Secondary Objectives: 
• To determine the objective response rate (ORR) of tipifarnib in subjects with Head and 
Neck Squamous Cell Carcinoma (HNSCC) with HRAS mutations of any VAF (All VAF 
population), as assessed by IRF. 
• To determine the Duration of Response (DOR) of tipifarnib in subjects with Head and 
Neck Squamous Cell Carcinoma (HNSCC) with HRAS mutations with a VAF≥20% 
(High VAF population), as assessed by IRF. 
• To determine the Duration of Response (DOR) of tipifarnib in subjects with Head and 
Neck Squamous Cell Carcinoma (HNSCC) with HRAS mutations of any VAF (All VAF 
population), as assessed by IRF. 
Other Secondary Objectives for AIM-HN: 
• To determine the anti-tumor activity of tipifarnib in terms of progression free survival, 
and rate of progression free survival at 6 and 9 months in both the high VAF and all VAF 
populations 
• To determine the anti-tumor activity of tipifarnib in terms of overall survival, and rate of 
overall survival at 12 months in both the high VAF and all VAF populations 
• To determine the anti-tumor activity of tipifarnib in terms of time to response in both the 
high and all VAF populations  
• To determine the anti-tumor activity of tipifarnib in terms of time to progression (TTP) in 
both the high and all VAF populations  
• To investigate the safety and tolerability of tipifarnib according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE 
v5.0).  
• To investigate the effects of tipifarnib treatment on quality of life measures, including 
EORTC QLQ-H&N35 and EQ-5D-5L. 
• To assess population pharmacokinetics (PK) of tipifarnib in subjects with HNSCC with 
HRAS mutations.   


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6 
TRIAL DESIGN 
6.1 
Study Endpoints 
Detailed operational definitions of all endpoints are given in Section 12.1.  
6.1.1 
Primary Endpoint 
The primary endpoint is the proportion of high VAF subjects with confirmed Objective 
Response (OR), defined as either Complete Response (CR) or Partial Response (PR), calculated 
using the mITT analysis set. 
6.1.2 
Key Secondary Endpoints 
The key secondary endpoints include: 
• The proportion of all VAF subjects with confirmed Objective Response (OR), defined as 
either Complete Response (CR) or Partial Response (PR), calculated using the mITT 
analysis set. 
• The duration of response (DOR) in high VAF subjects, calculated using the mITT analysis 
set. 
• The duration of response (DOR) in all VAF subjects, calculated using the mITT analysis 
set. 
 


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6.1.3 
Other Secondary Endpoints  
The following are additional secondary endpoints, evaluated in the AIM-HN part of the study in 
both the high VAF and all VAF populations: 
• Time to response 
• Time to progression (TTP) 
• Progression-free survival (PFS) 
• 6 month and 9 month progression-free survival rate  
• Overall survival (OS) 
• Overall survival rate at one year 
• Changes in measures of quality of life using the following tools: EORTC QLQ-H&N35 
and EQ-5D-5L 
• Population PK parameters of tipifarnib 
• Adverse Events 
• Laboratory test results 
• Vital Signs 
• ECG results 
Response and progression endpoints will be analyzed using both IRF and Investigator 
assessments, as well as using the mITT and per-protocol analysis sets. 
6.2 
Study Design 
KO-TIP-007 is an international, multicenter, open-label, pivotal study, with two non-
comparative sub-studies: (1) an interventional open label, single arm, pivotal study evaluating 
the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN) and (2) an observational study to 


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evaluate the impact of HRAS mutations on response to first line systemic therapies for HNSCC 
(SEQ-HN). 
 AIM-HN, includes HNSCC subjects with HRAS mutations. AIM-HN subjects will receive 
treatment with tipifarnib and the outcome of this sub-study will address the primary objective of 
the KO-TIP-007 study.  SEQ-HN, is an observational sub-study and includes wild type HRAS 
HNSCC subjects who consent to provide first line outcome data and additional follow up. 
HNSCC patients in whom HRAS mutations are identified during SEQ participation, and who 
meet eligibility criteria will be offered participation in AIM-HN. 
 
 
 
 
 
  
KO-TIP-007 will enroll a total of at least 305 subjects. AIM-HN, the tipifarnib treatment sub-
study of KO-TIP-007, will investigate the efficacy of tipifarnib in at least 80 subjects with head 
and neck tumors of confirmed squamous histology with HRAS mutations. SEQ-HN, the non-
interventional observational sub-study will enroll an additional, at least 225 subjects with HRAS 
wildtype HNSCC tumors. Additional HRAS mutant subjects that consent to pre-screening, but 
do not enroll in AIM-HN may have first line treatment data collected as well. 
The study design is shown in Figure 1. 
6.2.1 
AIM-HN Design 
AIM-HN will enroll patients with head and neck tumors of confirmed squamous histology with 
HRAS mutations. Subjects must have failed (e.g. tumor progression, clinical deterioration, or 
recurrence their most recent prior therapy, and at least one prior line of systemic platinum-based 
therapy (the most recent prior and platinum-based therapy may be the same regimen). However, 
subjects who, at the judgment of the investigator, are considered not to be candidates to receive 
standard therapy with a platinum-containing regimen may also be enrolled (further detailed in 
Section 4.6).  The primary objective of AIM-HN is to determine the ORR of tipifarnib in 
subjects with HNSCC with HRAS mutations and a VAF≥20%, as assessed by IRF.     
To participate in AIM-HN, all subjects must have measurable disease that meets the criteria for 
selection as a target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1. The presence of at least one measurable target lesion per RECIST v1.1 must be confirmed 
by local radiology prior to enrollment. Subjects without at least one measurable target lesion 
confirmed by local radiology will not be enrolled into AIM-HN.  
HNSCC diagnosis by local site pathology laboratory will be used for study entry; however, all 
subjects must provide pathology material for central pathology review.  Confirmation of 
pathological diagnosis of HNSCC will be required for inclusion of subjects in the per-protocol 


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analysis set.  Subjects in whom a diagnosis of HNSCC is not confirmed by central review may 
continue to receive study treatment and will be included in the mITT analysis set. 
All AIM-HN enrolled subjects must have a known missense HRAS tumor mutation based on 
centralized testing or other HRAS test used by the trial site that has been approved by the 
Sponsor.  HRAS status should be assessed on tumor obtained subsequent to the most recent prior 
therapy in order to obtain the most recent tumor biology; if tumor tissue that does not meet this 
criterion must be used (e.g. risk of biopsy is too high, patient refuses new biopsy), the 
Investigator should document the reason. If several samples are available, HRAS testing should 
be performed in the most recently obtained tumor sample.  All subjects must provide enough 
tumor material for confirmation of HRAS status by central lab. This tissue should be from the 
same source as that used for pre-screening, or the reason that is not possible documented.  
Subjects who were enrolled in the study based on HRAS mutation using a Sponsor approved test, 
but in whom a missense HRAS mutation is not confirmed by central testing, may continue to 
receive study treatment. SEQ-HN subjects who were initially identified as wild type HRAS but 
in whom an HRAS mutation is later detected during the course of their standard therapy, will 
become eligible to enroll in AIM-HN.   
AIM-HN enrolled subjects will receive tipifarnib administered at a dose of 600 mg, orally with a 
meal twice a day (bid) for 7 days in alternating weeks (Days 1-7 and 15-21) in 28-day cycles.  
Stepwise 300 mg dose reductions to control treatment-related, treatment-emergent toxicities are 
described in Section 8.1.2.  In the absence of unmanageable toxicities, subjects may continue to 
receive tipifarnib treatment until disease progression.  If a complete response is observed, and 
subject continues to tolerate therapy, therapy with tipifarnib will be maintained for at least 6 
months beyond the start of response.  
Tumor assessment for the primary analysis will be performed by the IRF according to RECIST 
v1.1 and assessed by an Independent Data Monitoring Board (IDMB).  Investigator assessment 
of tumor response will also be collected and reported as a supportive analysis. Assessments will 
be performed at screening and approximately every 8 weeks for the first 12 months of a subject’s 
participation in AIM-HN; thereafter, tumor response assessment should occur approximately 
every 12 weeks until disease progression.  Radiological assessments will be discontinued at the 
time of tumor progression.  If the subject initiates a new anticancer therapy without evidence of 
disease progression by RECIST v1.1, tumor scans should continue until there is evidence of 
disease progression unless withdrawal of subject’s consent to study procedures.  Local 
investigator evaluation of tumor assessment will guide on-study treatment decisions, including 
decisions to stop study treatment due to progressive disease.   
Upon disease progression, all subjects will be followed approximately every 12 weeks for 
survival and the use of subsequent therapy until either death or End of Study (up to 2 years since 
the enrollment of the last study subject in AIM-HN, see Section 6.7.1), whichever occurs first. 


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All subjects will be followed-up for safety through the End of Treatment visit which occurs 
approximately 30 days after treatment discontinuation or until immediately before the 
administration of another anticancer treatment, whichever occurs first. Additional safety follow-
up may be conducted if unresolved toxicity is present at this End of Treatment visit. The IDMB 
will provide periodic evaluations of safety and other data to ensure adequate benefit/risk as well 
as the validity and scientific merit of the study. 
An overview of the AIM-HN design is shown in Figure 2. 
6.2.2 
SEQ-HN Design 
SEQ-HN is an observational sub-study 
 
  Demographics, 
disease history, information on prior anti-cancer treatments and outcomes to prior treatments for 
HNSCC will be collected from all enrolled subjects. Approximately 225 control patients with 
HNSCC without known HRAS mutations, will be enrolled into SEQ-HN.  As part of their 
participation in SEQ-HN, patients will be followed up through initiation of second line therapies. 
At that point, a subset of the approximate 225 control patients will be matched to the HRAS 
mutant AIM-HN subjects to the greatest extent possible according to pre-defined patient 
characteristics. If necessary, additional follow up of the matched HRAS wildtype HNSCC 
patients enrolled into SEQ-HN may continue until all AIM-HN objectives are completed and 
KO-TIP-007 end of study is reached. Control patients with HNSCC with wildtype HRAS  will 
not receive tipifarnib treatment as part of their participation in SEQ-HN; however, they may be 
compensated for their participation in data collection, blood sampling, screening and follow up 
procedures according to institutional guidelines. 
An overview of the SEQ-HN design is shown in Figure 3. 
6.3 
Randomization 
KO-TIP-007 is a nonrandomized study. Subjects enrolled as part of AIM-HN will receive 
tipifarnib administered at a dose of 600 mg, orally with food, bid for 7 days in alternating weeks 
(Days 1-7 and 15-21) in 28-day cycles.   
SEQ-HN is noninterventional and used for data collection in subjects with HNSCC without 
HRAS mutations.  Subjects enrolled in SEQ-HN will not receive tipifarnib treatment. 
This is an open label study with no placebo or comparators. 
6.4 
Maintenance 
No randomization code will be used for this nonrandomized, open label study. 


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6.5 
Trial Treatment 
Subjects enrolled as part of AIM-HN will receive tipifarnib as monotherapy in this study. 
Subjects may continue to receive tipifarnib therapy in the absence of unacceptable tipifarnib 
related emergent toxicity or disease progression. 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.  Supportive measures may include, for example, the use of growth factors (i.e. granulocyte 
colony stimulating factor, GCSF) or blood transfusions. BSC will be provided by the study sites. 
Subjects with HNSCC without HRAS mutations will not receive tipifarnib treatment as part of 
their participation in SEQ-HN and may continue to receive other anticancer therapies and care 
for their disease according to institutional practice. 
The following sub-sections apply only to subjects enrolled as part of AIM-HN. 
6.5.1 
Investigational Product (IP) 
Tipifarnib is a small molecule being developed as a potent, selective inhibitor of FTase for the 
treatment of HRAS mutant HNSCC and other malignancies. Tipifarnib will be administered at a 
starting dose of 600 mg, orally, bid on days 1-7 and 15-21 of 28-day treatment cycles.  
6.5.2 
Product Characteristics 
Tipifarnib film-coated tablets for oral administration are supplied in high density polyethylene 
(HDPE) bottles. Two strengths (100 mg and 300 mg) of tablets are provided containing either 
100 mg or 300 mg of tipifarnib active substance, respectively. In addition to the active substance, 
the tablets contain 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 
contains the same quantitative composition of the same excipients. Further information can be 
obtained from the current version of the Tipifarnib Investigator’s Brochure.  
6.5.3 
Storage and Labeling 
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. 
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 (e.g. in the US, 
“New Drug – Limited by United States federal law to investigational use”). 


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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. 
6.5.4 
Emergency Medical Support and Subject Card 
Subjects enrolled in this clinical study will be provided with Emergency Medical Support cards 
during their study participation, which will be provided by the Sponsor or designee. The 
Emergency Medical Support card provides clinical study subjects with a way of identifying 
themselves as participating in a clinical study 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 study. Clinical study Investigators, who are already aware of the clinical study 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 study 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. 
6.6 
Duration 
Subjects enrolled as part of AIM-HN may receive treatment with tipifarnib until disease 
progression, unacceptable toxicity or any criteria for withdrawal from the trial or treatment 
occurs (see Section 7.3). Kura Oncology, Inc. or its designee will provide the study site with a 
supply of tipifarnib sufficient for the completion of the study. Upon disease progression, all 
subjects will be followed approximately every 12 weeks for survival and the use of subsequent 
therapy until either death or End of Study (see Section 6.7.1), whichever occurs first.  
Subjects enrolled into SEQ-HN will be followed through initiation of second line therapy, death, 
or consent withdraw, whichever occurs first. Additional follow up of the matched HRAS 
wildtype HNSCC patients enrolled into SEQ-HN may continue until all AIM-HN objectives are 
completed and End of Study (see Section 6.7.1) is reached. 


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6.7 
Discontinuation 
6.7.1 
Definition of End of Study 
For administrative and safety reporting purposes, the end of this clinical study is defined as 2 
years from enrollment of the last enrolled study subject in AIM-HN.  If the last enrolled study 
subject discontinues treatment within 2 years of study enrollment, the End of Study will occur no 
earlier than the date of the last enrolled subject’s safety follow-up assessment (End of Treatment 
visit) performed approximately 30 days after treatment discontinuation or until initiation of 
another anti-cancer therapy, whichever occurs first.  At the time of End of Study, provisions will 
be made to transition all remaining AIM-HN subjects who demonstrate sustained clinical benefit 
beyond the end of the study to other means of continued treatment with tipifarnib with 
appropriate safety monitoring, e.g. single patient treatment protocol, other clinical trial or 
expanded access protocol, as allowed by local law.   
6.7.2 
Premature Discontinuation of the Trial 
This trial may be discontinued prematurely in the event of any of the following: 
• IDMB recommendation based on observed safety leading to an unfavorable risk-benefit 
of tipifarnib. 
• IDMB recommendation based on futility criteria. 
• 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 
investigations scheduled for the End of Treatment visit should be performed and the appropriate 
electronic case report form (eCRF) section completed. 


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6.8 
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.  
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. 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. 
Documentation must be provided to the Sponsor or its designee and retained in the Investigator’s 
study files. 
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. 
6.9 
Data Identification 
6.9.1 
Subject Identification and Privacy 
Kura Oncology, Inc. or its designee will assign a subject number identifier for each subject that 
is enrolled into the study upon completion of informed consent for prescreening for HRAS 
mutations. This unique identifier will be on all eCRF pages and will serve as the subject’s 
identifier in the study as well as in the clinical study database. 
The subject’s data collected in the study will be stored under this number. Only the Investigator 
will be able to link the subject’s study 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. 


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6.9.2 
Case Report Form Management 
The Investigator or designee will be responsible for entering study 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.  
6.9.3 
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 study. This file will contain the available 
demographic and medical information for the subject and should be as complete as possible.  
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 study) 
• Study identification  
• Date of subject’s inclusion into the study (i.e. date of informed consent) 
• Subject identifier in the study 
• Dates of the subject’s visits to the site 
• Any medical examinations and clinical findings predefined in the clinical study protocol 
• All AEs observed in the subject 
• Date of subject’s end of study, and 
• Date of and reason for early withdrawal of the subject from the study 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 
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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 
• Description about study discontinuation 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Inclusion Criteria  
7.1.1 
Inclusion Criteria: AIM-HN 
For inclusion of a subject in the tipifarnib treatment portion of the study (AIM-HN), all of the 
following inclusion criteria must be fulfilled. If a subject does initially not meet any inclusion 
criteria, the subject may be re-screened at a later time:  
1. At least 18 years of age. 
2. Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, 
nasopharyngeal, or unknown primary) of squamous histology not amenable to local therapy 
with curative intent (surgery or radiation therapy with or without chemotherapy). Enrollment 
may proceed with local diagnosis but all subjects must consent to provide tumor tissue for a 
central pathology review. 
3. Documented treatment failure from most recent prior therapy (e.g. tumor progression, 
clinical deterioration, or recurrence), and from at least one prior platinum-containing 
regimen, in any treatment setting. The most recent prior and platinum-based therapy may be 
the same regimen. Those subjects who, at the judgment of the investigator, are considered 
clinically unsuitable to receive standard platinum-containing regimen, may also be enrolled 
and the reason for clinical unsuitability recorded. There is no limit on the number of prior 
lines of therapy.  
4. 
Known tumor missense HRAS mutation detected by Next Generation Sequencing (NGS) or 
any other methodology approved by the Sponsor. Variant allele frequency (VAF) needs to 
be determined and must be available.  HRAS status should be assessed on tumor tissue 
obtained subsequent to the most recent prior therapy so that the most accurate tumor biology 
is evaluated.  If tumor tissue that does not meet this criterion must be used (e.g. risk of new 


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biopsy is too high, patient refuses new biopsy), the investigator should document the reason. 
Enrollment may proceed with the identification of a missense HRAS mutation using a test 
preferred by the investigator and approved by the Sponsor during pre-screening, but all 
subjects must consent to provide tumor tissue for central HRAS confirmation.  
 
 
5. 
Measurable disease by RECIST v1.1 (Appendix I) that meets the criteria for selection as a 
target lesion according to RECIST v1.1.  The presence of at least one measurable target 
lesion per RECIST v1.1 must be confirmed by local radiology prior to subject entry. 
6. 
At least 2 weeks or 5 half-lives, whichever is longer, since the last systemic therapy regimen 
prior to Cycle 1 Day 1. Last dose of any prior checkpoint inhibitor therapy must have been 
administered at least 2 weeks prior to C1D1. Subjects must have recovered to NCI CTCAE 
v5.0 < Grade 2 from all acute toxicities (excluding Grade 2 toxicities that are not considered 
a safety risk by the Sponsor and Investigator) or toxicity must be deemed irreversible by the 
Investigator. 
7. 
At least 2 weeks since last radiotherapy. Subjects must have recovered from all acute 
toxicities from radiotherapy.  
8. 
ECOG performance status of 0-1 (Appendix II). 
9. 
Acceptable liver function: 
a) Bilirubin  1.5 times upper limit of normal (x ULN). 
b) AST (SGOT) and ALT (SGPT)  1.5 x ULN. 
The subject must meet/continue to meet these criteria at the time of first dosing, as 
confirmed by analysis within 72 hours of C1D1. 
10. Acceptable renal function with either serum creatinine  1.5 x ULN or a calculated creatinine 
clearance ≥ 60 mL/min using the Cockcroft-Gault or Modification of Diet in Renal Disease 
(MDRD) formulas. 
The subject must meet/continue to meet these criteria at the time of first dosing, as 
confirmed by review of analysis performed within 72 hours of C1D1. 
11. Acceptable hematologic status: 
a) ANC  1000 cells/μL. 
b) Platelet count  75,000/μL. 
c) Hemoglobin  8.0 g/dL. 
The subject must meet/continue to meet these criteria at the time of first dosing, as 
confirmed by review of analysis performed within 72 hours of C1D1. 


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12. Female subjects must be:  
a) Of non-child-bearing potential (surgically sterilized or at least 2 years post-
menopausal); or 
b) If of child-bearing potential, subject must use a highly effective method of 
contraception, such as combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation, progestogen-only hormonal 
contraception associated with inhibition of ovulation, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised 
partner or sexual abstinence.  Both females and male subjects with female 
partners of child-bearing potential must agree to use a highly effective method of 
contraception from the first dose of tipifarnib, during tipifarnib treatment, and at 
least 28 days after last dose of tipifarnib for females and 90 days for males. 
Female subjects must have a negative serum or urine pregnancy test within 72 
hours prior to start of trial medication. 
c) Not breast feeding at any time during the study. 
13. Written and voluntary informed consent understood, signed and dated. 
7.1.2 
Inclusion Criteria: SEQ-HN 
For inclusion of a subject in the noninterventional portion of the study (SEQ-HN), all of the 
following inclusion criteria must be fulfilled:  
1. At least 18 years of age. 
2. Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, 
nasopharyngeal, or unknown primary) of squamous histology.   
3. HRAS wildtype (i.e. have no identified tumor missense HRAS mutation) determined by a 
test preferred by the investigator and approved by the Sponsor or through central HRAS 
testing.  
4. Will or has received at least one systemic anti-cancer therapy for recurrent or metastatic 
HNSCC for which there is available outcome information in terms of ORR, or can be 
determined based on the subject’s records. Subjects who have not yet received or completed 
at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC must consent to 
the collection of treatment outcome information and additional follow up contact in order to 
participate in the SEQ-HN portion of the study.  
5. Written and voluntary informed consent understood, signed and dated. 


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7.2 
Exclusion Criteria 
7.2.1 
Exclusion Criteria: AIM-HN 
If a subject initially meets any exclusion criteria, the subject may be re-screened at a later time. 
1. Has disease that is suitable for local therapy administered with curative intent. 
2. Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or 
nonsquamous histologies (e.g. mucosal melanoma).  
3. Known additional malignancy that is progressing or requires active treatment (excluding 
non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and hormonal 
treatment for castration sensitive prostate cancer). 
4. Ongoing treatment with an anticancer agent not contemplated in this protocol (excluding 
adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive 
prostate cancer). 
5. Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor (FTI). 
6. Any use of investigational therapy within 2 weeks of Cycle 1 Day 1 (C1D1) or 5 half-lives 
(whichever is longer). Last dose of any prior checkpoint inhibitor therapy must have been 
administered at least 2 weeks prior to C1D1. 
7. Received treatment for unstable angina within prior year, myocardial infarction within the 
prior year, cerebro-vascular attack within the prior year, history of New York Heart 
Association grade III or greater congestive heart failure, or current serious cardiac arrhythmia 
requiring medication except atrial fibrillation. 
8. Non-tolerable Grade 2 or ≥ Grade 3 neuropathy or evidence of unstable neurological 
symptoms within 4 weeks of Cycle 1 Day 1. Non-tolerable Grade 2 toxicities are defined as 
those with moderate symptoms that the subject is not able to endure for the conduct of 
instrumental activities of daily life or that persists ≥ 7 days. 
9. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without 
complete recovery. 
10. Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy, 
including known history of infection with human immunodeficiency virus or an active 
infection with hepatitis B or hepatitis C. 
11. Subjects who have exhibited allergic reactions to tipifarnib or structural compounds similar 
to tipifarnib or to its excipients. This includes hypersensitivity to imidazoles, such as 
clotrimazole, ketoconazole, miconazole and others in this drug class. Subjects with 
hypersensitivity to these agents will be excluded from enrollment. 
12. Required use of concomitant medications classified as strong inhibitors or inducers of 
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13. Concomitant disease or condition that could interfere with the conduct of the study or that 
would, in the opinion of the investigator, pose an unacceptable risk to the subject in this 
study.  
14. Female subjects who are pregnant or lactating. 
15. Unwillingness or inability to comply with the study protocol for any reason. 
7.2.2 
Exclusion Criteria: SEQ-HN 
A subject may not be enrolled in the noninterventional portion of the study (SEQ-HN), if any of 
the following exclusion criteria apply:  
1. Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or 
nonsquamous histologies (e.g. mucosal melanoma).  
2. Concomitant disease or condition that could interfere with the conduct of the study or that 
would, in the opinion of the investigator, pose an unacceptable risk to the subject in this 
study.  
3. The subject has legal incapacity or limited legal capacity. 
7.3 
Subject Withdrawal 
7.3.1 
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 in 
AIM-HN subjects. 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 enrollment 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 medication prohibited by the protocol 


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• 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 
• Subject is lost to follow-up 
• Subject becomes pregnant 
Subjects enrolled in AIM-HN 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 enrollment 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 Health Insurance Portability and 
Accountability Act (HIPAA) in the United States (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. 
7.3.2 
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. 
7.3.3 
Replacement of Subjects 
Subject with HRAS mutant HNSCC who are enrolled in KO-TIP-007 and receive a dose of 
tipifarnib (mITT population for the primary objective) will not be replaced. 
SEQ-HN Subjects (HNSCC without HRAS mutations) who are enrolled as part of SEQ-HN and 
found to have an HRAS mutation following enrollment will be offered participation in AIM-HN 
(assuming all other eligibility criteria are met).  These subjects may be replaced. SEQ-HN 
subjects (HNSCC without known HRAS mutations) who are enrolled and discontinue 
participation prior to the collection of outcome data on first line systemic treatment for recurrent 
or metastatic HNSCC (dates of treatment, performance status, treatment outcome and date of 
progression) may be replaced. 


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8 
TREATMENT OF SUBJECTS 
KO-TIP-007 is a nonrandomized study. Subjects enrolled as part of AIM-HN will receive 
tipifarnib treatment.   
SEQ-HN is noninterventional and used for data collection in control subjects with HNSCC 
without HRAS mutations.  Subjects enrolled in SEQ-HN will not receive tipifarnib treatment and 
may continue to receive other anticancer therapies and care for their disease according to 
institutional practice. 
The following sub-sections apply only to subjects participating in AIM-HN, the tipifarnib 
treatment portion of KO-TIP-007. 
8.1 
Medication 
8.1.1 
Tipifarnib Administration 
Tipifarnib will be administered with food at a starting dose of 600 mg, orally, bid on days 1-7 
and 15-21 of 28-day treatment cycles.  
Tipifarnib should be administered orally with a meal, and again with a meal approximately 12 
hours later at approximately the same times each treatment day. The interval between 
administrations should be not less than 8 hours.  Subjects should be instructed on the importance 
of taking their tipifarnib dose 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.  
If a dose is vomited or partially vomited it should not be replaced with a new dose.  Dosing 
should resume at the next scheduled dose time. 
The first study dosing (Cycle 1 Day 1) will take place in the study clinic. On Cycle 1 Day 1, the 
investigator 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 
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8.1.3 
Treatment of Tipifarnib Overdose 
An overdose is defined as any dose greater than 20% over the daily intended tipifarnib dose. Any 
overdose must be recorded in the trial medication and AE 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. 
8.1.4 
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, rosuvastatin, pravastatin), bisphosphonates (e.g. pamidronate, risedronate, 
ibandronate, etidronate, alendronate) and nutritional agents (e.g. coenzyme Q₁₀, ubiquinone). 
Supportive care medications, e.g. transfusions, growth factors or intravenous hydration, 
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 necessary during the trial and any 


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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 is not anticipated to 
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 adjuvant hormonal therapy for breast cancer or hormonal treatment for 
castration sensitive prostate cancer.  
8.1.5 
Non-permitted Treatments 
Use of the following medications and therapies is not allowed during the trial in subjects 
participating in AIM-HN: 
• Investigational agents other than tipifarnib. 
• Any other anticancer therapy, including radiation or surgery, for the primary disease 
under study with the exception of palliative treatment of non-target lesions or 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 Systemic 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.  See Appendix III (Table 12) for a list of medications classified as strong 
inhibitors or inducers of CYP3A4.  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.  See Appendix III (Table 12) 
for a list of medications classified as sensitive CYP3A4 substrates. If continued 
concomitant therapy is needed, subjects should be transitioned to a medicine that is not a 
sensitive substrate of CYP3A4. 
• Enzyme-inducing anti-convulsants (e.g. phenytoin, phenobarbital, and carbamazepine) 
beginning at Cycle 1 Day 1 and during the subject’s participation in the tipifarnib 
treatment portion of this study.  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. 
8.1.6 
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). 
8.1.6.1 
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 


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contraception from the first dose of tipifarnib, during, and at least 4 weeks after last dose of trial 
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 90 days after the last dose of the study drug: 
o Abstinence (no sex) 
o Condom plus spermicidal agent (foam gel/cream/film/suppository) 
8.2 
Monitoring of Subject 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 
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 
STUDY PROCEDURES 
9.1 
Pre-screening for HRAS Mutation  
The pre-screening for HRAS mutation procedures to be performed in subjects enrolled in KO-
TIP-007 are outlined in Table 1. 


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Kura Oncology, Inc. or its designee will assign a subject number identifier for each subject that 
is enrolled into the study upon completion of informed consent for prescreening. Identification of 
HRAS mutations may be conducted using NGS gene panels that generate mutational information 
on tumor related genes, including variant allele frequency.  
Screening for HRAS mutation can occur at any time prior to initiating tipifarnib treatment in this 
study and may be performed in subjects who are not yet fully eligible for KO-TIP-007, e.g. pre-
screening for HRAS mutations may be performed in subjects currently receiving platinum-based 
or other 1firsttherapy.  Because a tumor’s biology changes over time and in response to anti-
cancer therapies, it is recommended that testing is performed on tumor tissue obtained 
subsequent to the most recent prior; if it is not possible to obtain tissue meeting this criterion 
(clinical risks too high, patient refusal, etc), the reason must be documented.  If several tumor 
samples are available, HRAS testing should be performed on the most recently obtained tumor 
sample.  
Subjects are required to have a missense HRAS mutation for enrollment in AIM-HN, the 
tipifarnib treatment portion of KO-TIP-007.  Subjects without a missense HRAS mutation may 
participate in SEQ-HN, the noninterventional portion of KO-TIP-007 (see Section 9.1.4 and 
Section 9.3).  Upon determination of subject HRAS mutational status, subject will proceed to 
cohort-specific screening procedures for participation in AIM-HN (HRAS mutant HNSCC 
subjects, Section 9.2.1) or SEQ-HN (HRAS wildtype HNSCC subjects, Section 9.3.1). 
9.1.1 
Subjects With Known HRAS Mutation  
If a subject has had HRAS mutation testing as part of their medical care or through another study 
protocol, the following circumstances need to be considered prior to enrolment into the AIM-HN 
part of KO-TIP-007: 
• If HRAS mutation data were obtained subsequent to the most recent prior therapy, and 
obtained using a Sponsor approved test, these data may be used for enrollment.  Re-biopsy 
should be considered for tumor tissue not meeting this requirement. If re-biopsy is not 
possible, the clinical justification should be recorded. Procedures as outlined in Section 
9.1.2 regarding obtaining tumor material for potential confirmatory testing at a central 
laboratory should be followed. 
• If HRAS mutation data were obtained using a test which is not approved by the Sponsor, 
these data may not be used for enrollment.  In such cases, HRAS testing procedures 
outlined in Section 9.1.2 should be followed for study eligibility. 
In addition, the following procedures are to be performed in all subjects with known HRAS 
mutation status irrespective of method for previous HRAS testing: 
• ICF for HRAS pre-screening: Subjects must be consented for study participation and should 
be documented in the subject’s medical chart.  


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• Collection of a blood sample for the analysis of HRAS mutations 
 
 in plasma and shipment to a Sponsor designated 
laboratory. 
• Collection of HRAS mutation data including: 
o Anatomical biopsy site, date of sampling and setting (e.g. primary, locally advanced, 
metastatic lesion) 
o HRAS mutation in sample including variant allele frequency or HRAS wildtype status 
o Test platform (e.g. NGS, PCR, other) 
 
9.1.2 
Subjects Without Known HRAS Mutational Status: Testing for HRAS 
mutation at a Sponsor Designated Laboratory 
The following procedures must be performed: 
• ICF for HRAS pre-screening: Subjects must be consented for study participation and should 
be documented in the subject’s medical chart. 
• Collection and shipment of tumor material for HRAS mutation testing at a Sponsor 
designated laboratory.  Additional details regarding HRAS testing procedures will be 
provided in a separate laboratory manual. 
• Collection of a blood sample for the analysis of HRAS mutations 
 
 in plasma and shipment to a Sponsor designated 
laboratory. 
• Collection of HRAS mutation data including: 
o Anatomical biopsy site, date of sampling and setting (e.g. primary, locally advanced, 
metastatic lesion) 
o HRAS mutation in sample including variant allele frequency or HRAS wildtype status 
 
9.1.3 
Subjects Without Known HRAS Mutational Status: Local testing for 
HRAS mutation using a Sponsor approved test: 
Subjects identified as HRAS mutant HNSCC using a Sponsor approved test used by the 
institution are eligible for enrollment in KO-TIP-007 based on the results of local HRAS testing.   
In order to proceed with approved local testing, the following procedures must be performed: 
• ICF for HRAS pre-screening: Subjects must be consented for study participation and should 
be documented in the subject’s medical chart. 


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• Collection and shipment of tumor material, preferably from the same sample as was used 
for local testing, for HRAS mutation testing at the central laboratory during AIM-HN 
Screening.  Additional details regarding HRAS testing procedures will be provided in a 
separate laboratory manual. 
• Collection of a blood sample for the analysis of HRAS mutations 
 
 in plasma and shipment to a Sponsor designated 
laboratory. 
• Collection of HRAS mutation data including: 
o Anatomical biopsy site, date of sampling and setting (e.g. primary, locally advanced, 
metastatic lesion) 
o HRAS mutation in sample including variant allele frequency or HRAS wildtype status 
o Test platform (e.g. NGS, PCR, other) 
9.1.4 
Subjects who have HNSCC without HRAS mutation  
Subjects who are determined to be HRAS wildtype through prescreening testing in KO-TIP-007 
will be offered participation in the SEQ-HN.  Further details on the study procedures for subjects 
participating in SEQ-HN can be found in Section 9.3. 
9.2 
AIM-HN 
The evaluations to be performed for subjects enrolled in AIM-HN are summarized in Table 2.  
The following subsections apply to subjects participating in AIM-HN. 
9.2.1 
Screening Procedures  
A signed ICF must be obtained before any study-specific screening evaluations are performed 
and should be documented in the subject’s medical chart.  A separate consent will be obtained 
for HRAS mutation pre-screening procedures and is further detailed in Section 9.1. 
The following evaluations and procedures will be performed within 28 days prior to the first 
study drug administration (Cycle 1 Day 1): 
• Signed ICF/ patient informed consent (PIC) and other forms required by local regulation 
(e.g. the Health Insurance Portability and Accountability Act (HIPAA)/Data Protection Act 
(DPA)) 
• Tumor 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. 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. 


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o The presence of at least one measurable target lesion per RECIST v1.1 must be 
confirmed by local radiology prior to enrollment. Subjects without at least one 
measurable target lesion confirmed by local radiology will not be enrolled into AIM-HN. 
Note: Confirmation of RECIST v1.1 measurable disease by local radiology is required 
for study eligibility. 
o Transfer of baseline tumor scans, historical tumor scans (see below) and related clinical 
information to IRF.   
 Efforts should be made to obtain historical scans to document tumor progression.  If 
additional time is needed to obtain the historical scans, these scans should be 
submitted no later than the first tumor response assessment (approximately 8 weeks 
following Cycle 1 Day 1).  These historical scans should include the scans that 
demonstrate most recent progression that occurred on the prior regimen and the scan 
demonstrating the nadir prior to the progression.  Confirmation of the prior 
progression will not be confirmed centrally, however these scans will be used by IRF 
for comparison of prior treatment effect with the baseline scans. 
• Demographics 
• Disease history including: 
o Primary diagnosis, date of initial diagnosis, stage of disease at diagnosis, anatomical 
disease site(s) at diagnosis 
o Current stage of disease 
o Smoking and betel nut exposure  
o Alcohol use  
o HPV status 
o Other relevant medical history  
• First line systemic treatment for recurrent or metastatic HNSCC including:  
o Anatomical (organ) disease site(s) at the time of first line therapy for recurrent or 
metastatic disease 
o Performance status at the time of first line therapy for treatment of recurrent or 
metastatic disease.  
o Name of treatment 
o Dates of treatment (start, end).  
o Treatment outcome (response and response criteria), duration of response 
o Date of progression   


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• Prior cancer therapy(ies) for HNSCC including: 
o Name(s) of treatment(s), dates (start, end) 
o Treatment outcome (response and response criteria), duration of response 
o Date of progression(s).  
o Prior cancer surgery(ies) for HNSCC including date(s) of surgery.  
o Prior/current radiological treatments for HNSCC including anatomical site(s) and date(s) 
of radiation treatment. 
• Buccal swab 
• Collection and shipment of tumor material for HRAS mutation testing and pathology 
review at the central laboratory.  Tumor material for central evaluation should preferentially 
be shipped by Cycle 1 Day 1.  Additional details regarding central HRAS testing and 
pathology review procedures will be provided in a separate laboratory manual. 
o Subject enrollment may be based on local pathology assessment and HRAS testing 
results from a Sponsor designated laboratory or Sponsor approved local tests.   
• Concomitant medications 
• Assessment of AEs, including ongoing AEs 
 
 
The following evaluations and procedures will be performed within 14 days prior to the first 
administration of study drug (Cycle 1 Day 1): 
• Complete physical examination 
• Height 
• Weight 
• Vital signs (heart rate, blood pressure, temperature) 
• 12-lead ECG 
• ECOG performance status. 
 
 
• Laboratory tests: Fasting is not required. 
o Serum Chemistry 
o Hematology 
o Coagulation 
o Urinalysis   


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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 
• Confirmation that the subject continues to meet laboratory prescribed eligibility criteria 
If the subject meets all eligibility criteria after the screening visit(s), the study site will complete 
the inclusion/ exclusion criteria evaluation and submit the enrollment form to the Sponsor or 
designee.  
9.2.2 
Day 1 of Cycle 1 
The following assessments will be conducted before the first dose of tipifarnib on Day 1 of Cycle 
1: 
• Collection of weight and vital signs (heart rate, blood pressure, temperature) 
• ECOG performance status  
• Symptom based physical examination 
• Completion of Quality of Life assessment questionnaires 
• Laboratory tests: Fasting is not required.  Laboratory tests do not need to be repeated on 
Cycle 1 Day 1 if the laboratory tests to confirm continued subject eligibility were conducted 
within 72 hours prior to the first dose of tipifarnib, and upon review the tests confirm 
subject’s continued eligibility for treatment.   
o Serum Chemistry 
o Hematology  
Subjects will be administered the first dose of tipifarnib (600 mg) with food. Time of dosing is to 
be recorded. 
The following assessments will be conducted after the first dose of tipifarnib on Day 1 of Cycle 
1: 
 
   
 
 
 
 
  
• Assessment of AEs 
• Concomitant medications  
• Subjects will continue to self-administer tipifarnib twice a day (approximately every 12 
hours, same time every morning and evening) with a meal on days 1 – 7 and days 15 – 21 


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in 28-day treatment cycles (i.e. alternating week schedule). The interval between dosing 
should not be less than 8 hours. 
9.2.3 
Day 7 of Cycle 1  
(required for Denmark only; all other regions should perform as clinically indicated) 
Subjects should self-administer tipifarnib prior to the Cycle 1 Day 7 visit.   
The following procedures will be performed at this visit:  
• Serum Chemistry  
• Hematology   
9.2.4 
Day 1 (± 2 days) of Cycle 2  
Subjects should self-administer tipifarnib prior to the Cycle 2 Day 1 visit.  
 
 
   
The following procedures will be performed at this visit: 
• Collection of weight and vital signs (heart rate, blood pressure, temperature) 
• ECOG performance status  
• Symptom based physical examination 
• Completion of Quality of Life assessment questionnaires 
• Laboratory Tests: Fasting not required. 
o Serum Chemistry 
o Hematology  
o Serum/urine pregnancy test for females of child-bearing potential only 
 
   
 
 
 
 
  
• Concomitant medications  
• Assessment of AEs 
In addition to the above procedures, the clinical site will conduct a drug accountability review on 
the returned empty bottles and unused medications and will also review the dosing diaries to 
assess compliance with the dosing schedule. 


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9.2.5 
Day 1 (± 2 days) of Cycle 3 and Beyond 
The following procedures will be performed at this visit: 
• Collection of weight and vital signs (heart rate, blood pressure, temperature) 
• ECOG performance status  
• Symptom based physical examination 
• Completion of Quality of Life assessment questionnaires 
• Laboratory Tests: Fasting not required. 
o Serum Chemistry 
o Hematology  
o Serum/urine pregnancy test for females of child-bearing potential only 
 
 
   
 
 
 
 
  
• Concomitant medications  
• Assessment of AEs  
In addition to the above procedures, the clinical site will conduct a drug accountability review on 
the returned empty bottles and unused medications and will also review the dosing diaries to 
assess compliance with the dosing schedule. 
9.2.6 
Tumor Response Assessment Visits 
Tumor response assessment should occur approximately every 8 weeks (± 5 days) for the first 12 
months of a subject’s participation in AIM-HN; thereafter, tumor response assessment should 
occur approximately every 12 weeks (± 5 days) until disease progression. The tumor response 
assessment schedule (every 8 or 12 weeks) should be maintained regardless of dosing delays or 
additional imaging assessments performed. 
The following procedures will be performed at this visit: 
• Radiographic Imaging:  
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. CT scan coverage should 
encompass scans of the neck (including the skull base), chest and abdomen (including 


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the liver and adrenals).  Any other areas of disease involvement should be scanned based 
on the subject’s signs and symptoms. 
o Transfer of tumor scans and related clinical information to IRF 
 
 
 
 
 
   
 
 
   
 
 
 
 
  
 
 
 
 
   
 
 
• Concomitant medications  
• Assessment of AEs  
 
 
9.2.7 
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: 
• Complete physical examination 
• Weight 
• Vital signs (heart rate, blood pressure, temperature) 
• ECOG performance status. 
• Completion of Quality of Life assessment questionnaires 
• Laboratory tests: Fasting is not required. 
o Serum Chemistry 
o Hematology 


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o Serum/urine pregnancy test for females of child-bearing potential only 
• Concomitant medications 
• Assessment of AEs 
• Radiographic Imaging: Applies only for subjects who terminated treatment for reasons 
other than death or disease progression.  In these subjects, imaging should be performed at 
the End of Treatment visit 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. CT scan coverage 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 Transfer of tumor scans and related clinical information to IRF 
• Conduct drug accountability and diary review on the returned empty bottles and unused 
medications. 
 
 
9.2.8 
Follow up Visit 
Follow up visit(s) are required only for subjects who terminated treatment for reasons other than 
disease progression and should occur approximately every 8 or12 weeks (± 5 days) until disease 
progression.  If the subject initiates a new anticancer therapy without evidence of disease 
progression by RECIST v1.1 criteria, tumor assessments should continue 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: 
• Ascertainment of details of any new anti-cancer treatments/surgeries (name, dates (start, 
end), treatment outcome (response and response criteria), duration of response) 
• 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.  CT scan coverage 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 Transfer of tumor scans and related clinical information to IRF 


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• Assessments of AEs and concomitant medications may also be conducted if AEs were not 
resolved at the time of the End of Treatment visit. 
 
 
9.2.9 
Follow Up Contact  
Upon disease progression or withdrawal of consent for additional study procedures, follow up 
contact with the subject and/or caregiver(s) (e.g. electronic technology-based, telephone or in 
person) is to occur approximately every 12 weeks (± 1 week) for survival and the use of 
subsequent therapy until End of Study (see Section 6.7.1). Information on survival and 
subsequent anticancer therapy for HNSCC will be collected including name, dates (start, end), 
treatment outcome (response and response criteria), duration of response, date of progression. 
Information will also be collected on subsequent cancer surgery(ies) for HNSCC including date 
of surgery.  Information will be collected on subsequent radiological treatments for HNSCC 
including anatomical site(s) and date(s) of radiation treatment. 
9.3 
SEQ-HN 
The evaluations to be performed for HRAS wildtype HNSCC subjects enrolled in SEQ-HN are 
summarized in Table 3.  The following subsections apply to HRAS wildtype HNSCC subjects 
participating in SEQ-HN. 
9.3.1 
Screening Procedures  
A signed ICF must be obtained before any study-specific evaluations are performed and should 
be documented in the subject’s medical chart.  A separate consent will be obtained for HRAS 
mutation pre-screening and is further detailed in Section 9.1. 
The following evaluations and procedures will be performed during screening: 
• Signed ICF for participation in the SEQ-HN portion of this study 
• Collection of HRAS wildtype status (blood sample and tissue sample) 
• Inclusion/exclusion criteria evaluation 
9.3.2 
Study Enrollment  
The following information will be collected from enrolled subjects: 
• Demographics 
• Disease history including: 
o Primary diagnosis, date of initial diagnosis, stage of disease at diagnosis, anatomical 
disease site(s) at diagnosis 
o Current stage of disease 


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o Smoking and betel nut exposure  
o Alcohol use  
o HPV status 
o Other relevant medical history  
• First line systemic treatment for recurrent or metastatic HNSCC including:  
o Anatomical (organ) disease site(s) at the time of first line therapy for recurrent or 
metastatic disease 
o Performance status at the time of first line therapy for treatment of recurrent or 
metastatic disease.  
o Name of treatment 
o Dates of treatment (start, end).  
o Treatment outcome (response and response criteria), duration of response 
o Date of progression   
In subjects who have not yet received or completed first line systemic treatment for 
recurrent or metastatic HNSCC, first line systemic treatment information (anatomical 
disease site, performance status, names and dates of treatment, treatment outcome, duration 
of response and date of progression) will be collected through follow-up contact (See 
Section 9.3.4). 
• Other prior cancer therapy(ies) for HNSCC including: 
o Name(s) of treatment(s), dates (start, end) 
o Treatment outcome (response and response criteria), duration of response 
o Date of progressions  
o Prior cancer surgery(ies) for HNSCC including date of surgery.  
o Prior/current radiological treatments for HNSCC including anatomical site(s) and date(s) 
of radiation treatment. 
9.3.3 
On Study Visit 
A blood sample will be collected from all control subjects during Weeks 16 – 24 since the time 
of SEQ-HN enrollment for the evaluation of acquired HRAS mutations during standard of care 
treatment, including surveillance or on treatment break.  If a subject experiences disease 
progression prior to Weeks 16 - 24, the blood sample for HRAS mutational analysis should be 
collected at that time.     


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Subjects who are found to have an HRAS mutation following enrollment will be offered 
participation in AIM-HN (assuming all other eligibility criteria are met).   
9.3.4 
Follow Up Contact  
Follow up contact with the subject and/or caregiver(s) (e.g. electronic technology-based, 
telephone or in person) is to occur approximately every 12 weeks (± 1 week) from the time of 
study enrollment through second line regimen initiation, consent withdraw or completion of 
AIM-HN.  Additional follow up of the matched HRAS wildtype HNSCC patients enrolled into 
SEQ-HN may continue until all AIM-HN objectives are completed and KO-TIP-007 end of 
study is reached. 
Information on survival and subsequent anticancer therapy for HNSCC may be collected by 
phone including name, dates (start, end), treatment outcome (response and response criteria), 
duration of response, date of progression. Information will also be collected on subsequent 
cancer surgery(ies) for HNSCC including date of surgery.  Information will be collected on 
subsequent radiological treatments for HNSCC including anatomical site(s) and date(s) of 
radiation treatment. 
10 
ASSESSMENT OF EFFICACY  
Table 1, Table 2, and Table 3 summarize the study required evaluations. 
10.1 
Efficacy Parameters 
The following subsections apply only to subjects participating in AIM-HN. 
10.1.1 
Efficacy Variables 
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(Appendix I) by IRF.  Confirmation of response is required.  An IRF charter providing the 
specific procedures will be filed with IRBs/IECs and regulatory authorities.  
Local/Investigator tumor response assessments will be collected and used to inform patient care 
decisions.   
 
  
10.1.2 
Method and Timing  
Radiological assessments of the tumor lesions will be made at screening (within 4 weeks prior to 
first study drug administration on Cycle 1 Day 1) and at least once approximately every 8 weeks 
(± 5 days) for 12 months, thereafter once approximately every 12 weeks (± 5 days).  Additional 
tumor assessments may be conducted at the judgment of the Investigator.  


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Radiological assessments will be discontinued at the time of tumor progression. Subjects who 
discontinue treatment for reasons other than disease progression must continue tumor 
assessments until disease progression. Collection of response data may continue upon initiation 
of another anticancer therapy unless the subject withdraws their consent to study procedures.  
Radiological 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 
conducted before subsequent 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 (See Appendix I). 
CT scan with a contrast agent is the preferred imaging method and the same technique should be 
used at screening and post-treatment assessments. 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. 
Subjects with contrast allergy or renal insufficiency may use non-contrast CT or MRI, whichever 
is required to adequately assess all disease. For subjects who develop a contraindication to 
contrast after screening scans are performed with a contrast agent, the decision to use non-
contrast CT or MRI (enhanced or non-enhanced) should be based on tumor type, anatomic 
location of disease and should be optimized to allow for comparison to the prior scans if 
possible.  The one exception where MRI would not be recommended is for the evaluation of 
parenchymal lung metastases.  In this instance, CT would be preferred.  If imaging of the brain is 
indicated, MRI of the brain with and without gadolinium should be performed for optimal 
evaluation of the brain.  If MRI is medically contraindicated, CT of the brain with and without 
contrast would be suggested.  Guidelines for imaging and instructions for transmission of the 
images to IRF will be provided to each study site. 
10.2 
Additional Variables 
10.2.1 
Population Pharmacokinetics 
The blood samples for population PK analysis will be collected from subjects participating in 
AIM-HN at the time points described in Table 9. 


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The time and date of blood sample collection will be collected and recorded in the eCRF.  
Additionally, on study visit days when a blood sample for population PK analysis is collected, 
the time, date and dosage (mg) of the subject’s last dose of tipifarnib (most recent dose to the PK 
blood sample) will be collected and recorded in the eCRF. 
The total blood volume to be collected for the purpose of characterizing the population PK of 
tipifarnib will be approximately 
  Additional blood samples for the 
determination of tipifarnib plasma concentration may be collected at the discretion of the 
Investigator. 
Samples for the evaluation of tipifarnib concentration will be collected, processed and shipped as 
detailed in the Laboratory manual. 
10.2.2 
Biomarkers 
Additional variables to be examined as a part of this study include somatic mutations in 
submitted tumor tissue and plasma samples 
 
 (Witzig 2017).  These variables may be examined in subjects enrolled in AIM-HN and in 
subjects enrolled in SEQ-HN.  
Genetic testing will be/was performed using Sponsor approved local tests or through central 
testing designated by the Sponsor.  Samples may be submitted to a laboratory CRO if deemed 
necessary by the Investigator or Sponsor or for convenience. Genetic markers (mutation, gene 
expression) include, but are not limited to, a panel of oncogenes commonly mutated in HNSCC 
or other alterations that could be relevant for the biology or treatment of HNSCC.  Gene 
expression analyses may include the characterization of alternative gene spliced transcripts, post-
transcriptional modifications, gene fusions, changes in gene expression and unsupervised gene 
expression analyses. 


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11 
ASSESSMENT OF SAFETY 
The following subsections apply only to subjects participating in AIM-HN. 
11.1 
Safety Parameters 
Adverse events will be graded according to the NCI CTCAE v5.0. Adverse events will be 
summarized by relationship to study drug and severity. The safety profile of the IP will be 
assessed through the recording, reporting and analyzing of baseline medical conditions, AEs, 
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 study, from the time of the subject’s signature of informed consent for AIM-HN. 
Incidental findings on radiological scans will not be reported by the IRF.  Study site personnel 
will report any AE, whether observed by the Investigator or reported by the subject.   
The IDMB will review all relevant safety data on a regular basis. 
11.2 
Method and Timing 
At each study visit, the subject will be queried on changes in his/her condition. During the 
reporting period of the study 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 SAEs must be additionally documented and reported using the 
Serious Adverse Event Report Form. It is important that each AE report include a description of 
the event, its duration (onset and resolution dates, including time when it is important to assess 
the time of AE onset relative to the recorded treatment administration time), its severity, its 
relationship with the study 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. 
11.2.1 
Monitoring of Subjects with Adverse Events 
Any AE that occurs during the course of a clinical study 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 study, however while this activity will continue for 


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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. 
11.2.2 
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator as related to study treatment (e.g. resulting from 
a drug interaction with a contraceptive medication) are considered as AEs. 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 eCRF. 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 study. 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 study, the subject must 
be discontinued from study medication immediately. The Sponsor must be notified without delay 
and the subject must be followed as mentioned above. 
11.2.3 
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. 
Clinically significant laboratory test abnormalities will be followed until resolution or 
stabilization and the overall clinical outcome has been ascertained (See Section 11.4.5). 
11.2.3.1 
Blood Sample Collection for General Clinical Laboratory Assessments 
Blood samples will be collected and reviewed for the following clinical laboratory tests within 
72 hours of C1D1 (or on C1D1 prior to dosing): 
• Serum Chemistry: Glucose, Blood Urea Nitrogen (or Urea), Creatinine, Sodium, 
Potassium, Chloride, Calcium, Magnesium, Phosphorus, Total Protein, Albumin, Total 
Bilirubin, Alkaline Phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), Gamma-Glutamyltransferase, and Lactate Dehydrogenase. 
Bicarbonate (or total CO2) is optional. 
• Hematology: White Blood Cell Count, Red Blood Cell Count, Hemoglobin, Hematocrit, 
Platelet Count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils 


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• Coagulation profile: activated partial thromboplastin time (APTT), prothrombin 
time/international normalized ratio (PT/INR) 
11.2.3.2 
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).  
11.2.3.3 
Pregnancy Testing 
Pregnancy testing will be performed in females of child-bearing potential and testing may be 
performed on urine or serum.  If a positive urine pregnancy test is obtained, a confirmatory 
serum pregnancy test should be conducted.  If confirmatory test is positive, subject must 
terminate tipifarnib treatment immediately and follow pregnancy reporting guidelines outlined in 
the protocol. 
Female subjects enrolled in AIM-HN must have a negative serum or urine pregnancy test within 
72 hours prior to start of study medication (Cycle 1 Day 1).  Pregnancy assessments will be 
performed on Day 1 of each cycle starting at Cycle 2. 
11.3 
Adverse Event Reporting 
11.3.1 
Procedure for Reporting Adverse Events 
The AE reporting period for safety surveillance begins when the subject is included into the 
study (date of first signature of AIM-HN informed consent) and continues through the study’s 
post-treatment follow-up period, defined as approximately 30 days from the final administration 
of the study treatment or immediately before initiation of any other anticancer therapy, 
whichever comes first. 
The Investigator is required to grade the severity/intensity of each AE. Investigators will 
reference the NCI-CTCAE v 5.0. This is a descriptive terminology that can be used for AE 
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 


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• Grade 2: Moderate 
• Grade 3: Severe or disabling 
• Grade 4: Life-threatening  
• Grade 5: Death related to AE. Note: Death (Grade 5 as defined by NCI-CTCAE version 
5.0) 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 an SAE as per Section 11.4.2. However, a 
laboratory abnormality with a severity/intensity of Grade 4, such as low white blood cell count or 
increased ALT, 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 IP. Decisive 
factors for the assessment of causal relationship of an AE to the study treatments include, but 
may not be limited to, temporal relationship between the AE and the study treatments, known 
side effects of the study treatments, medical history, concomitant medications and procedures, 
course of the underlying disease and study procedures. 
11.3.2 
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 of 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 Serious Adverse Event Report Form. 
All written reports should be transmitted using the Serious 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 Serious 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 SAE 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 
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11.3.3 
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 study. 
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 study or alter the 
IRB/IEC’s approval/favorable opinion to continue the study.” 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 
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. 
11.4 
Definitions 
11.4.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient 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 
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. 
Relatedness of an AE will be evaluated as follows: 
• Not related: Not suspected to be reasonably related to the IPs. AE could not medically 
(pharmacologically/clinically) be attributed to the IPs under study in this clinical study 
protocol. A reasonable alternative explanation must be available. 


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• Related: Suspected to be reasonably related to the IPs. AE could medically 
(pharmacologically/clinically) be attributed to the IPs under study in this clinical study 
protocol. 
11.4.2 
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. 
11.4.3 
Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations to administer, or to simplify study treatment or study 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. 
11.4.4 
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study 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 endpoint, unless deemed to be causally related to administration of IP. However, if 


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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. 
11.4.5 
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. low 
white blood cell count, increased ALT) must be reported as the AE rather than the abnormal 
value itself. 
11.5 
Adverse Event Follow-up 
All subjects will be followed-up for safety through approximately 30 days after treatment 
discontinuation or until immediately before the administration of another anticancer treatment, 
whichever occurs first.  Additional safety follow-up may be conducted if unresolved toxicity is 
present at the End of Treatment visit. The IDMB will provide periodic evaluations of safety and 
other data to ensure subject safety as well as the validity and scientific merit of the study.      
12 
STATISTICAL CONSIDERATIONS  
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). The modified Intent -to-Treat analysis will be the primary analysis set for efficacy 
analyses and the per-protocol analysis set will be used as the secondary population. 
12.1 
Statistical Methods 
12.1.1 
Efficacy 
For the AIM-HN analyses, the estimate of the ORR will be calculated based on the maximum 
likelihood estimator (i.e., crude proportion of tipifarnib treated subjects whose best overall 
response is Complete Response (CR) or Partial Response (PR) by IRF) using the mITT analysis 
population set. Confirmation of response is required.  The estimate of the objective response rate 
will be accompanied by 2-sided 95% exact binomial confidence interval. Efficacy will also be 
evaluated among the planned 80 subjects in the per-protocol analysis set, as well as summarized 
based on Investigator assessment of tumor response. 
 
 
 
 
 
Time to objective response (OR) and duration of objective response (DOR) will be calculated for 
tipifarnib treated subjects who achieve CR or PR. For such subjects, the time to OR is defined as 


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number of days from enrollment in AIM-HN until start of PR or CR (whichever occurs first), 
while 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 IRF using RECIST v1.1 but local 
treatment decisions will be made by the Investigator based on local tumor measurements and 
other clinical information. The duration of objective response will be right-censored for subjects 
who achieve CR or PR and meet one 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 analyses will be 
performed as determined by the IRF using RECIST v1.1. Additional supportive analyses will be 
conducted using the investigator assessment. 
The time to OR and DOR 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 and a 95% confidence interval for the median response duration will be computed. 
Progression-free survival (PFS) will be defined as the time (in months) from enrollment into 
AIM-HN 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, whatever occurs last. Progression-free survival 
analyses should consider tumor assessments after treatment discontinuation or metastatic 
surgery. Survival will be defined as the time (in months) from enrollment to the occurrence of 
death due to any cause. Sensitivity analyses for PFS and survival will be performed according to 
the FDA Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics (May 2007). 
Survival and PFS endpoints 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 
and overall survival and 95% confidence intervals for the median response duration will be 
computed. 
 


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Descriptive statistics will be primarily used to summarize the demographic data collected in this 
study. For continuous variables, the number of patients 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. 
Hierarchical testing to adjust for multiplicity will be employed, beginning with the primary 
objective and working downward until first p>0.025 1-sided, at which time testing for purposes 
of firm conclusions will stop. 
Sensitivity analyses will be performed to evaluate the robustness of statistical inferences, e.g., to 
assess the impact of missing data on the conclusions. In addition, a sensitivity analysis will be 
conducted to evaluate of the impact of the selected VAF cut point on the primary and key 
secondary analyses, and to determine the VAF cut point which is most predictive of clinical 
benefit. 
 
 
 
  
 


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12.1.2 
Safety and Tolerability  
Safety and tolerability of tipifarnib will be assessed based on the following: 
• Incidence, duration, and severity of treatment-emergent AEs, SAEs, AEs 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, heart rate and temperature 
• Changes in ECG results 
AEs will be coded using the using version 22.0 of the Medical Dictionary for Regulatory 
Activities (MedDRA) and upversioned prior to database lock. Treatment-emergent AEs are 
defined as AEs that start on or after the first dose of study drug and within approximately 30 
days of the last administration of study drug. AEs 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 AE 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 enrolled 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 v5.0 severity grade and by relationship to each 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. 


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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 v5.0. The use of 
blood transfusions (platelets, red blood cells) and/or growth factor support will be reported.  
Vital sign results (heart rate, blood pressure 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. 
12.1.3 
Population Pharmacokinetics 
Data collected in this study will be pooled with PK and clinical data from other tipifarnib studies 
to perform a population PK analysis. Details and methodology for this analysis will be described 
in the Population PK Statistical Analysis Plan. The population PK results will be reported 
separately from the KO-TIP-007 CSR. 
12.2 
Subject Population(s) for Analysis 
Details on any additional analysis population sets will be provided in the SAP. 
12.2.1 
Efficacy Analysis 
The mITT population will include all subjects who received at least one dose of tipifarnib and 
will be used for the primary efficacy analysis. Subjects who do not have IRF confirmed evidence 
of RECIST v1.1 measurable disease at baseline will be excluded. 
 
 
 
 
   
Dropouts will not be replaced.  For the primary efficacy analysis, all subjects with missing 
response status will be classified as treatment failures.   
12.2.2 
Safety Analysis 
The mITT population will be used for the analysis of safety data. 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. 


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12.3 
Significance 
All confidence intervals will be 95%. Any reported p-values reported as a part of secondary or 
exploratory analyses will be considered descriptive in nature. 


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12.4 
Termination Criteria 
The IDMB will consider the efficacy and futility stopping boundaries stated above as a guideline 
in evaluating the trial results with respect to ORR of tipifarnib.  In making a recommendation to 
terminate the study for any reason, the IDMB will also consider information on safety endpoints, 
as well as consistency of outcomes for secondary endpoints. 
12.5 
Accountability Procedure 
No data will be imputed; all analyses and summaries will be based on observed data only, and no 
data will be excluded.  
12.6 
Deviation Reporting 
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. 
13 
Regulatory, Ethical, and Study Oversight Considerations 
13.1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki and CIOMS International Ethical Guidelines 
Applicable International Council for Harmonisation (ICH) GCP Guidelines 
Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) 
must be submitted to an IRB/IEC by the Investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
The Investigator will be responsible for the following: 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 


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Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 Code of Federal Regulation (CFR), ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations 
13.2 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
13.3 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the patient and/or 
his/her legally authorized representative and answer all questions regarding the study. 
Patients or their guardians/legal representatives must be informed that the patient’s participation 
is voluntary. Patients or their legally authorized representative (parent or other legal guardian) 
will be required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability, and Accountability 
Act requirements, where applicable, and the IRB/IEC or study center. 
As used in the protocol, the term “informed consent” includes all informed assent given by 
patients, informed permission by legally authorized representative, or, as applicable, informed 
consent by the patient during study participation. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be reconsented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
A patient who is rescreened is not required to sign another ICF unless an updated ICF is 
available. 
13.4 
Data Protection 
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient. 


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The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
13.5 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on the US National Institutes of 
Health website www.clinicaltrials.gov, the EU website www.clinicaltrialsregister.eu/, or other 
publicly accessible websites as appropriate and in accordance with local regulations. 
13.6 
Data Quality Assurance 
All patient data relating to the study will be recorded in an eCRF unless transmitted to the 
Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. Study monitors will communicate with 
investigational sites on a regular basis regarding the study and all protocol deviations will be 
appropriately documented by the Investigator or designee, and study monitors. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 5 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
13.6.1 
Data Quality and Integrity Monitoring  
Customized to the needs of the study, real time data quality and integrity monitoring will be 
employed as part of the risk based central statistical monitoring. The monitoring will allow for 
optimal and multi-angle real time data quality assessments using various multivariate pattern 
detection algorithms powered by advanced interactive data visualization and root cause analysis 
modules. The monitoring will specifically be focused on the site and geography levels leading to 
early identification of accumulating data risks and issues.    


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13.7 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the investigational site. 
The Investigator or designee will prepare and maintain adequate and accurate source documents 
(medical records, electrocardiograms [ECGs], AE and concomitant medication reporting, and 
raw data collection forms) designed to record all observations and other pertinent data for each 
patient. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
13.8 
Study and Site Closure 
The Sponsor or designee reserves the right to close the investigational site or terminate the study 
at any time for any reason at their sole discretion. An investigational site is considered closed 
when all required documents and study supplies have been collected and an investigational site 
closure visit has been performed. Portable Document Format versions of data entered in the 
eCRF will be distributed to the sites at time of study closure and not during an individual site 
close-out visit. 
The Investigator may initiate investigational site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of an investigational site by the Sponsor or Investigator may 
include but are not limited to: 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, the Sponsor’s procedures, or GCP guidelines 
Inadequate recruitment of patients by the Investigator 
Discontinuation of further Tipifarnib development 
13.9 
Publication Policy 
The full terms regarding publication of the results of this study are outlined in the applicable 
Clinical Study Agreement. 
14 
Guidelines To Be Applied During Infectious Disease Outbreak 
– COVID-19 
Period:  
These guidelines only apply during any public health emergency related to COVID-19, declared 
by government authorities, in the countries where the trial sites are located. 
 


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The activities in this guideline include: 
- 
Safety reporting by Sites 
- 
Adherence to protocol specified activities  
- 
Informed Consent process 
- 
Provision of study drug to subjects 
- 
Site monitoring by CRAs 
- 
Documentation requirements 
. 
14.1 
Ensuring Continuity of Safety Reporting 
Investigators may conduct tele-medicine calls via phone/video to identify or to follow-up on 
adverse events.   
In the event that patients cannot complete a site visit, they may be directed to utilize local 
labs/primary care providers to collect labs and conduct patient assessments (e.g., vitals, physical 
exams), and use local imaging facilities where necessary.  
If the patient cannot get to an alternative location, then the decision to continue dosing in 
absence of required safety labs is made by the investigator in consultation with the Kura Medical 
Monitor.  These decisions will be made on a case by case basis. 
For any reports of flu-like symptoms, fevers and/or respiratory problems; the investigator should 
determine if the patient has been/should be tested for COVID-19.   
14.2 
Maintaining Protocol Requirements, Including Schedule of Activities 
Exposure to or instances of a confirmed positive result for COVID-19 will not mandate early 
termination of patient from the study.  Continued participation in the study will be at the 
investigator’s discretion. 
However, if investigators have suspected / confirmed positive patients, then they should notify 
Kura Oncology. The investigator and the Medical Monitor should make a case by case 
assessment of which procedures/samples are appropriate to continue.   
 
14.2.1 
Clinic Visits 
• If patients cannot travel to the study site or the investigator cannot accommodate a visit, but 
can still receive care via a local provider, efforts should be made to collect data from the 
local provider in accordance with local privacy/data protection requirements.  Data collected 
may include but is not limited to collection of weight and vital signs (heart rate, blood 
pressure, temperature).  If possible, the investigator should prospectively request that data be 
collected according to good documentation practices (i.e., ALCOA+). 
• Where applicable, patient visits may be conducted virtually via telephone or video 
conference.  Data collected during calls may include, but is not limited to adverse event 
assessment, concomitant medication assessment, ECOG assessments, survival follow-up, and 
IP compliance assessment.  Investigators should ensure:  


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o Site staff or investigators are appropriately trained on how to conduct real-time 
video conferencing visits (i.e. training on use of telemedicine for remote clinical 
trial visits) 
o Necessary procedures and safeguards are in place to maintain a trial participant’s 
privacy 
o Both the investigator and trial participant confirm their respective identities with 
one another before starting a real-time video conference visit (e.g. have the trial 
participant confirm their date of birth or, if the visit is conducted via 
videoconference, present a form of government issued photographic 
identification)  Consult with the Sponsor or designee to confirm the specifics of 
any process implemented. 
o Details about the date and time of the real-time video conference visit, the 
location of the trial subject, the location of the investigator or staff conducting the 
visit should be appropriately documented. 
• Radiographic imaging may be collected locally and reviewed by the investigator or 
applicable delegated staff member.   
14.2.2 
Clinical Laboratory Testing 
• Clinical laboratory testing may be completed by a certified (e.g., CAP) local provider and 
reviewed by the investigator.  Laboratory results should be reviewed prior to either 
administration or additional shipping of IP.  
• If a local clinical laboratory will collect samples that require use of study specific laboratory 
kits (
, buccal swabs), laboratory kits may be shipped to the study subject to 
take with them to the local laboratory for use during testing.   
• 
If a local laboratory is utilized, the normal ranges for this lab need to be collected and the 
source of these values (i.e. coming from a local laboratory) needs to be clearly documented   
14.2.3 
Disruptions for Shipping to Central Laboratories 
If the ability to ship samples to the Central Laboratory for analysis are impacted, then, if local 
facilities are available, it is permissible to store samples according to laboratory manual 
guidelines for analysis later when disruptions are resolved. Central laboratories should be 
consulted to resolve any questions.   
 
14.3 
Informed Consent Process 
When it is not possible to obtain informed consent in a face-to-face consent interview, it is 
permissible to obtain informed consent virtually.  Such virtual consent interviews need to ensure 
that an adequate exchange of information and documentation occurs.  In addition, there needs to 
be a method to ensure that the person who plans to enroll as a subject (or who is already enrolled 
as a subject in the case of a revised ICF) is actually the person who signs the ICF.  This virtual 
process can involve, for example, telephone or other video-conference mechanisms, along with 
the subject providing photographic or facsimile evidence of completing the ICF.                                                    
Consult with the Sponsor or designee to confirm the specifics of any process implemented. 


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14.4 
Ensuring Continuity of Drug Supply to Subjects 
 
Investigational Product (IP) Shipping: 
• If site visit restrictions are anticipated but are not yet in effect, additional IP (beyond one 
cycle) may be dispensed during on-site patient visits at the Investigator’s discretion.   
• If site visit restrictions are implemented between patient visits, IP may be shipped directly 
from sites to patients under the investigator’s supervision via overnight courier along with 
instructions for dosing and documentation of dosing.  Delivery signature confirmation should 
be requested whenever possible.  IP should be shipped at ambient temperature using an 
insulated package/container. Appropriate safeguards should be used to ensure appropriate 
shipping and receipt, including documentation of receipt (signature of receiver) and condition 
of package (e.g. ensuring no tamper proof seal had been broken, etc.) 
• 
The IP may be shipped at ambient temp in credo with no temperature monitoring device. 
• 
Consult with Sponsor, or designee, as needed to assign IP.   
 
14.5 
Managing Restrictions to Site Monitoring by CRAs 
Where there are physical access restrictions to clinical sites or country specific travel limitations, 
implementation of remote or off-site monitoring visits (OMVs) may be conducted in lieu of on-
site visits whenever possible.  
OMVs should not place an extra burden on trial sites, and subjects must consent to any sharing 
of their personal information outside the trial site. 
14.6 
Documentation of COVID-19 Related Guidelines or Other Measures. 
It is important to document the reason for implementing any of these contingency measures. 
Such documentation should include details on how restrictions related to COVID-19 led to the 
use of these contingency measures during study conduct, the duration of those changes, which 
trial participants were impacted and how those trial participants were impacted. When any non-
study site labs are needed, these should be clearly documented so that the Sponsor can align on 
usability of the data on a case-by-case basis.  When adopting or implementing these guidelines, 
investigators should make every effort to minimize any impacts on trial integrity.  If any 
additional changes are required that are not covered in these guidelines, investigators should act 
according to local guidelines and regulations, but above all to assure the safety of trial 
participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to 
trial integrity. Any changes made should be appropriately documented as protocol deviations. 
 
In advance of any interim analyses/planned database locks, the Sponsor will ensure that the 
impact from study visit changes are assessed and will revise the SAP accordingly. 
15 
LITERATURE 
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SAP_001.pdf: 
Protocol Number: KO-TIP-007 
 
Official Title: The AIM-HN and SEQ-HN Study: A Multi-national, Single Arm Pivotal Study Evaluating 
the Efficacy of Tipifarnib in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC) with 
HRAS Mutations (AIM-HN) and an Observational Study to Evaluate the Impact of HRAS Mutational 
Status on Response to First Line Systemic Therapies for HNSCC (SEQ-HN) 
NCT Number: NCT03719690 
 
Document Date: 06 June 2023 


Clinical Study Report
Confidential
Sponsor Name: Kura Oncology, Inc. 
Study Number: KO-TIP-007 
16.1.9 
Documentation of Statistical Methods 
Final SAP, Version 1.0, dated 06 June 2023 
Page 1 of 28


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Page 2 of 28


 
 
 
Sponsor: Kura Oncology, Inc. 
Statistical Analysis Plan 
Protocol no: KO-TIP-007 
Version 1.0 Date: 06-Jun--2023 
 
 
Strictly Confidential.  © 2017, 
  All rights reserved. 
Contents 
1 
Purpose .............................................................................................................................................................................. 4 
2 
Scope ................................................................................................................................................................................... 4 
3 
Changes from Protocol ................................................................................................................................................ 4 
4 
Study Objectives ............................................................................................................................................................. 5 
4.1 
Primary Objective ................................................................................................................................................ 5 
4.2 
Key Secondary Objectives ................................................................................................................................. 5 
4.3 
Other Secondary Objectives for AIM-HN .................................................................................................... 5 
 
 
5 
Study Design .................................................................................................................................................................... 6 
5.1 
AIM-HN Design ...................................................................................................................................................... 7 
5.2 
SEQ-HN Design ...................................................................................................................................................... 8 
 
 
5.4 
Randomization ...................................................................................................................................................... 9 
6 
Study Estimands ............................................................................................................................................................. 9 
7 
Endpoints Definitions ................................................................................................................................................ 11 
7.1 
Study Drug (Tipifarnib) Exposure Variables .......................................................................................... 12 
7.2 
Prior and Concomitant Medications ........................................................................................................... 12 
7.3 
Efficacy Variables ............................................................................................................................................... 12 
7.3.1 
Objective Response Rate (ORR).......................................................................................................... 13 
7.3.2 
Time to Response (TTR) ........................................................................................................................ 13 
7.3.3 
Duration of Response (DOR)................................................................................................................ 14 
7.3.4 
Progression-free Survival (PFS) ......................................................................................................... 14 
7.3.5 
Overall Survival (OS) ............................................................................................................................... 15 
7.4 
Clinical Laboratory Parameters ................................................................................................................... 16 
8 
Data Handling ................................................................................................................................................................ 16 
8.1 
Imputation of Missing Data ............................................................................................................................ 16 
8.1.1 
AE and Concomitant Medication Start and Stop Dates ............................................................. 16 
8.1.2 
Missing normal ranges for laboratory parameters .................................................................... 16 
9 
Statistical Methods ...................................................................................................................................................... 16 
9.1 
Analysis Sets ......................................................................................................................................................... 16 
9.1.1 
Modified Intent-to-Treat (mITT) Analysis Set .............................................................................. 17 
9.1.2 
Per Protocol Analysis Set (PPS) .......................................................................................................... 17 
9.1.3 
Safety Analysis Set (SAS) ....................................................................................................................... 17 
9.2 
Subject Disposition ............................................................................................................................................ 17 
9.3 
Important Protocol Deviations ..................................................................................................................... 17 
9.4 
Extent of Study Drug Exposure .................................................................................................................... 17 
9.5 
Prior and Concomitant Medications ........................................................................................................... 18 
9.6 
Demographic and Baseline Disease Characteristics ............................................................................ 18 
9.7 
Efficacy Analyses ................................................................................................................................................ 18 
9.7.1 
Primary Endpoint ..................................................................................................................................... 18 
9.7.2 
Key Secondary Endpoints and Other Secondary Endpoints for AIM-HN .......................... 19 
9.8 
Safety Analyses .................................................................................................................................................... 20 
9.8.1 
Adverse Events .......................................................................................................................................... 20 
9.8.2 
Deaths ............................................................................................................................................................ 21 
9.8.3 
Clinical Laboratory Parameters .......................................................................................................... 21 
9.8.4 
Vital Signs..................................................................................................................................................... 21 
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10 References ....................................................................................................................................................................... 23 
 
 
 
 
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Sponsor: Kura Oncology, Inc. 
Statistical Analysis Plan 
Protocol no: KO-TIP-007 
Version 1.0 Date: 06-Jun--2023 
 
 
Strictly Confidential.  © 2017, 
  All rights reserved. 
1 Purpose 
The statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Kura Oncology, Inc. Protocol KO-TIP-007. 
2 Scope 
This SAP supplements the study protocol and provides more details on the strategy, rationale, and 
statistical techniques to be used towards achieving the study objectives. 
The SAP outlines the following: 
Study objectives 
Study design 
Variables analyzed and analysis sets 
Applicable study definitions 
Statistical methods regarding important protocol deviations, study drug exposure, efficacy 
analysis, concomitant medications, adverse events handling, laboratory data and physical 
examinations  
See Appendix 1 for a list of abbreviations used throughout this document. The list of the mock tables, 
figures, and listings depicting the analyses described in this SAP are presented in a separate document. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol v3.0 dated 09JUN2020 and CRF v6.0 dated 11Nov2022. 
Any changes to the protocol may necessitate updates to the SAP. 
The final version of the SAP will be issued for sponsor approval prior to database lock. Any deviations from 
the final version of the SAP will be documented in the final Clinical Study Report (CSR). 
3 Changes from Protocol 
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4) Time to progression (TTP) analyses and some additional exploratory analyses as specified in the 
protocol will not be performed. 
The TTP analysis is removed because Progression Free Survival (PFS) is included as a secondary 
endpoint of the study. Compared to TTP, PFS is the preferred regulatory endpoint. PFS includes 
deaths and thus can be a better correlate to overall survival, while death events are censored in TTP 
analysis. 
 
5) The case-control analysis specified in the protocol will not be performed. 
Post-hoc case-control analysis may be conducted after the database is locked to expedite the 
delivery of the TFL for CSR.  
 
6) The analysis to assess the population pharmacokinetics (PK) of tipifarnib in HNSCC subjects with 
HRAS mutations will not be performed. In this study, only sparse PK samples were planned to be 
collected for population PK analysis. However, limited data were collected due to the early closure of 
this study and such analysis is not deemed feasible. 
4 Study Objectives 
4.1 Primary Objective 
To determine the objective response rate (ORR) of tipifarnib in subjects with Head and Neck Squamous 
Cell Carcinoma (HNSCC) with HRAS mutations with a VAF≥20% (High VAF population), as assessed by 
Independent Review Facility (IRF). 
4.2 Key Secondary Objectives 
To determine the ORR of tipifarnib in subjects with HNSCC with HRAS mutations of any VAF (All VAF 
population), as assessed by IRF. 
To determine the Duration of Response (DOR) of tipifarnib in subjects with HNSCC with HRAS mutations 
with a VAF≥20% (High VAF population), as assessed by IRF. 
To determine the DOR of tipifarnib in subjects with HNSCC with HRAS mutations with any VAF (All VAF 
population), as assessed by IRF. 
4.3 Other Secondary Objectives for AIM-HN 
To determine the anti-tumor activity of tipifarnib in terms of progression free survival (PFS) and rate of PFS 
at 6 and 9 months in both the high VAF and all VAF populations. 
To determine the anti-tumor activity of tipifarnib in terms of overall survival (OS) and rate of OS at 12 months 
in both the high VAF and all VAF populations. 
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To determine the anti-tumor activity of tipifarnib in terms of time to response (TTR) in both the high and all 
VAF populations.  
To determine the anti-tumor activity of tipifarnib in terms of time to progression (TTP) in both the high and 
all VAF populations.  
To investigate the safety and tolerability of tipifarnib according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0). 
To investigate the effects of tipifarnib treatment on quality-of-life measures, including EORTC QLQ-
H&N35 and EQ-5D-5L. 
To assess population pharmacokinetics (PK) of tipifarnib in subjects with HNSCC with HRAS mutations. 
5 Study Design 
KO-TIP-007 is an international, multicenter, open-label, single-arm pivotal study, with two non-comparative 
sub-studies: (1) an interventional open-label, single arm, pivotal study evaluating the efficacy of tipifarnib in 
HRAS mutant HNSCC (AIM-HN) and (2) an observational study to evaluate the impact of HRAS mutations 
on response to first line systemic therapies for HNSCC (SEQ-HN).  
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Statistical Analysis Plan 
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Figure 1. KO-TIP-007 Study Design 
 
5.1 AIM-HN Design 
AIM-HN will enroll subjects with head and neck tumors of confirmed squamous histology with HRAS 
mutations. Subjects must have failed (e.g. tumor progression, clinical deterioration, or recurrence) their 
most recent prior therapy  and at least one prior line of systemic therapy. See Figure 2 for a depiction of 
the design of AIM-HN. 
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Version 1.0 Date: 06-Jun--2023 
 
 
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Figure 2: AIM-HN Design 
 
All subjects must have measurable disease that meets the criteria for selection as a target lesion according 
to RECIST v1.1 and presence of at least measurable target lesion by local radiology prior to enrollment is 
required. HNSCC diagnosis will be by local laboratory. All AIM-HN enrolled subjects must have a known 
missense HRAS tumor mutation based on centralized testing or other HRAS test used by the trial site that 
has been approved by Kura Oncology, Inc.  
AIM-HN enrolled subjects will receive treatment with tipifarnib until disease progression, unacceptable 
toxicity or any criteria for withdrawal from the trial or treatment occurs. Tipifarnib will be administered with 
food at a starting dose of 600 mg, orally, bid on days 1-7 and 15-21 of 28-day treatment cycles. Stepwise 
300 mg dose reductions to control treatment-related, treatment-emergent toxicities may occur.  
Tumor assessment for the primary analysis will be performed by IRF according to RECIST v1.1 and 
provided to the IDMB. Investigator assessment of tumor response will also be collected and reported as a 
supportive analysis. Tumor response assessment should occur approximately every 8 weeks (± 5 days) for 
the first 12 months; thereafter, tumor response assessment should occur approximately every 12 weeks (± 
5 days) until disease progression. The tumor response assessment schedule (every 8-12 weeks) should 
be maintained regardless of dosing delays or additional imaging assessments performed. Upon disease 
progression, all subjects will be followed approximately every 12 weeks for survival and the use of 
subsequent therapy until either death or End of Study (up to 2 years after the enrollment of the last study 
subject, see protocol Section 6.7.1), whichever occurs first. All subjects will be followed-up for safety 
through the End of Treatment visit which occurs approximately 30 days after treatment discontinuation or 
immediately before the administration of another anticancer treatment, whichever occurs first. Additional 
safety follow-up may be conducted if unresolved toxicity is present at this End of Treatment visit. 
5.2 SEQ-HN Design 
SEQ-HN is an observational sub-study 
 
See Figure 3 for a depiction of the 
design of SEQ-HN. Demographics, disease history, information on prior anti-cancer treatments and 
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outcomes to prior treatments for HNSCC will be collected from all enrolled subjects. Approximately 225 
control subjects with HNSCC without known HRAS mutation, will be enrolled into SEQ-HN. As part of their 
participation in SEQ-HN, subjects will be followed up through initiation of second line therapies, death, or 
consent withdrawn, whichever occurs first.  
Figure 3: SEQ-HN Design  
 
 
 
 
 
 
 
 
 
 
5.4 Randomization 
KO-TIP-007 is a nonrandomized, open label study.  
6 Study Estimands 
Objectives  
Estimands 
Primary for AIM-HN 
 
To determine the objective response rate (ORR) of 
tipifarnib in subjects with Head and Neck Squamous 
x 
Population of interest: mITT Analysis Set for subjects 
with High VAF 
x 
Variable/endpoint of interest: ORR by IRF 
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Statistical Analysis Plan 
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Cell Carcinoma (HNSCC) with HRAS mutations with a 
VAF≥20% (High VAF population), as assessed by 
Independent Review Facility (IRF) 
Key Secondary for AIM-HN 
To determine the ORR of tipifarnib in subjects with 
HNSCC with HRAS mutations of any VAF (All VAF 
population), as assessed by IRF 
x 
Population of interest: mITT Analysis Set 
x 
Variable/endpoint of interest: ORR by IRF 
To determine the Duration of Response (DOR) of 
tipifarnib in subjects with HNSCC with HRAS 
mutations with a VAF≥20%, as assessed by IRF 
x 
Population of interest: mITT Analysis Set for subjects 
with High VAF and confirmed objective response 
(CR or PR) 
x 
Variable/endpoint of interest: DOR by IRF 
To determine the DOR of tipifarnib in subjects with 
HNSCC with HRAS mutations of any VAF, as 
assessed by IRF 
x 
Population of interest: mITT Analysis Set for subjects 
with confirmed objective response 
x 
Variable/endpoint of interest: DOR by IRF 
Other Secondary for AIM-HN 
To determine the anti-tumor activity of tipifarnib in 
terms of progression free survival (PFS), and rate of 
PFS at 6 and 9 months in both the high VAF and all 
VAF populations 
x 
Population of interest: mITT Analysis Set for subjects 
with High VAF/all VAF 
x 
Variable/endpoint of interest: PFS by IRF including 
the 6 month and 9 month progression-free rate  
To determine the anti-tumor activity of tipifarnib in 
terms of overall survival (OS), and rate of OS at 12 
months in both the high VAF and all VAF populations 
x 
Population of interest: mITT Analysis Set for subjects 
with High VAF/all VAF 
x 
Variable/endpoint of interest: OS including the 12 
month OS rate 
To determine the anti-tumor activity of tipifarnib in 
terms of time to response (TTR) in both the high and 
all VAF populations  
x 
Population of interest: mITT Analysis Set for subjects 
with confirmed objective response and High VAF/all 
VAF 
x 
Variable/endpoint of interest: TTR by IRF 
To determine the anti-tumor activity of tipifarnib in 
terms of time to progression (TTP) in both the high 
and all VAF populations  
This analysis is removed from the SAP 
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Statistical Analysis Plan 
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To investigate the safety and tolerability of tipifarnib 
according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events version 5.0 
(NCI CTCAE v5.0) 
x 
Population of interest: Safety Analysis Set 
x 
Variable/endpoint of interest: Incidence and severity 
of adverse events. Laboratory test results, Vital Signs 
and ECG results 
 
To investigate the effects of tipifarnib treatment on 
quality of life measures, including EORTC QLQ-
H&N35 and EQ-5D-5L 
x 
Population of interest: mITT Analysis Set 
x 
Variable/endpoint of interest: Changes in measures 
of quality of life using the following tools: EORTC 
QLQ-H&N35 and EQ-5D-5L 
To assess population pharmacokinetics (PK) of 
tipifarnib in subjects with HNSCC with HRAS 
mutations 
This analysis is removed from the SAP 
 
7 Endpoints Definitions 
In general, baseline is defined as the last measurement prior to the first dose of tipifarnib. If assessment 
time for an assessment on Cycle 1 Day 1 is missing, the assessment will also be considered baseline.  
Change from baseline is defined as (value at post-baseline visit – value at baseline). In summary tabulations 
over time, unscheduled post-baseline values will be excluded unless otherwise stated.  
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For safety variables, on-treatment refers to the period from the start of study treatment through 30 days 
post treatment termination (last dose day).  
7.1 Study Drug (Tipifarnib) Exposure Variables 
Duration of Exposure 
Duration of exposure (months) is defined as (last dose date with >0 mg – first dose date + 1)/30.4375. 
Dosing start and end dates can be found on the Tipifarnib Dosing Log CRF pages.  
Number of Cycles Initiated 
The number of cycles initiated where a dose > 0 mg was administered. 
Dose Interruptions 
Dose interruptions and the reason for dose interruption will be summarized.  
Dose Adjustments 
Dose adjustments of tipifarnib are captured as ‘Dose Decreased Per Protocol’, ‘Dose Increased Per 
Protocol’, ‘Drug Interrupted’, ‘Drug Withdrawn’ or ‘Other’ in the Dose Action field of the Tipifarnib Dosing 
Log CRF pages. Dose Interruptions and the reason for dose interruption will be summarized.  
Actual Cumulative Dose Administered 
Actual Cumulative Dose administered (mg) is defined as the total amount of tipifarnib received as recorded 
in the “Actual Total Daily Dose” field on the Tipifarnib Dosing Log CRF pages, i.e., the sum of all doses 
administered over the periods indicated by the dosing start and stop dates. 
Relative Dose Intensity (RDI) 
RDI (%) is defined as total dose taken by subject during exposure period divided by intended dose to be 
taken during exposure period.  
RDI (%) = 100*(Actual Dose Intensity) / (Intended Dose Intensity)  
              = 100*(Actual Cumulative Dose) / (Intended Cumulative Dose) as the intended treatment duration 
is considered the same as the actual treatment duration for the Study drug 
Intended Cumulative Dose = [(Number of Cycles Initiated -1) x 14 + actual dosing days in the last cycle] x 
600 mg x 2 
7.2 Prior and Concomitant Medications 
Concomitant medications are all medications (or treatments) other than study drugs that are taken or 
received by the subject at any time during the study starting at the time that the first dose of study drug was 
administered through the end of study treatment. Use of all concomitant medications, including any change 
in therapy, will be recorded, categorized and summarized by ATC Class and Preferred Term according to 
WHODrug Global B3 01MAR2021. Refer to Section 8.1.1 for rules of imputing partial/missing concomitant 
medications start and stop dates. 
Prior medications are medications that are taken within 28 days prior to a subject’s first dose of study drug 
and discontinued prior to the first dose of study drug. Prior medications will be listed.  
7.3 Efficacy Variables 
The primary efficacy measure is anti-tumor response assessed by an IRF every 8 weeks in the first 12 
months of study treatment and every 12 weeks thereafter until disease progression. Assessments will also 
be made by the Investigator. Response criteria will be based on RECIST v1.1. Baseline efficacy 
assessments are required to be completed within 28 days prior to Cycle 1 Day 1. Any tumor assessment 
completed within 42 days prior to Cycle 1 Day 1 will be considered as baseline assessment.  
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The following variables are defined for AIM-HN only. Efficacy variables will be reported for the High VAF 
subjects as well as all VAF subjects. 
7.3.1 Objective Response Rate (ORR) 
ORR is the proportion of subjects with Best Overall Response (BOR) of a confirmed CR or confirmed PR 
by RECIST v1.1.  
BOR is the best response recorded from the first dose date of the study drug until disease progression or 
death or the start of new anti-cancer therapy whichever occurs first. BOR per IRF will be assigned by IRF.  
The BOR by investigator assessment will be derived based on following order: Confirmed CR > Confirmed 
PR > SD > PD. All other cases will be categorized as NE.  
 
Confirmed Complete Response (CR):  
x 
(CR CR) within two consecutive visits (including unscheduled visits) at least 28 days apart, or  
x 
(CR NE CR) within three consecutive visits at least 28 days apart from the third visit to the first visit 
Confirmed Partial Response (PR):  
x 
(PR PR) within two consecutive visits at least 28 days apart, or  
x 
(PR NE PR) or (PR SD PR) within 3 consecutive visits at least 28 days apart from the third visit to 
the first visit 
Stable Disease (SD):  
x 
patient without confirmed CR or confirmed PR, but with one single assessment after 35 days from  
Cycle 1 Day 1 as CR or PR followed by NE (e.g. CR + NE or PR + NE), or  
x 
patient without confirmed CR or confirmed PR, but with one single assessment after 35 days from 
Cycle 1 Day 1 as CR or PR as the last assessment prior to the data cutoff date (e.g. CR/PR + no further 
evaluation), or 
x 
patient without confirmed CR or confirmed PR but with SD after 35 days from Cycle 1 Day 1 
Progressive Disease (PD):  
x 
patient without confirmed CR or confirmed PR, or SD, but with PD 
Not Evaluable (NE): All other cases will be categorized as NE. The reason for NE may include: 
x 
No baseline assessment 
x 
New anti-cancer therapy started before the first post-baseline assessment 
x 
No post-baseline assessments or all post-baseline assessments have an overall response as NE 
x 
CR, PR, or SD too early 
  
7.3.2 Time to Response (TTR) 
TTR (months) is defined as the time from the date of the first dose of study treatment to the date of the 
first response (CR or PR), whichever occurs first, in patients with a confirmed CR or PR, i.e., (date of 
assessment of first CR or PR – first dose date + 1)/30.4375. 
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7.3.3 Duration of Response (DOR) 
DOR (months) is defined as the time from the date of first response (CR or PR) to the date of progression 
of disease or death of any cause, whichever occurs first, in patients with a confirmed CR or PR, i.e., (date 
progression of disease or death – date of first CR or PR + 1)/30.4375.  
The censoring rules for DOR is identical to it for PFS as specified in Table 1.  
7.3.4 Progression-free Survival (PFS) 
PFS (months) is defined as the time from the first dose of the study drug to the first documented disease 
progression (PD) or death, whichever comes first. If a patient has not progressed or dies at the time of 
interim or final analysis (up to the date of data cutoff), PFS will be censored on the date of the last tumor 
assessment (up to the data cutoff). The censoring rules and censoring hierarchy for PFS is specified in 
Table 1. 
The PFS time will always be derived based on the tumor scan dates, not the assessment dates or visit 
dates. 
 
 
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Table 1 PFS Censoring Rules 
Hierarchy 
Censoring 
Situation 
Date of Event or 
Censor 
Event / 
Censor 
1 
No baseline radiological tumor assessment 
(confirmed measurable disease per RECIST v1.1) 
available 
Treatment start date 
Censor 
5 
No post baseline tumor assessment available and 
no death reported within 2 scan intervals following 
treatment start date 
Treatment start date 
Censor 
  
No post baseline tumor assessment available 
but death reported within 2 scan intervals following 
treatment start date 
Date of death 
Event 
6 
No tumor progression and no death reported within 
2 scan intervals following last adequate tumor 
assessment 
Date of last adequate 
assessment 
Censor 
  
No tumor progression but death reported within 2 
scan intervals following last adequate tumor 
assessment  
Date of death 
Event 
  
Tumor progression documented within 2 scan 
intervals following previous adequate tumor 
assessment 
Date of progression 
Event 
3 
Tumor progression documented after 2 scan 
intervals following previous adequate tumor 
assessment 
Date of previous 
adequate assessment 
Censor 
2 
New anticancer treatment started and no tumor 
progression 
Date of previous 
adequate assessment 
prior to new therapy  
Censor 
4 
No tumor progression and patient lost to follow-up 
or withdrawal of consent 
Date of last adequate 
assessment 
Censor 
Notes: Adequate tumor assessment refers to a baseline assessment or a post-baseline assessment with an overall response of CR, 
PR, SD, non-CR/non-PD, or PD. 
If target, non-target, and new lesion assessments have different dates within a visit, then the earliest of those dates will be 
considered as the date of the tumor assessment if the assessment for that visit is PD; otherwise, the latest date will be used. 
The 2 scan intervals are defined as below: 
The 2 scan interval from following treatment start date is 119 days (= 16 weeks + 7 days) 
If the previous adequate tumor scan (prior to PD) was prior to 365 days, the 2 scan interval is defined 
as 126 days (= 16 weeks + 14 days) 
If the previous adequate tumor scan (prior to PD) was on or after 365 days but prior to 469 days (= 68 
weeks -7 days), the 2 scan interval is 154 days (= 20 weeks + 14 days)  
If the previous tumor scan (prior to PD) was after 469 days, the 2 scan interval is 182 days (= 24 weeks 
+ 14 days) 
7.3.5 Overall Survival (OS) 
OS (months) is defined as the time from first dose date until death from any cause, i.e., (date of death – 
date of first dose date + 1)/30.4375. Patients who are still alive at the time of the final analysis data cutoff, 
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or who have become lost to follow-up will be censored at their last known to be alive date on or before the 
date of data cutoff. Last known alive dates will come from the Survival Status CRFs. 
7.4 Clinical Laboratory Parameters 
Clinical laboratory data including hematology and serum chemistry parameters will be entered into the 
electronic data capture (EDC) system and converted to International System (SI) units for analysis. 
Normal ranges will be merged in during dataset programming.  
8 Data Handling 
8.1 Imputation of Missing Data 
8.1.1 AE and Concomitant Medication Start and Stop Dates 
Start Date: If only ‘day’ is missing, and the month and year are not the same as the month and year of the 
first dose, then day will be imputed with ‘01’. Otherwise, if the month and year are the same as first dose 
date, first dose date will be used. If ‘day’ and ‘month’ are missing, and ‘year’ is not missing, then month and 
day will be imputed with month and day of first dose date (assuming same ‘year’). If year is not the same 
as first dose date, then Jan 1 will be imputed for the year provided. If the start date is completely missing, 
then the first dose date will be used. If the stop date is complete and the imputed start date is after the stop 
date, then the imputed start date will be set to the stop date. The original, non-imputed, dates will be retained 
in the clinical trial database and will be included in patient listings. 
 
Stop Date: If only ‘day’ is missing, day will be imputed with last day of the month. If ‘day’ and ‘month’ are 
missing, and ‘year’ is not missing, then month will be imputed with ‘12’ and day will be imputed with ‘31’ (or 
date of study discontinuation/completion if earlier than 12-31 and year is the same as the year of 
discontinuation). If the stop date is completely missing, it will be set to the date of study 
discontinuation/completion. A stop date will not be applied to ongoing AEs. If the imputed stop date is 
greater than last the contact date, then the imputed stop date will be set to last contact date. The original, 
non-imputed, dates will be retained in the clinical trial database and will be included in patient listings. 
8.1.2 Missing normal ranges for laboratory parameters 
No imputation will be applied to missing normal ranges.  
9 Statistical Methods 
All statistical analyses will be performed using SAS® Version 9.4 or higher, unless otherwise indicated. 
Categorical variables will be summarized using counts and percentages. Percentages will be rounded to 
one decimal place except 100% will be displayed without any decimal places and percentages will not be 
displayed for zero counts.  
Continuous variables will be summarized using the number of observations (n), mean, standard deviation, 
median, minimum, 25th and 75th percentiles, and maximum. The mean will be presented to one more and 
the standard deviation to 2 more decimal places than the precision of the original variable, while the 
quantiles will be presented at the same precision as the original variable. 
All tables will be accompanied by corresponding listings. 
9.1 Analysis Sets 
Enrolled subjects are those subjects who have signed informed consent and met inclusion and exclusion 
criteria for either AIM-HN or SEQ-HN. 
Subjects enrolled in AIM-HN fall under one of two analysis populations of interest: 
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High VAF = VAF>= 20% at screening 
All VAF = Low VAF and High VAF or all subjects 
9.1.1 Modified Intent-to-Treat (mITT) Analysis Set 
The mITT analysis set consists of all subjects in the AIM-HN who received at least one dose of tipifarnib.  
The analysis set will be used for all the efficacy analyses.  
9.1.2 Per Protocol Analysis Set (PPS) 
The PPS consists of all subjects in the AIM-HN who received at least one dose of tipifarnib, have confirmed 
measurable disease at baseline per RECIST v1.1 by IRF, have at least one post baseline efficacy 
assessment, and do not have any major protocol deviation that will impact the study outcome.  
9.1.3 Safety Analysis Set (SAS) 
The SAS consists of all subjects in the AIM-HN who received at least one dose of tipifarnib.  
The analysis set will be used for the analyses of safety. 
9.2 Subject Disposition 
The count and percentage of subjects pre-screened, screened, enrolled and treated in the AIM-HN of the 
study will be presented, along with the count and percentage of subjects with high VAF and subjects 
included in each analysis set defined in Section 9.1. The count of subjects who discontinue the study along 
with a breakdown of the corresponding reasons for discontinuation will also be summarized for subjects 
enrolled in AIM-HN and subjects enrolled in SEQ-HN. A similar summary will be presented for subjects 
discontinuing study treatment in the AIM-HN safety analysis set. 
9.3 Important Protocol Deviations 
Protocol deviations will be identified, including but not limited to, subjects that were enrolled even though 
they did not meet all eligibility criteria, subjects who took concomitant medications specifically prohibited by 
the protocol, and subjects who received the wrong study drug or incorrect dose. The reason for each 
protocol deviation will also be identified. 
Per PRA processes, important protocol deviations data will be entered into our Clinical Trials Management 
System (CTMS). The study team and the sponsor will conduct on-going reviews of the deviation data from 
CTMS and the resulting set of per-protocol subjects throughout the study, adjusting the deviation criteria 
as appropriate. The PPS must be finalized at the post-freeze data review meeting (or earlier), prior to 
database lock. 
Important protocol deviations for mITT in the AIM-HN and all enrolled subjects in the SEQ-HN will be 
summarized by deviation category. All the protocol deviations, including the protocol deviations related to 
COVID-19 effect on study assessments, will be listed. Data listings will present protocol deviations by 
subject. 
9.4 Extent of Study Drug Exposure 
Exposure to study drug will be summarized in the AIM-HN safety analysis set. Descriptive statistics will be 
provided for duration of exposure, the total number of cycles initiated, actual cumulative dose administered, 
and Relative Dose Intensity. 
The count and percentage of subjects with at least 1 dose interruption and at least 1 dose decreased per 
protocol will be presented along with a summary of the reasons for dose interruptions and dose decrease.  
A listing of tipifarnib exposure will also be created.  
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9.5 Prior and Concomitant Medications 
Using the AIM-HN safety analysis set, the count and percentage of subjects using at least one medication 
along with the count and percentage of subjects using at least one medication for each PT.  
All medications will also be listed.  In the listing, medications will be classified as prior or concomitant. 
9.6 Demographic and Baseline Disease Characteristics 
Demographics including age (years) at treatment start date, sex, race, ethnicity, height (cm) and weight 
(kg) will be summarized in the AIM-HN mITT analysis set, and AIM-HN PPS. 
The following baseline characteristics will be summarized in AIM-HN mITT analysis set:  
HRAS mutation type 
 
Months from diagnosis of metastatic disease to first dose of tipifarnib, i.e., (first dose date – date 
metastatic disease first diagnosed + 1)/30.4375. 
 
Disease history at primary diagnosis  
Anatomical disease site of primary tumor 
Disease stage 
Tumor, node, and metastasis stage 
Histologic grade  
Anti-cancer systemic treatment for HNSCC 
Prior lines of therapy 
Setting, type, anatomical site, performance status, best response, and treatment outcome 
response criteria for first line of therapy 
Best response, and treatment outcome response criteria for last line of therapy prior to screening 
Anti-cancer surgery for HNSCC 
Radiological treatment for HNSCC 
Anatomical Site 
Treatment Intent 
Radiation Therapy Type 
HPV status (positive/negative) 
Substance abuse (Tobacco/Alcohol/Betel nut)  
9.7 Efficacy Analyses 
The efficacy analyses will focus on anti-tumor response (primary and secondary endpoints) after treatment 
with tipifarnib in the mITT analysis set of the AIM-HN. The sensitivity efficacy analyses will be performed in 
the per-protocol analysis set.  
9.7.1 Primary Endpoint  
The count and proportion with confirmed OR by IRF for subjects with high VAF will be presented in the 
mITT analysis set as primary analysis. The estimate of the ORR will be calculated using the maximum 
likelihood estimator for the proportion of tipifarnib treated subjects whose Best Overall Response is 
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confirmed CR or confirmed PR as assessed by IRF. The exact (Clopper-Pearson) 95% confidence interval 
(CI) for the proportion will also be presented.
The above analysis will be repeated in the per-protocol analysis set and all VAF population. The ORR 
based on investigator’s assessment will also be summarized. 
9.7.2 Key Secondary Endpoints and Other Secondary Endpoints for AIM-HN 
DOR, PFS, and OS will be summarized using the Kaplan-Meier (KM) (Kaplan and Meier 1958) estimates 
in the AIM-HN mITT analysis set, which may also be summarized in the PPS. The 50% quartile (median) 
and 2-sided 95% confidence interval time to event endpoint will be calculated by the Brookmeyer and 
Crowley method (Brookmeyer R and Crowley JJ, 1982) with log-log transformation. The 6-month and 9-
month progression-free survival rate, and 12-month survival rate will be estimated as well. A KM plot for 
each endpoint will be presented as applicable.  
TTR will be summarized descriptively by summary statistics. 
Response related efficacy endpoints, including TTR, by independent review facility and investigator 
assessment will also be summarized. 
These analyses will be repeated for high VAF subjects and all VAF subjects. 
9.7.2.1 Quality of Life (QoL) 
The analysis window for QoL analysis for each scheduled visit are listed in Table . 
Table 2: QoL Analysis Window 
Scheduled Visit 
Target Day 
Analysis Window 
Baseline 
Day 1 
From Day -28 to Day 1 
Cycle 2 Day 1 
Day 29 
From Day 2 to Day 42 
Cycle n Day 1 
Day 28 x (n-1) + 1 
From Day 28n-41 to min {Day 28n-14, last dose date-1} 
End of Treatment 
Day 30 after the last dose 
>= last dose date 
Note: Study days are relative to Cycle 1 Day 1. 
If a subject has more than one questionnaire collected in an analysis window, the one closest to the target 
day will be selected; if multiple questionnaires have the same distance in days from the target date, the 
later one will be selected; if the multiple questionnaires are collected on the same date, the worst one will 
be selected.  
EORTC QLQ-H&N35 
The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC 
QLQ)-H&N35 is a 35-item questionnaire module designed to assess the QoL of head and neck (H&N) 
cancer patients. It consists of 7 multiple-item scales (Pain, Swallowing, Senses, Speech, Social eating, 
Social contact, and Sexuality) and 11 single items. Scoring of EORTC QLQ-H&N35 will be computed 
following the procedures recommended in the Scoring Manual provided by EORTC Data Center (Scott, N., 
Fayers, P., Aaronson, N., Bottomley, A., de Graeff, A., Groenvold, M., Gundy, C., Koller, M., Petersen, M.A. 
and Sprangers, M.A.G., 2008. EORTC QLQ-C30. Reference values. Brussels: EORTC. 2008). For each 
multiple-item scale or single item, a linear transformation will be used to standardize the raw score to range 
between 0 and 100. The detailed scoring procedures are specified in Appendix 2 Scoring Approach for 
EORTC QLQ-H&N35. For all items and scales, high scores indicate more problems.  
Actual and change from baseline score in Pain, Swallowing, Speech Problems, and Senses Problems 
scales of EORTC QLQ-H&N35 will be summarized at each applicable post-baseline visits. The individual 
multiple-item scale or single item score at each visit will be listed.  
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EQ-5D-5L 
EQ-5D-5L is a health status measure questionnaire composed of 5 health questions (descriptive system) 
and a visual analog scale (EQ-VAS). The descriptive system covers 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression) with 5 levels of answer in each dimension (no problems, 
slight problems, moderate problems, severe problems and unable to perform/extreme problems). The EQ-
VAS collects the self-rating health status from 0 (the worst imaginable health) to 100 (the best imaginable 
health).  
Actual and change from baseline score of EQ-VAS will be summarized at each post-baseline visits. EQ-
5D-5L results in each dimension and EQ-VAS at each visit will be listed. 
A shift table from baseline to the worst post-baseline record for each dimension will be presented. 
Percentages for shift tables will be based on the number of subjects with a value at both baseline and at 
least 1 post-baseline visit.  
9.8 Safety Analyses 
Safety analyses will be performed using the safety analysis set, defined as all subjects who receive at least 
one dose of study drug (tipifarnib).  
9.8.1 Adverse Events 
All summaries of AEs will be based on treatment-emergent AEs (TEAEs) unless otherwise indicated. 
TEAE is defined as AE that starts on or after the first dose of the study drug and within 30 days of the last 
administration of the study drug. 
Counting of AEs will be by subject, not by event; subjects will be counted only once within each SOC or 
PT.  
The count and percentage of subjects who report TEAEs will be summarized for AIM-HN safety analysis 
set  as follows: 
TEAEs by SOC and PT 
TEAEs by PT (Any Grade and Grade >= 3)  
TEAEs by SOC, PT, and maximum NCI-CTCAE grade 
Serious TEAEs by SOC and PT 
TEAEs related to tipifarnib by PT (Any Grade and Grade >= 3)  
TEAEs related to tipifarnib by SOC, PT, and maximum NCI-CTCAE grade 
Serious TEAEs related to tipifarnib by SOC and PT 
TEAEs leading to discontinuation of tipifarnib by SOC and PT 
TEAEs with an outcome of death by SOC and PT 
Non-Serious TEAE experienced by >= 5% of subjects by PT 
For grade summaries, subjects with multiple events within a particular SOC or PT will be counted under the 
category of their most severe event within that SOC or PT. Events will be sorted by descending frequency 
by SOC, and by PT within SOC for summaries.  
AEs will be listed for individual subjects, including information regarding onset, duration, severity, 
seriousness, outcome and relationship to study drug. 
AEs will not be summarized by Cycle, except for Overall Summary and AEs by SOC and PT for Cycle 1. 
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9.8.2 Deaths 
Death data from the survival status CRF will be summarized in a table and presented in a listing. Causes 
of death will be included. 
9.8.3 Clinical Laboratory Parameters 
Clinical laboratory assessments (hematology and clinical serum chemistry) will be summarized 
descriptively based on observed values at baseline and each post-baseline scheduled visit and change 
from baseline. All laboratory results (hematology, clinical serum chemistry, urinalysis, and coagulation) will 
be reflected in listings. 
Shift tables for some hematology and chemistry tests will be provided for the maximum post-baseline grade 
including data from any scheduled and unscheduled visits prior to or on end of treatment visit. These tables 
will compare the NCI-CTCAE grade for the baseline value relative to each post-baseline time point value 
for all non-missing post-baseline data. Subjects meeting shift criteria for high values as well as low values 
during the course of the trial will be summarized for both criteria. 
9.8.4 Vital Signs 
Body temperature will be summarized in °C. If body temperature is recorded as °F, then temperature will 
be converted to °C using: 
Temperature (°C) = 5/9 (Temperature [°F]-32).  
Summaries of post baseline abnormal vital signs, including systolic blood pressure, diastolic blood 
pressure, pulse rate, weight change, and temperature will be presented. Abnormal ranges for vital signs 
parameters are given in Table 3. Post baseline includes non-missing records from both scheduled and 
unscheduled visits after the first dose of study drug until 30 days following the last dose of study 
treatment. 
Table 3 Vital Sign Abnormal Values 
Parameter 
Abnormal (Low) 
Abnormal (High) 
Systolic Blood 
Pressure 
Absolute value ≤ 90 mmHg for post 
baseline, or  
a decrease from baseline ≥20 mmHg for 
change from baseline 
Absolute value ≥ 180 mmHg for post 
baseline, or  
an increase from baseline ≥20 mmHg 
for change from baseline 
Diastolic Blood 
Pressure 
Absolute value ≤ 50 mmHg for post 
baseline, or   
a decrease from baseline ≥15 mmHg for 
change from baseline 
Absolute value ≥ 105 mmHg for post 
baseline, or  
an increase from baseline ≥ 15 mmHg 
for change from baseline 
Pulse 
Absolute value ≤ 50 bpm for post 
baseline, or   
a decrease from baseline ≥ 15 bpm for 
change from baseline 
Absolute value ≥ 120 bpm for post 
baseline, or   
an increase from baseline ≥ 15 bpm for 
change from baseline 
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Weight Change 
Weight loss from baseline ≥ 20%  
 
Temperature 
≤ 35°C post baseline only 
≥ 40°C post baseline only 
 
A listing of vital sign results will also be presented in the Safety Analysis Set.  
  
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10 References 
Kaplan, EL and Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958; 
53:457-481. 
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. Biometrics. 38:29-41, 
1982. 
Rosenbaum, P. R., & Rubin, D. B. (1983). The central role of the propensity score in observational 
studies for causal effects. Biometrika, 70(1), 41-55. 
Scott, N., Fayers, P., Aaronson, N., Bottomley, A., de Graeff, A., Groenvold, M., Gundy, C., Koller, M., 
Petersen, M.A. and Sprangers, M.A.G., 2008. EORTC QLQ-C30. Reference values. Brussels: EORTC. 
 
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