Conditions: Relapsed or Refractory Peripheral T-Cell Lymphoma
Keywords: PTCL-NOS Lymphoma AITL Nodal T-follicular helper phenotype ALCL Hepatosplenic T-cell lymphoma EATL Extranodal (NK) T-cell lymphoma Wild Type CXCL12 3' UTR
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 65
Healthy volunteers: no

Brief summary:
Phase II study designed to investigate antitumor activity in terms of objective response rate (ORR) of tipifarnib subjects with advanced Peripheral T-Cell Lymphoma (PTCL). Tipifarnib will be administered orally until disease progression.

Detailed description:
This Phase II study will investigate the antitumor activity in terms of ORR of tipifarnib in subjects with relapsed or refractory PTCL. The first 18 subjects may be of the following PTCL sub-types: PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-positive and negative anaplastic large cell lymphoma (ALCL), hepatosplenic T-cell lymphoma, enteropathy-associate T-cell lymphoma (EATL), extranodal natural killer (NK) T-cell lymphoma, nasal type and subcutaneous panniculitis-like T-cell lymphoma. The AITL expansion cohort (N=32) will enroll only subjects with AITL. An additional cohort of patients (N=12) expressing the wild type CXCL12 3' UTR will be enrolled in order to explore the benefits of tipifarnib treatment observed in patients having an absence of this gene variation or single nucleotide variation (SNV).

Tumor response assessments will be conducted according to Lugano Classification and/or mSWAT criteria.

Tumor assessments will be performed approximately every 8 weeks (cycles 2-6) and at least once approximately every 12 weeks thereafter (Cycles 9, 12, 15, etc.), and will continue until disease progression. Subjects experiencing a complete response may be considered for bone marrow transplantation. Upon disease progression, all subjects will be followed for survival and the use of subsequent therapy. All subjects will be followed for safety during treatment and up to approximately 30 days after treatment discontinuation or until before the initiation of another anti-cancer therapy. Additional follow up may be implemented until the subject recovers from any emergent treatment related toxicity or the adverse event is considered irreversible by the investigator.

Arms:
arm 1: tipifarnib, oral

Interventions: intervention 1: Tipifarnib
Intervention descriptions: intervention 1: oral

Protocol document:
Prot_000.pdf: 
Protocol Number: KO-TIP-002 
 
Official Title: An Open Label Phase II Study of Tipifarnib in Subjects with Relapsed or Refractory 
Peripheral T-Cell Lymphoma 
 
NCT Number: NCT02464228 
 
Document Date: 12 July 2019 


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CLINICAL TRIAL PROTOCOL 
 
An Open Label Phase II Study of Tipifarnib in Subjects with Relapsed or 
Refractory Peripheral T-Cell Lymphoma 
 
CTP ID Number: KO-TIP-002 
Investigational Product: Tipifarnib (R115777; Zarnestra™) 
US IND Number: 52,302 
EudraCT Number: 2016-001396-69 
Indication: Peripheral T-Cell Lymphoma 
Development Phase: Phase II 
 
Sponsor: Kura Oncology, Inc. 
303 Science Park Drive, Suite 220 
San Diego, CA 92121 (USA) 
Phone: +1 858.500.8800  
 
Medical Responsible Officer: 
  
Version and Date: Protocol Amendment 7, 12 July 2019 
 
CONFIDENTIAL 
This is a Kura Oncology, Inc document that contains confidential information. It is intended solely for the 
recipient clinical Investigator(s) and must not be disclosed to any other party. This material may be used only 
for evaluating or conducting clinical investigations; any other proposed use requires written consent from Kura 
Oncology, Inc. 
 




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2 
SYNOPSIS 
 
TITLE: An Open Label Phase II Study of Tipifarnib in Subjects with Relapsed or Refractory 
Peripheral T-Cell Lymphoma 
SPONSOR: Kura Oncology, Inc 
PROTOCOL NUMBER: KO-TIP-002 
STUDY SITES: Multiple centers  
PHASE OF DEVELOPMENT: Phase II 
STUDY PERIOD: This trial was planned to initiate enrollment in the third quarter of 2015. This 
amendment was instituted in July, 2019.  It is estimated that an additional 12 months may be 
required to complete all its study objectives. 
OBJECTIVES: 
Primary Objective: To determine the antitumor activity in terms of objective response rate 
(ORR) of tipifarnib in subjects with relapsed or refractory peripheral T-cell lymphoma (PTCL). 
Secondary Objective 1:  To determine the antitumor activity in terms of progression free 
survival (PFS) and duration of response (DOR) of tipifarnib in subjects with relapsed or 
refractory PTCL. 
Secondary Objective 2:  Safety and tolerability of tipifarnib in subjects with relapsed or 
refractory PTCL. 
Exploratory Objective: To explore the feasibility of collecting tissue biopsies, buccal swabs 
and blood samples and analysing these samples for the detection of biomarkers potentially 
related to tipifarnib activity.  The biomarker analyses may include oncogene panel sequencing 
from tumor tissue samples, immune cytokine profiling from serum samples and Killer cell 
Immunoglobulin-like Receptor (KIR) genotyping from blood samples. 
 
 
STUDY DESIGN: 
This Phase II study will investigate the antitumor activity in terms of ORR of tipifarnib in 
subjects with relapsed or refractory PTCL. 
Eligible subjects will receive tipifarnib administered at a starting dose of 300 mg, orally with 
food, twice a day (bid) on Days 1-21 in 28 day cycles (i.e. 3 weeks on / 1 week off). Stepwise 
100 mg dose reductions to control treatment-related, treatment-emergent toxicities are also 
allowed.  In the absence of unmanageable toxicities, subjects may continue to receive tipifarnib 
treatment for up to 12 months in the absence of disease progression and unmanageable toxicity. 
Treatment may continue beyond 12 months upon agreement of the Investigator and Sponsor. 


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Tumor assessments will be performed at screening, at the Day 22 visit (± 5 days) performed 
during Cycles 2, 4, 6 and once every approximately 12 weeks (cycles 9, 12, 15, etc.) thereafter, 
until disease progression. Additional tumor assessments may be conducted if deemed necessary 
by the Investigator. Subjects who discontinue tipifarnib treatment for reasons other than disease 
progression must continue tumor assessments until disease progression, withdrawal of subject’s 
consent to study procedures or initiation of another anticancer therapy. 
Determination of objective tumor response will be performed based on the Lugano Classification 
(Cheson 2014, Appendix II: The Lugano Classification) and/or measurable cutaneous disease 
according to the modified Severity Weighted Assessment Tool (mSWAT, Olsen 2011, Appendix 
III: Modified Severity Weighted Assessment Tool).  Subjects who have experienced a complete 
response may be considered for transplantation. Information on this intervention and other 
subsequent anti-cancer therapies will be collected for these subjects. 
Upon disease progression, subjects will be followed approximately every 12 weeks for survival 
until either death or 12 months after accrual of the last study subject, whichever occurs first. 
Information on subsequent anticancer therapy will be collected. 
All subjects will be followed-up for safety during treatment and for approximately 30 additional 
days after treatment discontinuation (or until immediately before the administration of another 
anticancer treatment).  Additional safety follow up may be conducted if unresolved toxicity is 
present at the End of Treatment visit. 
NUMBER OF SUBJECTS PLANNED: Up to 70 study subjects. 
SUBJECT SELECTION:  
Inclusion Criteria 
For inclusion of a subject in the study, all of the following inclusion criteria must be fulfilled: 
1. Subject is at least 18 years of age. 
2. Subject has a diagnosis of PTCL according to the most recent edition of the World Health 
Organization (WHO) Classification of Tumors of Hematopoietic or Lymphoid Tissues as 
follows: 
a. Anaplastic large cell lymphoma (ALCL), ALK positive 
b. ALCL, ALK negative 
c. Angioimmunoblastic T-cell lymphoma (AITL) 
d. Enteropathy-associated T-cell lymphoma 
e. Extranodal natural killer (NK) T-cell lymphoma, nasal type 
f. Hepatosplenic T-cell lymphoma 


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g. Peripheral T-cell lymphoma, no otherwise specified (NOS) 
h. Subcutaneous panniculitis-like T-cell lymphoma 
For enrollment into the AITL expansion cohort, subjects must have the diagnosis of AITL, nodal 
PTCL with T-follicular helper phenotype or follicular PTCL. 
For enrollment into the CXCL12+ PTCL expansion cohort, subjects must have the diagnosis of 
PTCL (a – h subtypes listed above, except AITL), consent to provide buccal swabs for CXCL12 
SNP testing, and be found to be CXCL12+ based on testing by a Sponsor approved 
methodology. Once (if) the AITL cohort has completed accrual, subjects with AITL histology 
and CXCL12+ status may be enrolled in the CXCL12+ PTCL expansion cohort. 
3. Subject has relapsed or are refractory to at least 1 prior systemic cytotoxic therapy. Subjects 
must have received conventional therapy as a prior therapy.  
4. Subject has consented to provide at least 6 unstained tumor slides (10 preferred) or an FFPE 
block for biomarker testing. Tumor tissue may be obtained from prior archival diagnostic 
biopsies. If the site is unable to confirm during screening that sufficient archival biopsy is 
available, the subject must consent to a pretreatment biopsy for inclusion in this study.  
5. Subject has measurable disease as determined by the Lugano Classification and/or mSWAT. 
6. At least 2 weeks since the last systemic therapy regimen prior to enrollment. Subjects must 
have recovered to NCI CTCAE v. 4.03 < Grade 2 from all acute toxicities (excluding Grade 
2 toxicities that are not considered a safety risk by the Sponsor and Investigator) or toxicity 
must be deemed irreversible by the Investigator. 
7. At least 2 weeks since last radiotherapy if radiation was localized to the only site of 
measurable disease, unless there is documentation of disease progression of the irradiated 
site. Subjects must have recovered from all acute toxicities from radiotherapy.  
8. ECOG performance status of 0-2 (Appendix 1). 
9. Acceptable liver function:  
a. Bilirubin ≤ 1.5 times upper limit of normal (x ULN); does not apply to subjects with 
Gilbert’s syndrome diagnosed according to institutional guidelines. 
b. AST (SGOT) and ALT (SGPT) ≤ 3 x ULN; if liver lymphoma is present, then ≤ 5 x ULN 
is allowed. 
10. Acceptable renal function with serum creatinine ≤ 1.5 x ULN or a calculated creatinine 
clearance ≥ 60 mL/min using the Cockcroft-Gault or MDRD formulas. 
11. Acceptable hematologic status: 
a. ANC ≥ 1000 cells/μL. 
b. Platelet count ≥ 50,000/μL. 


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c. Hemoglobin ≥ 8.0 g/dL. 
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 for 2 weeks prior to screening, 
during, and at least 4 weeks after last dose of trial medication. Female subjects must have 
a negative serum or urine pregnancy test within 72 hours prior to start of trial medication. 
c. Not breast feeding at any time during the study. 
13. Written and voluntary informed consent understood, signed and dated. 
Exclusion Criteria 
1. Diagnosis of any of the following: 
a. Precursor T-cell lymphoma or leukemia 
b. Adult T-cell lymphoma/leukemia (ATLL) 
c. T-cell prolymphocytic leukemia 
d. T-cell large granular lymphocytic leukemia 
e. Primary cutaneous type anaplastic large cell lymphoma 
f. Mycosis fungoide/Sezary syndrome 
2. Ongoing treatment with an anticancer agent not contemplated in this protocol. 
3. Prior treatment (at least 1 full treatment cycle) with an FTase inhibitor. 
4. Any history of clinically relevant coronary artery disease or myocardial infarction within the 
last 3 years, New York Heart Association (NYHA) grade III or greater congestive heart 
failure, cerebro-vascular attack within the prior year, or current serious cardiac arrhythmia 
requiring medication except atrial fibrillation. 
5. Known central nervous system lymphoma. 
6. Stem cell transplant less than 3 months prior to enrollment. 
7. Non-tolerable > Grade 2 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 


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symptoms that the subject is not able to endure for the conduct of instrumental activities of 
daily life or that persists ≥ 7 days. 
8. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without 
complete recovery. 
9. Other active malignancy requiring therapy such as radiation, chemotherapy, or 
immunotherapy. 
10. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. Known 
infection with HIV, 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. 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.  
13. The subject has legal incapacity or limited legal capacity. 
14. Dementia or significantly altered mental status that would limit the understanding or 
rendering of informed consent and compliance with the requirements of this protocol. 
Unwillingness or inability to comply with the study protocol for any reason. 
STATISTICAL METHODS: 
As part of Amendment 6, up to 42 evaluable subjects could be enrolled (received tipifarnib), 
with the first 18 subjects designed to test the null hypothesis of ORR less than 10% vs alternative 
hypothesis is at least 30%.   
Up to 18 subjects may be initially enrolled. A two-stage design will be employed. Eleven study 
subjects will be enrolled; if 2-4 objective responses are observed, 7 additional study subjects will 
be enrolled. At the completion of the study, treatment will be considered of further interest if the 
true ORR is higher than 10%. To determine the total trial size, a response of interest of 30% is 
assumed. This design provides 80% power to detect a difference between 10% and 30% ORR at 
one-sided significance level of 0.087. Using this design, the probability of terminating the study 
at the end of stage 1 if the true ORR is 10% is 0.697 while the probability of terminating the 
study at the end of stage 1 if the true ORR is 30% is 0.113. 
Based on the observed antitumor activity during stage 1 and stage 2 of the study (2 subjects 
enrolled with AITL and both subjects achieved a partial response), an AITL cohort will be 
enrolled (N = 12) according to Amendment 4 to the protocol.  With this sample size, if 4 or more 
responses are observed, the probability that the true response rate in AITL subjects is at least 
30% is 82.6%.   


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Based on the observed antitumor activity during stage 1 and stage 2 of the study in which 
subjects who were found to have high levels of CXCL12 gene expression by retrospective 
analysis had a longer PFS compared to subjects with low expression, a CXCL12+ cohort will be 
enrolled (N = 12) according to Amendment 6 to the protocol.  With this sample size, if 2 or more 
responses are observed, the probability that the true response rate in CXCL12+ subjects is 10% 
or higher is at least 89%. 
Upon the observation of 5 confirmed responses in the AITL cohort, and 5 confirmed responses in 
the CXCL12+ cohort, including 2 of them in subjects with tumors of AITL histology, the trial 
was amended to include up to 20 additional subjects with AITL and related T follicular helper 
cell tumors in the AITL cohort in order to further characterize the safety and tolerability of 
tipifarnib in this patient population. The choice of 20 additional subjects was empirical based on 
the relative rarity of the patient population and no statistical hypotheses will be tested in this 
extension. Including Amendment 7, up to 70 evaluable subjects in total may be enrolled.   
STUDY ASSESSMENTS: 
The evaluations to be performed during the study are summarized in Table 1. 
 
Table 1: Schedule of Activities 
Activity 
Screening 
Cycle (28 days)16 
End of 
Treatment 
Visit10 
Follow 
Up 
Visit19 
Follow 
Up 
Contact12 
 
D113 
D7  
(- 2 d)15 
D22 
(± 5 d) 
ICF, Inclusion/exclusion 
criteria evaluation 
X 
 
Medical History17 
X 
Tumor tissue and buccal swabs6 
X 
Concomitant meds and AE 
assessment1 
X (assessed at each study visit and as clinically needed) 
 
12-Lead ECG 
X3 
X2 
X2 
 
X 
ECOG performance status 
X3 
X 
X 
 
X 
Physical Exam11 
X3 
X 
X 
 
X 
Height 
X3 
 
 
 
 
Weight 
X3 
X 
X 
 
X 
Temperature 
X3 
X 
X 
 
X 
Hematology5 
X3 
X4 
X 
 
X 
Chemistry5 
X3 
X4 
X 
 
X 
Coagulation5 
X3 
 
 
 
X 
Pregnancy test 
X21 
X22 
X 
 
X 
Tipifarnib administration9 
  
X 
X 
X18 
 
Drug accountability   
 
X20 
 
 
X 
Tumor assessment8  
X 
 
 
X 
X 
X19 
 




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15. Visit is to occur during Day 5 to Day 7 of Cycle 1 only. 
16. The visit schedule should be maintained regardless of dose delays or additional assessments performed. 
17. Medical history should include demographics, prior cancer therapy, response and duration of response to last prior therapy. 
18. Tipifarnib administration should occur if the Day 22 visit coincides with a dosing day (e.g. visit occurs on Days 17 - 21 of the 
current cycle). 
19. Required only for subjects who terminated treatment for reasons other than disease progression.  Tumor assessments will 
continue to be performed after treatment discontinuation in approximately 8-12 week intervals until progression 
20. Site staff should conduct a drug accountability on the returned empty bottles and unused medications beginning at Cycle 2.  
21. Assessment is to be done within 72 hours prior to first administration of study drug on Day 1 of Cycle 1. 
22. Assessment is to begin on Day 1 of Cycle 2.  
 
 
 
 


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3 
TABLE OF CONTENTS 
1 
PROTOCOL APPROVAL PAGE ........................................................2 
2 
SYNOPSIS ...........................................................................................3 
3 
TABLE OF CONTENTS ...................................................................11 
4 
ABBREVIATIONS ............................................................................15 
5 
INTRODUCTION ..............................................................................17 
5.1 
Tipifarnib ............................................................................................17 
5.1.1 
Mechanism of Action .........................................................................17 
5.1.2 
Clinical Pharmacology ........................................................................17 
5.2 
Clinical Experience .............................................................................18 
5.3 
Rationale for the Study .......................................................................20 
6 
OBJECTIVES .....................................................................................21 
6.1 
Primary Objectives and Endpoints .....................................................21 
6.2 
Secondary Objectives and Endpoints .................................................21 
6.3 
Exploratory Objective and Endpoints .................................................21 
7 
SUBJECT SELECTION .....................................................................21 
7.1 
Inclusion Criteria ................................................................................21 
7.2 
Exclusion Criteria ...............................................................................23 
8 
TRIAL DESIGN .................................................................................24 
8.1 
Study Design .......................................................................................24 
8.2 
Subject Identification and Replacement of Subjects ..........................26 
8.3 
Assignment to Treatment Groups .......................................................27 
8.4 
Removal of Subjects from Treatment or Assessment .........................27 
8.5 
Premature Discontinuation of the Trial ..............................................28 
8.6 
Definition of End of Study .................................................................28 
9 
TREATMENTS ..................................................................................29 
9.1 
Investigational Product (IP) ................................................................29 
9.1.1 
Product Characteristics .......................................................................29 
9.1.2 
Storage and Labeling ..........................................................................29 
9.2 
Treatment Administration ...................................................................30 
9.3 
Treatment Assignment ........................................................................30 
9.4 
Dose Selection ....................................................................................30 


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9.6 
Treatment of Overdose .......................................................................36 
9.7 
Blinding ..............................................................................................36 
9.8 
Treatment Compliance ........................................................................36 
9.9 
Investigational Product Accountability ..............................................37 
9.10 
Return and Disposition of Clinical Supplies ......................................37 
9.11 
Prior and Concomitant Medications ...................................................37 
9.12 
Non-permitted Treatments ..................................................................38 
9.13 
Dietary or Other Protocol Restrictions ...............................................38 
9.14 
Medical Care of Subjects after End of Trial .......................................39 
9.15 
Potential Effects on Reproduction and Development .........................39 
10 
EFFICACY AND SAFETY VARIABLES ........................................39 
10.1 
Efficacy Variables ..............................................................................40 
10.2 
Assessment of Safety ..........................................................................40 
10.3 
Adverse Events ...................................................................................41 
10.4 
Abnormal Laboratory Findings and Other Abnormal 
Investigational Findings ......................................................................42 
10.5 
Serious Adverse Event ........................................................................42 
10.6 
Events that Do Not Meet the Definition of an SAE ...........................43 
10.7 
Events Not to Be Considered as AEs/SAEs .......................................43 
10.8 
Methods of Recording and Assessing Adverse Events ......................43 
10.9 
Adverse Event Reporting Period ........................................................44 
10.10 
Procedure for Reporting Serious Adverse Events ..............................44 
10.11 
Safety Reporting to Health Authorities, Institutional Review 
Boards and Investigators .....................................................................44 
10.12 
Monitoring of Subjects with Adverse Events .....................................45 
10.13 
Pregnancy and In Utero Drug Exposure .............................................45 
10.14 
Laboratory Assessments .....................................................................46 
10.14.1 
Blood Sample Collection for General Clinical Laboratory 
Assessments ........................................................................................46 
10.15 
Additional Variables ...........................................................................46 
11 
STUDY PROCEDURES ....................................................................46 
11.1 
Screening and Baseline Assessments .................................................47 


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11.2 
Day 1 of Cycle 1 .................................................................................48 
11.3 
Day 7 (-2 days; can be Days 5, 6 or 7) of Cycle 1 only ......................48 
11.4 
Day 1 (± 2 days) of Cycle 2 and Beyond ............................................49 
11.5 
Day 22 (± 5 days) of Cycles 2, 4 and 6 and Cycles 9, 12, 15, etc. .....49 
11.6 
End of Treatment Visit .......................................................................50 
11.7 
Post Treatment Follow up ...................................................................50 
11.7.1 
Follow Up after Disease Progression .................................................51 
12 
STATISTICAL METHODS ...............................................................51 
12.1 
Populations .........................................................................................51 
12.1.1 
Efficacy Analysis ................................................................................51 
12.1.2 
Safety Analysis ...................................................................................52 
12.2 
Endpoints ............................................................................................52 
12.2.1 
Efficacy ...............................................................................................52 
12.2.2 
Safety and Tolerability .......................................................................54 
 
 
12.4 
Sample Size Determination ................................................................55 
12.5 
Changes in the Conduct of the Study or Planned Analyses ................56 
13 
ETHICAL AND REGULATORY ASPECTS ...................................56 
13.1 
Responsibilities of the Investigator ....................................................56 
13.2 
Subject Information and Informed Consent .......................................57 
13.3 
Subject Identification and Privacy ......................................................58 
13.4 
Emergency Medical Support and Subject Card ..................................58 
13.5 
Clinical Trial Insurance and Compensation to Subjects .....................58 
13.6 
Institutional Review Board/Independent Ethnic Committee ..............59 
13.7 
Communication to Health Authorities ................................................59 
14 
TRIAL MANAGEMENT ...................................................................59 
14.1 
Case Report Form Management .........................................................59 
14.2 
Source Data and Subject Files ............................................................59 
14.3 
Investigator Site File and Archiving ...................................................61 
14.4 
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................61 
14.5 
Changes to the Clinical Trial Protocol ................................................61 
14.6 
Clinical Trial Report ...........................................................................62 


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14.7 
Publication ..........................................................................................62 
14.8 
References ...........................................................................................62 
 
Tables 
Table 1: Schedule of Activities ............................................................................................8 
  
 
 
 


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4 
ABBREVIATIONS 
AE  
 
Adverse Event 
AITL  
Angioimmunoblastic T-cell lymphoma  
AKT   
Serine/Threonine Kinase AKT 
ALCL  
Anaplastic large cell lymphoma  
ALT   
Alanine Aminotransferase 
AML  
Acute Myeloid Leukemia 
ANC   
Absolute Neutrophil Count 
AST   
Aspartate Aminotransferase 
ATLL  
Adult T-cell lymphoma/leukemia 
AUC   
Area Under the Curve 
bid 
 
Twice a day 
BUN   
Blood Urea Nitrogen 
Cmax   
Maximum Concentration 
Cmin   
Minimum Concentration 
CBC   
Complete Blood Count 
CEA   
Carcinoembryonic antigen 
CFR   
Code of Federal Regulations 
CRF   
Case Report Form 
CT  
 
Computer Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
CSR   
Clinical Study Report 
D or d  
Day 
EC  
 
Ethics Committee 
ECG   
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
ERK   
Extracellular Signal-regulated Kinase 
FDA   
Food and Drug Administration 
GCP   
Good Clinical Practice 
GI 
 
Gastrointestinal 
HgB  
Hemoglobin 
HIPAA  
Health Insurance Portability and Accountability Act 
HIV   
Human Immunodeficiency Virus 
IB  
 
Investigator’s Brochure 
ICF   
Informed Consent Form 
ICH   
International Conference on Harmonization 
IP 
 
Investigational Product 
INR 
 
International normalized ratio 
IRB   
Institutional Review Board 
IV  
 
Intravenous, Intravenously 
IWC  
International Workshop Criteria 
KIR  
Killer cell Immunoglobulin-like Receptor  
KRAS  
Kirsten Rat Sarcoma Virus Gene Homolog 
MDRD 
Modification of the Diet in Renal Disease 
MDS  
Myelodysplastic Syndromes 
MedDRA  
Medical Dictionary for Regulatory Activities Terminology 
MRI   
Magnetic Resonance Imaging 
MTD   
Maximum Tolerated Dose 
mSWAT 
Modified Severity Weighted Assessment Tool  
NK 
 
Natural killer 
NOAEL 
No observed adverse effect level 
NOEL  
No observed effect level 
PD  
 
Pharmacodynamic 
PE  
 
Physical Examination 
PI  
 
Principal Investigator 


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PK  
 
Pharmacokinetic 
PTCL  
Peripheral T-cell lymphoma 
SAE   
Serious Adverse Event 
SAP   
Statistical Analysis Plan 
SGOT  
Serum Glutamic Oxaloacetic Transaminase 
SGPT   
Serum Glutamic Pyruvic Transaminase 
SNP  
Single Nucleotide Polymorphism 
T1/2   
Half-life 
Tmax   
Time of Maximum Concentration 
ULN   
Upper Limit of Normal 
 


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5 
INTRODUCTION 
5.1 
Tipifarnib 
Beginning in 1997, tipifarnib was the first specific inhibitor of farnesyl transferase (FTase) to 
enter clinical studies and has been evaluated in over 70 clinical oncology and hematology 
studies.  
Brief information on tipifarnib is presented in this section; more extensive information is 
provided in the Investigator’s Brochure (Tipifarnib Investigator’s Brochure, Edition 13, March 
2017).  
5.1.1 
Mechanism of Action 
Tipifarnib is a potent and selective nonpeptide inhibitor of FTase. FTase is an enzyme that 
couples an isoprenyl group, the 15 carbon farnesyl moiety, to proteins for membrane localization 
including the Ras family of oncoproteins. The Ras family (KRAS, NRAS and HRAS) are among 
the most frequently mutated oncogenes in human cancer.  Although FTase inhibitors were 
originally developed to target Ras mutant cancers, tipifarnib and other FTase inhibitors failed to 
demonstrate significant clinical activity specifically in Ras mutant cancers, likely due to the 
observation that KRAS and NRAS undergo an alternate prenylation, geranylgeranylation, when 
FTase is inhibited (Baines 2011, Takashima 2013).  
The correlative biology of FTase inhibition by tipifarnib has been studied extensively. FTase 
inhibitors likely exert their cytotoxic effects by inhibition of multiple farnesylated proteins in the 
cell that are important for proliferation and survival such as members of the Rho, Rheb and 
CENP families.  In vitro, the concentration resulting in 50% of maximum inhibition values for 
isolated human FTase depends on the nature of its substrate, ranging from 0.86 nM for lamin B, 
a nuclear protein, to 7.9 nM for KRAS.  
Tipifarnib has shown promising signs of clinical activity in a variety of cancers including 
hematological cancers such as AML, MDS and certain lymphomas in multiple clinical trials 
(Martinelli 2008). Defining the patient subset or biomarker-defined subset where tipifarnib 
shows high level of efficacy remains as a key focus in the tipifarnib development program. 
5.1.2 
Clinical Pharmacology 
Tipifarnib is rapidly absorbed after oral administration with maximum plasma concentrations 
observed within 2 to 4 hours after dosing. The absolute bioavailability of tipifarnib under fed 
conditions is 29.3% in cancer patients and similar in healthy subjects. Concomitant intake of a 
high fat meal increases the extent of absorption by an average of 26.8% compared with 
administration under fasting conditions.  
Tipifarnib has an initial fast distribution half-life of about 36 minutes, followed by a dominant 
elimination half-life of about 2.4 hours, and a slower terminal half-life of about 19 hours. 


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Tipifarnib does not accumulate with multiple dosing. Linear pharmacokinetics are observed for 
tablets over the dose range of 100 mg through 600 mg. Metabolism and elimination are primarily 
hepatic. Steady state is reached within 2 to 3 days, with no evidence of drug accumulation or 
induction of drug metabolism over time. In adults, the apparent oral clearance of tipifarnib is not 
influenced by age, sex, body weight, body surface area or the presence of liver metastases. 
Tipifarnib inhibits FTase activity in human peripheral blood lymphocytes isolated from study 
subjects after doses as low as 100 mg bid.  Following a single 600 mg dose, both total and 
unbound plasma concentrations of tipifarnib over a 12-hour interval exceed those required to 
inhibit farnesylation.  Inhibition of FTase is reversible within 3 to 7 days upon discontinuation of 
tipifarnib administration.  
Increases in tipifarnib bioavailability by 18% to 34% have been consistently observed after its 
administration with food and therefore, tipifarnib has been administered with food throughout 
most of its clinical development program.  However, the magnitude of the food effect is small 
compared to the variability of pharmacokinetic parameters.  
Pharmacokinetic data suggest that H2 antagonists and proton pump inhibitors do not alter the 
exposure to tipifarnib to a clinically significant extent. Subjects may use proton pump inhibitors 
or H2 antagonists during the treatment portion of this study. However, subjects should be 
instructed to use antacids (magnesium or aluminum containing products) at least 2 hours before 
or after intake of oral study drug. 
Tipifarnib is a substrate for cytochrome P450 (CYP450) enzymes and glucuronosyltransferase. 
Inhibitors of CYP450 enzymes, including azole antifungals and omeprazole, did not reduce the 
clearance of tipifarnib in humans. However, antiepileptic drugs that are potent inducers of 
CYP450 enzymes (e.g. phenytoin, phenobarbital and carbamazepine) reduce plasma 
concentrations of tipifarnib and caution is warranted if concomitant administration of such agents 
is necessary.  Therefore, it is recommended that subjects use non-enzyme-inducing anti-
convulsants (e.g., gabapentin, topiramate, valproate) if necessary while taking tipifarnib.  
In addition, population pharmacokinetic analyses evaluated the influence of various concomitant 
medications on the pharmacokinetics of tipifarnib in clinical studies. Amphotericin, antiemetics, 
5HT3 antagonists (dolasetron, granisetron, ondansetron, and tropisetron), antifungal azoles 
(econazole, fluconazole, itraconazole, ketoconazole, and miconazole), benzodiazepines, 
ciprofloxacin, and corticosteroids appeared to have no discernible impact on the plasma 
concentrations of tipifarnib.  
5.2 
Clinical Experience 
Promising activity of tipifarnib in an unselected hematology population was reported in poor-risk 
acute leukemias, in which clinical responses occurred in 10 (29%) of the 34 evaluable patients, 
including 2 complete remissions (Karp 2001). Subjects were dosed at doses ranging from 100 
mg to 1200 mg twice daily for 21 days. In a second phase 2 trial in subjects with MDS, tipifarnib 


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showed activity in 3 of 27 subjects, resulting in two complete remissions and one partial 
remission (Kurzrock 2004). The drug was administered at a dose of 600 mg twice daily for 4 
weeks, followed by 2 weeks of rest. Subsequent phase 2 and 3 studies in acute myeloid leukemia 
and MDS failed to confirm a clinical benefit derived from tipifarnib treatment in these 
indications. 
A phase 2 study of tipifarnib was conducted in 93 adult subjects with relapsed or refractory 
lymphoma (Witzig 2011). Subjects received tipifarnib 300 mg twice daily on days 1-21 of each 
28-day cycle. The median number of prior therapies was 5 (range, 1-17). For the aggressive B-
cell, indolent B-cell, and T-cell and Hodgkin lymphoma (HL/T) groups, the response rates were 
17% (7/42), 7% (1/15), and 31% (11/36), respectively. Of the 19 responders, 7 were diffuse large 
B-cell non-Hodgkin lymphoma (NHL), 7 T-cell NHL, 1 follicular grade 2, and 4 HL. The 
median response duration for the 19 responders was 7.2 months (mean, 15.8 months; range, 1.8-
62). Safety findings included (grade 3, 4) 37% neutropenia, 31% thrombocytopenia, and 11% 
anemia. 
Of the 11 responses observed in the T-cell and Hodgkin lymphoma group, 6 were complete 
(CR). Two responses were observed in 4 subjects with mycosis fungoides and 4 in 8 subjects 
with PTCL, including 3 CRs. Median time to progression and DOR for this group were 
respectively 2.5 and 11.3 months. Median overall survival was 19.7 months. Eighty one percent 
of the subjects enrolled in the T-cell and Hodgkin lymphoma group had 4 or more prior therapies 
and 67% (24/36) a prior stem cell transplant (Witzig 2011). 
A preliminary assessment of the first 50 subjects enrolled into the current trial was recently 
published (Witzig 2019).  In the initial stages of the study, a retrospective assessment had 
suggested a high-degree of anti-tumor activity of tipifarnib in AITL and in PTCL-NOS subjects 
whose tumors expressed high levels of CXCL12 and carried reference CXCL12 3’UTR 
sequences of the CXCL12 gene (Witzig 2017).  The median progression-free survival (mPFS) in 
subjects with reference 3’UTR sequences (n = 8) was 134 days, vs. a median PFS of 50 days (n = 
7) in subjects whose tumors expressed the rs2839695 A>G variant of the gene, which resulted in 
low levels of CXCL12 expression.  Based on those findings, a cohort of PTCL NOS subjects 
with reference CXCL12 3’UTR and a cohort enrolling AITL subjects were added to the trial. 
These cohorts investigated prospectively whether selection for subjects with high CXCL12 
expressing tumors enriches for the activity of tipifarnib. Of 15 subjects enrolled into the PTCL 
expansion cohort, 12 were evaluable for efficacy at the time of the report.  In the per protocol set 
(PPS, or all subjects who received at least 1 dose of tipifarnib and had 1 post-baseline efficacy 
assessment) the objective response rate (ORR) was 41.7% (3 CR, 2 PR) and the clinical benefit 
rate (CBR) was 91.7% (3 CR, 2 PR and 6 SD).  Four subjects of AITL histology were enrolled in 
the cohort.  Of the 3 CRs observed, 2 were experienced by AITL subjects.   
 


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In the AITL expansion cohort, 16 patients were enrolled with 11 being evaluable for efficacy.  
The ORR in the PPS was 45.4% and the CBR was 72.7% (3 CR, 2 PR, 3 SD).  If all AITL 
subjects enrolled in the study are considered (expansion cohort subjects plus the AITL subjects 
in the early phases of the trial, n = 23, 17 evaluable), the ORR was 52.9% and the CBR was 
70.6% (5CR, 4PR, 3 SD). 
5.3 
Rationale for the Study 
Lymphomas derived from mature (post-thymic) T-cell clones with T-cell receptor gene 
rearrangement are referred to as PTCL. Multiple subtypes have been identified. Lymphomas that 
do not fit into a defined category are referred to as PTCL NOS and comprise the largest group 
with 34% of all subjects with PTCL. PTCL, with the exception of the ALK-positive ALCL, is 
associated with a poor prognosis with a 5-year overall survival of less than 32%. The majority of 
these subjects experience recurrence of their disease. Pralatrexate, romidepsin and belinostat 
have been recently approved in the US and other countries for the treatment of subjects with 
relapsed PTCL; however, responses with these agents are generally seen only in less than one 
third of the subjects and overall progression free survival is short lived. Consequently, additional 
treatment options are still needed for these subjects.  
Tipifarnib was well tolerated and has shown initial activity in a small cohort of subjects with 
PTCL (Witzig 2011). The present study is designed to provide further evidence of safety and 
efficacy in this patient population. In addition, based on the observed antitumor activity during 
stage 1 and stage 2 of the present study (2 subjects enrolled with AITL and both subjects 
achieved a partial response), an AITL cohort will be enrolled (N = 12) according to Amendment 
4 to the protocol in order to further explore the antitumor activity of tipifarnib in this histological 
subtype of PTCL.  
In Amendment 6, a cohort (n=12) of subjects with CXCL12+ PTCL was added based on 
preliminary tumor mutational data and outcomes from 16 subjects enrolled in stage 1 and 2 of 
the current study which suggested that subjects with high levels of CXCL12 gene expression 
and/or absence of 3'UTR CXCL12 gene variation derive clinical benefit from tipifarnib.  In those 
16 subjects, a high rate of CXCL12 3’UTR single nucleotide variation (SNV) was observed. 
Seven of 16 pts carried the rs2839695 variant while an additional patient carried a novel variant. 
The presence of 3’UTR SNVs was associated with low levels of CXCL12 gene expression and 
disease progression while all pts deriving clinical benefit from tipifarnib carried reference (wild 
type) 3’UTR CXCL12 and had tumors that expressed high levels of mRNA for this chemokine 
(Witzig 2017). 
Given the results shown in Section 5.2 above, in the current amendment, additional subjects with 
AITL, nodal PTCL with T-follicular helper phenotype and follicular PTCL will be added to 
further assess the safety and tolerability of tipifarnib in this patient population.  
 


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6 
OBJECTIVES 
6.1 
Primary Objectives and Endpoints 
Primary Objective: To determine the antitumor activity in terms of objective response rate 
(ORR) of tipifarnib in subjects with relapsed or refractory peripheral T-cell lymphoma (PTCL).   
Primary endpoint: Response assessments according to the Lugano Classification and/or 
mSWAT.   
6.2 
Secondary Objectives and Endpoints 
Secondary Objective 1:  To determine the antitumor activity in terms of PFS and DOR of 
tipifarnib in subjects with relapsed or refractory PTCL. 
Secondary Endpoint 1: PFS and DOR according to the Lugano Classification and/or mSWAT.   
Secondary Objective 2: Safety and tolerability of tipifarnib in subjects with relapsed or 
refractory PTCL. 
Secondary Endpoint 2: Treatment-emergent adverse events (TEAE) and SAEs evaluated 
according to NCI CTCAE v.4.03.   
6.3 
Exploratory Objective and Endpoints 
Exploratory Objective: To explore the feasibility of collecting tissue biopsies, buccal swabs 
and blood samples and analysing these biopsies and samples for the detection of biomarkers 
potentially related to tipifarnib activity. The biomarker analyses may include oncogene panel 
sequencing from tumor tissue samples, immune cytokine profiling from serum samples and KIR 
genotyping from blood samples. 
 
Exploratory Endpoints 1: Molecular analyses of blood, buccal swabs tumor tissue samples. 
7 
SUBJECT SELECTION 
7.1 
Inclusion Criteria 
For inclusion of a subject in the study, all of the following inclusion criteria must be fulfilled: 
1. Subject is at least 18 years of age. 
2. Subject has a diagnosis of PTCL according to the most recent edition of the World Health 
Organization (WHO) Classification of Tumors of Hematopoietic or Lymphoid Tissues as 
follows: 
a. ALCL, ALK positive 
b. ALCL, ALK negative 
c. AITL 


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d. Enteropathy-associated T-cell lymphoma 
e. Extranodal natural killer (NK) T-cell lymphoma, nasal type 
f. Hepatosplenic T-cell lymphoma 
g. PTCL, NOS 
h. Subcutaneous panniculitis-like T-cell lymphoma 
For enrollment into the AITL expansion cohort, subjects must have the diagnosis of AITL, nodal 
PTCL with T-follicular helper phenotype or follicular PTCL. 
For enrollment into the CXCL12+ PTCL expansion cohort, subjects must have the diagnosis of 
PTCL (a – h subtypes listed above, except AITL), consent to provide buccal swabs for CXCL12 
SNP testing, and be found to be CXCL12+ based on testing by a Sponsor approved 
methodology. Once (if) the AITL cohort has completed accrual, subjects with AITL histology 
and CXCL12+ status may be enrolled in the CXCL12+ PTCL expansion cohort. 
3. Subject has relapsed or are refractory to at least 1 prior systemic cytotoxic therapy. Subjects 
must have received conventional therapy as a prior therapy.  
4. Subject has consented to provide at least 6 unstained tumor slides (10 preferred) or an FFPE 
block for biomarker testing. Tumor tissue may be obtained from prior archival diagnostic 
biopsies. If the site is unable to confirm during screening that sufficient archival biopsy is 
available, the subject must consent to a pretreatment biopsy for inclusion in this study.  
5. Subject has measurable disease according to the Lugano Classification and/or mSWAT. 
6. At least 2 weeks since the last systemic therapy regimen prior to enrollment. Subjects must 
have recovered to NCI CTCAE v. 4.03 < Grade 2 from all acute toxicities (excluding Grade 
2 toxicities that are not considered a safety risk by the Sponsor and Investigator) or toxicity 
must be deemed irreversible by the Investigator. 
7. At least 2 weeks since last radiotherapy if radiation was localized to the only site of 
measurable disease, unless there is documentation of disease progression of the irradiated 
site. Subjects must have recovered from all acute toxicities from radiotherapy.  
8. ECOG performance status of 0-2 (Appendix 1). 
9. Acceptable liver function:  
a. Bilirubin ≤ 1.5 times upper limit of normal (x ULN); does not apply to subjects with 
Gilbert’s syndrome diagnosed according to institutional guidelines. 
b. AST (SGOT) and ALT (SGPT) ≤ 3 x ULN; if liver lymphoma is present, then ≤ 5 x ULN 
is allowed. 
10. Acceptable renal function with serum creatinine ≤ 1.5 x ULN or a calculated creatinine 
clearance ≥ 60 mL/min using the Cockcroft-Gault or MDRD formulas. 


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11. Acceptable hematologic status: 
a. ANC ≥ 1000 cells/μL. 
b. Platelet count ≥ 50,000/μL. 
c. Hemoglobin ≥ 8.0 g/dL. 
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 for 2 weeks prior to screening, 
during, and at least 4 weeks after last dose of trial medication. Female subjects must have 
a negative serum or urine pregnancy test within 72 hours prior to start of trial medication. 
c. Not breast feeding at any time during the study. 
13. Written and voluntary informed consent understood, signed and dated. 
7.2 
Exclusion Criteria 
1. Diagnosis of any of the following: 
a. Precursor T-cell lymphoma or leukemia 
b. ATLL 
c. T-cell prolymphocytic leukemia 
d. T-cell large granular lymphocytic leukemia 
e. Primary cutaneous type anaplastic large cell lymphoma 
f. Mycosis fungoide/Sezary syndrome 
2. Ongoing treatment with an anticancer agent not contemplated in this protocol. 
3. Prior treatment (at least 1 full treatment cycle) with an FTase inhibitor. 
4. Any history of clinically relevant coronary artery disease or myocardial infarction within the 
last 3 years, New York Heart Association (NYHA) grade III or greater congestive heart 
failure, cerebro-vascular attack within the prior year, or current serious cardiac arrhythmia 
requiring medication except atrial fibrillation. 


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5. Known central nervous system lymphoma. 
6. Stem cell transplant less than 3 months prior to enrollment. 
7. Non-tolerable ≥ Grade 2 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. 
8. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without 
complete recovery.  
9. Other active malignancy requiring therapy such as radiation, chemotherapy, or 
immunotherapy. 
10. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. Known 
infection with HIV, 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. 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.  
13. The subject has legal incapacity or limited legal capacity. 
14. Dementia or significantly altered mental status that would limit the understanding or 
rendering of informed consent and compliance with the requirements of this protocol. 
Unwillingness or inability to comply with the study protocol for any reason. 
8 
TRIAL DESIGN 
8.1 
Study Design 
This Phase II study will investigate the antitumor activity in terms of ORR of tipifarnib in 
subjects with relapsed or refractory PTCL. Only consented subjects who meet all the eligibility 
criteria will be enrolled in the study. All screening evaluations will be completed within 4 weeks 
(28 days) of Cycle 1 Day 1. Any screening evaluation, including disease status, will need to be 
repeated if performed more than 4 weeks from Cycle 1 Day 1.  
Up to 70 subjects may be enrolled (receive tipifarnib) in the study.  The first 18 subjects may be 
of the following PTCL sub-types: PTCL, not otherwise specified (PTCL-NOS), 
angioimmunoblastic T-cell lymphoma (AITL), ALK-positive and -negative anaplastic large cell 
lymphoma (ALCL), hepatosplenic T-cell lymphoma, enteropathy-associate T-cell lymphoma 


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(EATL), extranodal natural killer (NK) T-cell lymphoma, nasal type and subcutaneous 
panniculitis-like T-cell lymphoma.  The AITL expansion cohort (N=12) will enroll only subjects 
with AITL.   
A two-stage study design for the first 18 subjects will be used in order to minimize the number of 
study subjects treated if tipifarnib were considered not sufficiently efficacious to grant further 
development in this subject population. This design is intended to allow the termination of 
accrual in case of unacceptably low efficacy after objective responses in the first 11 evaluable 
subjects (stage 1) assessed in a Full Analysis Set (FAS) basis. If 0-1 objective responses are 
observed after the first 11 evaluable subjects, the study will be closed to further enrollment. If 2-
4 responses are observed, 7 additional subjects will be enrolled (stage 2). Treatment will be 
considered of further interest if at least 4 responses are observed (out of 18 subjects).  
Based on the observed antitumor activity during stage 1 and stage 2 of the study (2 subjects 
enrolled with AITL and both subjects achieved a partial response), an AITL cohort will be 
enrolled (N = 12) according to Amendment 4 to the protocol.  With this sample size, if 4 or more 
responses are observed, the probability that the true response rate in AITL subjects is at least 
30% is 82.6%.   
Based on the observed antitumor activity during stage 1 and stage 2 of the study in which 
subjects who were found to have high levels of CXCL12 gene expression by retrospective 
analysis had a longer PFS compared to subjects with low expression, a CXCL12+ cohort will be 
enrolled (N = 12) according to Amendment 6 to the protocol.  With this sample size, if 2 or more 
responses are observed, the probability that the true response rate in CXCL12+ subjects is at 
least 10% is at least 89%.  
Based on the high antitumor activity observed in AITL subjects in the AITL cohort and other 
portions of the study, enrolment in the AITL cohort has been expanded to include up to 20 
additional subjects with tumors of AITL and related T follicular helper cell histologies in order 
to further characterize the safety and tolerability of tipifarnib in this relatively rare population. 
The selection of 20 subjects was empirical and no statistical hypotheses will be tested. 
Descriptive statistics will be used to report response rate. 
Eligible subjects will receive tipifarnib administered at a starting dose of 300 mg, orally with 
food, bid on days 1 - 21 in 28 day cycles. Stepwise 100 mg dose reductions to control treatment-
related, treatment-emergent toxicities are allowed and further detailed in Section 9.5. Subjects 
who received tipifarnib bid on days 1 – 7 and days 15 – 21 in 28 day cycles during the conduct 
of earlier versions of this protocol may remain on that dose regimen at the discretion of the 
investigator.  Alternatively, the subject may transition to receive a dose of 300 mg, orally with 
food, bid on days 1-21 of 28 day treatment cycles beginning on Day 1 of their next cycle. 
Subjects may use proton pump inhibitors or H2 antagonists during the treatment portion of this 
study. However, subjects should be instructed to use antacids (magnesium or aluminum 
containing products) at least 2 hours before or after intake of oral study drug. 


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In the absence of emerging unmanageable toxicity, subjects may continue tipifarnib treatment for 
as long as the investigator considers that the treatment is providing clinical benefit up to 12 
months since the subject’s enrollment. Treatment may continue beyond 12 months upon 
agreement by the Investigator and Sponsor if there is documented evidence of sustained clinical 
benefit. 
Tumor assessments will be performed at screening, at the Day 22 visit (± 5 days) performed 
during Cycles 2, 4, 6 and once every approximately 12 weeks (cycles 9, 12, 15, etc.) thereafter, 
until disease progression. Tumor assessments will be performed more frequently if deemed 
necessary by the investigator. A tumor assessment will be performed upon treatment 
discontinuation (End of Treatment visit) if the reason for discontinuation is other than disease 
progression and no tumor assessment was performed in the prior 8 weeks. Subjects who 
discontinue treatment for reasons other than disease progression must continue tumor 
assessments until disease progression, withdrawal of subject’s consent or initiation of another 
anticancer therapy. Determination of objective tumor response will be performed by the 
Investigator according to the Lugano Classification and/or mSWAT criteria.  Subjects who have 
experienced a complete response may be considered for transplantation.  
Efforts will be made to collect information on the subject’s response and duration of response to 
the last prior therapy.  
Upon disease progression, all subjects will be followed approximately every 12 weeks for 
survival and the use of subsequent therapy until either death or 12 months after accrual of the last 
study subject, whichever occurs first. Information on survival and subsequent anticancer therapy 
may be collected by phone.  
All subjects will be followed-up for safety during treatment and up to approximately 30 days (+/- 
7 days) after treatment discontinuation or until immediately before the initiation of another anti-
cancer therapy, whichever occurs first. Additional follow up may be implemented until the 
subject recovers from any emergent treatment related toxicity or the adverse event is considered 
irreversible by the investigator. Target organ toxicities will be monitored via clinical and 
laboratory assessments using the National Cancer Institute Common Terminology Criteria for 
Adverse Events version 4.03 (CTCAE v 4.03). 
8.2 
Subject Identification and Replacement of Subjects 
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
eCRF pages.  
Subjects within the initial trial subset of 18 subjects (stage 1 and 2) and in the AITL expansion 
cohort who do not receive at least one dose of tipifarnib will be replaced. Subjects within the 
initial trial subset of 18 subjects (stage 1 and 2) and in the AITL expansion cohort who are 
unable to provide archival tumor tissue by the end of Cycle 1 and who did not have a biopsy 
performed prior to initiation of tipifarnib treatment will be replaced. Replacement subjects will 


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have available tumor tissue identified at the time of screening. In addition, subjects with archival 
tissue that is of insufficient quality for biomarker evaluation, may be replaced. 
8.3 
Assignment to Treatment Groups 
This is a nonrandomized study. Subjects will be enrolled sequentially.  
8.4 
Removal of Subjects from Treatment or Assessment 
Subjects may withdraw their consent to participate in this study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. A 
subject’s participation in the study may also be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. Every effort should be made to 
complete, whenever possible, the tests and evaluations listed for the End of Treatment visit. The 
Sponsor must be notified of all subject withdrawals as soon as possible. The Sponsor also 
reserves the right to discontinue the study at any time for either clinical research or 
administrative reasons and to discontinue participation by an individual Investigator or site for 
poor 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 requires more than 2 dose reductions 
• Subject experiences toxicity that is deemed by the Investigator to be no longer safe for 
the subject to continue therapy 
• Subject requests to withdraw from the study treatment 
• Subject requires or has taken medication prohibited by the protocol 
• Subject is unwilling or unable to comply with the study requirements 
• Subject withdraws consent to collect health information 
• Subject was erroneously admitted into the study or does not meet entry criteria 
• Subject is lost to follow-up 
• Subject becomes pregnant 
Subjects will return for an End of Treatment visit within approximately 30 days after the last 
administration of the study drug (or sooner if another anticancer therapy is to be initiated). If a 
subject fails to return for scheduled visits, a documented effort must be made to determine the 
reason. If the subject cannot be reached by telephone after 2 attempts, a certified letter should be 


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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 analyse and evaluate study results. 
It is the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as HIPAA in the US, from each subject, 
or if appropriate, the subject’s legally authorized representative. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written request 
from the subject, to ensure that no further data will be collected from the subject and the subject 
will be removed from the study. 
8.5 
Premature Discontinuation of the Trial 
This trial may be discontinued prematurely in the event of any of the following: 
• New information leading to a judgment of unfavorable risk-benefit of tipifarnib becomes 
available, e.g. due to: Evidence of inefficacy of tipifarnib in PTCL, 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 PTCL patient population. Evidence of inefficacy may arise from this trial or from 
other trials; 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 assessment should be performed and the 
appropriate eCRF section completed. 
8.6 
Definition of End of Study 
For administrative and safety reporting purposes, the end of this clinical study is defined as 12 
months from enrollment of the last enrolled study subject.  If the last enrolled study subject 
discontinues treatment within 12 months of study enrollment, the End of Study will occur no 
earlier than the date of the last enrolled subject’s safety follow-up assessment performed 


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approximately 30 days after treatment discontinuation (or until initiation of another anti-cancer 
therapy).  At the time of End of Study, provisions will be made to transition all remaining study 
subjects who demonstrate sustained clinical benefit beyond the end of the study to other means 
of continued treatment with appropriate safety monitoring, e.g. single patient treatment protocol. 
9 
TREATMENTS 
Subjects will receive tipifarnib as monotherapy in this study. In the absence of unacceptable 
tipifarnib related emergent toxicity or disease progression, subjects may receive treatment with 
tipifarnib for up to 12 months at the discretion of the Investigator. Treatment beyond 12 months 
may continue upon agreement of the Investigator and the Sponsor. Kura Oncology, Inc or its 
designee will provide the study site with a supply of tipifarnib sufficient for the completion of 
the study. 
All study subjects will be also eligible to receive best supportive care (BSC) defined as any 
standard supportive measures that are not considered a primary treatment of the disease under 
study, including the use of growth factors (i.e. GCSF) for myelosuppression. BSC will be 
provided by the study sites. 
9.1 
Investigational Product (IP) 
Tipifarnib is a small molecule being developed as a potent, selective inhibitor of FTase for the 
treatment of cancer and other malignancies. 
9.1.1 
Product Characteristics 
Tipifarnib film-coated tablets for oral administration are supplied in HDPE bottles. Two 
strengths (100 mg and 300 mg) of tablets are provided containing either 100 or 300 mg of 
tipifarnib active substance, respectively. In addition to the active substance, the tablets contain 
the following inactive ingredients: lactose monohydrate, maize starch, hypromellose, 
microcrystalline cellulose, crospovidone, colloidal anhydrous silica, and magnesium stearate. 
The nonfunctional, taste-masking film coatings contain hypromellose, titanium dioxide, lactose 
monohydrate, polyethylene glycol, and triacetin. Each strength of tablet has the same excipients 
but the quantitative composition is slightly different. Further information can be obtained from 
the current version of the Investigator’s Brochure.  
9.1.2 
Storage and Labeling 
At a minimum, the label of each bottle of tipifarnib tablets shipped to the study sites will provide 
the following information: batch number/lot number, study identification, required storage 
conditions, directions for use, and country specific required caution statements (including “New 
Drug – Limited by United States federal law to investigational use” language). 


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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. 
Tipifarnib should be stored at controlled room temperature 15 to 30 C (59 to 86 F). All study 
supplies must be kept in a restricted access area. 
9.2 
Treatment Administration 
Tipifarnib will be administered with food at a starting dose of 300 mg, orally, bid on days 1 - 21 
of 28 day treatment cycles.  Subjects who received tipifarnib bid on Days 1 – 7 and Days 15 – 21 
during the conduct of earlier versions of this protocol may remain on that dose regimen at the 
discretion of the investigator. Alternatively, the subject may transition to receive a dose of 300 
mg, orally with food, bid on days 1-21 of 28 day treatment cycles beginning on Day 1 of their 
next cycle. 
The first study dosing (Cycle 1 Day 1) will take place in the study clinic.  Tipifarnib will be 
administered orally with a meal in the morning and again approximately 12 hours later at 
approximately the same times each treatment day. Tablets should be swallowed whole with 
water (~8 oz. or 250 mL), but may be chewed or crushed if the Investigator deems it necessary. 
Use of percutaneous endoscopic gastrostomy tubes is allowed at the judgment of the 
Investigator.  If a dose is vomited or partially vomited, it should not be replaced with a new dose. 
Subjects may use proton pump inhibitors or H2 antagonists during the treatment portion of this 
study. However, subjects should be instructed to use antacids (magnesium or aluminum 
containing products) at least 2 hours before or after intake of oral study drug. 
Subjects will be provided with diaries with instructions to record the date and time of each dose 
and asked to bring the diaries and tablet bottles to each clinic visit for subject compliance and 
drug accountability review by the site staff. 
9.3 
Treatment Assignment 
Treatment will be conducted in an open label manner.  Kura Oncology, Inc or its designee will 
assign a subject number identifier for each subject that is enrolled into the study. Study sites 
cannot enroll or start dosing the subject without receiving the assigned subject number.  
9.4 
Dose Selection 
In the majority of its phase 2 program, tipifarnib was given orally at a dose of 300 mg bid for 21 
days, followed by 1 week of rest, in 28 day treatment cycles (3 weeks on/1 week off schedule).  
Prior studies have shown that 
 
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studies which administered tipifarnib at doses up to 600 mg bid for 21 days in 28-day treatment 
cycles, the most common adverse events were myelosuppression, gastrointestinal disorders, 
fever, fatigue, hypokalemia, rash, renal impairment, and dyspnea. The most common 
drug-related grade 3 or 4 events were myelosuppression, hypokalemia, fatigue, and rash. 
Thrombocytopenia, renal impairment, rash, and sepsis were the most common adverse events 
that led to discontinuation. In the completed MDS study (INT-28) which administered tipifarnib 
at a dose of 300 mg bid for 21 days in 28-day treatment cycles, the most common adverse events 
were myelosuppression, fatigue, diarrhea, nausea, and rash. The most common drug-related 
grade 3 or 4 events were myelosuppression, fever, pneumonia, bacterial infection, and rash. The 
most common adverse events that lead to discontinuation were thrombocytopenia and rash. 
No data are currently available in the sponsor’s database on the safety and tolerability of 
tipifarnib from prior studies in subjects with lymphoma. However, a phase 2 investigator-
initiated study of tipifarnib was conducted in 93 adult patients with relapsed or refractory 
lymphoma.  Patients received tipifarnib 300 mg twice daily on days 1-21 of each 28-day cycle. 
The median number of prior therapies was 5 (range, 1-17).  For the aggressive B-cell, indolent 
B-cell, and T-cell and Hodgkin lymphoma (HL/T) groups, the response rates were 17% (7/42), 
7% (1/15), and 31% (11/36), respectively. Of the 19 responders, 7 were diffuse large B-cell non-
Hodgkin lymphoma (NHL), 7 T-cell NHL, 1 follicular grade 2, and 4 HL. The median response 
duration for the 19 responders was 7.2 months (mean, 15.8 months; range, 1.8-62). The grade 3/4 
toxicities observed were fatigue and reversible myelosuppression (Witzig 2011). 
In the original version and amendments 1 – 4 of the current study, an effort was made to evaluate 
the safety and tolerability of administering tipifarnib
 
 
 two 
trials in MDS and AML subjects investigating alternate week dosing, i.e. 7-day bid dosing 
followed by 7 days of rest (Kurzrock 2008, Kirschbaum 2011).  
Based on these data, a 
 for evaluation in this 
study.  However, 
 
 in 
amendment 3.  Ongoing review of preliminary data from subjects enrolled in stages 1 and 2 of 
the current study suggested that toxicities were consistent with known safety profile of tipifarnib.  
No subject discontinued due to AEs.  Grade ≥ 3 TEAEs occurring in > 10% of subjects were 
hematology-related and included neutropenia (83%), thrombocytopenia (61%), leukopenia 
(50%), anemia (39%), febrile neutropenia (33%) and lymphopenia (17%). Myelosuppression 
was manageable with treatment interruption, dose reductions and/or growth factor support.   
As of July 2017, four subjects required further dose 
 in alternating 
weeks, including the two ongoing subjects enrolled in stages 1 and 2 of the study.  
 
 over a 28-day treatment 
cycle achieved with the prior regimen (300 mg bid on days 1 – 21 of 28-day treatment cycles).  


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Based on these preliminary data, it was concluded that the 
 
 over a 28-
day cycle.   
Therefore, in Amendment 5 the dose and dose regimen was revised to tipifarnib 300 mg bid for 
21 days in 28-day treatment cycles.  This dose and dose regimen is expected to be well tolerated 
and to provide potential clinical benefit to subjects with PTCL.  In addition, the current study 
allows for step-wise 100 mg dose de-escalation based on subject tolerability.  Subjects who 
received tipifarnib 
 during the conduct of earlier versions of 
this protocol may remain on that dose regimen at the discretion of the investigator. Alternatively, 
the subject may transition to receive a dose of 300 mg, orally with food, bid on days 1-21 of 28 
day treatment cycles beginning on Day 1 of their next cycle. 
The data obtained from this study will be used to select the optimal dose and dose regimen to 
support the further development of tipifarnib in subjects with PTCL. 


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9.6 
Treatment of Overdose 
An overdose is defined as any dose greater than 20% over the scheduled daily tipifarnib dose. 
Any overdose must be recorded in the trial medication section of the eCRF. There is no known 
antidote for tipifarnib. In the event of overdose of tipifarnib, subjects should receive appropriate 
advice and supportive medical care by the investigator or his/her designee and be followed-up 
accordingly. 
For monitoring purposes, any case of overdose – whether or not associated with an AE (serious 
or non-serious) – must be reported to the Sponsor in an expedited manner. 
9.7 
Blinding 
This is an open label study with no placebo or comparators. 
9.8 
Treatment Compliance 
The importance of treatment compliance should be emphasized to the subject. Subjects will be 
given study drug, dose diaries 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, 
unless otherwise specified per site SOP. 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 before dispensing new medication to the 
study subject. 


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9.9 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates and 
quantities) of IP received, subjects to whom IP is dispensed (subject by subject specific 
accounting), and IP lost or accidentally or deliberately destroyed. The Investigator or designee 
must retain all unused or expired study supplies until the Sponsor’s designated trial monitor has 
confirmed the accountability data or a waiver for site drug destruction prior to monitoring visits 
is provided by the Sponsor. 
9.10 
Return and Disposition of Clinical Supplies 
Unused 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 granted approval for drug destruction. All study drug destroyed 
on site must be documented. 
Documentation must be provided to the Sponsor or its designee and retained in the Investigator’s 
study files. If a site is unable to destroy study drug appropriately, the site can return unused study 
drug to the Sponsor or its designee upon request. The return of study drug or study drug 
materials must be accounted for on a form provided by the Sponsor or its designee. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed or 
returned according to applicable state and federal regulations and study procedures. 
9.11 
Prior and Concomitant Medications 
All prescription and over-the-counter medications taken by a subject within 28 days before the 
first study drug administration will be recorded in the eCRF. 
Supportive care medications considered necessary for the subject’s safety and well-being may be 
given at the discretion of the Investigator. Any concomitant medications added or discontinued 
during the study should be recorded on the eCRF. 
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: 
• IV hydration 
• Correction of electrolyte deficiency. 
• Hematopoietic growth factors and transfusions of blood or blood products in subjects 
who are experiencing hematological toxicity in accordance with standard institutional 
practice. 


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• Radiotherapy for pain control against non-target lesions as long as it does not influence 
bone marrow function. 
• Total tumor resection in responding subjects who have become candidates for curative 
resection. 
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration and indication of each drug. 
9.12 
Non-permitted Treatments 
Use of the following medications and therapies is not allowed during the trial: 
• Investigational agents other than tipifarnib. 
• Any other anticancer therapy, including radiation or surgery, for the primary disease 
under study with the exceptions of palliative treatment. 
• Subjects should not use enzyme-inducing anti-convulsants (e.g. phenytoin, phenobarbital, 
and carbamazepine) while taking tipifarnib. If needed, subjects may use non-enzyme-
inducing anti-convulsants (e.g. gabapentin, topiramate, valproate) while taking tipifarnib.  
• High dose systemic corticosteroids or any other immunosuppressive drugs except 
glucocorticosteroid treatment administered with a daily dose of ≤ 20mg prednisone or 
equivalent, and single doses for the management of treatment-related adverse events or 
for premedication of BSC agents. 
If the administration of a non-permitted concomitant drug becomes necessary during the trial, 
e.g., because of AEs or disease progression, the subject in question will be withdrawn from the 
trial, and the subject’s data which will have been obtained before the withdrawal may be used for 
safety and efficacy evaluations. 
9.13 
Dietary or Other Protocol Restrictions 
No dietary restrictions related to tipifarnib are required. 


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9.14 
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. 
9.15 
Potential Effects on Reproduction and Development 
Male and female fertility and reproductive capacity has been shown to be impaired in rats.  
In a fertility study conducted in male rats, the no observed effect level (NOEL) for tipifarnib 
 
  Although toxicokinetic data were not generated in this study, systemic exposure 
can be estimated from the 3-month oral toxicity study conducted with tipifarnib in rats (Study 
No. 4389).  In that study, steady state (Day 87) systemic exposure (AUC0-24) to tipifarnib in 
male rats at 
 
 
Tipifarnib was shown to have adverse effects on the developing embryo/fetus in rats. The no 
observed adverse effect level (NOAEL) for embryo-fetal toxicity 
. Maternal 
systemic exposure data at this dose level are not available. 
There were no adverse effects on the developing embryo/fetus when tipifarnib was administered 
to pregnant rabbits during the period of organogenesis.  The NOAEL for embryo-fetal toxicity in 
this study 
. Maternal systemic exposure 
(AUC0-24) to tipifarnib at this dose level was 
 on Gestation Day 18 (the last day 
of dosing). 
When tipifarnib was administered to pregnant rats from Gestation Day 6 through Lactation Day 
21, the NOAEL for effects on pre- and post-natal development 
.  Maternal 
systemic exposure (AUC0-t) to tipifarnib was 
 on Gestation Day 16 and 
 
 on Lactation Day 8. 
In light of these observations, both female subjects and male subjects with female partners of 
child-bearing potential must agree to use a highly effective method of contraception for 2 weeks 
prior to screening, during, and at least 4 weeks after last dose of trial medication.  Female 
subjects must have a negative serum or urine pregnancy test within 72 hours prior to start of trial 
medication. 
In addition, 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. 
10 
EFFICACY AND SAFETY VARIABLES 
Table 1 summarizes the study required evaluations. 


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10.1 
Efficacy Variables 
Radiological and/or physical assessments of the tumor lesions will be made at screening (4 
weeks before the first study drug administration) and at regular intervals as indicated in the 
schedule of activities (Table 1). Additional tumor assessments may be conducted at the judgment 
of the investigator. The imaging schedule (approximately every 8 weeks during the subject’s first 
6 months on study, thereafter every 12 weeks) should be maintained regardless of dosing delays 
or additional imaging assessments performed. Subjects who discontinue treatment for reasons 
other than disease progression must continue tumor assessments until disease progression, 
withdrawal of their consent to study procedures or initiation of another anticancer therapy. 
Efficacy assessments may also be conducted at treatment discontinuation (End of Treatment 
visit) if the reason for the treatment termination is other than disease progression and a tumor 
assessment was not done within 8 weeks before treatment discontinuation (assessment must be 
conducted before additional anti-tumor therapy is started). Scans at the End of Treatment visit 
will be also conducted if required to confirm response to treatment. 
Lesions to be included in the tumor assessments should follow the Lugano Classification criteria 
and/or mSWAT. In subjects with FDG avid lymphomas, PET-CT is the preferred scanning 
method for screening and all subsequent tumor assessments (Cycle 2, Cycle 4, Cycle 6, etc.).  In 
subjects with low or variable FDG avid lymphomas, Spiral CT with contrast is the preferred 
scanning method for screening and all subsequent tumor assessments (Cycle 2, Cycle 4, Cycle 6, 
etc.).  Subjects with contrast allergy may use non-contrast CT or MRI, whichever is required to 
adequately assess all disease. The same method of imaging must be used throughout a subject’s 
participation on this study.   
Bone marrow assessment (biopsy or PET assessment) will be performed at screening within 28 
days of Cycle 1 day 1. If baseline bone marrow assessment was positive for lymphoma, a bone 
marrow biopsy or PET evaluation would be mandatory to confirm a complete response (i.e. after 
radiographic assessment). 
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 the Lugano 
Classification and/or mSWAT.  
Upon disease progression, all subjects will be followed approximately every 12 weeks for 
survival and the use of subsequent therapy until either death or 12 months after accrual of the last 
study subject, whichever occurs first. Information on survival and subsequent anticancer therapy 
may be collected by phone.  
10.2 
Assessment of Safety 
Adverse events will be graded according to the NCI-CTCAE version 4.03. Adverse events will 
be summarized by relationship to trial drug, severity and grade. The safety profile of the IPs will 
be assessed through the recording, reporting and analyzing of baseline medical conditions, 


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adverse events, physical examination findings including vital signs and laboratory tests. 
Comprehensive assessment of any apparent toxicity experienced by the subject will be 
performed throughout the course of the trial, from the time of the subject’s signature of informed 
consent. Trial site personnel will report any adverse event (AE), whether observed by the 
Investigator or reported by the subject. 
The Investigators and Sponsor clinicians or designees will review all relevant safety data by 
teleconference on a regular basis (at least monthly or more frequently if required to monitor 
emerging adverse events). No external independent data safety monitoring board is planned for 
this study. Any decisions affecting the conduct of the study will be minuted. Institutional IRBs 
and regulatory authorities will be informed of any major changes that might require a 
modification of the study protocol. 
10.3 
Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. In cases of 
surgical or diagnostic procedures, the condition/illness leading to such a procedure is considered 
as the AE rather than the procedure itself. In case of a fatality, the cause of death is considered as 
the AE, and the death is considered as its outcome. 
The Investigator is required to grade the severity/intensity of each adverse event. Investigators 
will reference the NCI-CTCAE version 4.03. This is a descriptive terminology that can be used 
for adverse event reporting. A general grading (severity/intensity) scale is provided at the 
beginning of the referenced document, and specific event grades are also provided. If a particular 
AE’s severity/intensity is not specifically graded by the guidance document, the Investigator is to 
revert to the general definitions of Grade 1 through Grade 5 and use his or her best medical 
judgment. 
The 5 general grades are: 
• Grade 1: Mild 
• Grade 2: Moderate 
• Grade 3: Severe; disabling 
• Grade 4: Life-threatening  
• Grade 5: Death related to AE. Note: Death (Grade 5 as defined by NCI-CTCAE version 
4.03) is mainly regarded as an outcome, to be documented as described below. 


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According to the Sponsor’s convention, if a severity/intensity of Grade 4 or 5 is applied to an 
AE, then the Investigator must also report the event as a serious adverse event (SAE; see 
definition below) according to Section 10.5. However, a laboratory abnormality with a 
severity/intensity of Grade 4, such as anemia or neutropenia, is considered serious only if the 
condition meets one of the serious criteria described below. 
In the case of death, the primary cause of death (the event leading to death) should be recorded 
and reported as an SAE. “Fatal” will be recorded as the outcome of this respective event; death 
will not be recorded as separate event. Only if no cause of death can be reported (e.g., sudden 
death, unexplained death), the death per se might be reported as an SAE. 
Investigators must also systematically assess the causal relationship of AEs to the IPs, other 
medicinal products using the following definitions. Decisive factors for the assessment of causal 
relationship of an AE to the trial treatments include, but may not be limited to, temporal 
relationship between the AE and the trial treatments, known side effects of the trial treatments, 
medical history, concomitant medications and procedures, course of the underlying disease, trial 
procedures. 
Relatedness of an AE will be evaluated as follows: 
• Not related: Not suspected to be reasonably related to the IPs. AE could not medically 
(pharmacologically/clinically) be attributed to the IPs under trial in this clinical trial 
protocol. A reasonable alternative explanation must be available. 
• Related: Suspected to be reasonably related to the IPs. AE could medically 
(pharmacologically/clinically) be attributed to the IPs under trial in this clinical trial 
protocol. 
10.4 
Abnormal Laboratory Findings and Other Abnormal 
Investigational Findings 
Abnormal laboratory findings and other abnormal investigational findings (e.g. on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead 
to treatment discontinuation or are considered otherwise medically important by the Investigator. 
If an abnormality fulfills these criteria, the identified medical condition (e.g. anemia, increased 
ALT) must be reported as the AE rather than the abnormal value itself. 
10.5 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening. NOTE: The term “life-threatening” in this definition refers to an event 
in which the subject is at risk of death at the time of the event; it does not refer to an 
event that hypothetically might cause death if it were more severe. 


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• 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. 
10.6 
Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (e.g. an 
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered as SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (e.g., undesirable effects of any administered 
treatment) must be documented and reported as SAEs. 
10.7 
Events Not to Be Considered as AEs/SAEs 
Medical conditions are present at the initial trial visit that do not worsen in severity or frequency 
during the trial are defined as Baseline Medical Conditions, and are NOT to be considered AEs. 
Progression of underlying disease is not an AE and therefore not an SAE per se, rather an 
efficacy end-point, unless deemed to be causally related to administration of IPs. However, if 
adverse signs or symptoms occur in association with disease progression then these should be 
recorded as AEs and reported as SAEs if meeting any seriousness criteria. 
10.8 
Methods of Recording and Assessing Adverse Events 
At each trial visit, the subject will be queried on changes in his/her condition. During the 
reporting period of the trial any unfavorable changes in the subject’s condition will be recorded 
as AEs, whether reported by the subject or observed by the investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the 
eCRF. Among these AEs, all serious AEs must be additionally documented and reported using 


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an Adverse Event Report Form. It is important that each AE report include a description of the 
event, its duration (onset and resolution dates (/times “/times” to be completed when it is 
important to assess the time of AE onset relative to the recorded treatment administration time)), 
its severity, its relationship with the trial treatment, any other potential causal factors, any 
treatment given or other action taken (including dose modification or discontinuation of the IPs) 
and its outcome. In addition, serious cases should be identified and the appropriate seriousness 
criteria documented. Specific guidance can be found in the eCRF completion and monitoring 
conventions provided by the Sponsor. 
10.9 
Adverse Event Reporting Period 
The adverse event reporting period for safety surveillance begins when the subject is included 
into the trial (date of first signature of informed consent) and continues through the trial’s post-
treatment follow-up period, defined as 30 days from the final administration of the trial treatment 
or immediately before initiation of any other anticancer therapy, whichever comes first. 
10.10 
Procedure for Reporting Serious Adverse Events 
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (i.e. within a maximum 24 HOURS after becoming aware of the event) inform the 
person (s) identified in the Serious Adverse Event Report Form by telephone, by fax or by email. 
When an event (or follow-up information) is reported by telephone, a written report must be sent 
immediately thereafter by fax or e-mail. Reporting procedures and timelines are the same for any 
new information on a previously reported SAE. For names, addresses, telephone and fax 
numbers for SAE reporting, see information included in the Adverse Event Report Form. All 
written reports should be transmitted using the Adverse Event Report Form, which must be 
completed by the Investigator following specific completion instructions. 
The AE section of the eCRF must be completed and a copy of the information transmitted with 
the Adverse Event Report Form. Other relevant pages from the eCRF may also be provided (e.g., 
medical history, concomitant drugs). The Investigator/Reporter must respond to any request for 
follow-up information (e.g. additional information, outcome and final evaluation, specific 
records where needed) or to any question the Sponsor may have on the AE within the same 
timelines as described for initial reports. This is necessary to permit a prompt assessment of the 
event by the Sponsor to allow for strict regulatory timelines associated with expedited safety 
reporting obligations. 
10.11 
Safety Reporting to Health Authorities, Institutional Review 
Boards and Investigators 
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. The Investigator must comply with any applicable site-specific 


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requirements related to the reporting of SAEs (and in particular deaths) involving his/her 
subjects to the IRB/IEC that approved the trial. 
In accordance with ICH GCP guidelines, the Sponsor will inform the Investigator of “findings 
that could adversely affect the safety of subjects, impact the conduct of the trial or alter the 
IRB/IEC’s approval/favorable opinion to continue the trial.” In particular and in line with 
respective regulations, the Sponsor will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (“suspected unexpected 
serious adverse reactions”, SUSARs). The 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 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. 
10.12 
Monitoring of Subjects with Adverse Events 
Any AE that occurs during the course of a clinical trial and is considered to be possibly related to 
the IP must be monitored and followed up by the Investigator until stabilization or until the 
outcome is known, unless the subject is documented as “lost to follow-up”. Reasonable attempts 
to obtain this information must be made and documented. It is also the responsibility of the 
Investigator to ensure that any necessary additional therapeutic measures and follow-up 
procedures are performed. The Sponsor will actively follow-up and collect information on any 
AE that occurs during the course of a clinical trial, however while this activity will continue for 
any serious AEs until stabilization or until the outcome is known, it will be discontinued at the 
time of database lock for non-serious AEs. 
10.13 
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator as related to trial treatment (e.g., resulting from 
a drug interaction with a contraceptive medication) are considered as adverse events. However, 
all pregnancies with an estimated conception date during the study safety period must be 
recorded by convention in the AE page/section of the e-CRF. The same rule applies to 
pregnancies in female subjects and in female partners of male subjects. The Investigator must 
notify the Sponsor in an expedited manner of any pregnancy using the Pregnancy Report Form, 
which must be transmitted according to the same process as described for SAE reporting. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial. The Investigator must notify the 


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Sponsor of these outcomes using the Pregnancy Report Form, and in case of abnormal outcome, 
the Adverse Event Report Form when the subject sustains an event and the Parent-Child/Fetus 
Report Form when the child/fetus sustains an event. 
Any abnormal outcome must be reported in an expedited manner, while normal outcomes must 
be reported within 45 days from delivery. 
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor must be notified without delay 
and the subject must be followed as mentioned above. 
10.14 
Laboratory Assessments 
All clinical safety laboratory tests listed in the sections 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. 
10.14.1 
Blood Sample Collection for General Clinical Laboratory 
Assessments 
Blood samples will be collected for the following clinical laboratory tests: 
• Serum Chemistry: Blood Urea Nitrogen (or Uric Acid), Creatinine, Sodium, Potassium, 
Calcium, Total Protein, Albumin, Total Bilirubin, Alkaline Phosphatase, ALT, AST, 
Lactate Dehydrogenase. 
• Hematology: White Blood Cell Count, Hemoglobin, Platelet Count, Neutrophils, 
Lymphocytes, Monocytes 
• Coagulation panel: PT/INR, APTT 
10.15 
Additional Variables 
Additional variables to be examined as a part of this study include somatic mutations and 
immunohistochemistry stainings in tumor tissue. 
 
. A training cohort of archival samples from the prior tipifarnib study NCT0008288 
in subjects with advanced lymphoma may be also examined.
 
11 
STUDY PROCEDURES 
The visit schedule (Table 1) should be maintained regardless of dose delays or additional 
assessments performed. 


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11.1 
Screening and Baseline Assessments 
A signed ICF must be obtained before any study-specific screening evaluations are performed 
and should be documented in the subject’s medical chart. 
The following evaluations and procedures will be performed within 28 days prior to the first 
study drug administration (Cycle 1 Day 1): 
• Signed informed consent form (ICF)/ patient informed consent (PIC) and form for the 
Health Insurance of Portability and Accountability Act (HIPAA)/Protection of Personal 
Data (DPA) 
• Medical history (including demographics, prior cancer therapy, response and duration of 
response to last prior therapy) 
• Assessment of adverse events  
• Concomitant medications 
• Tumor assessments (unless the previous tumor assessment was performed within 28 days 
of the first day of dosing) 
• Buccal swabs for the evaluation of CXCL12 status and presence of other germline gene 
variants:  Sample may be collected at any time prior to study enrollment (> 28 days prior 
to first dose of study drug administration) for the determination of subject eligibility. 
• Collection of available archival tumor tissue in paraffin embedded block or a minimum 
of 6 unstained slides (10 preferred). The archival tumor tissue may be collected during 
Cycle 1 if additional time is needed to locate the samples but must be shipped to the 
Sponsor (or designee) by the end of Cycle 1. Efforts should be made to collect these 
materials as early as possible. If the site is unable to confirm during screening that 
sufficient archival tissue is available, a new biopsy must be taken at any time prior to the 
initiation of dosing. 
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. Record subject height, weight and temperature. Record 
weight, temperature and other physical examination parameters as AE if they meet AE 
criteria. 
• ECOG performance status 
• Hematology 
• Chemistry (fasting not required) 
• Coagulation 
 
 


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• 12-lead ECG 
The following evaluations and procedures will be performed within 72 hours prior to the first 
administration of study drug (Cycle 1 Day 1): 
• Pregnancy test (serum or urine) for females of child-bearing potential only 
If the subject meets all eligibility criteria after the screening visit(s), the study site will request an 
assigned subject number using the Sponsor’s computerized system.  
11.2 
Day 1 of Cycle 1 
The following assessments are to be conducted before the first dose of tipifarnib on Day 1 of 
Cycle 1: 
• Record subject weight and temperature 
• ECOG performance status  
• Symptom based physical examination 
• Hematology: Assessment does not need to be performed if the screening labs were 
performed within 72 hours of Cycle 1 Day 1. 
• Chemistry (fasting not required): Assessment does not need to be performed if the 
screening labs were performed within 72 hours of Cycle 1 Day 1. 
 
 
• Concomitant medications 
• Assessment of adverse events  
Subjects will be administered the first dose of tipifarnib with food. 
Assessments post dosing: 
• 12-Lead ECG, within 2-4 hours post dose 
Subjects will continue to self-administer tipifarnib twice a day (approximately every 12 hours, 
same time every morning and evening, with food) on days 1 – 21 of every 28-day treatment 
cycle. The interval between dosing should not be less than 6 hours.  
11.3 
Day 7 (-2 days; can be Days 5, 6 or 7) of Cycle 1 only 
The following procedures are to be performed: 
• Record subject weight and temperature 
• ECOG performance status  


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• Symptom based physical examination 
• Hematology  
• Chemistry (fasting not required)  
 
 
• Pregnancy test (serum or urine) for females of child-bearing potential only 
• 12-Lead ECG, within 2-4 hours post tipifarnib dose 
• Concomitant medications 
• Assessment of adverse events  
11.4 
Day 1 (± 2 days) of Cycle 2 and Beyond 
The following procedures are to be performed: 
• Record subject weight and temperature 
• ECOG performance status  
• Symptom based physical examination 
• Hematology  
• Chemistry (fasting not required)  
• Pregnancy test (serum or urine) for females of child-bearing potential only 
 
 
 
• Concomitant medications 
• Assessment of adverse events  
In addition to the above procedures, the clinical site will conduct a drug accountability on the 
returned empty bottles and unused medications. 
Allowances of ± 2 days will be permitted on the date of the Day 1 of Cycle 2 and beyond visit in 
cases of scheduling conflicts or for convenience. 
11.5 
Day 22 (± 5 days) of Cycles 2, 4 and 6 and Cycles 9, 12, 15, etc. 
The following procedures are to be performed: 
• Review of adverse events and concomitant medications 
• Tumor assessments will be conducted as in the screening visit. 
o Tumor assessment including radiological assessment should maintain actual time 
schedule regardless of treatment delays or interruptions.  In other words, subjects 


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should have their tumor assessed approximately every 8 weeks from starting 
tipifarnib treatment through the first 6 months of study participation.  Thereafter, 
the tumor assessment is to be performed approximately every 12 weeks.  The 
frequency of tumor assessment (every 8 or 12 weeks depending on duration of 
study participation) is to be maintained regardless of the subject’s treatment cycle.   
o For the purposes of tumor assessment recording, the nomenclature Cycle 2 Day 
22, Cycle 4 Day 22, Cycle 6 Day 22, Cycle 9 Day 22, Cycle 12 Day 22, etc. is 
used to name the tumor assessment visits.  However, due to treatment delays or 
interruptions, it may happen that the tumor assessment visit will not coincide with 
the current treatment cycle for a given subject.  
11.6 
End of Treatment Visit 
The following assessments will occur approximately 30 days (± 7 days) after the last 
administration of study drug or immediately before the administration of another anti-cancer 
drug, whichever takes place first: 
Complete physical examination. Record subject weight and temperature. Record weight, 
temperature and other physical examination parameters as AE if they meet AE criteria. 
• ECOG performance status. 
• 12-lead ECG 
• Hematology 
• Coagulation 
• Chemistry (fasting not required) 
• Pregnancy test (serum or urine) for females of child-bearing potential only 
• Circulating biomarkers samples (one plasma, one serum) 
• Tumor assessments for subjects who have not previously demonstrated disease 
progression in the study unless completed within the previous 8 weeks. 
• Assessments of adverse event and concomitant medications. 
• Conduct drug accountability on the returned empty bottles and unused medications. 
11.7 
Post Treatment Follow up 
If the reason for the discontinuation was other than disease progression, tumor assessments will 
continue to be performed after treatment discontinuation in approximately 8-12 week intervals 
until progression. 


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Tumor assessments to be conducted at these visits. 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. 
In subjects who have experienced a response and in whom only residual tumor tissue remains, 
irradiation of the remaining tumor lesions will be permitted as per standard of care. 
11.7.1 
Follow Up after Disease Progression 
Upon disease progression, all subjects will be followed approximately every 12 weeks for 
survival and the use of subsequent therapy until either death or 12 months after accrual of the last 
study subject, whichever occurs first. Information on survival and subsequent anticancer therapy 
may be collected by phone.  
12 
STATISTICAL METHODS  
This section outlines the statistical analysis strategy and procedures for the study. Specific details 
of the primary and key secondary analyses will be provided in the Statistical Analysis Plan 
(SAP). If, after the study has begun, but prior to the final analysis, important changes are made to 
the protocol that affect principal features of the primary or key secondary analyses, then the 
protocol and/or SAP will be amended, as appropriate. Any other changes made to the planned 
analyses after the protocol and SAP have been finalized, along with an explanation as to when 
and why they occurred, will be listed in the Clinical Study Report (CSR) for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR. 
12.1 
Populations 
12.1.1 
Efficacy Analysis 
The FAS population will serve as the primary population for the analysis of tumor response and 
other efficacy-related data. Subjects will be excluded for FAS for the following reasons: 
• No baseline data 
• Failure to receive at least one dose of tipifarnib 
• No post-baseline endpoint data subsequent to at least 1 dose of study drug 


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12.1.2 
Safety Analysis 
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data. The 
ASaT population consists of all enrolled subjects who receive at least one dose of tipifarnib. At 
least one laboratory or vital sign measurement obtained subsequent to at least one dose of study 
drug is required for inclusion in the analysis of a specific safety parameter. To assess change 
from baseline, a baseline measurement is also required. 
12.2 
Endpoints 
12.2.1 
Efficacy 
The objective response rate will be estimated for each tumor histology type evaluated.  The 
estimate of the objective response rate will be calculated based on the maximum likelihood 
estimator (i.e., crude proportion of subjects whose best overall response is CR or PR). The 
estimate of the objective response rate will be accompanied by 2-sided 95% exact binomial 
confidence intervals. 
The duration of objective response will be calculated for subjects who achieve CR or PR. For 
such subjects, the duration of objective response is defined as the number of days from the start 
date of PR or CR (whichever response is achieved first) to the first date that progressive disease 
is objectively documented. Disease progression will be determined by the Investigator using the 
Lugano Classification and/or mSWAT. The duration of objective response will be right-censored 
for subjects who achieve CR or PR and meet 1 of the following conditions: 1) non-protocol 
anticancer treatment started before documentation of disease progression, 2) death or 
documented disease progression after more than 1 missed disease assessment visit, or 3) alive 
and does not have documentation of disease progression before a data analysis cutoff date.  
The duration of objective response will be summarized descriptively using the Kaplan-Meier 
method. The 50th percentile of the Kaplan-Meier distribution will be used to estimate the median 
response duration. 
Progression free survival will be defined as the time (in months) from enrollment to either first 
observation of progressive disease or occurrence of death due to any cause within 126 days 
(approximately 2 time intervals for tumor assessments) of either first administration of tipifarnib 
or the last tumor assessment. In subjects without a progression date or with a death date more 
than 126 days after the first administration of study drugs or the last tumor assessment, the PFS 
time should be censored on the date of last tumor assessment or date of first administration of 
study tipifarnib. Progression free survival analyses should consider tumor assessments after 
treatment discontinuation or metastatic surgery. 
The PFS will be summarized descriptively using the Kaplan-Meier method. The 50th percentile 
of the Kaplan-Meier distribution will be used to estimate the median PFS. 


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12.2.2 
Safety and Tolerability  
Safety and tolerability of tipifarnib will be assessed based on the following: 
• Incidence, duration, and severity of treatment-emergent adverse events, serious adverse 
events, adverse events resulting in permanent discontinuation of study drug, and deaths 
within approximately 30 days from the last dose of study drug (or immediately before the 
administration of another anti-cancer treatment) 
• Changes in vital signs including blood pressure, pulse, and temperature 
• Changes in electrocardiogram results 
Adverse events will be coded using the latest available version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Treatment-emergent adverse events are defined as adverse 
events that start on or after the first dose of study drug and within approximately 30 days of the 
last administration of study drug. Adverse events will be summarized by the number and 
percentage of subjects who experienced the event, according to system organ class and preferred 
term. A subject reporting multiple cases of the same adverse event will be counted once within 
each system organ class and similarly counted once within each preferred term. 
Unless specified otherwise, the denominator for these calculations will be based on the number 
of subjects who received at least one administration of tipifarnib, irrespective of the total number 
of doses or treatment cycles administered. These conventions will be appropriately modified to 
calculate AE incidence rates separately for each cycle that study therapy is administered. AE 
incidence rates may also be calculated based on other measures of subject exposure (e.g., total 
number of treatment cycles administered). AEs will also be summarized by NCI-CTCAE version 
4.03 severity grade and by relationship to each study drug. Additional summaries may also be 
provided for SAEs, and events resulting in the permanent discontinuation of therapy. All AEs 
will be included in individual subject listings. 
The incidence of grade 3 and 4 hematological toxicities (including neutropenia, 
thrombocytopenia, and anemia) will be provided by treatment cycle and across all treatment 
cycles. The toxicity grades for laboratory tests will be based on NCI-CTCAE version 4.03 
criteria. The use of blood transfusions (platelets, red blood cells) and/or growth factor support 
will be reported. Similar analyses will be done for selected chemistry tests (including liver and 
renal function tests). 
Vital sign results (blood pressure, pulse, 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. 


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12.4 
Sample Size Determination 
A two-stage study design was used in the initial cohort of PTCL subjects without histological or 
genetic selection in order to minimize the number of study subjects treated if tipifarnib were to 
be not efficacious. This design is intended to allow the termination of accrual in case of 
unacceptably low efficacy after the first subjects are evaluated in a Full Analysis Set (FAS) 
basis.  
A two-stage design will be employed. Eleven initial study subjects will be enrolled; if 2-4 
responses are observed, 7 additional subjects will be enrolled. At the completion of this cohort, 
treatment will be considered of further interest if the true ORR is higher than 10%. To determine 
the total trial size of the initial cohort of subjects, a response of interest of 30% is assumed. This 
design provides 80% power to detect a difference between 10% and 30% ORR at one-sided 
significance level of 0.087. Using this design, the probability of terminating the study at the end 
of stage 1 if the true ORR is 10% is 0.697 while the probability of terminating the study at the 
end of stage 1 if the true ORR is 30% is 0.113.  
An AITL cohort will be enrolled (N = 12) according to Amendment 4 to the protocol.  With this 
sample size, if 4 or more responses are observed, the probability that the true response rate in 
AITL subjects is at least 30% is 82.6% (Table 6).  
Based on the observed antitumor activity during stage 1 and stage 2 of the study in which 
subjects who were found to have high levels of CXCL12 gene expression and reference CXCL12 
3’UTR by retrospective analysis had better outcomes in terms of response and PFS compared to 
subjects with low CXCL12 expression and CXCL12 3’UTR variant sequences, a CXCL12+ 
cohort will be enrolled (N = 12) according to Amendment 6 to the protocol.  With this sample 
size, if 2 or more responses are observed, the probability that the true response rate in CXCL12+ 
subjects is 10% or higher is at least 87% (Table 7).  
It is assumed that the presence of CXCL12 3’UTR gene variants is of germinal, not somatic, 
origin. By default, CXCL12+ subjects are defined as those who present with reference CXCL12 
reference gene sequence in a buccal swab assay and in whom no CXCL12 3’UTR variant or 


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unknown status is observed in subsequent tumor CXCL12 gene sequencing. Subjects who were 
enrolled in the CXCL12+ cohort based on CXCL12+ status in the buccal swab test and later 
demonstrated to have a somatic tumor 3’UTR CXCL12 sequence variant will be allowed to 
continue treatment but may be replaced and not included in the evaluable study population for 
efficacy analyses. 
Upon the observation of 5 confirmed responses in the AITL cohort, and 5 confirmed responses in 
the CXCL12+ cohort, including 2 of them in subjects with tumors of AITL histology, the trial 
was amended to include up to 20 additional subjects with AITL and related T follicular helper cell 
tumors in the AITL cohort in order to further characterize the safety and tolerability of tipifarnib 
in this patient population.  The choice of 20 additional subjects was empirical based on the 
relative rarity of the patient population and no statistical hypotheses will be tested in this 
extension.  Including Amendment 7, up to 70 evaluable subjects in total may be enrolled (dosed).   
12.5 
Changes in the Conduct of the Study or Planned Analyses 
Only the Sponsor, upon consultation with the principal investigator may modify the protocol. 
The Sponsor will issue a formal protocol amendment to implement any changes. The only 
exception is when an Investigator considers that a subject’s safety is compromised without 
immediate action. In these circumstances, immediate approval of the chairman of the IRB/IEC 
must be sought, and the Investigator should inform the Sponsor and the full IRB/IEC within 2 
working days after the emergency has occurred. 
The IRBI/EC must review and approve all protocol amendments. Protocol amendments that have 
an impact on subject risk or the study objectives, or require revision of the ICF, must receive 
approval from the IRB/IEC prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to subjects, the ICF will be amended and approved by the Sponsor and the IRB/IEC, and all 
active subjects must again provide informed consent. 
13 
ETHICAL AND REGULATORY ASPECTS 
13.1 
Responsibilities of the Investigator 
The Investigator is responsible for the conduct of the trial at his/her site. He/she will ensure that 
the trial is performed in accordance with the clinical trial protocol and with the ethical principles 
that have their origin in the Declaration of Helsinki, as well as with the ICH Note for Guidance 
on Good Clinical Practice (ICH Topic E6, 1996) and applicable regulatory requirements. In 
particular, the Investigator must ensure that only subjects who have given their informed consent 
are included into the trial. 


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


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


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


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


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


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Minor (non-substantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and by the Investigator at the clinical study site. They will be submitted to the 
relevant IRB/IEC or to Health Authorities only where requested by pertinent regulations. 
Any amendment that could have an impact on the subject’s agreement to participate in the trial 
requires the renewal of the subject’s informed consent prior to implementation. 
14.6 
Clinical Trial Report 
After completion of the trial, a clinical trial report according to ICH E3 will be generated by the 
Sponsor in consultation with the Principal Investigator. 
14.7 
Publication 
The first publication will be a publication of the results of the analysis of the primary endpoint, 
that will include data from all trial sites. Lead Investigators will be identified based on accrual and 
Good Publication Practices and the decision to publish or present initial data will reside in the 
Sponsor in consultation with the lead Investigators. Publications or presentations prior to the 
generation of a final clinical study report will be clearly marked as preliminary reports. 
Investigators will inform the Sponsor in advance about any subsequent plans to publish or present 
data from any portion of the trial. Any publications and presentations of the results (abstracts in 
journals or newspapers, oral presentations, etc.), either in whole or in part, by Investigators or their 
representatives will require a pre-submission review by the Sponsor. The Sponsor will not suppress 
or veto publications, but maintains the right to a reasonable delay of a publication in order to 
protect intellectual property rights. 
14.8 
References 
Baines AT, Xu D, Der CJ. Inhibition of RAS for cancer treatment: the search continues. Future 
Med Chem. 2011 Oct;3(14):1787-808 
Cheson BD, Fisher RI, Barrington SF,et. al. Recommendations for Initial Evaluation, Staging, and 
Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J 
Clin Oncol. 2014 Sep 11;32(27):3059 – 3067.  
Karp JE, Lancet JE, Kaufmann SH, et al: Clinical and biologic activity of the farnesyltransferase 
inhibitor R115777 in adults with refractory and relapsed acute leukemias: A phase I 
clinicallaboratory correlative trial. Blood. 2001;97:3361-3369.  
Kirschbaum MH, Synold T, Stein AS, et. al. A phase 1 trial dose-escalation study of tipifarnib on 
a week-on, week-off schedule in relapsed, refractory or high-risk myeloid leukemia. Leukemia. 
2011 Oct;25(10):1543-7.  
Kurzrock R, Albitar M, Cortes JE, Estey EH, Faderl SH, Garcia-Manero G, Thomas DA, Giles FJ, 
Ryback ME, Thibault A, De Porre P, Kantarjian HM. Phase II study of R115777, a farnesyl 
transferase inhibitor, in myelodysplastic syndrome. J Clin Oncol. 2004 Apr 1;22(7):1287-92 


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Kurzrock R, Kantarjian HM, Blascovich MA, et. al. Phase I study of alternate-week administration 
of tipifarnib in patients with myelodysplastic syndrome. Clin Cancer Res. 2008 Jan 15;14(2):509-
14. 
Martinelli G1, Iacobucci I, Paolini S, Ottaviani E. Farnesyltransferase inhibition in hematologic 
malignancies: 
the 
clinical 
experience 
with tipifarnib. 
 
Clin 
Adv 
Hematol 
Oncol. 2008 Apr;6(4):303-10. 
Olsen E A, Whittaker S, Kim Y, et al.  Clinical End Points and Response Criteria in Mycosis 
Fungoides and Sézary Syndrome: A Consensus Statement of the International Society for 
Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous 
Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer.  J 
Clin Oncol. 2011 June 20; 29(18): 2598–2607.  
Takashima A, Faller DV. Targeting the RAS oncogene. Expert Opin Ther Targets. 2013 
May;17(5):507-31 
Witzig TE, Tang H, Micallef IN, Ansell SM, Link BK, Inwards DJ, Porrata LF, Johnston PB, 
Colgan JP, Markovic SN, Nowakowski GS, Thompson CA, Allmer C, Maurer MJ, Gupta M, 
Weiner G, Hohl R, Kurtin PJ, Ding H, Loegering D, Schneider P, Peterson K, Habermann TM, 
Kaufmann SH. Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib 
(R115777) in patients with relapsed and refractory lymphomas. Blood. 2011 Nov 3;118(18):4882-
9. 
Witzig TE, Sokol L, Jacobsen E, Advani R, Mondejar R, Piris M, Burrows F, Melvin C, Mishra 
V, Scholz C, Gualberto A. Preliminary results from an open-label, phase ii study of tipifarnib in 
relapsed or refractory peripheral t-cell lymphoma. European Hematology Association 22nd 
Annual Congress, Madrid, Spain, 2017. Poster 571.  
Kim WS, Foss F, Jacobsen E, de la Cruz Vicente F, Caballero D, Advani R, Roncero Vidal MJ, 
Marin Niebla A, Rodriguez Izquierdo A, de Ona Navarrete R, Terol MJ, Domingo-Domenech E, 
Rodriguez M, Piris M, Bolognese J, Janes MR, Burrows F, Kessler L, Mishra V, Curry R, Kurman 
M, Scholz C, Gualberto A. Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-Cell 
Lymphoma (AITL) and CXCL12+ Peripheral T cell Lymphoma (PTCL): Preliminary Results 
from and Open-Label Phase 2 Study.  EHA Library. Witzig T. Jun 15, 2019; 267452; S869 

SAP_001.pdf: 
Protocol Number: KO-TIP-002 
Official Title: An Open Label Phase II Study of Tipifarnib in Subjects with Relapsed or Refractory 
Peripheral T-Cell Lymphoma 
NCT Number: NCT02464228 
Document Date: 03 June 2021 


STATISTICAL ANALYSIS PLAN 
Protocol Title: 
An Open Label Phase 2 Study of Tipifarnib in Subjects with Relapsed or 
Refractory Peripheral T-Cell Lymphoma   
SAP Version: 
4.0 
SAP Date: 
03 June 2021 
Study Drug: 
Tipifarnib (R115777; Zarnestra™) 
Phase of Study: 
Phase 2 
Protocol Number: 
KO-TIP-002 
Protocol Version 
Protocol Amendment Version 7 
Protocol Date: 
12 July 2019 
Sponsor: 
Kura Oncology, Inc.   
303 Science Park Drive, Suite 220  
San Diego, CA 92121 (USA)   
Phone: +1 858.500.8800  
CRO Preparing SAP:   
 
 
  


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SIGNATURE PAGE 
 
This document has been prepared, reviewed and approved by: 
STUDY BIOSTATISTICIAN APPROVAL: 
 
 
 
 
------
---------------------------------------------------- 
Printe
Signature 
 
 
Date 
 
 
SPONSOR APPROVAL: 
 
 
 
 
--------
---------------------------------------------------- 
Printe
Signature 
 
 
Date 
 
 
 


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TABLE OF CONTENTS  
SIGNATURE PAGE .......................................................................................................................2 
 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
INTRODUCTION ......................................................................................................10 
2. 
STUDY OBJECTIVES ..............................................................................................10 
2.1. 
Primary Objective and Endpoint ................................................................................10 
2.2. 
Secondary Objectives and Endpoints .........................................................................11 
2.3. 
Exploratory Objectives and Endpoints .......................................................................11 
3. 
STUDY DESIGN .......................................................................................................12 
3.1. 
General Study Design and Plan ..................................................................................12 
3.2. 
Study Population .........................................................................................................14 
3.2.1. 
Selection of Study Population ....................................................................................14 
3.2.2. 
Removal of Subjects from Treatment or Assessment .................................................14 
3.3. 
Premature Discontinuation of the Trial ......................................................................14 
3.4. 
Definition of End of Study .........................................................................................14 
3.5. 
Randomization and Blinding ......................................................................................15 
4. 
SAMPLE SIZE CONSIDERATIONS .......................................................................15 
5. 
ANALYSIS POPULATIONS ....................................................................................17 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................18 
6.1. 
Interim Analysis and Data Monitoring .......................................................................18 
6.2. 
Multi-Center Studies ...................................................................................................18 
6.3. 
Multiple Comparisons ................................................................................................18 
6.4. 
Handling of Dropouts or Missing Data ......................................................................18 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................18 
7.1. 
Subject Disposition .....................................................................................................18 
7.2. 
Protocol Deviations ....................................................................................................19 
7.3. 
Demographics and Baseline Characteristics ...............................................................19 


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7.4. 
Dosing and Extent of Exposure ..................................................................................20 
7.5. 
Concomitant Medications ...........................................................................................20 
7.6. 
Follow Up Assessments ..............................................................................................20 
8. 
EFFICACY ANALYSIS ............................................................................................20 
8.1. 
Primary Efficacy Analysis ..........................................................................................20 
8.2. 
Secondary Efficacy Analysis ......................................................................................21 
8.3. 
Exploratory Efficacy Analysis ....................................................................................23 
9. 
SAFETY ANALYSIS ................................................................................................24 
9.1. 
Adverse Events ...........................................................................................................25 
9.2. 
Clinical Laboratory Evaluations .................................................................................26 
9.3. 
Vital Signs ..................................................................................................................26 
9.4. 
ECGs ...........................................................................................................................26 
9.5. 
Other Safety Measures ................................................................................................27 
10. 
CLINICAL PHARMACOLOGY ANALYSES .........................................................27 
11. 
OTHER ANALYSES .................................................................................................27 
12. 
DATA HANDLING CONVENTIONS ......................................................................27 
13. 
REPORTING CONVENTIONS ................................................................................28 
14. 
CHANGES IN THE STATISTICAL METHODS FROM THOSE STATED 
IN THE PROTOCOL .................................................................................................28 
15. 
TABLES, FIGURES, LISTINGS ...............................................................................28 
 
LIST OF FIGURES 
Figure 1: 
Operating Characteristics of Study Design .................................................................16 
Figure 2: 
Two-sided 95% Confidence Intervals for ORR ..........................................................17 
 
 
 


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LIST OF ABBREVIATIONS 
AE   
adverse event  
AITL  
angioimmunoblastic T-cell lymphoma  
ALCL  
anaplastic large cell lymphoma  
ALT  
alanine aminotransferase  
ANC  
absolute neutrophil count  
APTT  
activated partial thromboplastin time  
AST  
aspartate aminotransferase  
ASaT  
all subjects as treated  
ATLL  
adult T-cell lymphoma/leukemia  
bid  
twice a day  
CR  
complete response  
CSR 
clinical study report 
CT  
computer tomography  
DOR  
duration of response  
eCRF 
electronic case report form 
ECG  
electrocardiogram  
ECOG  
Eastern Cooperative Oncology Group (ECOG) Performance Status  
FAS  
full analysis set  
FTase  
farnesyl transferase  
HIV  
human immunodeficiency virus  
PT/INR  
Prothrombin Time and International Normalized Ratio  
K-M  
Kaplan-Meier  


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MedDRA  
Medical Dictionary for Regulatory Activities  
MRI  
magnetic resonance imaging  
NCI-CTCAE  
National Cancer Institute – Common Terminology Criteria for Adverse 
Events  
NK  
natural killer  
ORR  
objective response rate  
PE   
physical examination  
PFS  
progression free survival  
  
  
PR  
partial response  
PT  
preferred term  
PTCL  
peripheral T-cell lymphoma  
SAE  
serious adverse event  
SAP  
statistical analysis plan  
SGOT  
serum glutamic oxaloacetic transaminase  
SGPT  
serum glutamic pyruvic transaminase  
SOC  
system organ class  
TEAE  
treatment emergent adverse event  
WHODRUG 
World Health Organization Drug Dictionary 
ULN  
upper limit of normal  
 


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1. 
INTRODUCTION 
Tipifarnib is a selective nonpeptide inhibitor of farnesyl transferase (FTase), an enzyme that 
couples an isoprenyl group to a number of intracellular proteins. Prenylation is essential for 
membrane localization and functional activity of those proteins. By inhibiting farnesylation, a 
blockade of prenylated protein-mediated signal transduction pathway is accomplished, with 
attenuation of cell growth. Consequently, inhibition of signaling using highly potent and 
selective farnesyl transferase inhibitors was proposed as an effective therapeutic approach in 
multiple oncology indications.  
Tipifarnib was the first specific inhibitor of FTase to enter clinical studies. The clinical 
development of tipifarnib began in 1997 and has consisted of over 70 clinical oncology and 
hematology studies. More details on tipifarnib are provided in the clinical study protocol as well 
as the Investigator’s Brochure (Tipifarnib’s Investigator’s Brochure, Edition 16, 29 January 
2021).  
This statistical analysis plan (SAP) is intended to describe the planned analyses and presentation 
of study data to be included in the clinical study report (CSR) for Protocol KO-TIP-002. This 
SAP has been developed according to 
 Standard Operating Procedure (SOP) 700: 
Developing and Maintaining a Statistical Analysis Plan, and accordingly, this plan and any 
deviations from this plan must be finalized, approved, and placed on file before the study 
database is locked. As per ICH E9 guidelines [FDA 1998] the purpose of this statistical analysis 
plan (SAP) is to provide a more technical and comprehensive elaboration of the principal 
features of the analysis described in the protocol document and to include detailed procedures for 
executing the statistical analyses of the study endpoints and other collected data. This SAP is 
based on Amendment 7 of the Clinical Trial Protocol (dated 12 July 2019) and on the version of 
the electronic case report forms (eCRFs) current as of the date of this version of the SAP. If there 
are additional amendments to the protocol or eCRFs, this SAP will be updated, as appropriate.   
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective and Endpoint  
Primary Objective: To determine the antitumor activity in terms of objective response rate 
(ORR) of tipifarnib in subjects with relapsed or refractory peripheral T-cell lymphoma (PTCL).  
Primary Endpoint: Response assessments according to the Lugano Classification (Protocol 
Appendix II). 


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2.2. 
 Secondary Objectives and Endpoints  
Secondary Objectives 
Secondary Endpoints 
To determine the antitumor activity in terms of 
progression free survival (PFS) and duration of 
response (DOR) of tipifarnib in subjects with 
relapsed or refractory PTCL.   
• Progression Free Survival (PFS) 
• Duration of Response (DOR) with the 
response assessed according to the Lugano 
Classification (Protocol Appendix II).  
Safety and tolerability of tipifarnib in subjects 
with relapsed or refractory PTCL.  
Treatment-emergent adverse events (TEAE) and 
serious adverse events (SAEs) evaluated 
according to NCI CTCAE v.4.03. 
Assessment of ORR, PFS, and DOR in study 
population subgroups defined according to the 
genetic subtypes. 
ORR, PFS, and DOR in subgroups defined by 
AITL, PTCL-NOS, CXCL12+, and Other. 
2.3. 
Exploratory Objectives and Endpoints  
Exploratory Objectives 
Exploratory Endpoints 
Assessment of the longitudinal data on tumor 
assessment.  
Tumor size  


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Exploratory Objectives 
Exploratory Endpoints 
Exploration of the feasibility of collecting tissue 
biopsies, buccal swabs, and blood samples and 
analyzing these biopsies and samples for the 
detection of biomarkers potentially related to 
tipifarnib activity. The biomarker analyses may 
include oncogene panel sequencing from tumor 
tissue samples, immune cytokine profiling from 
serum samples, and Killer cell Immunoglobulin-
like Receptor (KIR) genotyping from blood 
samples. 
 
   
Molecular results of blood, buccal swabs, and 
tumor tissue samples will be listed.  
 
3. 
STUDY DESIGN 
3.1. 
General Study Design and Plan 
This Phase 2 study will investigate the antitumor activity in terms of ORR of tipifarnib in 
subjects with relapsed or refractory PTCL. Only consented subjects who meet all the eligibility 
criteria will be enrolled in the study. All screening evaluations will be completed within 4 weeks 
(28 days) of Cycle 1 Day 1. Any screening evaluation, including disease status, will need to be 
repeated if performed more than 4 weeks from Cycle 1 Day 1.  
Up to 70 subjects may be enrolled (receive tipifarnib) in the study. The first 18 subjects may be 
of the following PTCL sub-types: PTCL, not otherwise specified (PTCL-NOS), 
angioimmunoblastic T-cell lymphoma (AITL), ALK-positive and -negative anaplastic large cell 
lymphoma (ALCL), hepatosplenic T-cell lymphoma, enteropathy-associate T-cell lymphoma 
(EATL), extranodal natural killer (NK) T-cell lymphoma, nasal type and subcutaneous 
panniculitis-like T-cell lymphoma. The AITL expansion cohort (N=12) will enroll only subjects 
with AITL.   
A multi-stage study design which assumes enrollment of the patients in potentially three 
consecutive groups (11, 7, and up to 52 participants) will be employed. This design is intended to 
allow the termination of accrual in case of unacceptably low efficacy after objective responses in 
the first 11 evaluable subjects (Stage 1) assessed in a Full Analysis Set (FAS) basis. If 0-1 
objective responses are observed after the first 11 evaluable subjects, the study will be closed to 
further enrollment. If 2-4 responses are observed, 7 additional subjects will be enrolled (Stage 2). 
Treatment will be considered of further interest if at least 4 responses are observed (out of 
18 subjects).  
Based on the observed antitumor activity during Stage 1 and Stage 2 of the study (2 subjects 
enrolled with AITL and both subjects achieved a partial response), an AITL cohort will be 
enrolled (N=12) according to Amendment 4 to the protocol. 


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Based on the observed antitumor activity during Stage 1 and Stage 2 of the study in which 
subjects who were found to have high levels of CXCL12 gene expression by retrospective 
analysis had a longer PFS compared to subjects with low expression, a CXCL12 + cohort will be 
enrolled (N = 12) according to Amendment 6 to the protocol. 
Based on the high antitumor activity observed in AITL subjects in the AITL cohort and other 
portions of the study, enrolment in the AITL cohort has been expanded to include up to 
20 additional subjects with tumors of AITL and related T follicular helper cell histologies in 
order to further characterize the safety and tolerability of tipifarnib in this relatively rare 
population. The selection of 20 subjects was empirical and no statistical hypotheses will be 
tested. Descriptive statistics will be used to report response rate. 
Eligible subjects will receive tipifarnib administered at a starting dose of 300 mg, orally with 
food, BID on days 1 - 21 in 28-day cycles. Stepwise 100 mg dose reductions to control 
treatment-related, treatment-emergent toxicities are allowed and further detailed in Section 9.5. 
Subjects who received tipifarnib bid on Days 1 – 7 and Days 15 – 21 in 28-day cycles during the 
conduct of earlier versions of this protocol may remain on that dose regimen at the discretion of 
the investigator. Alternatively, the subject may transition to receive a dose of 300 mg, orally with 
food, bid on Days 1-21 of 28-day treatment cycles beginning on Day 1 of their next cycle. 
Subjects may use proton pump inhibitors or H2 antagonists during the treatment portion of this 
study. However, subjects should be instructed to use antacids (magnesium or aluminum 
containing products) at least 2 hours before or after intake of oral study drug. 
In the absence of emerging unmanageable toxicity, subjects may continue tipifarnib treatment for 
as long as the investigator considers that the treatment is providing clinical benefit up to 
12 months since the subject’s enrollment. Treatment may continue beyond 12 months upon 
agreement by the Investigator and Sponsor if there is documented evidence of sustained clinical 
benefit. 
Tumor assessments will be performed at screening, at the Day 22 visit (± 5 days) performed 
during Cycles 2, 4, 6 and once every approximately 12 weeks (Cycles 9, 12, 15, etc.) thereafter, 
until disease progression. Tumor assessments will be performed more frequently if deemed 
necessary by the investigator. A tumor assessment will be performed upon treatment 
discontinuation (End of Treatment visit) if the reason for discontinuation is other than disease 
progression and no tumor assessment was performed in the prior 8 weeks. Subjects who 
discontinue treatment for reasons other than disease progression must continue tumor 
assessments until disease progression, withdrawal of subject’s consent or initiation of another 
anticancer therapy. Determination of objective tumor response will be performed by the 
Investigator according to the Lugano Classification. Subjects who have experienced a complete 
response may be considered for transplantation.  
Efforts will be made to collect information on the subject’s response and duration of response to 
the last prior therapy.  
Upon disease progression, all subjects will be followed approximately every 12 weeks for 
survival and the use of subsequent therapy until either death or 12 months after accrual of the last 


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study subject, whichever occurs first. Information on survival and subsequent anticancer therapy 
may be collected by phone.  
All subjects will be followed-up for safety during treatment and up to approximately 30 days 
(± 7 days) after treatment discontinuation or until immediately before the initiation of another 
anti-cancer therapy, whichever occurs first. Additional follow up may be implemented until the 
subject recovers from any emergent treatment related toxicity or the adverse event is considered 
irreversible by the investigator. Target organ toxicities will be monitored via clinical and 
laboratory assessments using the National Cancer Institute Common Terminology Criteria for 
Adverse Events version 4.03 (CTCAE v 4.03). 
3.2. 
Study Population  
3.2.1. 
Selection of Study Population  
Subjects within the initial trial subset of 18 subjects (Stage 1 and 2) and in the AITL expansion 
cohort who do not receive at least one dose of tipifarnib will be replaced. Subjects within the 
initial trial subset of 18 subjects (Stage 1 and 2) and in the AITL expansion cohort who are 
unable to provide archival tumor tissue by the end of Cycle 1 and who did not have a biopsy 
performed prior to initiation of tipifarnib treatment will be replaced. Replacement subjects will 
have available tumor tissue identified at the time of screening. In addition, subjects with archival 
tissue that is of insufficient quality for biomarker evaluation, may be replaced.  
3.2.2. 
Removal of Subjects from Treatment or Assessment  
Subjects may withdraw their consent to participate in this study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. A 
subject’s participation in the study may also be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. Every effort should be made to 
complete, whenever possible, the tests and evaluations listed for the End of Treatment visit. 
More details are available in Protocol Section 8.4.  
3.3. 
Premature Discontinuation of the Trial  
This trial may be discontinued prematurely in the event of any of the reasons listed in Protocol 
Section 8.5.  
3.4. 
Definition of End of Study  
For administrative and safety reporting purposes, the end of this clinical study is defined as 
12 months from enrollment of the last enrolled study subject. If the last enrolled study subject 
discontinues treatment within 12 months of study enrollment, the End of Study will occur no 
earlier than the date of the last enrolled subject’s safety follow-up assessment performed 
approximately 30 days after treatment discontinuation (or until initiation of another anti-cancer 
therapy). At the time of End of Study, provisions will be made to transition all remaining study 


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subjects who demonstrate sustained clinical benefit beyond the end of the study to other means 
of continued treatment with appropriate safety monitoring, e.g., single patient treatment protocol.  
3.5. 
Randomization and Blinding  
This is a single arm open label study. There is no randomization or blinding involved in this 
study.  
4. 
SAMPLE SIZE CONSIDERATIONS 
The study can enroll up to 70 participants. A multi-stage study design, which potentially assumes 
enrollment of the patients in three consecutive groups (11, 7, and up to 52 participants) will be 
employed. This design is intended to allow for the termination of accrual in case of unacceptably 
low efficacy. The objective responses will be evaluated in the first 11 participants (Stage 1) 
assessed in a Full Analysis Set (FAS). If 0-1 objective responses are observed after the first 
11 evaluable subjects, the study will be closed to further enrollment. If 2-4 responses are 
observed, 7 additional subjects will be enrolled (Stage 2). Treatment will be considered of further 
interest (successfully passing Stage 2 to full enrollment) if at least 4 responses are observed (out 
of 18 subjects) in Stage 2.  
In order to assess the operating characteristics of the design the following assumptions are made: 
• Null hypothesis of ORR = 10% is tested using a two-sided binomial test (based 
normal approximation) with significance level α≤0.05.  
• All participants, despite population heterogeneity in terms of sub-types, have the 
same true ORR. 
• Study total sample size is 65 evaluable participants given successful transition from 
stages 1 and 2 to full enrollment.   
Figure 1 depicts the relationship between the true ORR and power (red line) – probability of 
rejecting the null hypothesis given the assumptions above. It also shows the likelihood of passing 
Stage 1 (blue line) and Stage 2 (green line).  When the true ORR is 30%, the probability of 
passing Stage 2 and rejecting the null hypothesis at the end of the study (N = 65) is 
approximately 80%. These probabilities are increasing to approximately 99% when the true ORR 
is 50%. For ORR = 10%, the probability of passing Stage 1 is 30% (and 8% to pass Stage 2).   


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Figure 1: 
Operating Characteristics of Study Design 
Further sample size considerations are related to assessment of ORR in the subgroup of 
participants with AITL (N = 12) and CXCL12 (N = 12) subtypes. Figure 2 visualizes a 95% 
two-sided confidence interval for a hypothetical observed number of responders in the cohort 
consisting of 12 participants. It should be noted that the method of evaluating the confidence 
interval changes from Wilson1 to Pearson-Clopper2  if the number of responders falls below 
three. 
 
 
1 Wilson, E. B. (1927). "Probable inference, the law of succession, and statistical inference". Journal of the  
American Statistical Association. 22 (158): 209–212. 
2 Clopper, C.; Pearson, E. S. (1934). "The use of confidence or fiducial limits illustrated in the case of the  
binomial". Biometrika. 26 (4): 404–413. 
 


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Figure 2: 
Two-sided 95% Confidence Intervals for ORR 
5. 
ANALYSIS POPULATIONS  
Full Analysis Set (FAS) 
FAS will include the data on study participants who received at least one dose of tipifarnib and 
had at least one post-dose disease response assessment.    
 
 
  
All Subjects as Treated (ASaT) Population 
The ASaT population consists of all enrolled subjects who received at least one dose of tipifarnib 
and have at least one post-dose safety assessment (any laboratory, vital sign, or other safety 
assessment). 


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6. 
GENERAL STATISTICAL CONSIDERATIONS  
6.1. 
Interim Analysis and Data Monitoring  
One or more Interim Analysis (IA) may be conducted. The first IA will assess number of 
responders in Stage 1 (first 11 participants). Data may be monitored on ongoing basis which will 
include monitoring of enrollment of population sub-groups.  
6.2. 
Multi-Center Studies 
This is a multi-center study. Given the small sample size of the study, no site effect will be 
considered in primary or secondary statistical analysis. Site or geography impact may be 
considered in the exploratory analysis if deemed appropriate.   
6.3. 
Multiple Comparisons 
No adjustment of P-values for multiple comparisons will be conducted.  
6.4. 
Handling of Dropouts or Missing Data  
The primary analysis will be based on the observed available data – no data imputations will be 
conducted. For the survival analysis, dropouts without confirming events will be treated as 
censored.  
As part of the exploratory analysis, sensitivity analysis using appropriate data imputation models 
may be conducted. The impact of different imputation models will be assessed and compared to 
main analysis.  
7. 
SUMMARY OF STUDY POPULATION DATA   
7.1. 
Subject Disposition  
Subject disposition will be provided for all subjects screened. The disposition table will include 
the total number of subjects screened, total number of screen failures, and total number who 
received any study drug will be displayed. Among subjects who received any study drug, 
frequency and percentage of subjects who completed treatment, prematurely discontinued and 
reasons for premature discontinuation and reason for end of study will be tabulated. Subjects will 
be presented throughout by their genetic subtype:  AITL, PTCL, CXCL12+, and an Other 
category, which includes one subject that is ALCL-ALK negative and one that is PTCL sub-type 
not otherwise specified in the protocol.  
Detailed subject disposition information, subject eligibility, and analysis population assignment 
will be displayed in separate listings.  


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7.2. 
Protocol Deviations  
All protocol deviations will be documented and classified (minor, major, critical) prior to study 
data base lock. Listing and appropriate summary tables of all protocol deviations will be 
produced as part of the final analysis.  
7.3. 
Demographics and Baseline Characteristics 
Descriptive statistics will be provided for subject demographics and baseline characteristics. The 
following summary tables will be provided:  
• Demographics and baseline characteristics at screening to include age and sex.  
• Ethnicity and race will be stated where allowed by local regulatory authorities. 
Measurements of height, weight, and ECOG performance status score will be 
summarized for the ASaT, FAS,
 Populations.  
• Medical and surgical history/physical findings will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) version 19.0 and summarized by 
system organ class (SOC)/preferred term (PT) for the ASaT population.   
• Cancer history at screening will be summarized by diagnosis and stage for the ASaT 
population.  
• Prior anti-cancer therapy, cancer surgery and radiation therapy will be summarized 
for the ASaT population and for the FAS population. For prior anti-cancer therapy, 
descriptive statistics on the number of regimens per subject and best overall response on 
last prior therapy will be presented.  
• Last therapy progression free survival will be presented. Progression free survival on last 
prior therapy will be calculated as follows:  
([Progression Date – Earliest Treatment Initiation Date of Most Recent Prior Cancer Therapy] + 
1)/30.4375. If date of progression is not available for the last prior therapy, then the start date of 
Tipifarnib will be used to calculate PFS.  
• Kaplan Meier curves will present a comparison PFS on last prior therapy for the ASaT 
population by cohort compared to PFS on tipifarnib using a Cox Proportional Hazards 
model. 
The following listings will be provided:  
• Subject demographics 
• Baseline medical, surgical history/physical findings 
• Biopsy sample at screening 
• Buccal swab sample at screening 
• Cancer history at screening 


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• Previous anti-cancer therapy 
• Prior cancer surgery 
• Prior radiation therapy 
• Disease related symptom assessment at screening 
• Prior stem cell transplants at screening 
• ECOG performance status 
7.4. 
Dosing and Extent of Exposure 
Number of treatment cycles and average dose intensity per treatment cycle will be summarized 
using descriptive statistics. Total incidences of drug modification (dose reduction, dose 
interruption, dose increase, or drug withdrawn), frequency and percentage of subjects who 
experienced drug modification, and summary statistics of number of drug modifications per 
subject will also be summarized. 
Per subject log of study drug number of pills returned and dispensed will be displayed in a 
listing; tipifarnib dosing log will also be displayed in a listing. 
7.5. 
Concomitant Medications  
Prior and concomitant medications (other than cancer treatment) will be coded by World Health 
Organization Drug Dictionary (WHODRUG) version Dec-2015 B2 and summarized by preferred 
Anatomical Therapeutic Chemical 3 terms and preferred terms. Prior cancer-treatment 
medications will be similarly summarized.  
Prior and concomitant medication (other than cancer treatment) will be displayed in a listing. 
Non-drug treatments or procedures will also be listed. 
7.6. 
Follow Up Assessments  
Information on subsequent therapy and survival from follow up contacts will be displayed in 
separate listings.  
8. 
EFFICACY ANALYSIS  
8.1. 
Primary Efficacy Analysis 
The primary endpoint will be based on response assessments according to the Lugano 
Classification (Protocol Appendix II). Either complete or partial responses can contribute to an 
objective response. The objective response rate,  𝑝𝑝ෝ𝑂𝑂𝑂𝑂𝑂𝑂 , will be estimated as a ratio of subjects 
with an objective response to the number of subjects (N) in the FAS data set.  


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The 95% Confidence Interval for ORR will be calculated using Wilson3 approximation. 
If  𝑃𝑃෠𝑂𝑂𝑂𝑂𝑂𝑂× 𝑁𝑁≤4, the exact Clopper-Pearson4 method will be used for interval estimation.  
Null hypothesis 𝐻𝐻0:  𝑃𝑃෠𝑂𝑂𝑂𝑂𝑂𝑂= 10% versus 𝐻𝐻𝐴𝐴:  𝑃𝑃෠𝑂𝑂𝑂𝑂𝑂𝑂> 10% will be tested at 𝛼𝛼= 0.05 
significance level using a two-sided binomial test. The choice of test statistics will be driven by 
the method used for interval estimation.  
The ORR analysis will be presented by means of a summary table and visualization. A summary 
table of the objective response rates will be provided for the primary efficacy endpoint for both 
the FAS 
 populations. 
 
  
The ORR will also be analyzed by study population subgroups (part of the secondary analysis) 
which are based on the genetic sub-types. 
Sensitivity analysis, as part of the exploratory analysis, may also include analysis using different 
statistical approaches (different methods for interval estimation variants of normal 
approximation, Agresti-Coull, Pearson-Clopper, etc.), one-sided confidence intervals, test 
statistics, or a modelling framework). Exploratory analyses may also include a logistic regression 
modeling framework to evaluate the effect of genetic sub-types and other covariates on ORR. 
Additional sensitivity and subgroup analysis, as part of exploratory analysis, may be conducted 
as deemed appropriate.  
8.2. 
Secondary Efficacy Analysis  
The secondary efficacy analysis will focus on DOR and PFS analysis in the study population 
(FAS analysis data set), as well as on subgroup analysis of ORR, PFS, and DOR in genetic 
sub-types (AITL, PTCL-NOS, CXCL12+, and Other).  
The duration of the response will be calculated for subjects who achieve an objective response 
(either CR or PR, whichever comes first). For such subjects, the duration of the objective 
response is defined as the number of days from the start date of the objective response to the first 
date of either documented progressive disease or death. All efforts will be made to objectively 
define the endpoint by collecting the necessary data and reducing the likelihood of missing data. 
In the event of a maintained response, the DOR will be censored at the last evaluable non-PD 
assessment.  
Disease progression will be determined by the investigator using the primary efficacy endpoint 
assessment. Progression free survival will be defined as the time (in months) from first dose 
(Cycle 1 Day 1) to the minimum date of progression or death, if death occurred within 126 days 
 
3 Wilson, E. B. (1927). "Probable inference, the law of succession, and statistical inference". Journal of the 
American Statistical Association. 22 (158): 209–212. 
4 Clopper, C.; Pearson, E. S. (1934). "The use of confidence or fiducial limits illustrated in the case of the  
binomial". Biometrika. 26 (4): 404–413. 
 


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of the last treatment or assessment. If the subject goes off study with no documentation of PD, 
the censoring date will be the date of the last evaluable assessment.  
Sensitivity analyses may be conducted to explore the effect of different censoring on DOR and 
PFS. 
The duration of the objective response and progression free survival will be analyzed using the 
Kaplan-Meier (KM) method. 95% CI for KM curve will be constructed using Greenwood's5 
formula in the log−log scale. 
The median DOR and PFS will be evaluated using the 50th percentile of KM distribution.  95% 
CIs for the median will be constructed based on a robust nonparametric method of Brookmeyer 
and Crowley6.  
Summary tables and advanced data visualizations will be used for presenting KM plots, 95% CIs 
for probabilities of surviving X months, and a median survival estimate with its 95% CIs.  The 
analysis will be conducted on FAS (primary) 
 populations.  
Secondary analysis also involves subgroup analyses by genetic sub-types for ORR, DOR, and 
PFS. For each sub-type, the survival curves (DOR and PFS) and ORR rates will be estimated 
along with the relevant confidence intervals according to the methodology described above 
(Section 8.1 and Section 8.2). 
Listings with participant level summary of DOR, such as treatment initiation date, progression 
date, first response date, durations, censoring status, best overall response, and analysis 
belonging to the population will be presented. 
Multiple sensitivity analyses, as part of the exploratory analysis, may be conducted. Parametric 
survival regression framework (including Cox-regression and exponential regression) may be 
used to provide an alternative assessment of the survival curves and hazard function estimation. 
Sensitivity analysis may also include alternative methods for KM analysis (using interpolation 
estimators for median survival estimation, different methods for constructing CIs, etc.). 
Parametric modelling may also be used for identification of potentially influential covariates and 
estimation of their impact. These exploratory analyses will be conducted as deemed appropriate. 
Parametric modelling may be used to assess and compare the response in the subgroups of 
interest. A logistic regression framework may be used for ORR subgroups analysis. The models 
may be extended to control for influential covariates identified during the model building 
process. Parametric modelling (Cox regression) may also be used for subgroup analysis for DOR 
and PFS. As for the ORR case, the models may be extended to have influential covariates. 
Extensive data visualization will be used to present interval estimates of the response rate and 
survival summaries comparing the subgroups. 
 
5 Greenwood, M. (1926). Reports on Public Health and Medical Subjects. Ministry of Health.  No.33 pp. iv + 26 pp.  
6 Brookmeyer, R.; Crowley, J. (1982). "A Confidence Interval for the Median Survival Time." Biometrics 38, no. 1: 
29-41.  


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It should be noted that the subgroup analysis may encounter problems related to small sample 
sizes. These issues may potentially lead to degenerate estimation of median survival or quartile 
estimation (and to other estimation problems). Model based analysis may also suffer from small 
N limitations. It is critical to provide sensitivity analysis for all the main subgroup analysis as 
well as goodness of fit diagnostics and robustness testing whenever appropriate. All small 
sample size analysis may undergo stability analysis including data point perturbations. 
Alternative approaches, such as using interpolation-based estimation for median survival may be 
exercised for ensuring comprehensive sensitivity analysis. 
8.3. 
Exploratory Efficacy Analysis  
Exploratory analysis will be conducted as deemed appropriate. It will include sensitivity analysis 
described in Section 8.1 and Section 8.2. Exploratory analysis can be based on either or both 
FAS 
 data sets.  
An analysis of overall survival to estimate median overall survival time and corresponding 95% 
confidence interval and provide per subject summary of overall survival will be conducted 
overall and for each subtype (AITL, PTCL-NOS, CXCL12+, and Other). Overall survival will be 
defined as the time (in months) from first dose (Cycle 1 Day 1) to the occurrence of death due to 
any cause. In subjects without a death date, the OS will be censored on 1) the date a subject has 
end of study reason of ‘ended study per protocol’ for subjects with no survival status 
documentation, or 2) the date a subject withdraws consent from study or is lost to follow-up, if 
there is no additional information.  Subjects who ended study per protocol were no longer 
followed for survival status.   
ORR, PFS, and DOR will be evaluated in the subgroups of partial and complete responders. 
Further analysis may be conducted to evaluate the impact of age, disease duration and severity, 
IPI scores, geography, and other potentially influential covariates on ORR, PFS, and DOR. This 
analysis will be conducted using parametric models – logistic for ORR and Cox-regression for 
PFS and DOR.   
Tumor data may be analyzed using longitudinal mixed-effect models. Models will be explored to 
include covariates that can affect the tumor dynamics. Tumor data will also undergo subgroup 
analysis in AITL, PTCL-NOS, CXCL12+, and Other sub-populations. The analysis will be 
visualized using model summary plots, waterfall plots for maximum reduction in tumor lesion 
size, and spider plots to depict the reduction in tumor lesion by subject for the FAS 
 
populations. 
Biomarkers will be listed and may be further analyzed outside of this report. 
Exploratory analysis may also include sensitivity analysis to the statistical methodology and 
stability analysis when a small sample is present. 
Other exploratory analysis can be conducted as deemed appropriate. 


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9. 
SAFETY ANALYSIS  
Safety and tolerability of tipifarnib will be assessed based on the following: 
• Incidence, duration and severity of treatment-emergent adverse events, serious 
adverse events, adverse events resulting in permanent discontinuation of study drug, 
and deaths within approximately 30 days from the last dose of study drug (or 
immediately before the administration of another anti-cancer treatment) 
• Laboratory test results  
− Serum Chemistry: Blood Urea Nitrogen (or Uric Acid), Creatinine, Sodium, 
Potassium, Calcium, Total Protein, Albumin, Total Bilirubin, Alkaline 
Phosphatase, ALT/SGOT, AST/SGPT, Lactate Dehydrogenase;  
− Hematology: White Blood Cell Count, Hemoglobin, Platelet Count, Neutrophils, 
Lymphocytes, Monocytes;  
− Coagulation Panel: Prothrombin Time and International Normalized Ratio 
(PT/INR), Activated Partial Thromboplastin Time (APTT);  
• Changes in vital signs including blood pressure, pulse, and temperature;   
• Changes in electrocardiogram results.   
Adverse events will be coded using MedDRA per the Data Coding Plan. Treatment-emergent 
adverse events are defined as adverse events that start on or after the first dose of study drug and 
within 30 days of the last administration of study drug or immediately before the initiation of any 
other anticancer therapy. Adverse events will be summarized by the number and percentage of 
subjects who experienced the event, according to system organ class and preferred term. A 
subject reporting multiple cases of the same adverse event will be counted once within each 
system organ class and similarly counted once within each preferred term.  
Unless specified otherwise, the denominator for these calculations will be based on the number 
of subjects who received at least one administration of tipifarnib regardless of the total number 
of doses or treatment cycles administered. These conventions will be appropriately modified to 
calculate AE incidence rates separately for each cycle that study therapy is administered. AE 
incidence rates may also be calculated based on other measures of subject exposure (e.g., total 
number of treatment cycles administered).   
AE durations will be calculated using all TEAEs. For AEs that are still ongoing at the end of 
study, we will use the last contact date as the end of AE stop date for calculating the duration of 
AEs.  Median, minimum and maximum of AE durations will be reported.  
AEs will also be summarized by National Cancer Institute – Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) version 4.03 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 all Grade 3 and 4 hematological NCI-CTCAE severity grades will be provided 
by treatment cycle and across all treatment cycles. The severity grades for laboratory tests will be 
based on NCI-CTCAE version 4.03 criteria. The use of blood transfusions (platelets, red blood 
cells) and/or growth factor support will be reported. Similar analyses will be done for chemistry 
tests.   
Hematologic abnormalities reported as AEs that were coded to preferred terms in the 
Investigations SOC will be mapped to appropriate terms in the Blood and Lymphatic System 
SOC for tabulation for the following categories:  
• Platelet count decreased = Thrombocytopenia;  
• Neutrophil count decreased = Neutropenia;  
• White blood cell count decreased = Leukopenia;  
• Lymphocyte count decreased = Lymphopenia.  
Vital sign results (blood pressure, pulse, respirations, and temperature) will be summarized 
descriptively for each scheduled and unscheduled protocol time point. Changes will be 
calculated relative to the assessments at baseline and on the first day of each cycle of therapy.  
9.1. 
Adverse Events  
The following adverse event tables will be displayed:  
• Overall summary of TEAEs, to include total number of TEAE, frequency of subjects 
with TEAEs, drug-related TEAEs, SAEs, drug-related SAEs, Grade 3 or higher 
TEAEs, drug-related Grade 3 or higher TEAE, or death within 30-days within 
administration of study-drug, and AEs leading to permanent discontinuation of study 
drug   
• Overall summary of exposure-adjusted TEAE incident rates, calculated as number of 
events per cycle, and corresponding 95% confidence intervals frequency and 
percentage of TEAEs by SOC and preferred term (PT)   
• Frequency and percentage of TEAEs by SOC/PT by maximum CTCAE toxicity 
grade  
• Frequency and percentage of hematology-related TEAEs by SOC and PT   
• Frequency and percentage of hematology-related TEAEs by SOC/PT by maximum 
CTCAE toxicity grade  
• Frequency and percentage of chemistry-related TEAEs by SOC and PT   
• Frequency and percentage of chemistry-related TEAEs by SOC/PT by maximum 
CTCAE toxicity grade   
• Frequency and percentage of renal-related TEAEs by SOC and PT   


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• Frequency and percentage of renal-related TEAEs by SOC/PT by maximum CTCAE 
toxicity grade   
• Frequency and percentage of Grade 3 or 4 toxicities with PT of Fatigue 
• Frequency and percentage of Grade 3 or 4 toxicities with SOC of Gastrointestinal 
Disorders 
• Median duration in days for all TEAEs by SOC/PT   
• Frequency and percentage of study-drug related TEAEs by SOC/PT  
• Frequency and percentage of Grade 3 or higher study-drug related TEAEs by 
SOC/PT  
• Frequency and percentage of SAEs by SOC/PT   
• Frequency and percentage of study-drug related SAEs by SOC/PT   
• Frequency and percentage of TEAEs leading to permanent discontinuation of study 
drug   
Per subject listing of AE information will be provided. Per subject detailed information of SAE, 
Death on Study, and AEs that lead to study discontinuation will also be provided in separate 
listings.  
9.2. 
Clinical Laboratory Evaluations  
The following summary tables will be provided by treatment cycle:  
• Incidence of hematological severities Grade 3 or above  
• Incidence of chemistry severities Grade 3 or above  
• Incidence of blood transfusion or growth factor support   
Per subject laboratory results for selected hematology and clinical chemistry will be displayed in 
listings. Laboratory values outside normal limits will be identified and flags for high and low 
values along with normal limits will also be presented in these listings. 
9.3. 
Vital Signs  
Summary statistics of vital signs and changes of vital signs relative to the assessments at baseline 
and to the first day of each cycle will be provided   
Individual vital sign records will be displayed in Listings.  
9.4. 
ECGs  
Summary statistics of ECG Overall Category (Normal, Abnormal Not Clinically Significant, or 
Abnormal Clinically Significant) will be displayed in a table. Shift of ECG Overall Category 
from Screening to Cycle 1 Day 1, Cycle 1 Day 7, and End of Treatment will also be provided.   


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Per subject ECG test results at Screening, Cycle 1 Day 1, Cycle 1 Day 7, repeat assessment and 
End of Treatment will be displayed in a Listing.  
9.5. 
Other Safety Measures  
ECOG performance status per subject during the trial will be displayed in a listing.  
10. 
CLINICAL PHARMACOLOGY ANALYSES  
None.  
11. 
OTHER ANALYSES  
Not applicable.  
12. 
DATA HANDLING CONVENTIONS  
Analyses will be performed using SAS® [SAS Institute 2011] Version 9.3 or higher.  
The clinical database will be locked prior to the initiation of the final statistical analyses. A 
database lock is defined as a stable database that can be analyzed and reported. Changes to a 
locked database must be authorized in writing by the study sponsor and 
 
standard operating procedures (SOPs).  
The data conventions include the following.  
• Data will be described and summarized by cohort, according to Protocol Amendment 
version.  
• Summary tables for continuous variables will contain the following statistics: N 
(number of subjects in the population); n (number of subjects with data for that 
variable); mean; standard deviation; median; minimum; and maximum. Selected 
statistics may also include 2 sided 95% normal approximation confidence intervals 
(CI) on the mean.  
• Summary tables for categorical variables will include: N (number of subjects in the 
denominator); n (number of subjects in the numerator); and percent. Selected 
statistics also may include a 2-sided 95% CI.   
• The baseline value for a given parameter is the last value prior to the first dose. A 
value is considered to be post-baseline if it is obtained after the first dose. A value is 
considered to be post-dose on a given cycle day if it is obtained after the dose is 
administered on that day.  
• Data from all study centers will be pooled for all analyses.   


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• Unless otherwise specified, statistical testing will be 2-sided at a nominal 0.05 level 
of significance.   
• Study day is defined as calendar date – date of first treatment + 1 if the calendar date 
is on or after the date of first treatment, and calendar date – date of first treatment if 
the calendar date is before the date of first treatment  
• Missing data conventions for individual endpoints are described in the SAP section 
for the endpoint.  
• Listings will be provided for all data collected in the eCRF.  
13. 
REPORTING CONVENTIONS  
The table, listing and figure reporting layout will be detailed in the companion document 
KO-TIP-002 Table, Listing and Figure Shells.  
14. 
CHANGES IN THE STATISTICAL METHODS FROM THOSE 
STATED IN THE PROTOCOL  
For the efficacy analysis, the estimation of the objective response rate will be estimated for all 
subjects in the indicated study population and will not be done separately for each tumor 
histology type evaluated.  
An exploratory Efficacy Analysis (to be performed if results warrant) has been added and is 
described in Section 8.3 of this document.   
Summaries for hematology and chemistry-related AEs have been added to the safety analysis.  
Laboratory change and shift from baseline will not be performed.  
15. 
TABLES, FIGURES, LISTINGS  
Tables, listings and, if applicable, figures will be generated according to the companion 
document which details the layout of the output. Minor style deviation from specification defined 
in the shell document in the final production is permissible.