Clinical trial NCT02807272
Conditions: Leukemia, Myelomonocytic, Chronic
Sponsor: Kura Oncology, Inc.
Start date: 2017-01-10; Completion date: 2020-11-30
Enrollment: 44 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase 2 study to investigate the antitumor activity in terms of overall response rate (ORR) of tipifarnib in approximately 36 eligible subjects with Myelodysplastic/Myeloproliferative Neoplasias (MDS/MPN), including Chronic Myelomonocytic Leukemia (CMML), and 36 eligible subjects with Acute Myeloid Leukemia (AML). Subjects received tipifarnib 1200 mg to be taken orally with food, twice daily, for 7 days in alternating weeks (Days 1 to 7 and Days 15 to 21) in 28-day cycles. Following amendment 3 subjects (Cohorts 1-4) will receive tipifarnib administered at a dose of 400 mg, orally with food, twice a day (bid) for 21 days in 28-day cycles.

Detailed description:
This Phase 2 study will investigate the antitumor activity in terms of ORR of tipifarnib in subjects with Myelodysplastic/Myeloproliferative Neoplasias (MDS/MPN cohorts) and Acute Myeloid Leukemia (AML cohorts). For MDS/MPN cohorts, this study will assess the antitumor activity of tipifarnib, in terms of ORR, in subjects with MDS/MPN, including CMML, who have a high ratio of expression of CXCR4 to CXCR2 (CXCR4/2 ratio) in their bone marrow and in those with a low CXCR4/2 ratio. For AML cohorts, this study will assess the antitumor activity of tipifarnib, in terms of ORR, in subjects with AML who have a high ratio of expression of CXCR4 to CXCR2 (CXCR4/2 ratio) in their bone marrow and in those with low CXCR4/2 ratio. Subjects enrolled in the study will consist of patients with KRAS, NRAS wild type status.

1. Subjects with MDS/MPN with high CXCR4/2 ratio
2. Subjects with MDS/MPN with low CXCR4/2 ratio
3. Subjects with AML with high CXCR4/2 ratio
4. Subjects with AML with low CXCR4/2 ratio

Arms: arm 1: Single arm
Interventions: intervention 1: Tipifarnib
Intervention descriptions: intervention 1: Oral tablet

Protocol documents:
Prot_000.pdf: 
Protocol Number: KO-TIP-004 
 
Official Title:  
 A Phase 2 Study of Tipifarnib in Subjects with Chronic Myelomonocytic Leukemia, Other 
Myelodysplastic /Myeloproliferative Neoplasias, and Acute Myeloid Leukemia 
 
NCT Number: NCT02807272 
 
Document Date: 21 March 2018 


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CLINICAL TRIAL PROTOCOL 
 
A Phase 2 Study of Tipifarnib in Subjects with  
Chronic Myelomonocytic Leukemia, Other Myelodysplastic 
/Myeloproliferative Neoplasias, and Acute Myeloid Leukemia  
 
CTP ID Number: KO-TIP-004 
Investigational Product: Tipifarnib (R115777; Zarnestra™) 
US IND Number: 052,302 
EudraCT Number: 
Indication: Advanced Hematological Malignancies 
Development Phase: Phase 2 
 
Sponsor: Kura Oncology, Inc. 
11119 N. Torrey Pines Rd., Suite 125 
La Jolla, CA 92037 (USA) 
Phone: +1 858.500.8800  
 
Protocol Authors: 
  
Version and Date: Protocol Amendment 3, 21 March 2018 
 
 
 
CONFIDENTIAL 
This is a Kura Oncology, Inc. document that contains confidential information. It is intended solely for the 
recipient clinical Investigator(s) and must not be disclosed to any other party. This material may be used 
only for evaluating or conducting clinical investigations; any other proposed use requires written consent 
from Kura Oncology, Inc. 
 




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2 
SYNOPSIS 
TITLE: A Phase 2 Study of Tipifarnib in Subjects with Chronic Myelomonocytic Leukemia 
(CMML), Other Myelodysplastic/Myeloproliferative Neoplasias (MDS/MPN), and Acute 
Myeloid Leukemia (AML)  
SPONSOR: Kura Oncology, Inc. 
PROTOCOL NUMBER: KO-TIP-004 
STUDY SITES: Multiple centers in the United States (U.S.). Additional study centers may be 
open outside the U.S.  
PHASE OF DEVELOPMENT: Phase 2 
STUDY PERIOD: This trial is planned to initiate enrollment in the second half of 2016. It is 
estimated that it may require approximately 3 years to complete all its study objectives. 
OBJECTIVES: 
Primary Objective 1: To assess the antitumor activity of tipifarnib, in terms of Objective 
Response Rate (ORR), in subjects with CMML and in subjects with CMML whose disease is 
KRAS/NRAS wild type. 
Primary Objective 2 (MDS/MPN cohorts): To assess the antitumor activity of tipifarnib, in 
terms of ORR, in subjects with MDS/MPN, including CMML, who have a high ratio of 
expression of CXCR4 to CXCR2 (CXCR4/2 ratio) in their bone marrows and in those with 
low CXCR4/2 ratio. 
Primary Objective 3 (AML cohorts): To assess the antitumor activity of tipifarnib, in terms 
of ORR, in subjects with AML who have a high ratio of expression of CXCR4 to CXCR2 
(CXCR4/2 ratio) in their bone marrows and in those with low CXCR4/2 ratio. 
Secondary Objective 3:  To assess the effect of tipifarnib on the following: 
• Rate of complete response (CR), complete cytogenetic remission, partial remission, 
marrow response, and clinical benefit 
• Duration of Response 
• Rate of progression free survival (PFS) at 1 year 
• Rate of survival at 1 year 
• Adverse event (AE) profile according to National Cancer Institute Common 
Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v 4.03) 
Exploratory Objective: To explore potential biomarkers and their association with clinical 
benefit from tipifarnib including cancer gene mutations, monocyte and immune cell subsets 
and other candidate biomarkers of tipifarnib in bone marrow and blood samples.   
STUDY DESIGN: 


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Amendment 3 (2018-03-9): This Phase 2 study will investigate the antitumor activity in terms 
of ORR of tipifarnib in approximately 36 eligible subjects with MDS/MPN, including CMML, 
and 36 eligible subjects with AML.   
Prior to amendment 3, subjects with CMML were enrolled in the study and retrospectively 
stratified by RAS mutational status.  The study met its primary endpoint with 3 objective 
responses observed in 9 evaluable subjects with RAS wildtype CMML (Patnaik 2017).  No 
responses were observed in 7 evaluable CMML subjects with RAS mutations.  
Analysis of gene expression in bone marrows obtained at baseline (prior to the first dose of 
tipifarnib) from the CMML subjects enrolled in the study indicated that a high ratio of 
expression of the C-X-C motif chemokine receptors CXCR4 and CXCR2 was significantly 
associated with clinical benefit from tipifarnib (Gualberto 2017). Prior data in AML and 
peripheral T cell lymphoma indicated that tipifarnib interferes with the activity of CXCL12 
pathway (Gualberto 2017, Witzig 2017). CXCR4 mediates the effects of CXCL12 in myeloid 
cells, inducing bone marrow homing, while CXCR2, the IL-8 receptor, has an antagonistic 
function, inducing mobilization of myeloid cells from the bone marrow (Coffelt 2016). Bone 
marrow homing is associated with clinical benefit from tipifarnib (Gualberto 2017). The 
farnesylated proteins responsible for these effects of tipifarnib are under investigation. 
Based on these data, the study protocol has been amended to prospectively test the hypothesis 
that a high ratio of expression between CXCR4 and CXCR2 (CXCR4/2 ratio) receptors could 
be associated with responsiveness to tipifarnib in myeloid neoplasias. For that purpose, four 
additional cohorts will be enrolled in the study as follows: 
1. Subjects with MDS/MPN with high CXCR4/2 Ratio 
2. Subjects with MDS/MPN with low CXCR4/2 Ratio 
3. Subjects with AML with high CXCR4/2 Ratio 
4. Subjects with AML with low CXCR4/2 Ratio 
Provision of a bone marrow aspirate during screening procedures for biomarker analyses is 
necessary for the assignment of a subject to a treatment cohort.  
Each cohort has a 2-stage design. Seven subjects will be enrolled in the first stage of each 
cohort.  If at least one objective response is observed, the cohort will be expanded to enroll an 
additional 11 subjects in stage 2.  The cohort will be considered positive if 4 or more responses 
are observed in the 18 subject cohort (Figure 1). Based on the absence of objective responses 
observed in the initial cohort of CMML subjects, all enrolled subjects enrolled in amendment 
3 cohorts 1-4 will have RAS wild type tumor status at study entry. 
Subjects (amendment 3 cohorts 1-4) will receive tipifarnib administered at a dose of 400 mg, 
orally with food, bid for 21 days in 28 day cycles.  This dose regimen was selected based on 
the average dose intensity for tipifarnib in the INT-17 study that enrolled 252 subjects with 
relapsed/refractory AML, and the results of the North American Intergroup Phase II study 
SWOG S0432 that investigated 4 different regimens of tipifarnib in 348 older, previously 
untreated, AML subjects. The average dose intensity for all treated subjects in INT-17 was 892 
mg/day, with a target dose intensity of 900 mg/day (1200 mg/day for 21 days of every 28 day 


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cycle). The average dose intensity for the ‘per protocol’ INT-17 population was 852 mg/day, 
equivalent to 567 mg/day bid for 21 days in 28 day cycles. SWOG S0432 randomized AML 
subjects to receive either 600 mg or 300 mg of tipifarnib orally twice daily on days 1–21 or 
days 1–7 and 15–21, repeated every 28 days (4 treatment regimens). Responses were seen in 
all regimens, with overall response rate (CR + CRi + PR) highest (20%) among patients 
receiving tipifarnib 300 mg twice daily on days 1–21. Fatal toxicity was highest in the 600 mg 
bid days 1–21 regimen (8%). Stepwise 100 mg dose reductions to control treatment-related, 
treatment-emergent toxicities are allowed.  In the absence of unmanageable toxicities, subjects 
may continue to receive tipifarnib treatment until disease progression.  If a complete response 
is observed, therapy with tipifarnib will be maintained for at least 6 months beyond the start of 
response.  
Figure 1: Study Design 
Disease assessments will be performed at screening, at the Day 25 visit (± 5 days) performed 
during Cycles 2, 4, 6, 9 and every approximately 12 weeks thereafter (Cycles 12, 15, etc.), at 
the End of Treatment visit and during follow up.  As part of the disease assessment at screening 
and at the Day 25 visit performed during Cycles 2, 4, 6 and 9, bone marrow evaluations will 
be conducted.  Thereafter, bone marrow evaluations will occur during disease assessments in 
accordance with institutional standard practice.  Hematologic assessments, including peripheral 
blood evaluations and review of transfusion requirements, will be performed at screening and 
at least monthly until disease progression.  Additional disease or hematologic assessments may 
be conducted if deemed necessary by the Investigator. The timing of the disease and 
hematologic assessments should be maintained as much as possible independently of potential 
treatment cycle delays. 
Determination of disease response in subjects with MDS/MPN subjects will be performed by 
the Investigator according to the Myelodysplastic/Myeloproliferative International Working 
Group (MDS/MPN IWG) criteria (Table 9).  Similarly, disease progression will also be 
determined based on the MDS/MPN IWG criteria (Table 10).  Determination of disease 
response in subjects with AML will be performed by the Investigator according to the 
International Working Group criteria (Cheson 2003).  Similarly, disease progression will also 
be determined based on the IWG criteria (Cheson 2003). 
Cohort 3: AML High CXCR4/2      
N=7 
Cohort 1: MDS/MPN High CXCR4/2 
Cohort 2: MDS/MPN Low CXCR4/2  
 Cohort 3: AML Low CXCR4/2       
N=7 
N=7 
N=7 
N=11 
N=11 
N=11 
N=11 
Stage 1 
Stage 2 
Interim: At least one objective response 
required to proceed from stage 1 to stage 2   
Amendment 3 Cohorts 
Success criteria: 
4 or more 
responses in 18 
subjects to 
determine that 
true ORR>10% 


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Upon disease progression, all subjects in the study 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 study cohort has been completed, whichever occurs first. Information on survival 
and subsequent anticancer therapy may be collected by phone. 
Subjects who terminate treatment for reasons other than death or disease progression will be 
assessed at regular intervals for disease progression (approximately every 2 months through 
the first 6 months from the start of the subject’s participation in this study and every 
approximately 12 weeks thereafter) and leukemic transformation (monthly blood counts).  
Disease assessments performed during the first 9 months from the start of the subject’s 
participation in the study will include bone marrow evaluation.  Thereafter, bone marrow 
evaluations will occur during disease assessments in accordance with institutional standard 
practice. These assessments will continue until disease progression, withdrawal of subject’s 
consent to study procedures or initiation of another anticancer therapy.   
All subjects will be followed-up for safety during treatment and up to approximately 30 days 
(30 ± 7 days) after treatment discontinuation or until immediately before the initiation of 
another anticancer therapy, whichever occurs first. Additional follow up may be implemented 
until the subject recovers from any emergent treatment related toxicity or the AE is considered 
irreversible by the Investigator. Target organ toxicities will be monitored via clinical and 
laboratory assessments using the NCI CTCAE v.4.03 criteria. 
NUMBER OF SUBJECTS PLANNED: Up to approximately 92 evaluable study subjects. 
Twenty in the initial CMML cohort and up to 72 additional evaluable subjects in cohorts 1-4 
of amendment 3. 
SUBJECT SELECTION:  
Inclusion Criteria 
For inclusion of a subject in the study, all of the following inclusion criteria must be fulfilled: 
1. Subject is at least 18 years of age. 
2. For subjects to be enrolled in the CMML or MDS/MPN cohorts: 
a. Diagnosis of CMML or MDS/MPN as defined by the World Health Organization 
(WHO) criteria (2008). 
3. For subjects enrolled in the AML cohort: 
a. Documented pathological evidence of AML, as defined by WHO criteria (2008) 
b. Refractory to previous induction chemotherapy, relapsed disease, or age ≥ 60 and 
not appropriate for standard cytotoxic therapy due to age, performance status, 
and/or adverse risk factors according to the treating physician 
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2. 


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5. Subject is willing and able to comply with scheduled visits, treatment plans, laboratory tests 
and other procedures (including bone marrow assessments). 
6. At least 1 week since the last systemic therapy regimen prior to Cycle 1 Day 1.  Subjects 
on a stable dose of hydroxyurea for at least 2 weeks prior to Cycle 1 Day 1 may continue 
on hydroxyurea until Cycle 1 Day 14.  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. Acceptable liver function:  
a. Total bilirubin ≤ upper limit of normal (ULN). 
b. AST (SGOT) and ALT (SGPT) ≤ 1.5 x ULN. 
8. Acceptable renal function with serum creatinine ≤ 1.5 x ULN or a calculated creatinine 
clearance ≥ 60 mL/min using the Cockcroft-Gault or Modification of Diet in Renal Disease 
formulas. 
9. Female subjects must be: 
a. Of non-child-bearing potential (surgically sterilized or at least 2 years post-
menopausal); or 
b. If of child-bearing potential, subject must use a highly effective method of 
contraception, such as combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation, progestogen-only hormonal 
contraception associated with inhibition of ovulation, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised 
partner or sexual abstinence.  Both females and male subjects with female partners 
of child-bearing potential must agree to use a highly effective method of 
contraception for 2 weeks prior to screening, during, and at least 28 days after last 
dose of trial medication for females and 90 days for males. Female subjects must 
have a negative serum or urine pregnancy test within 72 hours prior to start of trial 
medication. 
c. And, not breast feeding at any time during the study. 
10. Written and voluntary informed consent understood, signed and dated. 
Exclusion Criteria 
1. Neoplasia harbours RAS mutation (NRAS mutant, KRAS mutant or double mutant) 
2. Acute promyelocytic leukemia or Bcr-Abl positive leukemia (chronic myelogenous 
leukemia in blast crisis) 
3. Clinically active CNS leukemia 
4. CMML with t(5;12) that have not yet received imatinib. 


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5. Participation in any interventional study within 1 week of randomization or 5 half-lives of 
the prior treatment agent (whichever is longer). 
6. Ongoing treatment with an anticancer agent for CMML, MDS/MPN or AML not 
contemplated in this protocol.  Subjects on a stable dose of hydroxyurea for at least 2 weeks 
prior to Cycle 1 Day 1 may continue on hydroxyurea until Cycle 1 Day 14.   
7. Hematopoietic stem cell transplantation (HSCT) performed within 3 months prior to Cycle 
1 Day 1. 
8. Concurrent use of granulocyte macrophage colony-stimulating factor (GM-CSF). 
9. Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor. 
10. Active coronary artery disease requiring treatment, myocardial infarction within the prior 
year, New York Heart Association grade III or greater congestive heart failure, cerebro-
vascular attack within the prior year, or current serious cardiac arrhythmia requiring 
medication except atrial fibrillation. 
11. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, 
without complete recovery. 
12. Active, concurrent malignancy requiring radiation, chemotherapy, or immunotherapy 
(excluding non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and 
hormonal treatment for castration sensitive prostate cancer).  
13. Active and uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. 
Known infection with human immunodeficiency virus (HIV), or an active infection with 
hepatitis B or hepatitis C. 
14. 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.  
15. The subject has legal incapacity or limited legal capacity. 
16. 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 
• CMML 
This initial trial cohort was planned as a single treatment trial with statistical comparison to 
historical ORR rate 0.10 (10%).  The primary objective is to provide evidence that the TRUE 
underlying ORR in all patients and/or in the KRAS/NRAS wild-type subgroup exceeds 0.10.  
The evidence will be quantified by calculation of the Bayesian posterior probability that the 
TRUE underlying ORR exceeds 0.10 based on the OBSERVED ORR in the trial using both an 
informative and uninformative Bayesian prior distribution for TRUE ORR.  If this probability 


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is over 80%, then it will be concluded that the TRUE ORR exceeds 0.10, i.e. the trial results 
will have met success criteria to demonstrate efficacy. 
Prior data on tipifarnib in CMML (Study INT-28) yielded ORR ~0.20 in subjects with 
unknown KRAS/NRAS status.  However, it is assumed that ORR in KRAS/NRAS wild type 
patients will be higher; hence, a Bayesian prior distribution with ORR=0.30 is assumed.  The 
Bayesian prior will be given equal weight to the estimate from the trial, and, in order to be 
conservative, it will be evaluated with minimal weight of a single subject.  If the TRUE 
underlying ORR for tipifarnib is 0.30, then a sample size of N=10 KRAS/NRAS wild type 
patients has ~85% probability to achieve the success criteria, assuming the minimally 
informative prior.  Nonclinically, it has been demonstrated using a large panel of cell lines that 
Ras wild-type cell lines are more sensitive to tipifarnib than Ras mutant lines (End 2001), 
therefore it could be possible that subjects without KRAS and/or NRAS mutations may be 
more sensitive to tipifarnib therapy. If the TRUE ORR is 0.4, the probability of achieving 
success is 95%.  Thus, the trial is adequately powered with N=10 KRAS/NRAS wild type 
subjects if the TRUE ORR in CMML is 0.4. 
• Amendment 3 Cohorts: MDS/MPN and AML 
The cohorts introduced in amendment 3 employ a 2-stage design. In the first stage, 28 eligible 
subjects (7 subjects per cohort in Stage 1) will be enrolled and stratified into one of four 
neoplasia and biomarker-defined cohorts based on diagnosis and subject CXCR4/2 expression 
ratio level (high vs low) determined from a bone marrow sample. Each cohort will be 
terminated if 0 responses are observed at end of first stage.  Otherwise, an additional 11 subjects 
will be enrolled for the second stage.   
At the completion of a two-stage cohort, the cohort will be considered as failed if there are 3 
or less responses out of 18 evaluable subjects, indicating the true ORR is 10% or less.  If 
there are 4 or more responses, the treatment will be considered of further interest indicating 
the true ORR is higher than 10%.   
For this two-stage study design, a null response rate of 10% and alternative response rate of 
30% are assumed.  It provides 80% power to detect a difference between 10% and 30% ORR 
at one-sided significance level of 0.089.  Using this design, the probability of terminating the 
cohort at the end of first stage is 0.48 if the true ORR is 10% or less while the probability of 
terminating the cohort at the end of first stage is 0.13 if the true ORR is 30%.   
Tolerability/safety data will be evaluated descriptively. 
Data will be summarized by standard summary statistics and additional descriptive methods 
including individual data listings and plots of individual data and summary statistics.  
Summaries will be by type of neoplasia (MDS/MPN or AML), KRAS/NRAS subgroup (wild 
type and mutant status, Initial CMML cohort), CXCR4/2 expression ratio (high vs low) and for 
all subjects combined. 
A detailed statistical analysis plan (SAP) will be written to describe details of the planned 
analyses. The endpoints will be analyzed based on methodology found in the SAP. 
 
 


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STUDY ASSESSMENTS: 
Table 1: Schedule of Activities 
Activity 
Screening1 
Cycle (28 days) 
End of 
Treatment 
Visit3 
Follow 
Up 
Visit4  
Follow 
Up 
Contact5 
D1  
(± 2d) 
D15 
(± 2d)23 
D25   
(± 5d)2 
ICF, 
Inclusion/exclusion 
criteria evaluation, 
HIPAA form 
X 
 
Medical History 6 
X 
Concomitant meds and 
AE assessment 7 
 
X (assessed at each study visit and as clinically 
needed) 
 
Complete physical 
examination, including 
vital signs (heart rate, 
blood pressure, 
temperature) 
X 8 
 
 
 
X 
 
 
Weight 
X 
X 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
ECOG performance 
status 
X 8 
X 
 
 
X 
 
 
Symptom based 
physical examination  
 
X 
X 23 
X 
 
 
 
Pregnancy test 9 
X 10 
X 11 
 
 
X 
 
 
Serum chemistry 12 
X 8 
X 13 
X 
 
X 
 
 
Hematology 12 
X 8 
X 13 
X 
X 
X 
X 21 
 
Coagulation 12 
X 8 
 
 
 
X 
 
 
Perform bone marrow 
aspirate for disease 
assessment, cytogenetic 
assessment and bone 
marrow biomarkers, 
including CXCR4/2 
ratio 14  
X 15 
 
 
X 24 
X  
X 22 
 
Completion of MPN-
SAF TSS 14, 26 
X 
 
 
X 
X 
X 22 
 
Record the number of 
RBC, whole blood and 
platelet transfusions 16 
X 
X 
 
X 
X 
X 22 
 
Blood sample for NGS 
oncogene panel 
sequencing including 
KRAS, NRAS 17 
X  
 
 
 
X 
 
 
Plasma and serum 
samples for biomarkers 
18       
 
X 
 
X 
 
 
 
Tipifarnib 
administration 19 
  
X 
X 
X 24 
 
 
 


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1. 
Screening evaluations will be completed within 4 weeks (28 days) of Cycle 1 Day 1. Evaluations performed as part of 
the standard of care within 28 days of dosing but prior to consent do not need to be repeated. By signing the consent form, 
study subjects agree to the collection of standard of care health information.  The following screening evaluations should 
be completed within 14 days of Cycle 1 Day 1: complete physical exam, ECOG performance status, serum chemistry, 
hematology and coagulation.  Female subjects must have a negative serum or urine pregnancy test within 72 hours prior 
to start of study medication (Cycle 1 Day 1).     
2. 
Day 25 visit (± 5 days) should be performed during Cycles 2, 4, 6, 9 and every approximately 12 weeks thereafter (Cycles 
12, 15, etc.) until disease progression. 
3. 
An End of Treatment visit will be conducted within 30 days (± 7 days) from the last dose of tipifarnib or immediately 
before the initiation of any other anticancer therapy. 
4. 
Follow up visit required only for subjects who terminated treatment for reasons other than death or disease progression. 
5. 
Information on subject’s survival and use of subsequent anticancer therapy may be collected by phone. Upon disease 
progression, all subjects will be followed approximately every 12 weeks for survival and the use of subsequent therapy 
until either death or 12 months after accrual in the subject’s study cohort has been completed, whichever occurs first. 
6. 
Medical history is to include demographics, primary diagnosis and WHO classification, outcome and duration of response 
to prior cancer therapy and any ongoing AEs 
7. 
Assessed throughout the course of the treatment and approximately 30 days after treatment discontinuation. Additional 
assessments may be performed until AE resolution or the AE is deemed irreversible by the Investigator. 
8. 
Assessment to be performed within 14 days of Cycle 1 Day 1 
9. 
In women with childbearing potential, pregnancy tests (urine or serum) will be conducted at screening (must be performed 
within 72 hours of Cycle 1 Day 1), on Day 1 of each treatment cycle beginning at Cycle 2 and at the End of Treatment 
visit. If a positive urine pregnancy test is obtained, a confirmatory serum pregnancy test should be conducted. 
10. Assessment to be performed within 72 hours of Cycle 1 Day 1. 
11. Assessment to be performed beginning at Cycle 2. 
12. During screening, hematology, serum chemistry and coagulation must be done within 14 days prior to first administration 
of study drug on Day 1 of Cycle 1. Hematology and serum chemistry laboratory tests do not need to be repeated on Cycle 
1 Day 1 if the screening laboratory tests were conducted within 72 hours prior to the first dose of tipifarnib.  Fasting for 
laboratory testing is not required. Laboratory tests may need to be conducted on additional time points if deemed 
necessary by the Investigator. Samples will be analyzed locally at the clinical site or its reference laboratory. Laboratory 
assessments may be repeated if values are borderline to inclusion level or may change due to best supportive care 
measures.  Hematology should include: hemoglobin, platelets, WBCs, neutrophils, neutrophil precursors, monocytes, 
lymphocytes and blasts.  Serum chemistry should include: AST, ALT, total bilirubin, creatinine, potassium and calcium.  
Coagulation should include: PT/INR, APTT.   
13. Laboratory tests do not need to be repeated on Cycle 1 Day 1 if the screening laboratory tests were conducted within 72 
hours prior to the first dose of tipifarnib. 
14. As part of the disease assessment at screening and at the Day 25 visit performed during Cycles 2, 4, 6 and 9, bone marrow 
evaluation will be performed.  Thereafter, bone marrow evaluations will occur during disease assessments in accordance 
with institutional standard practice.  If a CR or PR is observed on the bone marrow sample, a bone marrow aspirate must 
be repeated 1 month later, i.e. prior to the end of the next cycle.  If the bone marrow aspiration results in an inadequate 
sample for disease assessment, a bone marrow biopsy should be performed. RNA samples for biomarker analyses will be 
taken at Screening and Cycle 2 only.   
15. Samples for RT-PCR of CXCR4, CXCR2, and CXCL12, and gene expression profiling by RNASeq (PAXgene RNA 
tubes) will be provided at screening, C2D25 and EOT. A bone marrow sample for whole exome next generation DNA 
sequencing (NGS) of common myeloid mutations, including sequencing of KRAS and NRAS, will be provided at 
screening (PAXgene DNA tubes). Bone marrow aspirates will be collected as per institutional standard practice.  
16. At the screening visit, record the number of red blood cell (RBC), whole blood and platelet transfusions for the four 
months prior to Cycle 1 Day 1; for all other visits, the number of transfusions should be recorded since the last study visit. 
17. A whole blood sample will be collected for DNA for a NGS oncogene panel test including KRAS, NRAS and oncogenes 
most commonly mutated in CMML and AML.  Samples will be collected at Screening and at the EOT visit. A protocol 
will be provided in the lab manual. Subjects with known wild type KRAS, NRAS status can be enrolled in the study prior 
Drug accountability 
 
X 20 
 
 
X 
 
 
Buccal swabs 25 
X 
 
 
 
 
 
 
Collection of survival 
and anticancer 
treatment information 
 
X 


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to receiving the outcome of the oncogene panel test; however, if wild type RAS status is not confirmed in the NGS panel 
test, the subject will be replaced and continuation of treatment should be discussed with the Sponsor. 
18. Two blood samples (one serum and one plasma) are to be collected prior to dosing on Cycle 1 Day 1 and during the first 
disease assessment visit on Cycle 2 Day 25 (one serum and one plasma sample at each occasion).  A protocol will be 
provided in a separate lab manual for collection of these samples. 
19. Subjects will receive tipifarnib 400 mg orally bid with food on days 1-21 of 28 day treatment cycles. Food intake increases 
tipifarnib’s bioavailability. The relevance of food intake with tipifarnib administration should be highlighted to study 
subjects. 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. 
20. Site staff should conduct a drug accountability on the returned empty bottles and unused medications. Drug accountability 
on Day 1 should begin at Cycle 2 and be conducted on Day 1 of each cycle thereafter. 
21. Required only for subjects who terminated treatment for reasons other than death or disease progression and assessments 
should be performed monthly. 
22. Required only for subjects who terminated treatment for reasons other than death or disease progression.  Assessment is 
to be performed approximately every 2 months through the first 6 months from the start of the subject’s participation in 
this study and every approximately 12 weeks thereafter. Bone marrow evaluation will be included as part of the 
assessments performed during the first 9 months from the start of the subject’s participation in the study.  Thereafter, 
bone marrow evaluations will occur during disease assessments in accordance with institutional standard practice.   
23. Day 15 visit is to occur during Cycles 1 and 2 only. 
24. Tipifarnib administration should occur if the Day 25 visit coincides with a dosing day (e.g. visit occurs on Day 20, 21 or 
on Day 1 or 2 of the following cycle). 
25. Buccal swabs will be collected at screening as a control sample for the analysis of tumor mutations using kits provided 
by the Sponsor. If swabs are not collected at screening for any reason, collection can be conducted at any time during the 
study. 
26. MPN-SAF TSS to be completed for subjects with CMML or MDS/MPN only. 
 


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3 
TABLE OF CONTENTS 
1 
PROTOCOL APPROVAL PAGE ........................................................2 
2 
SYNOPSIS ...........................................................................................3 
3 
TABLE OF CONTENTS ...................................................................13 
4 
ABBREVIATIONS ............................................................................17 
5 
INTRODUCTION ..............................................................................19 
5.1 
Tipifarnib ............................................................................................19 
5.1.1 
Mechanism of Action .........................................................................19 
5.1.2 
Clinical Pharmacology ........................................................................19 
5.1.3 
Prior Clinical Experience in CMML ..................................................20 
5.2 
Rationale for the Study .......................................................................21 
6 
OBJECTIVES .....................................................................................22 
6.1 
Primary Objectives .............................................................................22 
6.2 
Secondary Objectives and Endpoints .................................................22 
6.3 
Exploratory Objective and Endpoints .................................................23 
7 
SUBJECT SELECTION .....................................................................23 
7.1 
Inclusion Criteria ................................................................................23 
7.2 
Exclusion Criteria ...............................................................................24 
8 
TRIAL DESIGN .................................................................................25 
8.1 
Study Design .......................................................................................25 
8.2 
Subject Identification and Replacement of Subjects ..........................27 
8.3 
Assignment to Treatment Groups .......................................................28 
8.4 
Removal of Subjects from Treatment or Assessment .........................28 
8.5 
Premature Discontinuation of the Trial ..............................................29 
8.6 
Definition of End of Study .................................................................29 
9 
TREATMENTS ..................................................................................30 
9.1 
Investigational Product .......................................................................30 
9.1.1 
Product Characteristics .......................................................................30 
9.1.2 
Storage and Labeling ..........................................................................30 
9.2 
Treatment Administration ...................................................................31 
9.3 
Treatment Assignment ........................................................................31 
9.4 
Dose Selection ....................................................................................31 
 
 
9.6 
Treatment of Overdose .......................................................................34 
9.7 
Blinding ..............................................................................................34 


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9.8 
Treatment Compliance ........................................................................35 
9.9 
Investigational Product Accountability ..............................................35 
9.10 
Return and Disposition of Clinical Supplies ......................................35 
9.11 
Prior and Concomitant Medications ...................................................35 
9.12 
Non-permitted Treatments ..................................................................36 
9.13 
Photosensitivity Precaution ................................................................36 
9.14 
Dietary or Other Protocol Restrictions ...............................................37 
9.15 
Medical Care of Subjects after End of Trial .......................................37 
10 
EFFICACY AND SAFETY VARIABLES ........................................37 
10.1 
Efficacy Variables ..............................................................................37 
10.2 
Assessment of Safety ..........................................................................38 
10.3 
Adverse Events ...................................................................................38 
10.4 
Abnormal Laboratory Findings and Other Abnormal 
Investigational Findings ......................................................................39 
10.5 
Serious Adverse Event ........................................................................39 
10.6 
Events that Do Not Meet the Definition of an SAE ...........................40 
10.7 
Events Not to Be Considered as AEs/SAEs .......................................40 
10.8 
Methods of Recording and Assessing Adverse Events ......................40 
10.9 
Adverse Event Reporting Period ........................................................41 
10.10 
Procedure for Reporting Serious Adverse Events ..............................41 
10.11 
Safety Reporting to Health Authorities, Institutional Review 
Boards and Investigators .....................................................................41 
10.12 
Monitoring of Subjects with Adverse Events .....................................42 
10.13 
Pregnancy and In Utero Drug Exposure .............................................42 
10.14 
Laboratory Assessments .....................................................................43 
10.15 
Additional Variables ...........................................................................43 
11 
STUDY PROCEDURES ....................................................................43 
11.1 
Screening and Baseline Assessments .................................................43 
11.2 
Day 1 of Cycle 1 .................................................................................44 
11.3 
Day 1 (± 2 days) of Cycle 2 and every cycle thereafter .....................45 
11.4 
Day 15 (± 2 days) of Cycle 1 and Cycle 2 ..........................................46 
11.5 
Day 25 (± 5 days) of Cycles 2, 4, 6, 9 and every approximately 
12 weeks thereafter (Cycles 12, 15, etc.) ............................................46 
11.6 
End of Treatment Visit .......................................................................47 
11.7 
Post Treatment Follow up ...................................................................48 






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4 
ABBREVIATIONS 
 
AE 
Adverse event 
ALT 
Alanine Aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate Aminotransferase 
bid 
Twice a day 
BSC 
Best supportive care 
CMML 
Chronic myelomonocytic leukemia 
CR 
Complete response 
CRp 
Complete response with incomplete platelet count recovery 
CRF 
Case report form 
CTEP 
Cancer therapy evaluation program 
CYP450 
Cytochrome P450 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
FACS 
Fluorescence-activated cell sorting 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
HI 
Hematological improvement 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IP 
Investigational product 
IRB 
Institutional Review Board 
IV 
Intraveous 
IWG 
International Working Group 
JMML 
Juvenile myelomonocytic leukemia 
KIR 
Killer cell Immunoglobulin-like receptor 
LDH 
Lactic dehydrogenase 
MDS 
Myelodysplastic syndromes 
MDS 
Myelodysplastic syndromes 
MDS/MPN IWG 
Myelodysplastic syndromes/Myeloproliferative neoplasms International Working Group 
MPN 
Myeloproliferative neoplasm 
MPN-SAF TSS 
Myeloproliferative neoplasm symptom assessment form total symptom score 
MTD 
Maximum tolerated dose 
N 
Sample size 
NCI 
National Cancer Institute 
NCI CTCAE  
National Cancer Institute Common Terminology Criteria for Adverse Events  
NGS 
Next generation sequencing 
ORR 
Overall response rate 
PDGFR 
Platelet derived growth factor receptor 
PR 
Partial response 
PFS 
Progression free survival 
PoS 
Probability of meeting success criteria 
PPS 
Per protocol set 
PT/INR 
Prothrombin time/international normalized ratio 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


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SGOT 
Serum glutamic oxaloacetic transaminase  
SGPT 
Serum glutamic pyruvic transaminase 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World health organization 
 
 


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5 
INTRODUCTION 
5.1 
Tipifarnib 
Beginning in 1997, tipifarnib was the first specific inhibitor of farnesyltransferase 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 12, Jan 
2015).  
5.1.1 
Mechanism of Action 
Tipifarnib is a potent and selective nonpeptide inhibitor of farnesyltransferase. 
Farnesyltransferase 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 farnesyltransferase inhibitors were originally developed to target Ras 
mutant cancers, tipifarnib and other farnesyltransferase 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 
farnesyltransferase is inhibited (Baines 2011, Takashima 2013).  
The correlative biology of inhibition by tipifarnib has been studied extensively. 
Farnesyltransferase 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 farnesyltransferase 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 has demonstrated acceptable oral bioavailability and linear pharmacokinetics 
reaching maximum concentration 0.5 to 3 hours following oral administration with a terminal 
half-life of 16 hours. 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 farnesyltransferase 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 


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required to inhibit farnesylation.  Inhibition of farnesyltransferase 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. Importantly, 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.  
5.1.3 
Prior Clinical Experience in CMML 
While there has been no dedicated study of tipifarnib for the treatment of CMML, prior studies 
of tipifarnib in other hematological malignancies have enrolled CMML patients. 
A phase 2 study of tipifarnib was performed in intermediate to high risk MDS in which 82 
patients received tipifarnib 300 mg orally bid for the first 21 days of each 28 day cycle. Twenty-
six patients (32%) responded to tipifarnib: 12 (15%) CRs and 14 (17%) HIs; 37 patients (45%) 
had stable disease (modified International Working Group criteria, 2006). Among the 12 CRs, 
the median response duration was 11.5 months (range, 2.0-21.9 months), the median time to 
progression was 12.4 months (range, 3.9-23.8 months), and 7 were still alive at time of analysis 
(all > 3 years). Median overall survival was 11.7 months (95% CI, 9.4-15.0).  In the 17 patients 
with CMML enrolled in this study, 3 patients achieved a CR.   Grade 3-4 neutropenia (18%) 
and thrombocytopenia (32%) were the most common treatment-related adverse events; severe 
nonhematologic adverse events were rarely reported. In this study, durable responses and 
acceptable side effects were observed and the authors concluded that tipifarnib is an active 
agent for the treatment of patients with intermediate to high risk MDS (Fenaux 2007). 


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A phase 2, open-label, single-arm, multicenter study was supported by and conducted under 
the supervision of the United States National Cancer Institute (NCI) Cancer Therapy 
Evaluation Program (CTEP) and assessed the efficacy and safety of tipifarnib in subjects with 
previously untreated poor-risk hematologic malignancies (AML, n = 160; high-risk MDS, n = 
4; CMML, n = 6).  Study subjects received tipifarnib 600 mg orally twice daily for 21 days in 
28-day cycles.   An overall response rate (CR + PR) of 34% was observed in 148 of 170 patients 
who were evaluable for response (Lancet 2004).   
A phase 1 dose escalation study of tipifarnib in advanced hematological malignancies was 
performed in a total of 21 patients, of which 10 had CMML.  Tipifarnib was administered twice 
daily (3-weeks-on/1-week-off schedule for 8 weeks) (starting dosage, 300 mg by mouth twice 
daily; total, 600 mg). Objective responses (HI, 3; partial remission, 2; or complete remission, 
1) were seen in 6 of 20 (30%).  Three of the six responding patients had CMML and achieved 
a PR (n=2, duration of responses were 6 and 16+ months) or HI (n=1, duration of response was 
2 months.  The maximum tolerated dose was 400 mg by mouth twice a day. The most frequent 
side effect was myelosuppression. Dose-limiting toxicities (fatigue and confusion) occurred at 
900 mg by mouth total daily dose (Kurzrock 2003). 
Additional details, including data on the use of tipifarnib in other hematological malignancies, 
as well as non-hematological malignancies, can be found in the Investigator’s Brochure. 
5.2 
Rationale for the Study 
The observations of objective CR and PR induced by single agent tipifarnib in heavily 
pretreated patients with CMML warrants further research. Its ease of administration and 
documented toxicity profile allow for outpatient treatment.  Furthermore, given the high unmet 
medical need and lack of therapeutic options for patients with CMML, tipifarnib may provide 
a critical new therapeutic option in the armamentarium for CMML therapy.  
Moreover, there are molecular biological arguments for the use of tipifarnib, such as the role 
of interference with the Ras signalling pathway which is frequently activated in CMML 
(~35%).  In a phase 1 study of tipifarnib in advanced haematological malignancies performed 
by Kurzrock et. al. (2008), 3 of 10 patients with CMML achieved a response to tipifarnib.  Of 
the 3 responding patients, 2 were found to carry a KRAS (hematologic improvement best 
response) or a NRAS mutation (PR best response) with duration of response of 2 and 6 months, 
respectively.  The remaining patient with KRAS/NRAS wildtype achieved a PR with a duration 
of response of 16+ months.  The KRAS/NRAS mutational status in the non-responding CMML 
patients were not reported. 
Nonclinically, it has been demonstrated using a large panel of cell lines that Ras wild-type cell 
lines are more sensitive to tipifarnib than Ras mutant lines (End 2001). However, more recently 
it has been shown that models containing the more rarely mutated HRAS family member are 
more sensitive to farnesyl transferase inhibition since HRAS is exclusively farnesylated (Chen 
2014). KRAS and NRAS, on the other hand, can undergo an alternative pathway for 
prenylation, (i.e. geranylgernylation) enabling these cancer cells to overcome signalling 
inhibition by farnesyl transferase inhibition alone (Morgan 2003).  In CMML, mutations 
commonly occur in NRAS and KRAS, but not HRAS (Padron, 2015; Parikh 2013). 


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Thus the assessment of the effect of tipifarnib in CMML was warranted. Prior to amendment 
3, subjects with CMML were enrolled in the study and retrospectively stratified by RAS 
mutational status.  The study met its primary endpoint with 3 objective responses observed in 
9 evaluable subjects with RAS wildtype CMML (Patnaik 2017).  No responses were observed 
in 7 evaluable CMML subjects with RAS mutations.  
Analysis of gene expression in bone marrows obtained at baseline (prior to the first dose of 
tipifarnib) from the CMML subjects enrolled in the study indicated that a high ratio of 
expression of the C-X-C motif chemokine receptors CXCR4 and CXCR2 was significantly 
associated with clinical benefit from tipifarnib (Gualberto 2017). Prior data in AML and 
peripheral T cell lymphoma indicated that tipifarnib interferes with the activity of CXCL12 
pathway (Gualberto 2017, Witzig 2017). CXCR4 mediates the effects of CXCL12 in myeloid 
cells, inducing bone marrow homing, while CXCR2, the IL-8 receptor, has an antagonistic 
function, inducing mobilization of myeloid cells from the bone marrow (Coffelt 2016). Bone 
marrow homing is associated with clinical benefit from tipifarnib (Gualberto 2017). The 
farnesylated proteins responsible for these effects of tipifarnib are currently under 
investigation. 
6 
OBJECTIVES 
6.1 
Primary Objectives 
Primary Objective 1: To assess the antitumor activity of tipifarnib, in terms of Objective 
Response Rate (ORR), in subjects with CMML and in subjects with CMML whose disease is 
KRAS/NRAS wild type. Primary Objective 1 was met in the initial cohort of CMML subjects 
whose disease had RAS wild type status. 
Primary Objective 2 (MDS/MPN cohorts): To assess the antitumor activity of tipifarnib, in 
terms of ORR, in subjects with MDS/MPN, including CMML, who have a high ratio of 
expression of CXCR4 to CXCR2 (CXCR4/2 ratio) in their bone marrows and in those with 
low CXCR4/2 ratio. 
Primary endpoint (MDS/MPN cohorts): Response assessments according to the 
MDS/MPN IWG criteria (Table 9 and Table 10).   
Primary Objective 3 (AML cohorts): To assess the antitumor activity of tipifarnib, in terms 
of ORR, in subjects with AML who have a high ratio of expression of CXCR4 to CXCR2 
(CXCR4/2 ratio) in their bone marrows and in those with low CXCR4/2 ratio. 
Primary endpoint (AML cohorts): Response assessments according to the International 
Working Group criteria (Cheson 2003).   
6.2 
Secondary Objectives and Endpoints 
Secondary Objective: To assess the effect of tipifarnib on the following: 
• Rate of CR, complete cytogenetic remission, partial remission, marrow response, and 
clinical benefit 


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• Duration of Response 
• Rate of PFS at 1 year 
• Rate of survival at 1 year 
• AE profile according to NCI CTCAE v 4.03 
Secondary Endpoint: Response assessments according to the MDS/MPN IWG criteria 
(MDS/MPN cohorts) or International Working Group criteria (AML cohorts); treatment 
emergent adverse events (TEAEs) and serious adverse events (SAEs) evaluated according to 
NCI CTCAE v.4.03.   
6.3 
Exploratory Objective and Endpoints 
Exploratory Objective: To explore potential biomarkers and their association with clinical 
benefit from tipifarnib including cancer gene mutations, monocyte and immune cell subsets 
and other candidate biomarkers of tipifarnib in bone marrow, and blood samples.   
Exploratory Endpoint: Molecular analyses of blood and bone marrow. 
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. For subjects to be enrolled in the CMML or MDS/MPN expansion cohorts: 
a. Diagnosis of CMML or MDS/MPN as defined by the World Health 
Organization (WHO) criteria (2008). 
3. For subjects enrolled in the AML cohort: 
a. Documented pathological evidence of AML, as defined by WHO criteria (2008) 
b. Refractory to previous induction chemotherapy, relapsed disease, or age ≥ 60 
and not appropriate for standard cytotoxic therapy due to age, performance 
status, and/or adverse risk factors according to the treating physician 
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2. 
5. Subject is willing and able to comply with scheduled visits, treatment plans, laboratory 
tests and other procedures (including bone marrow assessments). 
6. At least 1 week since the last systemic therapy regimen prior to Cycle 1 Day 1.  Subjects 
on a stable dose of hydroxyurea for at least 2 weeks prior to Cycle 1 Day 1 may continue 
on hydroxyurea until Cycle 1 Day 14.  Subjects must have recovered to NCI CTCAE 
v. 4.03 < Grade 2 from all acute toxicities (excluding Grade 2 toxicities that are not 


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considered a safety risk by the Sponsor and Investigator) or toxicity must be deemed 
irreversible by the Investigator. 
7. Acceptable liver function:  
a. Total bilirubin ≤ upper limit of normal (ULN). 
b. AST (SGOT) and ALT (SGPT) ≤ 1.5 x ULN. 
8. Acceptable renal function with serum creatinine ≤ 1.5 x ULN or a calculated creatinine 
clearance ≥ 60 mL/min using the Cockcroft-Gault or Modification of Diet in Renal 
Disease formulas. 
9. Female subjects must be: 
a. Of non-child-bearing potential (surgically sterilized or at least 2 years post-
menopausal); or 
b. If of child-bearing potential, subject must use a highly effective method of 
contraception, such as combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-
only hormonal contraception associated with inhibition of ovulation, 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal 
occlusion, vasectomised partner or sexual abstinence.  Both females and male 
subjects with female partners of child-bearing potential must agree to use a 
highly effective method of contraception for 2 weeks prior to screening, during, 
and at least 28 days after last dose of trial medication for females and 90 days 
for males. Female subjects must have a negative serum or urine pregnancy test 
within 72 hours prior to start of trial medication. 
c. And, not breast feeding at any time during the study. 
10. Written and voluntary informed consent understood, signed and dated. 
7.2 
Exclusion Criteria 
1. Neoplasia harbours RAS mutation (NRAS mutant, KRAS mutant or double mutant) 
2. Acute promyelocytic leukemia or Bcr-Abl positive leukemia (chronic myelogenous 
leukemia in blast crisis) 
3. Clinically active CNS leukemia 
4. CMML with t(5;12) that have not yet received imatinib. 
5. Participation in any interventional study within 1 week of randomization or 5 half-lives 
of the prior treatment agent (whichever is longer). 
6. Ongoing treatment with an anticancer agent for CMML, MDS/MPN or AML not 
contemplated in this protocol.  Subjects on a stable dose of hydroxyurea for at least 2 
weeks prior to Cycle 1 Day 1 may continue on hydroxyurea until Cycle 1 Day 14.   


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7. Hematopoietic stem cell transplantation (HSCT) performed within 3 months prior to 
Cycle 1 Day 1. 
8. Concurrent use of granulocyte macrophage colony-stimulating factor (GM-CSF). 
9. Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor. 
10. Active coronary artery disease requiring treatment, myocardial infarction within the 
prior year, New York Heart Association grade III or greater congestive heart failure, 
cerebro-vascular attack within the prior year, or current serious cardiac arrhythmia 
requiring medication except atrial fibrillation. 
11. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, 
without complete recovery. 
12. Active, concurrent malignancy requiring radiation, chemotherapy, or immunotherapy 
(excluding non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and 
hormonal treatment for castration sensitive prostate cancer).  
13. Active and uncontrolled bacterial, viral, or fungal infections, requiring systemic 
therapy. Known infection with human immunodeficiency virus (HIV), or an active 
infection with hepatitis B or hepatitis C. 
14. 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.  
15. The subject has legal incapacity or limited legal capacity. 
16. 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 
Amendment 3 (2018-03-9): This Phase 2 study will investigate the antitumor activity in terms 
of ORR of tipifarnib in approximately 36 eligible subjects with MDS/MPN, including CMML, 
and 36 eligible subjects with AML.   
Prior to amendment 3, subjects with CMML were enrolled in the study and retrospectively 
stratified by RAS mutational status.  The study met its primary endpoint with 3 objective 
responses observed in 9 evaluable subjects with RAS wildtype CMML (Patnaik 2017).  No 
responses were observed in 7 evaluable CMML subjects with RAS mutations.  
Analysis of gene expression in bone marrows obtained at baseline (prior to the first dose of 
tipifarnib) from the CMML subjects enrolled in the study indicated that a high ratio of 
expression of the C-X-C motif chemokine receptors CXCR4 and CXCR2 was significantly 
associated with clinical benefit from tipifarnib (Gualberto 2017). Prior data in AML and 
peripheral T cell lymphoma indicated that tipifarnib interferes with the activity of CXCL12 


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pathway (Gualberto 2017, Witzig 2017). CXCR4 mediates the effects of CXCL12 in myeloid 
cells, inducing bone marrow homing, while CXCR2, the IL-8 receptor, has an antagonistic 
function, inducing mobilization of myeloid cells from the bone marrow (Coffelt 2016). Bone 
marrow homing is associated with clinical benefit from tipifarnib (Gualberto 2017). The 
farnesylated proteins responsible for these effects of tipifarnib are under investigation. 
Based on these data, the study protocol has been amended to prospectively test the hypothesis 
that a high ratio of expression between CXCR4 and CXCR2 (CXCR4/2 ratio) receptors could 
be associated with responsiveness to tipifarnib in myeloid neoplasias. For that purpose four 
additional cohorts will be enrolled in the study as follows: 
1. Subjects with MDS/MPN with high CXCR4/2 Ratio 
2. Subjects with MDS/MPN with low CXCR4/2 Ratio 
3. Subjects with AML with high CXCR4/2 Ratio 
4. Subjects with AML with low CXCR4/2 Ratio 
A bone marrow aspirate sample will be taken during screening procedures for the testing of the 
CXCR4/2 Ratio at a central laboratory using a standardized procedure. 
Each cohort has a 2-stage design. Seven subjects will be enrolled in the first stage of each 
cohort.  If at least one objective response is observed, the cohort will be expanded to enroll an 
additional 11 subjects in stage 2.  The cohort will be considered positive if 4 or more responses 
are observed in the 18 subject cohort (Figure 1). Based on the absence of objective responses 
observed in the initial cohort of RAS mutant CMML subjects, all enrolled subjects enrolled in 
amendment 3 cohorts 1-4 will have RAS wild type tumor status at study entry. 
Only consented subjects who meet all eligibility criteria will be enrolled in the study. 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. Evaluations performed as part of the standard of care within 28 days of 
dosing but prior to consent, do not need to be repeated. By signing the consent form, study 
subjects agree to the collection of standard of care health information.   
Subjects (amendment 3 cohorts 1-4) will receive tipifarnib administered at a dose of 400 mg, 
orally with food, bid for 21 days in 28 day cycles.  Food intake is important for tipifarnib 
bioavailability. The relevance of food intake with tipifarnib administration should be 
highlighted to study subjects. 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. 
Stepwise 100 mg dose reductions to control treatment-related, treatment-emergent toxicities 
are indicated in the body of the study protocol.  In the absence of unmanageable toxicities, 
subjects may continue to receive tipifarnib treatment until disease progression.  In the absence 
of unmanageable toxicities, subjects may continue to receive tipifarnib treatment until disease 
progression.  Provisions will be made for the continuation of study treatment in subjects whose 
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Disease assessments will be performed at screening, at the Day 25 visit (± 5 days) performed 
during Cycles 2, 4, 6, 9 and every approximately 12 weeks thereafter (Cycles 12, 15, etc.), at 
the End of Treatment visit and during follow up.  As part of the disease assessment at screening 
and at the Day 25 visit performed during Cycles 2, 4, 6 and 9, bone marrow evaluations will 
be conducted.  Thereafter, bone marrow evaluations will occur during disease assessments in 
accordance with institutional standard practice.  Hematologic assessments, including peripheral 
blood evaluations and review of transfusion requirements, will be performed at screening and 
at least monthly until disease progression.   
Additional disease or hematologic assessments may be conducted if deemed necessary by the 
Investigator. The timing of the disease and hematologic assessments should be maintained as 
much as possible independently of potential treatment cycle delays. 
Determination of disease response in subjects with MDS/MPN subjects will be performed by 
the Investigator according to the Myelodysplastic/Myeloproliferative International Working 
Group (MDS/MPN IWG) criteria (Table 9).  Similarly, disease progression will also be 
determined based on the MDS/MPN IWG criteria (Table 10).  Determination of disease 
response in subjects with AML will be performed by the Investigator according to the 
International Working Group criteria (Cheson 2003).  Similarly, disease progression will also 
be determined based on the IWG criteria (Cheson 2003). 
Upon disease progression, all subjects in the study 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 study cohort has been completed, whichever occurs first. Information on survival 
and subsequent anticancer therapy may be collected by phone. 
Subjects who terminate treatment for reasons other than death or disease progression will be 
assessed at regular intervals for disease progression (approximately every 2 months through 
the first 6 months from the start of the subject’s participation in this study and every 
approximately 12 weeks thereafter) and leukemic transformation (monthly blood counts).  
Disease assessments performed during the first 9 months from the start of the subject’s 
participation in the study will include bone marrow evaluation.  Thereafter, bone marrow 
evaluations will occur during disease assessments in accordance with institutional standard 
practice. These assessments will continue until disease progression, withdrawal of subject’s 
consent to study procedures or initiation of another anticancer therapy.   
All subjects will be followed-up for safety during treatment and up to approximately 30 days 
(30 ± 7 days) after treatment discontinuation or until immediately before the initiation of 
another anticancer therapy, whichever occurs first. Additional follow up may be implemented 
until the subject recovers from any emergent treatment related toxicity or the AE is considered 
irreversible by the Investigator. Target organ toxicities will be monitored via clinical and 
laboratory assessments using the NCI CTCAE v.4.03 criteria.   
8.2 
Subject Identification and Replacement of Subjects 
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
case report form (CRF) pages. Subjects who do not receive at least one dose of tipifarnib will 


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be replaced. Subjects who do not have at least one post baseline disease assessment will be 
replaced. 
8.3 
Assignment to Treatment Groups 
All eligible subjects will receive tipifarnib treatment. Assignment to a high CXCR4/2 ratio or 
a low CXCR4/2 ratio cohort will be provided by the Sponsor based on the results of the testing 
of screening bone marrow samples at a central laboratory. 
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 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 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 
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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 Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) in order to analyze and evaluate study results. It is the Investigator’s (or 
designee’s) responsibility to obtain written permission to use protected health information per 
country-specific regulations, such as Health Information Portability and Accountability Act 
(HIPAA) in the United States, from each subject, or if appropriate, the subject’s legally 
authorized representative. If permission to use protected health information is withdrawn, it is 
the Investigator’s responsibility to obtain a written request, to ensure that no further data will 
be collected from the subject and the subject will be removed from the study. 
8.5 
Premature Discontinuation of the Trial 
This study 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. evidence of inefficacy of tipifarnib in subjects with CMML, 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 CMML patient population. Evidence of inefficacy may arise from this study 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 study is unjustifiable for medical or ethical 
reasons. 
• Poor enrollment of subjects making completion of the study 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 study 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 CRF section completed. 
8.6 
Definition of End of Study 
For administrative and safety reporting purposes, the end of this clinical study is defined as the 
day when the last remaining study subject in the study completes the last follow-up assessment 
no later than 12 months after the last study subject is enrolled in the study. Provisions will be 
made for the continuation of study treatment in subjects whose disease has not progressed 
beyond the end of the study, e.g. a single patient treatment protocol. 


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9 
TREATMENTS 
Subjects will receive tipifarnib as monotherapy in this study. In the absence of unmanageable 
toxicities, subjects may continue to receive tipifarnib treatment until disease progression.  If a 
complete response is observed, therapy with tipifarnib will be maintained for at least 6 months 
beyond the start of response.  
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. BSC will be provided by the study sites. 
9.1 
Investigational Product 
Tipifarnib is a small molecule being developed as a potent, selective inhibitor of 
farnesyltransferase for the treatment of cancer and other malignancies. 
9.1.1 
Product Characteristics 
Tipifarnib film-coated tablets for oral administration will be supplied in high-density 
polyethylene 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 tablet strength 
has the same qualitative composition.  Further information can be obtained from the current 
version of the Investigator’s Brochure. 
9.1.2 
Storage and Labeling 
At a minimum, the label of each bottle of tipifarnib tablets shipped to the study sites will 
provide the following information: batch number/lot number, study identification, required 
storage conditions, directions for use, and country specific required caution statements 
(including “New Drug – Limited by United States federal law to investigational use” language). 
Tipifarnib accountability records will be maintained by the pharmacy or designated drug 
preparation area at the study sites. Upon receipt of tipifarnib supplies, the pharmacist or 
designated study site investigational drug handler will inventory tipifarnib (separately for each 
strength, if applicable) and complete the designated section of the shipping form. The 
shipping/inventory form must be sent to Kura Oncology, Inc. or its designee, as instructed. 
Tipifarnib should be stored at controlled room temperature 15o to 30o C (59o to 86o F). All 
study supplies must be kept in a restricted access area. 


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9.2 
Treatment Administration 
Tipifarnib will be administered with food at a starting dose of 400 mg, orally, bid on days 1-
21 of 28 day treatment cycles.  Tipifarnib should be administered orally with a meal in the 
morning and again with a meal approximately 12 hours later at approximately the same times 
each treatment day. Subjects should be instructed on the importance of taking their tipifarnib 
dose with a meal as the presence of food has been shown to improve the absorption of tipifarnib, 
as well as to reduce variability in the pharmacokinetic profile.  Tablets should be swallowed 
whole with water (~8 oz. or 250 mL) and may be chewed or crushed if the Investigator deems 
it necessary.  
If a dose is vomited or partially vomited it should not be replaced with a new dose.  Dosing 
should resume at the next scheduled dose time. 
On Cycle 1 Day 1, the study site will provide tipifarnib to the subject from bulk supplies.  
Subjects will be provided with diaries with instructions to record the date and time of each dose 
and asked to bring the diaries and tablet bottles to each clinic visit for subject compliance and 
drug accountability review by the site staff.  For convenience, subjects may receive only one 
dose (e.g. the evening dose) on Cycle 1 Day 1. 
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 
Subjects (amendment 3 cohorts 1-4) will receive tipifarnib administered at a dose of 400 mg, 
orally with food, bid for 21 days in 28 day cycles.  This dose regimen was selected based on 
the average dose intensity for tipifarnib in the INT-17 study that enrolled 252 subjects with 
relapsed/refractory AML, and the results of the North American Intergroup Phase II study 
SWOG S0432 that investigated 4 different regimens of tipifarnib in 348 older, previously 
untreated, AML subjects. The average dose intensity for all treated subjects in INT-17 was 892 
mg/day, with a target dose intensity of 900 mg/day (1200 mg/day for 21 days of every 28 day 
cycle). The average dose intensity for the ‘per protocol’ INT-17 population was 852 mg/day, 
equivalent to 567 mg/day bid for 21 days in 28 day cycles. SWOG S0432 randomized AML 
subjects to receive either 600 mg or 300 mg of tipifarnib orally twice daily on days 1–21 or 
days 1–7 and 15–21, repeated every 28 days (4 treatment regimens). Responses were seen in 
all regimens, with overall response rate (CR + CRi + PR) highest (20%) among patients 
receiving tipifarnib 300 mg twice daily on days 1–21. Fatal toxicity was highest in the 600 mg 
bid days 1–21 regimen (8%).   
 
 
 
   








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9.8 
Treatment Compliance 
The importance of treatment compliance should be emphasized to the subject. Subjects will be 
given study drug and detailed instructions on how to take medications at home. Subjects will 
be instructed to return all used and unused study drug containers at each study visit. Subject 
compliance with the dosing schedule will be assessed by reconciliation of the used and unused 
study drug at each clinic visit and review of the dosing diaries. The quantity dispensed, 
returned, used, lost, etc. must be recorded on the dispensing log provided.  
Compliance will be monitored and documented by site personnel on the appropriate form. The 
site personnel will question the subject regarding adherence to the dosing schedule by 
reviewing the dosing diaries, recording the number of tablets (and strengths, if applicable) 
returned, the date returned, and determining treatment compliance (at least 80% of the total 
assigned dose) before dispensing new medication to the study subject. 
9.9 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of receipt of investigational product (IP), subjects to whom IP is dispensed 
(subject by subject specific accounting), and loss or accidental or deliberate destruction of IP.  
9.10 
Return and Disposition of Clinical Supplies 
Unused tablets returned by the subject from a prior cycle of treatment may be re-dispensed to 
the subject. Study drug must be kept in a secure location for accountability and reconciliation 
by the Sponsor’s designated clinical study monitor. The Investigator or designee must provide 
an explanation for any destroyed or missing study drug or study materials. 
Study drug may be destroyed on site, per the site’s standard operating procedures, but only 
after the Sponsor or its designee has been notified and granted approval for drug destruction. 
All study drug destroyed on site must be documented. 
Documentation must be provided to the Sponsor or its designee and retained in the 
Investigator’s study files. If a site is unable to destroy study drug appropriately, the site can 
return unused study drug to the Sponsor or its designee upon request. The return of study drug 
or study drug materials must be accounted for on a form provided by the Sponsor or its 
designee. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures. 
9.11 
Prior and Concomitant Medications 
All prescription and over-the-counter medications taken by a subject within 28 days before the 
first study drug administration will be recorded in the CRF.  Any additional concomitant 
therapy that becomes necessary during the study and any change to concomitant drugs must be 
recorded in the corresponding section of the CRF, noting the name, dose, duration and 
indication of each drug. 


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Supportive care medications, including transfusions and intravenous (IV) hydration, 
considered necessary for the subject’s safety and well-being may be given at the discretion of 
the Investigator according to local guidelines and standard practices. For concomitant therapy 
given as a treatment for a new condition or a worsening of an existing condition, the condition 
must be reported on the AE form of the CRF. 
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. 
9.12 
Non-permitted Treatments 
Use of the following medications and therapies is not allowed during the study: 
• Investigational agents other than tipifarnib. 
• Any other anticancer therapy, including radiation or surgery, for the primary disease under 
study. 
• 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.  
 
 
 
 
 
 
 
   
Any additional concomitant therapy that becomes necessary during the study and any change 
to concomitant drugs must be recorded in the corresponding section of the CRF, noting the 
name, dose, duration and indication of each drug. 
If the administration of a non-permitted concomitant drug becomes necessary during the study, 
e.g. because of AEs or disease progression, the subject in question will be withdrawn from the 
study, and the subject’s data obtained before the withdrawal may be used for safety and efficacy 
evaluations. 
9.13 
Photosensitivity Precaution 
As development of tipifarnib preceded finalization of the ICH S10 guidance document, no 
photosafety studies were conducted with tipifarnib to support clinical development and/or 
intended registration.  The Sponsor intends to conduct a photosafety assessment in 
accordance with the ICH S10 guideline.   
Based on the safety data analyzed from 1,314 subjects who received treatment with tipifarnib 
as a single-agent across 16 clinical studies, photosensitivity reactions have been uncommon 


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with an incidence of  ≥0.1% to <1% (Table 6).  In these studies, there were no protocol 
mandated light protective measures or recommendations.    
Table 6: Expected, Observed, Drug-Related Adverse Reactions and Associated 
Manifestations in Tipifarnib Clinical Studies by Incidence through 30 November 2016 
Skin and appendages disorders 
Very Commona 
Rash (incl. rash erythematous/rash maculopapular and exfoliative rash) 
Commonb 
Increased sweating, pruritus, dry skin, skin disorder, skin reaction localized 
Uncommonc 
Urticaria, dermatitis, photosensitivity reaction 
 
Alopecia 
Rared 
Toxic epidermal necrolysis 
a Incidence of ≥10%,   b Incidence of ≥1% to <10%,   c Incidence of ≥0.1% to <1%,  d Incidence of ≥0.01% to 
<0.1%. 
 
Based on the available clinical experience with tipifarnib, the Sponsor considers the risk of 
photosensitivity reactions to be low in subjects who do not use light protective measures 
while on tipifarnib therapy.     
However, due to the potential for phototoxicity while on tipifarnib treatment, subjects 
enrolled in the study should be encouraged to avoid sun exposure during the hours between 
10 AM to 4 PM.  Subjects should be instructed to use a broad-spectrum sunscreen with a 
minimum sun protection factor (SPF) of 30 on a daily basis, even on cloudy days.  Sunscreen 
should be reapplied every two hours and after swimming or excessive sweating.  Tight woven 
clothing and wide brimmed hats can also be used to block out ultraviolet 
radiation.  Sunglasses should be worn when outdoors during daylight hours. 
9.14 
Dietary or Other Protocol Restrictions 
No dietary restrictions related to tipifarnib are required.  Subjects will be instructed to 
administer their dose of tipifarnib with a meal as the presence of food has been shown to 
improve the absorption of tipifarnib, as well as to reduce variability in the pharmacokinetic 
profile.  Tablets should be swallowed whole with water (~8 oz. or 250 mL). 
9.15 
Medical Care of Subjects after End of Trial 
After a subject has completed the study or has withdrawn from the study, standard treatment 
will be administered, if required, in accordance with the study site’s standard of care and 
generally accepted medical practice and according to the subject’s individual medical needs. 
10 
EFFICACY AND SAFETY VARIABLES 
Table 1 summarizes the study required evaluations. 
10.1 
Efficacy Variables 
Disease assessments will be performed at screening, at the Day 25 visit (± 5 days) performed 
during Cycles 2, 4, 6, 9 and every approximately 12 weeks thereafter (Cycles 12, 15, etc.), at 
the End of Treatment visit and during follow up.  As part of the disease assessment at screening 


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and at the Day 25 visit performed during Cycles 2, 4, 6 and 9, bone marrow evaluation will be 
performed.  Thereafter, bone marrow evaluations will occur during disease assessments in 
accordance with institutional standard practice.  Hematologic assessments, including peripheral 
blood evaluations and review of transfusion requirements, will be performed at screening and 
at least monthly until disease progression.  Additional disease or hematologic assessments may 
be conducted if deemed necessary by the Investigator.  
10.2 
Assessment of Safety 
AEs will be graded according to the NCI CTCAE v4.03. AEs will be summarized by 
relationship to study drug, severity and grade. The safety profile of tipifarnib will be assessed 
through the recording, reporting and analyzing of baseline medical conditions, adverse events, 
physical examination findings including vital signs and laboratory tests. Comprehensive 
assessment of any apparent toxicity experienced by the subject will be performed throughout 
the course of the study, from the time of the subject’s signature of informed consent. Study site 
personnel will report any AE, whether observed by the Investigator or reported by the subject. 
A safety monitoring committee comprised of the Investigator(s) and Sponsor clinicians or 
designees will review all relevant safety data on a regular basis. 
10.3 
Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. In cases of 
surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself. In case of a fatality, the cause of death is 
considered as the AE, and the death is considered as its outcome. 
The Investigator is required to grade the severity/intensity of each adverse event. Investigators 
will reference the NCI-CTCAE v 4.03. This is a descriptive terminology that can be used for 
adverse event reporting. A general grading (severity/intensity) scale is provided at the 
beginning of the referenced document, and specific event grades are also provided. If a 
particular AE’s severity/intensity is not specifically graded by the guidance document, the 
Investigator is to revert to the general definitions of Grade 1 through Grade 5 and use his or 
her best medical judgment. 
The 5 general grades are: 
• Grade 1: Mild 
• Grade 2: Moderate 
• Grade 3: Severe 
• Grade 4: Life-threatening or disabling 


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• Grade 5: Death related to AE. Note: Death (Grade 5 as defined by NCI-CTCAE version 
4.03) is mainly regarded as an outcome, to be documented as described below. 
According to the Sponsor’s convention, if a severity/intensity of Grade 4 or 5 is applied to an 
AE, then the Investigator must also report the event as a SAE as per Section 10.5. However, a 
laboratory abnormality with a severity/intensity of Grade 4, such as anemia or neutropenia, is 
considered serious only if the condition meets one of the serious criteria described below. 
In the case of death, the primary cause of death (the event leading to death) should be recorded 
and reported as an SAE. “Fatal” will be recorded as the outcome of this respective event; death 
will not be recorded as separate event. Only if no cause of death can be reported (e.g., sudden 
death, unexplained death), the death per se might be reported as an SAE. 
Investigators must also systematically assess the causal relationship of AEs to the IPs, other 
medicinal products using the following definitions. Decisive factors for the assessment of 
causal relationship of an AE to the study treatments include, but may not be limited to, temporal 
relationship between the AE and the study treatments, known side effects of the study 
treatments, medical history, concomitant medications and procedures, course of the underlying 
disease, study 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 study in this clinical study 
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 study in this clinical study 
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 alanine aminotransferase (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 study treatment or study procedures (e.g. 
an overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered as SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (e.g., undesirable effects of any administered 
treatment) must be documented and reported as SAEs. 
10.7 
Events Not to Be Considered as AEs/SAEs 
Medical conditions that are present at the initial study visit that do not worsen in severity or 
frequency during the study are defined as Baseline Medical Conditions and are NOT to be 
considered AEs. Progression of underlying disease is not an AE and therefore not an SAE per 
se, rather an efficacy 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 study visit, the subject will be queried on changes in his/her condition. During the 
reporting period of the study any unfavorable changes in the subject’s condition will be 
recorded as AEs, whether reported by the subject or observed by the Investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the 
CRF. Among these AEs, all SAEs must be additionally documented and reported using an AE 
report form. It is important that each AE report include a description of the event, its duration 
including 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 


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relationship with the study treatment, any other potential causal factors, any treatment given or 
other action taken (including dose modification or discontinuation of the IPs) and its outcome. 
In addition, serious cases should be identified and the appropriate seriousness criteria 
documented. Specific guidance can be found in the CRF completion and monitoring 
conventions provided by the Sponsor. 
10.9 
Adverse Event Reporting Period 
The AE reporting period for safety surveillance begins when the subject is included into the 
study (date of first signature of informed consent) and continues through the study’s post-
treatment follow-up period, defined as 30 days from the final administration of the study 
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 of 24 HOURS after becoming aware of the event) inform 
the person(s) identified in the SAE 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 AE Report Form. All written 
reports should be transmitted using the AE Report Form, which must be completed by the 
Investigator following specific completion instructions. 
The AE section of the CRF must be completed and a copy of the information transmitted with 
the AE Report Form. Other relevant pages from the CRF may also be provided (e.g., medical 
history, concomitant drugs). The Investigator/Reporter must respond to any request for follow-
up information (e.g. additional information, outcome and final evaluation, specific records 
where needed) or to any question the Sponsor may have on the AE within the same timelines 
as described for initial reports. This is necessary to permit a prompt assessment of the event by 
the Sponsor to allow for strict regulatory timelines associated with expedited safety reporting 
obligations. 
10.11 
Safety Reporting to Health Authorities, Institutional 
Review Boards and Investigators 
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. The Investigator must comply with any applicable site-specific 
requirements related to the reporting of SAEs (and in particular deaths) involving his/her 
subjects to the IRB/IEC that approved the study. 
In accordance with International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) guidelines, the Sponsor will inform the Investigator of “findings that could adversely 
affect the safety of subjects, impact the conduct of the study or alter the IRB/IEC’s 
approval/favorable opinion to continue the study.” In particular and in line with respective 


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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 study and is considered to be possibly related 
to the IP must be monitored and followed up by the Investigator until stabilization or until the 
outcome is known, unless the subject is documented as “lost to follow-up”. Reasonable 
attempts to obtain this information must be made and documented. It is also the responsibility 
of the Investigator to ensure that any necessary additional therapeutic measures and follow-up 
procedures are performed. The Sponsor will actively follow-up and collect information on any 
AE that occurs during the course of a clinical study, however while this activity will continue 
for any SAEs 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 study treatment (e.g., resulting 
from a drug interaction with a contraceptive medication) are considered as AEs. However, all 
pregnancies with an estimated conception date during the study safety period must be recorded 
by convention in the AE page/section of the 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 study. The Investigator must notify 
the Sponsor of these outcomes using the Pregnancy Report Form, and in case of abnormal 
outcome, the AE report form when the subject sustains an event and the Parent-Child/Fetus 
Report Form when the child/fetus sustains an event. 
Any abnormal outcome must be reported in an expedited manner, while normal outcomes must 
be reported within 45 days from delivery. 
In the event of a pregnancy in a subject occurring during the course of the study, the subject 
must be discontinued from study medication immediately. The Sponsor must be notified 
without delay and the subject must be followed as mentioned above. 


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10.14 
Laboratory Assessments 
All clinical safety laboratory tests listed in the section below will be performed at local 
laboratories. Subject eligibility will be determined based on the baseline laboratory results. 
Clinically significant laboratory test abnormalities will be followed until resolution or 
stabilization and the overall clinical outcome has been ascertained (See Section 10.4). 
Blood samples will be collected for the following clinical laboratory tests: 
• Serum Chemistry: aspartate aminotransferase (AST), ALT, total bilirubin, creatinine, blood 
urea nitrogen (BUN), potassium and calcium 
• Hematology: hemoglobin, platelets, white blood cells (WBCs), neutrophils, neutrophil 
precursors, lymphocytes, monocytes and blasts  
• Coagulation: activated partial thromboplastin time (APTT), prothrombin time/international 
normalized ratio (PT/INR) 
10.15 
Additional Variables 
Additional variables to be examined as a part of this study include exploratory biomarkers such 
as oncogenic mutations in CMML tumor cells by next generation sequencing (NGS).  The 
biomarker samples (bone marrow aspirate and blood) will be collected at time points described 
in Table 1. 
11 
STUDY PROCEDURES 
11.1 
Screening and Baseline Assessments 
A signed Informed Consent Form (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). Any screening evaluation, including disease status, 
will need to be repeated if performed more than 28 days from Cycle 1 Day 1. Evaluations 
performed as part of the standard of care within 28 days of dosing but prior to consent, do not 
need to be repeated. By signing the consent form, the subject agrees to the collection of this 
health information. 
• Obtain signed ICF and form for the HIPAA/Data Protection Act  
• Record subject’s medical history, including demographics, primary diagnosis and 
WHO classification, outcome and duration of response to prior cancer therapy and any 
ongoing AEs 
• Record concomitant medications 
• Record subject weight 
• Record subject height 


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• Perform bone marrow aspirate for disease assessment, cytogenetic assessment and 
RNA bone marrow biomarker analysis.   
• In MDS/MPN subjects, complete symptom assessment as per the myeloproliferative 
neoplasm symptom assessment form total symptom score (MPN-SAF TSS, Emmanuel 
2012) 
• Record the number of RBC, whole blood and platelet transfusions for the 4 months 
prior to Cycle 1 Day 1. 
• Collection of buccal swabs.  If swabs are not collected at screening for any reason, 
collection can be conducted at any time during the study. 
• Blood sample for NGS oncogene panel sequencing including KRAS, NRAS. Subjects 
with known wild type KRAS, NRAS status can be enrolled in the study prior to 
receiving the outcome of the oncogene panel test; however, if wild type RAS status is 
not confirmed in the NGS panel test, the subject will be replaced and continuation of 
treatment should be discussed with the Sponsor. 
•  
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 including vital signs (heart rate, blood pressure, 
temperature) 
• Assess ECOG performance status. 
• Perform hematology tests (hemoglobin, platelets, WBCs, neutrophils, neutrophil 
precursors, lymphocytes, monocytes and blasts) 
• Perform serum chemistry laboratory tests (AST, ALT, total bilirubin, creatinine, 
potassium and calcium).  Subjects are not required to be fasting.   
• Perform coagulation tests (APTT, PT/INR) 
The following evaluations and procedures will be performed within 72 hours prior to the first 
administration of study drug (Cycle 1 Day 1): 
• Perform urine or serum pregnancy test for females of child-bearing potential only 
Laboratory assessments may be repeated if values are borderline to inclusion level or may 
change due to best supportive care measures.   
If the subject meets all eligibility criteria after the screening visit(s), the study site will request 
an assigned subject number and treatment assignment from the Sponsor or designee.  
11.2 
Day 1 of Cycle 1 
The following assessments will be conducted before the first dose of tipifarnib on Day 1 of 
Cycle 1: 
• Record concomitant medications 


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• Assessment of AEs 
• Record subject weight 
• Assess ECOG performance status. 
• Symptom based physical examination 
• Perform serum chemistry laboratory tests (AST, ALT, total bilirubin, creatinine, 
potassium and calcium).  Subjects are not required to be fasting.  Serum chemistry tests 
do not need to be repeated on Cycle 1 Day 1 if the screening laboratory tests were 
conducted within 72 hours prior to the first dose of tipifarnib.   
• Perform hematology tests (hemoglobin, platelets, WBCs, neutrophils, neutrophil 
precursors, lymphocytes, monocytes and blasts).  Hematology tests do not need to be 
repeated on Cycle 1 Day 1 if the screening hematology tests were conducted within 72 
hours prior to the first dose of tipifarnib.   
• Record any RBC, whole blood and platelet transfusions that were received between the 
screening visit and Cycle 1 Day 1. 
• Collect serum and plasma samples for biomarker evaluation 
Tipifarnib should always be administered with a meal. For convenience, subjects may receive 
only one dose of tipifarnib on Cycle 1 Day 1, with subjects self-administering the first dose of 
tipifarnib with food in the evening. Subjects will continue to self-administer tipifarnib twice a 
day (approximately every 12 hours, same time every morning and evening, with a meal). The 
interval between dosing should not be less than 6 hours. 
11.3 
Day 1 (± 2 days) of Cycle 2 and every cycle thereafter 
Subjects will self-administer their morning dose of tipifarnib with food prior to the following 
procedures: 
• Record concomitant medications 
• Assessment of AEs 
• Record subject weight 
• Assess ECOG performance status. 
• Symptom based physical examination 
• Perform urine or serum pregnancy test for females of child-bearing potential only 
• Perform serum chemistry laboratory tests (AST, ALT, total bilirubin, creatinine, 
potassium and calcium).  Subjects are not required to be fasting.  If clinically indicated, 
serum chemistry tests may be repeated more frequently. 
• Perform hematology tests (hemoglobin, platelets, WBCs, neutrophils, neutrophil 
precursors, lymphocytes, monocytes and blasts).  If clinically indicated, hematology 
tests may be repeated more frequently. 


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• Record any RBC, whole blood and platelet transfusions that were received since the 
last study visit. 
• Conduct a drug accountability on the returned empty bottles and unused medications. 
11.4 
Day 15 (± 2 days) of Cycle 1 and Cycle 2 
Subjects will self-administer their morning dose of tipifarnib with food prior to the following 
procedures: 
• Record concomitant medications 
• Assessment of AEs 
• Symptom based physical examination 
• Perform serum chemistry laboratory tests (AST, ALT, total bilirubin, creatinine, 
potassium and calcium).  Subjects are not required to be fasting.  If clinically indicated, 
serum chemistry tests may be repeated more frequently. 
• Perform hematology tests (hemoglobin, platelets, WBCs, neutrophils, neutrophil 
precursors, lymphocytes, monocytes and blasts).  If clinically indicated, hematology 
tests may be repeated more frequently. 
11.5 
Day 25 (± 5 days) of Cycles 2, 4, 6, 9 and every 
approximately 12 weeks thereafter (Cycles 12, 15, etc.)  
The following procedures will be performed during the Day 25 visit.  If the Day 25 visit 
coincides with a dosing day (e.g. visit occurs on Day 20, 21 or on Day 1 or 2 of the following 
cycle), subjects will self-administer their morning dose of tipifarnib with food prior to the 
procedures. 
• Record concomitant medications 
• Assessment of AEs 
• Symptom based physical examination 
• Perform hematology tests (hemoglobin, platelets, WBCs, neutrophils, neutrophil 
precursors, lymphocytes, monocytes and blasts) 
• Perform bone marrow aspirate for disease and cytogenetic assessment during Cycles 2, 
4, 6 and 9 only. A sample for biomarker analyses (PAXgene RNA tubes) will be taken 
at Cycle 2 only. Thereafter, bone marrow evaluations will occur as per institutional 
standard practice.  If the bone marrow aspirate is inadequate for disease assessment, a 
bone marrow biopsy should be performed. If on this bone marrow sample, a CR or PR 
is observed, a bone marrow aspirate with cytogenetic assessment must be repeated 1 
month later, i.e. prior to the end of the next cycle. Efforts should be made to document 
disease progression in subjects that discontinue treatment for reasons other than 
progression of disease. 
• In MDS/MPN subjects, complete symptom assessment as per the MPN-SAF TSS 


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• Record any RBC, whole blood and platelet transfusions that were received since the 
last study visit. 
• Collect serum and plasma samples for biomarker evaluation (Cycle 2 Day 25 visit only) 
If the Day 25 visit coincides with a dosing day subjects will self-administer their evening dose 
of tipifarnib using the supplies provided by the study site.  
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 anticancer 
drug, whichever takes place first: 
• Record concomitant medications 
• Assessment of AEs 
• Assess ECOG performance status 
• Complete physical examination including vital signs (heart rate, blood pressure, 
temperature) 
• Record subject weight 
• Perform urine or serum pregnancy test for females of child-bearing potential only 
• Perform serum chemistry laboratory tests (AST, ALT, total bilirubin, creatinine, 
potassium and calcium).  Subjects are not required to be fasting.   
• Perform hematology tests (hemoglobin, platelets, WBCs, neutrophils, neutrophil 
precursors, lymphocytes, monocytes and blasts) 
• Perform coagulation tests (APTT, PT/INR) 
• Perform bone marrow aspirate for disease, cytogenetic and biomarker assessment if in 
accordance with institutional standard practice.  If the bone marrow aspirate is 
inadequate, a bone marrow biopsy should be performed. If on this bone marrow sample, 
a CR or PR is observed, a bone marrow aspirate with cytogenetic assessment must be 
repeated 1 month later. 
• In MDS/MPN subjects, complete symptom assessment as per the MPN-SAF TSS 
• Record any RBC, whole blood and platelet transfusions that were received since the 
last study visit. 
• Blood sample for NGS oncogene panel sequencing 
• Conduct drug accountability on the returned empty bottles and unused medications. 


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11.7 
Post Treatment Follow up 
11.7.1 
Follow-up Visit: Subjects who Terminate Treatment for 
Reasons other than Death or Disease Progression 
Subjects who terminated treatment for reasons other than death or disease progression will be 
assessed at regular intervals for disease progression and leukemic transformation.  
The assessments to be conducted at each monthly visit are: 
o Perform hematology tests (hemoglobin, platelets, WBCs, neutrophils, neutrophil 
precursors, lymphocytes, monocytes and blasts) 
The assessments to be conducted at each approximately every 2 months through the first 6 
months from the start of the subject’s participation in this study and every approximately 12 
weeks thereafter are:  
o Perform bone marrow aspirate for disease assessment and cytogenetic assessment 
as part of the assessments conducted during the first 9 months from the start of the 
subject’s participation in the study.  Thereafter, bone marrow evaluations will occur 
during disease assessments in accordance with institutional standard practice.  If the 
bone marrow aspirate is inadequate, a bone marrow biopsy should be performed. If 
on this bone marrow sample, a CR or PR is observed, a bone marrow aspirate with 
cytogenetic assessment must be repeated 1 month later. 
o In MDS/MPN subjects, Complete symptom assessment as per the MPN-SAF TSS  
o Record any RBC, whole blood and platelet transfusions that were received since the 
last study visit. 
Assessments of AEs and concomitant medications may also be conducted if AEs were not 
resolved at the time of the End of Treatment visit. 
11.7.2 
Follow Up after Disease Progression 
Upon disease progression, all subjects in the study 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 study cohort has been completed, whichever occurs first. Information on survival 
and subsequent anticancer therapy may be collected by phone. 
12 
STATISTICAL METHODS  
12.1 
Populations 
12.1.1 
Efficacy Analysis 
The primary population for the efficacy analysis is the Per Protocol analysis set (PPS) that 
includes subjects who received at least one dose of tipifarnib, and have a baseline disease 
assessment and at least one post baseline disease assessment. Subjects who do not receive at 


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least one dose of tipifarnib will be replaced. Subjects who do not have at least one post baseline 
disease assessment may be replaced.  
12.1.2 
Safety Analysis 
The primary population for the safety analysis is the Full Analysis Set (FAS), defined as all 
subjects who received at least one dose of tipifarnib in this study. 
12.2 
Endpoints 
12.2.1 
Efficacy 
The efficacy objectives and endpoints are listed in section 6. Response assessment in the 
MDS/MPN cohorts will be conducted according to the MDS/MPN IWG criteria (Table 9 and 
Table 10).  Response assessments in the AML cohorts will be conducted according to the 
International Working Group criteria (Cheson 2003).  
 
 
  Additional categories of 
response may be defined and assessed based on the observed data during exploratory analyses. 
12.2.2 
Safety and Tolerability  
12.2.2.1 
Patient Adherence 
Number of treatment cycles per patient will be summarized by numbers and percents of 
subjects who received each number of treatment cycles. 
12.2.2.2 
Concurrent Medications 
Number and percent of subjects in the FAS and in the PPS who took each individual concurrent 
medication and each class of concurrent medication will be provided.  
12.2.2.3 
Safety Analyses 
Safety and tolerability endpoints will be summarized descriptively, based on the FAS. These 
summaries will be made in several ways in consideration of the varying durations of treatments: 
(1) for all subjects across the entire study; (2) by an appropriately chosen time segment, 
depending on the duration of therapy, e.g., by 3-, 6-, or 12-month intervals from start of therapy; 
and (3) by rates per patient year (i.e., %/year) or month. 
12.2.2.4 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized across all subjects in the FAS, 
and across all subjects in the PPS. Continuous endpoints will be summarized by n, mean, 
median, minimum, maximum, and standard deviation. Categorical endpoints (includes binary 
endpoints) will be summarized by counts and percents per category. 


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12.3 
Sample Size Determination 
• 
Initial CMML Cohort 
The primary aim of the initial CMML cohort of this was to evaluate the ORR for tipifarnib in 
CMML subjects with KRAS/NRAS wild type (biomarker-positive subgroup, referred to below 
as "pos-subgroup"; and in CMML subjects with KRAS/NRAS mutations referred to as the 
"neg-subgroup"; those two subgroups comprise the entire population sampled in the trial.  This 
trial is planned as a single treatment trial with statistical comparison to historical ORR rate 0.10 
(10%).  The statistical objective is to provide evidence that the TRUE underlying ORR in all 
subjects and/or in the pos-subgroup exceeds 0.10. 
Prior data on tipifarnib in CMML subjects with unknown NRAS and KRAS mutational status 
yielded ORR~0.20.  Nonclinically, it has been demonstrated using a large panel of cell lines 
that Ras wild-type cell lines are more sensitive to tipifarnib than Ras mutant lines (End 2001), 
therefore it could be possible that subjects without KRAS and/or NRAS mutations may be 
more sensitive to tipifarnib therapy. The availability of prior data suggest that use of Bayesian 
statistics, which can incorporate use of the prior information to yield more precise statistical 
estimates of response rates than traditional methods that rely only on data to be observed in the 
prospective trial.  Thus, the probability that the TRUE underlying ORR exceeds 0.10 (i.e., 
success criteria) can be computed from the observed data, assuming a prior estimated TRUE 
ORR from the prior data.  This probability is referred to as "posterior probability" in Bayesian 
analysis, since it is estimated from the observed data incorporating the prior estimate.  If this 
probability is high (e.g., at least 0.80, i.e., meets the success criteria; probability of meeting the 
success criteria is referred to as "PoS"), then it can be concluded that the TRUE ORR exceeds 
0.10, i.e., that the success criteria is met. 
The probability that ORR exceeds 0.10 was computed for several potential scenarios to span 
the range of potential designs and design outcomes: 
• Success Criteria: Probability that TRUE rate >0.10 is at least 0.80 
• Assumed TRUE underlying ORR = 0.2, 0.3, 0.4 (0.2 useful for evaluating the entire 
population, 0.4 and 0.3 for evaluating the pos-subgroup) 
• Sample Sizes: 10, 20 
• Prior ORR = 0.3 (as a conservative estimate for the pos-subgroup) 
• Prior data influence (measured by assumed sample size "N" that yielded the prior 
data)  
o = 1 (to minimize the influence of the prior data on the PoS estimate, i.e., to let 
the observed data drive the estimate), and  
o = 10 (to limit the influence of the prior data to an amount equal to the smallest 
reasonable sample size of observed data, which is N=10) 
These probabilities are in Table 7.  For example, after ORR is observed in 10 subjects, if the 
TRUE ORR is 0.3, there is 0.85 PoS prior ORR estimate 0.3 with minimal (N=1) prior 
information; this result is highlighted in yellow in Table 7.  If the assumption on prior 
information is increased to N=10, PoS increases to 0.97, which is akin to over 95% power; this 
result is highlighted in green in Table 7.  PoS increases if TRUE ORR is higher (values for 0.4 
are shown in Table 7), and decreases if TRUE ORR is lower (values for 0.2 are shown in Table 
7).  Thus, assessment using N=10 for the pos-subgroup yields sufficient power / precision based 


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on assumed ORR on par with prior AML data.  Table 7 also shows the corresponding values 
for N=7 for prior ORR based on N=1 and on N=7; NOTE that N=7 prior is used instead of 
N=10 since the prior assumption is given equal weight as the observed sample size. 
Table 7: Probability of success for various sample sizes 
Declare 
Success if 
prob.(TRUE 
rate>0.1) at 
least: 
Prior Overall 
Response Rate 
Assumed 
Probability of Success 
after N=10 if TRUE rate 
is: 
Probability of Success 
after N=7 if TRUE rate 
is: 
0.2 
0.3 
0.4 
0.2 
0.3 
0.4 
0.8 
0.30 (N=1) 
0.62 
0.85 
0.95 
0.43 
0.66 
0.84 
0.30 (N=10 or 7) 
0.9 
0.97 
>0.99 
0.78 
0.93 
0.97 
When assuming prior ORR=0.3 from prior N=10, observing at least 1 response from 10 
subjects will meet the success criteria.  When assuming N=1 for prior ORR=0.3, at least 2 
responses from 10 subjects will meet the success criteria.  For assumed prior from N=7, at least 
1 responses from 7 subjects will meet the success criteria; for assumed prior from N=1, at least 
2 responses from 7 subjects will meet the success criteria. 
• Amendment 3 Cohorts: MDS/MPN and AML 
The cohorts introduced in amendment 3 employ a 2-stage design. In the first stage, 28 eligible 
subjects (7 subjects per cohort in Stage 1) will be enrolled and stratified into one of four 
neoplasia and biomarker-defined cohorts based on diagnosis and subject CXCR4/2 expression 
ratio level (high vs low) determined from a bone marrow sample. Each cohort will be 
terminated if 0 responses are observed at end of first stage.  Otherwise, an additional 11 subjects 
will be enrolled for the second stage.   
At the completion of a two-stage cohort, the cohort will be considered as failed if there are 3 
or less responses out of 18 evaluable subjects, indicating the true ORR is 10% or less.  If 
there are 4 or more responses, the treatment will be considered of further interest indicating 
the true ORR is higher than 10%.   
For this two-stage study design, a null response rate of 10% and alternative response rate of 
30% are assumed.  It provides 80% power to detect a difference between 10% and 30% ORR 
at one-sided significance level of 0.089.  Using this design, the probability of terminating the 
cohort at the end of first stage is 0.48 if the true ORR is 10% or less while the probability of 
terminating the cohort at the end of first stage is 0.13 if the true ORR is 30%.   
12.4 
Interim Analysis 
No interim analysis was planned in the CMML cohort. The MDS/MPN and AML cohorts 
introduced in amendment 3 will employ a 2-stage design as indicated in the prior section.  


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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 IRB/IEC 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 study at his/her site. He/she will ensure 
that the study is performed in accordance with the clinical study 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 study. 
13.2 
Subject Information and Informed Consent 
An unconditional prerequisite for a subject’s participation in the study is his/her written 
informed consent. The subject’s written informed consent to participate in the study 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 study 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 study and to decide if they would participate in the study. All 


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the queries related to the study 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 designee will inform the subject verbally of all pertinent aspects of the study. 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 ICF. Where the information is provided by the Investigator, the ICF 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 ICF 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 study 
for signing and dating. The Investigator will explain the changes to the previous version. 
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 
study as well as in the clinical study database. 
The subject’s data collected in the study will be stored under this number. Only the Investigator 
will be able to link the subject’s study data to the subject via an identification list kept at the 
site. The subject’s original medical data that are reviewed at the site during source data 
verification by the Monitor, audits and Health Authority inspections will be kept strictly 
confidential. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing subject data. Subjects will be informed accordingly and will be requested to give 
their consent on data handling procedures in accordance with national regulations. 
13.4 
Emergency Medical Support and Subject Card 
Subjects enrolled in this clinical study will be provided with Emergency Medical Support cards 
during their study participation, which will be provided by the Sponsor or designee. The 
Emergency Medical Support card is based on the need to provide clinical study subjects with 
a way of identifying themselves as participating in a clinical study, and subsequently to give 
health care providers access to the information about this participation that may be needed to 
determine the course of the subject’s medical treatment. 
This service is designed to provide information to health care providers who are not part of the 
clinical study. Clinical study investigators, who are already aware of the clinical study protocol 


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and treatment, have other means of accessing the necessary medical information for the 
management of emergencies occurring in their subjects. 
The first point of contact for all emergencies will be the clinical study Investigator caring for 
the affected subject. The Investigator agrees to provide his or her emergency contact 
information on the card for this purpose. If the Investigator is available when an event occurs, 
s/he will answer any questions. Any subsequent action will follow the standard processes 
established for the Investigators. 
In cases where the Investigator is not available, the Sponsor or designee will provide a 24 hour 
contact number whereby health care providers will be given access to the appropriate Sponsor’s 
physician or designee to assist with any information regarding tipifarnib in case of a medical 
emergency. 
13.5 
Clinical Trial Insurance and Compensation to Subjects 
The Sponsor is entirely responsible for AEs that are associated with this study 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 study site, and/or the subject. Insurance coverage 
shall be provided for participating in the study. Insurance conditions shall meet good local 
standards, as applicable. 
13.6 
Institutional Review Board/Independent Ethics Committee 
Prior to commencement of the study at a given site, the clinical study protocol will be submitted 
together with its associated documents (Investigator’s brochure, Subject Information and ICFs) 
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 study 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 study, the clinical study protocol version 
and the Subject Information and ICF version reviewed should be provided. Where possible, 
copies of the meeting minutes should be obtained. 
Amendments to the clinical study 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 study in accordance with national regulations and 
requirements. 
13.7 
Communication to Health Authorities 
The clinical study protocol and its amendments and any applicable documentation (e.g. 
Investigator’s Brochure, Subject Information and ICF) will be submitted or notified to the 
Health Authorities. 


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14 
TRIAL MANAGEMENT 
14.1 
Case Report Form Management 
The Investigator or designee will be responsible for entering study data in the CRFs 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 CRFs. 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 study. This file will contain the available 
demographic and medical information for the subject and should be as complete as possible.  
In particular, the following data should be available in this file: 
• Subject’s full name 
• Date of birth 
• Gender 
• Height 
• Weight 
• Relevant medical history and concomitant diseases 
• Prior and concomitant therapies (including changes during the study) 
• Trial identification  
• Date of subject’s inclusion into the study (i.e. date of informed consent) 
• Subject identifier in the study 
• Dates of the subject’s visits to the site 
• Dates and number of RBC, whole blood and platelet transfusions 
• Any medical examinations and clinical findings predefined in the clinical study protocol 
• All AEs observed in the subject 
• Date of subject’s end of study, and 
• Date of and reason for early withdrawal of the subject from the study or from treatment, if 
applicable. 
It must be possible to identify each subject by using this subject file. Additionally, any other 
documents containing source data must be filed. This includes original printouts of data 
recorded or generated by automated instruments, bone marrow evaluation, laboratory value 
listings, etc. Such documents must bear at least the subject identifier and the date when the 
procedure was performed. Information should be printed by the instrument used to perform the 


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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 CRFs is regarded as the source data: 
• Any Investigator’s comments 
• Subject identifier 
• Information on AEs (e.g. seriousness, severity, outcome, and causality to the IP) 
• Reason for providing concomitant medications and procedures (if applicable) 
• Assessment of disease response 
• Description about study discontinuation 
14.3 
Investigator Site File and Archiving 
The Investigator will be provided with an Investigator Site File upon initiation of the study. 
This file will contain all documents necessary for the conduct of the study and will be updated 
and completed throughout the study. 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 study, 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 study. The documents to be thus 
archived include the Subject Identification List and the signed subject ICFs. If archiving of the 
Investigator Site File is no longer possible at the site, the Investigator must notify the Sponsor. 
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per 
ICH GCP guidelines or ordinance of GCP, whichever is longer. In any case, the Investigator 
should ensure that no destruction of medical records is performed without the written approval 
of the Sponsor. 
14.4 
Monitoring, Quality Assurance and Inspection by Health 
Authorities 
This study 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 study site at regular 
intervals. 
The Sponsor, as well as Health Authorities, must be permitted to inspect all study-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 study protocol, each step of the data captures procedure, and the handling of the 
data, including the final clinical study report, will be subject to independent Quality Assurance 
activities. Audits may be conducted at any time during or after the study to ensure the validity 
and integrity of the study data. 


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14.5 
Changes to the Clinical Trial Protocol 
Changes to the clinical study 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. 
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 
study requires the renewal of the subject’s informed consent prior to implementation. 
14.6 
Clinical Trial Report 
After completion of the study, a clinical study 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 
and will include data from all study sites. Lead investigators will be identified based on accrual 
and Good Publication Practices and the decision to publish or present the initial data from all 
the study sites, or a presentation indicating the design or progress of the study, 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 study. Any publications or 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 will maintain the right to a reasonable delay 
of a publication in order to protect intellectual property rights. 
15 
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. 
Chen X, Makarewicz JM, et al. Transformation by HrasG12V is consistently associated ith 
mutant allel copy gains and is reversed by farnesyl transferase inhibition. Oncogene 
2014;33:5542-9. 
Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev 
Cancer. 2016;16:431-46 
Emanuel RM, Dueck AC, Geyer HL, et. al. Myeloproliferative neoplasm (MPN) symptom 
assessment form total symptom score: prospective international assessment of an abbreviated 
symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012 Nov 
20;30(33):4098-103. 


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End DW, Smets G, Todd AV et al. Characterization of the antitumor effects of the selective 
farnesyl protein transferase inhibitor R115777 in vivo and in vitro.  Cancer Res 2001;61:31-7. 
Fenaux P, Beuscart R, Lai JL, et al. Prognostic factors in adult chronic myelomonocytic 
leukemia: An analysis of 107 cases. J Clin Oncol 1988;6:1417–1424. 
Gualberto A, Scholz C, Janes MR, et al. The CXCL12/CXCR4 Pathway As a Potential Target 
of Tipifarnib in Acute Myeloid Leukemia and Myelodysplastic Syndromes. Blood 2017 
130:3957 
Kantarjian H, Issa JP, Rosenfeld CS, et. al. Decitabine improves patient outcomes in 
myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006 Apr 
15;106(8):1794-803. 
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, 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. 
Kurzrock R, Kantarjian HM, Cortes JE, et. al. Farnesyltransferase inhibitor R115777 in 
myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting. Blood. 2003 
Dec 15;102(13):4527-34. 
Lancet JE, Gotlib J, Gojo I, et al. Tipifarnib (ZARNESTRA™) in previously untreated poor-
risk AML of the elderly: updated results of a multicenter phase 2 trial [abstract]. 
Blood 2004; 104:pt 1–249a Abstract 874. 
Martinelli G, Iacobucci I, Paolini et al. Farnesyltransferase inhibition in hematologic 
malignancies: the clinical experience with tipifarnib. Clin Adv Hematol Oncol 2008; 4:303-10. 
Morgan MA, Wegner J, Aydilek E, et. al. Synergistic cytotoxic effects in myeloid leukemia 
cells upon cotreatment with farnesyltransferase and geranylgeranyl transferase-1 inhibitors. 
Leukemia 2003;17:1508-1520. 
Onida F, Barosi G, Leone G, Malcovati L, Morra E, Santini V, et al. Management 
recommendations for chronic myelomonocytic leukemia: consensus statements from the SIE, 
SIES, GITMO groups. Haematologica. 2013;98:1344–1352. 
Onida F, Kantarjian HM, Smith TL, et al. Prognostic factors and scoring systems in chronic 
myelomonocytic leukemia: A retrospective analysis of 213 patients. Blood 2002;99:840–849 
Padron, E. Surveying the landscape of MDS/MPN research: overlap among the overlap 
syndromes? Hematology Am Soc Hematol Educ Program. 2015 Dec 5;2015(1):349-54. 
Patnaik M, Sallman DA, Sekkeres MA, et al. Preliminary results from an open-label, phase 2 
study of tipifarnib in chronic myelomonocytic leukemia (CMML). ASH 59th Annual Metting, 
Abstract 2963.   
Silverman LR, Demakos EP, Peterson BL, et. al. Randomized controlled trial of azacitidine in 
patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J 
Clin Oncol. 2002 May 15;20(10):2429-40. 
Takashima A, Faller DV. Targeting the RAS oncogene. Expert Opin Ther Targets. 2013 
May;17(5):507-31. 
Tipifarnib Investigator’s Brochure, Edition 12, Jan 2015. 


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Witzig T, Sokol L, Jaccobsen E, et al. Preliminary results from an open-label, phase II study 
of tipifarnib in relapsed or refractory peripheral T-cell lymphoma. Hematological Oncology 
2017; 35,S2: 251–252 
 
 
 










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SAP_001.pdf: 
Protocol Number: KO-TIP-004 
 
Official Title:  
 A Phase 2 Study of Tipifarnib in Subjects with Chronic Myelomonocytic Leukemia, Other 
Myelodysplastic /Myeloproliferative Neoplasias, and Acute Myeloid Leukemia 
 
NCT Number: NCT02807272 
 
Document Date: 11 June 2020 


 
 
 
 
 
 
 
 
 
A Phase 2 Study of Tipifarnib in Subjects with Chronic Myelomonocytic 
Leukemia (CMML), Other Myelodysplastic/Myeloproliferative Neoplasias 
(MDS/MPN), and Acute Myeloid Leukemia (AML) 
Protocol #: KO-TIP-004 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
Statistical Analysis Plan (SAP) 
Author: 
 
Contact Information: 
 
 
 
 
 
 
Date of SAP: 
11-June-2020 
SAP Version: 
Draft 2.0 




 
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SAP Version: 
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2. TABLE OF CONTENTS 
Page 
1. 
APPROVAL PAGE ................................................................................................. 2 
2. 
TABLE OF CONTENTS .......................................................................................... 3 
3. 
LIST OF ABBREVIATIONS AND SYMBOLS ......................................................... 5 
4. 
INTRODUCTION ..................................................................................................... 6 
5. 
STUDY DESIGN AND OBJECTIVES ..................................................................... 6 
5.1 
Study objectives ........................................................................................................... 6 
5.1.1 
Primary objectives and endpoints ................................................................................. 6 
5.1.2 
Secondary objectives and endpoints ............................................................................ 7 
5.1.3 
Exploratory objectives ................................................................................................... 7 
5.2 
Trial design .................................................................................................................. 7 
5.3 
Sample size justification ............................................................................................... 9 
5.3.1 
Initial CMML Cohort ...................................................................................................... 9 
5.3.2 
Amendment 3 Cohorts: MDS/MPN and AML .............................................................. 10 
5.3.3 
Replacement of Subject .............................................................................................. 10 
5.4 
Treatment randomization ........................................................................................... 11 
6. 
GENERAL ANALYSIS DEFINITIONS .................................................................. 11 
6.1 
Study period and visit window definitions ................................................................... 11 
6.1.1 
Study periods .............................................................................................................. 11 
6.1.2 
Baseline, study day, and visit windows ....................................................................... 11 
6.2 
Protocol deviations .................................................................................................... 11 
6.3 
Study populations ...................................................................................................... 11 
6.3.1 
Full analysis set ........................................................................................................... 11 
6.3.2 
Per protocol analysis set ............................................................................................. 11 
6.4 
Treatment assignment and treatment groups ............................................................ 11 
6.5 
Subgroups ................................................................................................................. 11 
6.6 
Global analysis and reporting rules ............................................................................ 12 
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..................................... 12 
8. 
SUBJECT DISPOSITION ...................................................................................... 13 
9. 
DRUG EXPOSURE AND TREATMENT ............................................................... 13 
9.1 
Drug exposure ........................................................................................................... 14 
9.2 
Prior and concomitant medications ............................................................................ 14 
9.3 
Other treatments/procedures and transfusions .......................................................... 14 
10. EFFICACY ANALYSES ........................................................................................ 14 
10.1 Definition of endpoints ............................................................................................... 14 
10.2 Efficacy analyses for the primary endpoint ................................................................ 15 
10.3 Efficacy analyses for the secondary endpoints .......................................................... 15 
10.3.1 Rate of Best Response ............................................................................................... 15 
10.3.2 Duration of response ................................................................................................... 15 
10.3.3 Rate of PFS at 1 year .................................................................................................. 15 
10.3.4 Rate of survival at 1 year ............................................................................................ 15 


 
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11. SAFETY ANALYSES ............................................................................................ 16 
11.1 Adverse events .......................................................................................................... 16 
11.2 Clinical laboratory evaluations ................................................................................... 17 
11.3 Bone marrow ............................................................................................................. 17 
11.4 Myeloproliferative neoplasm symptom assessment score ......................................... 17 
11.5 ECOG performance status ........................................................................................ 17 
11.6 Physical exam and vital signs .................................................................................... 18 
11.7 Cytogenetics .............................................................................................................. 18 
11.8 Other data related to safety ....................................................................................... 18 
12. INTERIM ANALYSIS ............................................................................................. 18 
13. REFERENCES ...................................................................................................... 19 




 
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4. INTRODUCTION 
The observations of objective Complete Response (CR) and Partial Response (PR) induced by 
single agent tipifarnib in heavily pretreated subjects with chronic myelomonocytic leukemia 
(CMML) warrants further research. Its ease of administration and documented toxicity profile 
allow for outpatient treatment. Furthermore, given the high unmet medical need and lack of 
therapeutic options for subjects with CMML, tipifarnib may provide a critical new therapeutic 
option in the armamentarium for CMML therapy. This open label phase 2 study is designed to 
assess the effect of tipifarnib in CMML. Prior to amendment 3, subjects with CMML were 
enrolled in the study and retrospectively stratified by RAS mutational status. The study met its 
primary endpoint with 3 objective responses observed in 9 evaluable subjects with RAS wildtype 
CMML (Patnaik 2017). No responses were observed in 7 evaluable CMML subjects with RAS 
mutations. Analysis of gene expression in bone marrows obtained at baseline (prior to the first 
dose of tipifarnib) from the CMML subjects enrolled in the study indicated that a high ratio of 
expression of the C-X-C motif chemokine receptors CXCR4 and CXCR2 was significantly 
associated with clinical benefit from tipifarnib (Gualberto 2017). In amendment 3, four additional 
cohorts will be enrolled: 
1. Subjects with MDS/MPN with high CXCR4/2 Ratio 
2. Subjects with MDS/MPN with low CXCR4/2 Ratio 
3. Subjects with AML with high CXCR4/2 Ratio 
4. Subjects with AML with low CXCR4/2 Ratio 
Data will be collected to satisfy the protocol stated objectives, and statistical analysis and 
reporting of these data are required. This document represents the statistical analysis plan 
(SAP) of the data and associated reporting requirements. 
Upon Kura’s request, the enrollment of AML cohort was held. The CSR will summary CMML 
and MDS/MPN only. 
 
 
 
5. STUDY DESIGN AND OBJECTIVES 
5.1 Study objectives 
5.1.1 Primary objectives and endpoints 
Primary Objective 1: To assess the antitumor activity of tipifarnib, in terms of Objective 
Response Rate (ORR), in subjects with CMML and in subjects with CMML whose disease is 
KRAS/NRAS wild type. 
Primary Objective 2 (MDS/MPN cohorts): To assess the antitumor activity of tipifarnib, in 
terms of ORR, in subjects with MDS/MPN, including CMML, who have a high ratio of expression 
of CXCR4 to CXCR2 (CXCR4/2 ratio) in their bone marrows and in those with low CXCR4/2 
ratio. 
Primary Objective 3 (AML cohorts): To assess the antitumor activity of tipifarnib, in terms of 
ORR, in subjects with AML who have a high ratio of expression of CXCR4 to CXCR2 (CXCR4/2 
ratio) in their bone marrows and in those with low CXCR4/2 ratio. 
Primary endpoint: Response assessments of CMML and MDS/MPN will be evaluated 
according to the MDS/MPN IWG criteria (Protocol Table 9 and Table 10). Response 


 
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assessments of AML will be evaluated according to the International Working Group criteria 
(Cheson 2003). 
5.1.2 Secondary objectives and endpoints 
Secondary Objective: To assess the effect of tipifarnib on the following: 
• 
Rate of CR, complete cytogenetic remission, partial remission, marrow response, and 
clinical benefit 
• 
Duration of Response 
• 
Rate of PFS at 1 year 
• 
Rate of survival at 1 year 
• 
AE profile according to NCI CTCAE v 4.03 
Secondary Endpoint: Response assessments according to the MDS/MPN IWG criteria 
(MDS/MPN and CMML) or International Working Group criteria (AML cohorts); treatment 
emergent adverse events (TEAEs) and serious adverse events (SAEs) evaluated according to 
NCI CTCAE v.4.03. 
5.1.3 Exploratory objectives 
Exploratory Objective: To explore potential biomarkers and their association with clinical 
benefit from tipifarnib including cancer gene mutations, monocyte and immune cell subsets and 
other candidate biomarkers of tipifarnib in bone marrow and blood samples. 
Exploratory Endpoint: Molecular analyses of blood and bone marrow. 
5.2 Trial design 
Prior to Amendment 3 (2018-03-9), the phase 2 study investigated the antitumor activity in 
terms of ORR of tipifarnib in approximately 20 eligible subjects with CMML. Eligible subjects 
received tipifarnib administered at a starting dose of 1200 mg, orally with food, bid for 7 days in 
alternating weeks (Days 1-7 and 15-21) in 28-day cycles. Stepwise 300 mg dose reductions to 
control treatment-related, treatment-emergent toxicities were allowed. This trial was planned as 
a single treatment trial with statistical comparison to historical ORR rate 0.10 (10%). The 
primary objective was to provide evidence that the TRUE underlying ORR in all subjects and/or 
in the KRAS/NRAS wild-type subgroup exceeds 0.10. That evidence was quantified by 
calculation of the Bayesian posterior probability that the TRUE underlying ORR exceeds 0.10 
based on the OBSERVED ORR in the trial using both an informative and uninformative 
Bayesian prior distribution for TRUE ORR. If this probability would be over 80%, then it would 
be concluded that the TRUE ORR exceeds 0.10, i.e. the trial results would have met success 
criteria to demonstrate efficacy. 
Amendment 3 (2018-03-9): This Phase 2 study will investigate the antitumor activity in terms of 
ORR of tipifarnib in approximately 36 eligible subjects with MDS/MPN, including CMML, and 36 
eligible subjects with AML. 
Each cohort has a 2-stage design. Seven subjects will be enrolled in the first stage of each 
cohort. If at least one objective response is observed, the cohort will be expanded to enroll an 
additional 11 subjects in stage 2. The cohort will be considered positive if 4 or more responses 
are observed in the 18-subject cohort. Based on the absence of objective responses observed 
in the initial cohort of RAS mutant CMML subjects, all enrolled subjects enrolled in amendment 
3 cohorts 1-4 will have RAS wild type tumor status at study entry. 


 
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Only consented subjects who meet all eligibility criteria will be enrolled in the study. 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. Evaluations performed as part of the standard of care within 28 days of 
dosing but prior to consent, do not need to be repeated. By signing the consent form, study 
subjects agree to the collection of standards of care health information. 
Subjects (amendment 3 cohorts 1-4) will receive tipifarnib administered at a dose of 400 mg, 
orally with food, bid for 21 days in 28-day cycles. Food intake is important for tipifarnib 
bioavailability. The relevance of food intake with tipifarnib administration should be highlighted 
to study subjects. 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. 
Stepwise 100 mg dose reductions to control treatment-related, treatment-emergent toxicities are 
indicated in the body of the study protocol. In the absence of unmanageable toxicities, subjects 
may continue to receive tipifarnib treatment until disease progression. Provisions will be made 
for the continuation of study treatment in subjects whose disease has not progressed beyond 
the end of the study, e.g. a single subject treatment protocol. 
Disease assessments (bone marrow, hematology and quality of life evaluations) will be 
performed at screening, and at the Day 25 visit (± 5 days) performed during Cycles 2, 4, 6, 9 
and every approximately 12 weeks thereafter (Cycles 9, 12, 15, etc.), at the End of Treatment 
visit and during follow up. As part of the disease assessment at screening and at the Day 25 
visit performed during Cycles 2, 4, 6 and 9, bone marrow evaluations will be conducted. 
Thereafter, bone marrow evaluations will occur during disease assessments in accordance with 
institutional standard practice. 
Hematologic assessments, including peripheral blood 
evaluations and review of transfusion requirements, will be performed at screening and at least 
monthly until disease progression. 
Additional disease or hematologic assessments may be conducted if deemed necessary by the 
Investigator. The timing of the disease and hematologic assessments should be maintained as 
much as possible independently of potential treatment cycle delays. 
Determination of disease response in subjects with MDS/MPN will be performed by the 
Investigator according to the Myelodysplastic/Myeloproliferative International Working Group 
(MDS/MPN IWG criteria, Protocol Table 9). Similarly, disease progression will also be 
determined based on the MDS/MPN IWG criteria (Protocol Table 10). Determination of disease 
response in subjects with AML will be performed by the Investigator according to the 
International Working Group criteria (Cheson 2003). Similarly, disease progression will also be 
determined based on the IWG criteria (Cheson 2003). 
Upon disease progression, all subjects in this study 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 study cohort has been completed, whichever occurs first. Information on survival 
and subsequent anticancer therapy may be collected by phone. 
Subjects who terminate treatment for reasons other than death or disease progression will be 
assessed at regular intervals for disease progression (approximately every 2 months through 
the first 6 months from the start of the subject’s participation in this study and every 
approximately 12 weeks thereafter) and leukemic transformation (monthly blood counts). 
Disease assessments performed during the first 9 months from the start of the subject’s 


 
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participation in the study will include bone marrow evaluation. Thereafter, bone marrow 
evaluations will occur during disease assessments in accordance with institutional standard 
practice. These assessments will continue until disease progression, withdrawal of subject’s 
consent to study procedures or initiation of another anticancer therapy. 
All subjects will be followed-up for safety during treatment and up to approximately 30 days (30 
± 7 days) after treatment discontinuation or until immediately before the initiation of another 
anticancer 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 NCI CTCAE v.4.03 criteria. 
5.3 Sample size justification 
5.3.1 Initial CMML Cohort 
The primary aim of the initial CMML cohort was to evaluate the ORR for tipifarnib in CMML 
subjects with KRAS/NRAS wild type (biomarker-positive subgroup, referred to below as "pos- 
subgroup"; and in CMML subjects with KRAS and/or NRAS mutations referred to as the "neg- 
subgroup"; those two subgroups comprise the entire population sampled in the trial. This trial is 
planned as a single treatment trial with statistical comparison to historical ORR rate 0.10 (10%). 
The statistical objective is to provide evidence that the TRUE underlying ORR in all subjects 
and/or in the pos-subgroup exceeds 0.10. 
Prior data on tipifarnib in CMML subjects with unknown NRAS and KRAS mutational status 
yielded ORR~0.20. Non clinically, it has been demonstrated using a large panel of cell lines 
that Ras wild-type cell lines are more sensitive to tipifarnib than Ras mutant lines (End 2001), 
therefore it could be possible that subjects with both KRAS and NRAS wild type may be more 
sensitive to tipifarnib therapy. The availability of prior data suggests that use of Bayesian 
statistics, which can incorporate use of the prior information to yield more precise statistical 
estimates of response rates than traditional methods that rely only on data to be observed in the 
prospective trial. Thus, the probability that the TRUE underlying ORR exceeds 0.10 (i.e., 
success criteria) can be computed from the observed data, assuming a prior estimated TRUE 
ORR from the prior data. This probability is referred to as "posterior probability" in Bayesian 
analysis, since it is estimated from the observed data incorporating the prior estimate. If this 
probability is high (e.g., at least 0.80, i.e., meets the success criteria; probability of meeting the 
success criteria is referred to as "PoS"), then it can be concluded that the TRUE ORR exceeds 
0.10, i.e., that the success criteria is met. 
The probability that OR exceeds 0.10 was computed for several potential scenarios to span the 
range of potential designs and design outcomes: 
• 
Success Criteria: Probability that TRUE rate >0.10 is at least 0.80 
• 
Assumed TRUE underlying ORR = 0.2, 0.3, 0.4 (0.2 useful for evaluating the entire 
population, 0.4 and 0.3 for evaluating the pos-subgroup) 
• 
Sample Sizes: 10, 20 
• 
Prior ORR = 0.3 (as a conservative estimate for the pos-subgroup) 
• 
Prior data influence (measured by assumed sample size "N" that yielded the prior data) 
o = 1 (to minimize the influence of the prior data on the PoS estimate, i.e., to let the 
observed data drive the estimate), and 




 
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SAP Version: 
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Subjects who do not receive at least one dose of tipifarnib will be replaced. Subjects who do 
not have at least one post baseline disease assessment will be replaced. 
5.4 Treatment randomization 
This trial is planned as a single treatment trial; no randomization will be used. 
 
6. GENERAL ANALYSIS DEFINITIONS 
6.1 
Study period and visit window definitions 
6.1.1 
Study periods 
The study includes the following time and events schedules: screening (Day -28 to Day -1), Day 
1, Day 15, and Day 25 of each cycle (28 days per cycle), End of Treatment visit (30 ± 7 days 
from the last dose of tipifarnib or immediately before the initiation of any other anticancer 
therapy), Follow up visit, Follow up contact. A detailed description of the time and events 
schedule of planned study assessments and visit procedures is outlined in Protocol Table 1. 
6.1.2 
Baseline, study day, and visit windows 
Analyses requiring use of baseline data will use the last information collected pre-dose on or 
prior to first dosing on Day 1. Baseline assessments may be taken during screening if Day 1 
pre-dose assessments are not available. 
Subject’s time on study will be determined in Study Days. The study day is defined as the 
number of days since or prior to the first dose date of tipifarnib. The day of the first dose of 
tipifarnib is defined as Day 1 while the last day prior to Day 1 is defined as Day -1. 
Visit windows will not be used for this study. 
6.2 
Protocol deviations 
will provide a complete list of all identified deviations to Kura. The Sponsor will 
categorize the deviations. 
6.3 
Study populations 
6.3.1 
Full analysis set 
The Full Analysis Set (FAS) is defined as all subjects who received at least one dose of 
tipifarnib in this study. It is the primary population for the safety analysis 
6.3.2 
Per protocol analysis set 
The Per Protocol Analysis Set (PPS) includes subjects who received at least one dose of 
tipifarnib, and have a baseline disease assessment and at least one post baseline disease 
assessment. It is the primary population for the efficacy analysis. 
6.4 
Treatment assignment and treatment groups 
Prior to protocol amendment 3.0, all eligible subjects with CMML were assigned to receive 
tipifarnib 1200 mg to be taken orally with food bid for 7 days in alternating weeks (days 1-7 and 
days 15-21) in 28-day cycles. Additionally, stepwise 300 mg dose de-escalation based on 
subject tolerability is allowed. In amendment 3.0, all eligible subjects will be assigned to receive 
tipifarnib 400 mg to be taken orally with food on days 1-21) in 28-day cycles. Additionally, 
stepwise 100 mg dose de-escalation based on subject tolerability is allowed. 
6.5 
Subgroups 


 
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For demography, baseline characteristics and efficacy, 4 subgroups will be presented: 
1. Subjects with CMML and KRAS/NRAS wild type 
2. Subjects with CMML and KRAS/NRAS mutation 
3. Subjects with MDS/MPN and high CXCR4/2 ratio 
4. Subjects with MDS/MPN and low CXCR4/2 ratio 
In CMML efficacy analyses, additional 6 subgroups will be presented: 
1. Subjects with CMML1 and KRAS/NRAS wild type 
2. Subjects with CMML1 and KRAS/NRAS mutation 
3. Subjects with CMML2 and KRAS/NRAS wild type 
4. Subjects with CMML2 and KRAS/NRAS mutation 
5. Subjects with CMML and high CXCR4/2 ratio 
6. Subjects with CMML and low CXCR4/2 ratio 
The total for each of CMML and MDS/MPN will be summarized. 
6.6 
Global analysis and reporting rules 
Data will be summarized using standard summary statistics and additional descriptive methods 
including individual data listings and plots of individual data and summary statistics. For 
continuous variables, summaries will include the number of non-missing subjects, mean, 
standard, median, minimum, and maximum. For categorical variables, summaries will present 
the number and percentage of subjects in each subgroup or category. 
 
 
 
7. DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Unless specified otherwise, subject baseline demographics and disease status variables will be 
summarized on the full analysis set. 
Baseline Demographics summary will include the following: 
• 
Age in years, will be calculated as INT [(date of informed consent - date of birth)/365.25], 
where INT is the integer value of the calculation. 
• 
Sex (male or female) 
• 
Race (white, black or African American, native Hawaiian or other Pacific Islander, Asian, 
American Indian or Alaska Native, other, not reported) 
• 
Ethnicity (Hispanic or Latino, not Hispanic or Latino, not reported) 
• 
Height in cm 
• 
Weight in kg 
Subject disease status will be summarized among the following items: 
• 
Time since diagnosis in months (calculated relative to the date of consent signed) 


 
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Final 2.0 
 
• 
Disease diagnosis (CMML-1, CMML-2, MDS/MPN, and AML) 
• 
Any prior anti-cancer therapy (Yes, No) 
• 
Baseline ECOG performance status (0, 1) 
All demographic and baseline characteristic data including disease history, medical history, and 
surgical history will be presented in the subject data listings. 
 
8. SUBJECT DISPOSITION 
The frequency and percent of subjects who terminate the treatment, complete the study, 
discontinue the study prior to completion will be summarized. 
Reasons for terminating the study treatment include: 
• 
Adverse event 
• 
Death 
• 
Physician’s decision 
• 
Study terminated by sponsor 
• 
Progressive disease 
• 
Subject non-compliance/protocol violation 
• 
Withdrawal of consent 
• 
Other 
Reasons for early discontinuation of the study include: 
• 
Completed 
• 
Adverse event 
• 
Death 
• 
Lost to follow up 
• 
Permanent withdrawal of consent 
• 
Physician decision 
• 
Pregnancy 
• 
Protocol defined disease progression 
• 
Study terminated by sponsor 
• 
Subject non-compliance / protocol violation 
• 
Other 
The disposition data will be listed for all subjects. 
 
9. DRUG EXPOSURE AND TREATMENT 


 
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9.1 Drug exposure 
The following parameters will be summarized: 
• 
Duration of treatment (weeks) is defined as: (the date of last dose of tipifarnib - date of 
first dose tipifarnib + 1)/7. 
• 
The number of planned doses is defined as the total planned AM and PM dose before 
treatment discontinuation. 
• 
The number and percent of planned dosing is defined as the number of actual doses/the 
number of planned dosing time) *100. 
• 
The number and percentage of subjects skipping doses (AM or PM dose) before 
treatment discontinuation. 
• 
Daily Dose (mg) is defined as the cumulative dose/duration of treatment (day) before 
treatment discontinuation. 
• 
The number and percentage of subjects experiencing any vomited dose before 
treatment discontinuation. 
Drug treatment and exposure parameters will be listed. 
9.2 Prior and concomitant medications 
Prior and concomitant medications will be coded using the WHO Drug dictionary June 2016. 
Medications initiated prior to start of treatment and maintained during the study or initiated after 
start of treatment will be considered as concomitant medications. Medications administrated 
prior to and not continuing the study treatment will be considered as prior medications. 
Medications with partial or missing start date will be assumed to be concomitant medications, 
unless there is clear evidence (through comparison of partial dates or end date with the date of 
tipifarnib treatment) to suggest that the medications are not taken during study. Prior and 
concomitant medications will be summarized separately by anatomical therapeutic class (ATC) 
and preferred name. The by-subject listing for all prior/concomitant medications will be provided. 
9.3 Other treatments/procedures and transfusions 
Data of non-drug treatment/procedures, subsequent anti-cancer therapy, transfusions will be 
listed, but will not be summarized. 
 
 
 
10. EFFICACY ANALYSES 
The efficacy analyses will be performed on the Per Protocol Analysis Set. 
10.1 
Definition of endpoints 
Disease assessments other than bone marrow (hematology and quality of life evaluations) will 
be performed at screening, and at the Day 25 visit (± 5 days) performed during Cycles 2, 4, 6, 9 
and every approximately 12 weeks thereafter (Cycles 9, 12, 15, etc.), at the End of Treatment 
visit and during Follow Up. Bone marrow evaluation will be performed as part of the disease 
assessment at screening and at the Day 25 visit (± 5 days) performed during Cycles 2, 4, 6 and 
9. Thereafter, bone marrow evaluations will occur during disease assessments in accordance 
with institutional standard practice. Hematologic assessments, including peripheral blood 
evaluations and review of transfusion requirements, will be performed at screening and at least 


 
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monthly until disease progression. Additional disease or hematologic assessments may be 
conducted if deemed necessary by the Investigator. 
For subjects with CMML and MDS/MPN, determination of disease response will be performed 
by the Investigator according to the MDS/MPN IWG criteria (Protocol Table 9 and 10); Objective 
Response (OR) is achieved if the investigator indicates complete response, complete 
cytogenetic remission, partial remission, marrow response, or clinical benefit. 
10.2 
Efficacy analyses for the primary endpoint 
The primary objective of the study is to assess the antitumor activity of tipifarnib. Objective 
Response Rate (ORR) will be estimated based on the crude proportion of subjects who achieve 
an objective response (as defined in section 10.1). ORR will be presented with a two-sided 
95% confidence interval (CI) using the Clopper-Pearson method. For the CMML subjects, 
Bayesian posterior probabilities that TRUE underlying rates exceed several meaningful levels of 
response rate (e.g., exceeding 0.1 for the primary endpoint ORR) will be computed. Informative 
and uninformative prior distributions of rates will be used. Traditional 90% confidence intervals 
for TRUE underlying rates will also be computed and reported. 
10.3 
Efficacy analyses for the secondary endpoints 
10.3.1 
Rate of Best Response 
The disease response of CMML and MDS/MPN will be ordered in the sequence of Complete 
Response, Complete Cytogenetic Remission, Partial Remission, Marrow Response, Clinical 
Benefit, Stable Disease, and Progressive Disease. The best response will be presented with a 
two-sided 95% CI using the Clopper-Pearson method. 
10.3.2 
Duration of response 
Duration of response is measured from the date that the subject first meets the criteria of 
objective response (as defined in section 10.1) to the date that the subject progresses, or until 
death from any cause during the period of disease assessments. For the subjects who are not 
known to have progressed or died, they will be censored at the date of last disease assessment. 
For the subjects who receive subsequent anti-cancer therapy, they will be censored at the date 
of last disease assessment before subsequent anti-cancer therapy. The median survival and 
corresponding 95% confidence interval will be estimated using Kaplan-Meier method. 
10.3.3 
Rate of PFS at 1 year 
Progression-free Survival (PFS) will be defined as the time from date of the consent signed to 
the date of documented disease progression or death due to any cause, whichever comes first. 
The subjects without progression or death will be censored at the date of last disease 
assessment. For the subjects who receive subsequent anti-cancer therapy, they will be 
censored at the date of last disease assessment before subsequent anti-cancer therapy. For 
analysis purpose, 1 month is equal to 30.4375 days; and 1 year (12 months) is defined as 
365.25 days. The Kaplan-Meier product-limit method will be used to estimate the 1-year PFS 
rate, as well as the corresponding 95% confidence interval. 
10.3.4 
Rate of survival at 1 year 
Overall Survival (OS) will be defined as the time from date of the consent signed to the date of 
death due to any cause. Subjects who are alive or lost to follow-up by the end of study will be 
censored at the date of last known to be alive, which will be derived from the date reported in 
vital signs, laboratory, disease assessments, death, study discontinuation, and end of study 
CRFs. OS will be analyzed using Kaplan-Meier method. Rate of survival at 1 year, along with 


 
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the corresponding 95% confidence interval will be estimated in the same manner as 1-year 
PFS. Median survival with 95% confidence interval will also be reported. 
The hazard ratio along with 95% CI (KRAS/NRAS WT vs KRAS/NRAS MUT, and CXCR4/2 
High vs CXCR4/2 Low) will be estimated using a Cox proportional hazards model. The 
KRAS/NRAS MUT and CXCR4/2 Low will be used as the reference groups (ie, denominator of 
the hazard ratio). A time-to-event hazard ratio less than 1.0 would indicate an KRAS/NRAS WT 
benefit over KRAS/NRAS MUT or an CXCR4/2 High benefit over CXCR4/2 Low. Additionally, 
Log-rank P-value will be estimated using Kaplan-Meier method. 
 
 
 
11. SAFETY ANALYSES 
Unless otherwise specified, all safety analyses will be performed on the Full Analysis Set. The 
summaries will not be separated by mutational subtypes. CMML, MDS/MPN, and Total will be 
reported. 
11.1 
Adverse events 
Adverse events (AEs), including laboratory-related adverse events, will be coded by System 
Organ Class (SOC) and Preferred Term (PT) using MedDRA dictionary 19.0. The Investigator 
will grade each adverse event with NCI-CTCAE v4.03, and category the relatedness of AE to 
tipifarnib as either “Related” or “Not related”. Treatment-emergent AEs (TEAEs) are defined as 
AEs with an onset on or after start of tipifarnib and within 30 days of the last dose of tipifarnib. 
Incidence rates and percentages will be summarized for each SOC and preferred term. A 
subject reporting multiple cases of the same TEAE will be counted once, at worst grade, within 
each system organ class and similarly counted once within each preferred term. All adverse 
events will be included in the listings. TEAEs will be tabulated in summary tables including: 
• 
Overview of TEAE 
• 
TEAEs by system organ class and preferred term 
• 
TEAEs by preferred term, ordered by incidence 
• 
TEAEs by system organ class, preferred term, and maximum CTCAE grade 
• 
Treatment-related TEAEs by system organ class and preferred term 
• 
Serious TEAEs by system organ class and preferred term 
• 
Treatment-related serious TEAEs by system organ class and preferred term 
• 
Treatment-related TEAEs by preferred term, ordered by incidence 
• 
Serious TEAEs by preferred term, ordered by incidence 
• 
Treatment-related TEAEs by system organ class, preferred term, and maximum CTCAE 
grade 
Listings will be presented as follows: 
• 
All AEs 
• 
Serious AEs 


 
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• 
Treatment-related serious AEs 
• 
AEs leading to discontinuation of tipifarnib 
• 
AEs leading to death 
Imputation rule for the missing AE onset date 
AE onset date will be imputed only if day is missing, and only for the purposes of determining 
whether or not an AE is treatment emergent. All efforts will be made to query the sites to 
provide the missing information. For the partial date with missing day, the following imputation 
rule will be applied: 
• 
If only day is missing, and if the year and month are equal to the first dose date, the day 
will be imputed as day of the first dose date. Otherwise, the day will be imputed as “01”. 
11.2 
Clinical laboratory evaluations 
All clinical safety laboratory tests listed in the section below will be performed at local 
laboratories. Subject eligibility will be determined based on the baseline laboratory results. 
Clinically significant laboratory test abnormalities will be followed until resolution or stabilization 
and the overall clinical outcome has been ascertained (See protocol Section 10.4). 
Blood samples will be collected for the following clinical laboratory tests: 
• 
Serum Chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
total bilirubin, creatinine, potassium and calcium 
• 
Hematology: hemoglobin, platelets, white blood cells (WBCs), neutrophils, neutrophil 
precursors, lymphocytes, monocytes and blasts 
• 
Coagulation: activated partial thromboplastin time (APTT), prothrombin time/international 
normalized ratio (PT/INR) 
All hematology, blood chemistry, coagulation results will be listed per subject for each 
assessment. Descriptive statistics will be tabulated by visit based on actual value and change 
from baseline value. 
Laboratory values will be graded and summarized based on NCI CTCAE v4.03. Shift tables will 
be provided for applicable laboratory tests to summarize the frequencies of subjects by CTCAE 
grade at baseline contrasted with worst post-baseline values. 
11.3 
Bone marrow 
Data of bone marrow aspirate and biopsy will be tabulated by visit. Descriptive statistics will be 
presented for tests with continuous results (i.e., Myeloblasts (%) and cellularity (%)). Counts 
and percentages of subjects will be provided for tests with categorical results. The by-subject 
listing will be provided. 
11.4 
Myeloproliferative neoplasm symptom assessment score 
Data of MPN symptom assessments will be listed per subject for each assessment. Descriptive 
statistics will be tabulated for each symptom based on actual value and change from baseline 
value. 
11.5 
ECOG performance status 
Data for ECOG performance status are collected on Screening, Day 1 of each cycle, and End of 
Treatment visit.  Subject counts and percentage under each ECOG category will be 


 
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summarized by visit for both actual value and change from baseline value. The by-subject listing 
for all ECOG data will be provided. 
11.6 
Physical exam and vital signs 
Complete physical examination, including vital signs, is performed on Screening and End of 
Treatment visit. Symptom-based physical exam is performed on Day 1, Day 15 and Day 25 of 
each cycle and as needed throughout the study. Data of vital signs (heart rate, blood pressure, 
and temperature) will be tabulated using descriptive statistics based on actual value and change 
from baseline value at each scheduled time point.  The by-subject listings will be provided for 
all data of physical exam and vital signs. 
Body weight will be listed per subject for each assessment. Descriptive statistics will be 
presented by visit based on actual value and change from baseline value. 
11.7 
Cytogenetics 
Cytogenetics data will be listed by assessment and subject. 
11.8 
Other data related to safety 
A by-subject listing will be provided for pregnancy tests and other data. 
 
12. INTERIM ANALYSIS 
No interim analysis was planned in the CMML cohort. The MDS/MPN and AML cohorts 
introduced in amendment 3 will employ a 2-stage design as indicated in the prior section. A 
formal interim analysis will not be performed. 


 
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13. REFERENCES 
Cheson BD, et al Revised recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for 
Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9 
End DW, Smets G, Todd AV et al. Characterization of the antitumor effects of the selective 
farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001;61:31-7. 
Gualberto A, Scholz C, Janes MR, et al. The CXCL12/CXCR4 Pathway As a Potential 
Target of Tipifarnib in Acute Myeloid Leukemia and Myelodysplastic Syndromes. Blood 
2017 130:3957 
Patnaik M, Sallman DA, Sekkeres MA, et al. Preliminary results from an open-label, phase 2 
study of tipifarnib in chronic myelomonocytic leukemia (CMML). ASH 59th Annual Meeting, 
Abstract 2963. 
Savona MR, Malcovati L, Komrokji R, et. al. MDS/MPN International Working Group. An 
international consortium proposal of uniform response criteria for 
myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 2015 Mar 
19;125(12):1857-65. 


 
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