Clinical trial NCT03496766
Conditions: Non Small Cell Lung Cancer
Sponsor: Spanish Lung Cancer Group
Start date: 2018-05-07; Completion date: 2022-11-09
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This Phase II study consists of 2 parts: 1) pre-screening phase and 2) treatment phase.

The pre-screening phase will investigate the presence of HRAS mutations in subjects with a histologically or cytologically confirmed diagnosis of squamous non-small cell lung cancer (SQ-NSCLC). Subjects may participate in the pre-screening phase at initial diagnosis or following prior lines of therapy for SQ-NSCLC.

The treatment phase will investigate the antitumor activity in terms of ORR of tipifarnib in subjects with locally advanced squamous non-small cell lung cancer (SQ-NSCLC) with HRAS mutations and for whom there is no curative therapy available.

Detailed description:
Subject enrolment may proceed with information available on tumor HRAS status previously generated during the pre-screening phase, but all subjects must consent to provide tumor slides (or tumor tissue block) from a prior diagnostic biopsy for a retrospective testing of RAS gene status, including T81C polymorphism, and other potential biomarkers at a central facility.

Tipifarnib will be administered at a starting dose of 600 mg, po, bid daily on days 1-7 and 15-21 of 28-day treatment cycles. In the absence of unmanageable toxicities, subjects may continue to receive tipifarnib treatment for up to 24 months in the absence of disease progression and unmanageable toxicity. Treatment may continue beyond 24 months if there is documented evidence of continued clinical benefit.

Tumor assessments will be performed at screening and approximately every 8 weeks for the first 6 months (cycles 2, 4, 6) and then every 12 weeks (cycles 9, 12, 15, etc.) until disease progression, starting at the end of Cycle 2. Additional tumor assessments may be conducted if deemed necessary by the Investigator or for a confirmation of an objective response. Subjects who discontinue tipifarnib treatment for reasons other than disease progression must continue tumor assessments until disease progression, withdrawal of subject's consent to study procedures or initiation of another anticancer therapy.

Determination of objective tumor response will be performed by the Investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Electronic copies of tumor images may be de-identified of subject's personal information at the clinical sites and collected by the Sponsor to undergo an external independent radiological review if the sponsor deems it necessary for the final assessment of treatment efficacy. Subjects with a solitary site of disease who have experienced a response may be considered for surgical resection. Subjects with a best response of a partial response and residual disease after salvage surgery will be eligible to continue on study therapy. Information on the duration of response to the last prior therapy will be collected.

Upon disease progression, subjects will be followed approximately every 12 weeks for survival until either death or 24 months after accrual in the subject's study cohort has been completed, whichever occurs first. Information on subsequent anticancer therapy will be collected.

All subjects will be followed-up for safety during treatment and for approximately 30 additional days after treatment discontinuation (or until immediately before the administration of another anticancer treatment). Additional safety follow up may be conducted if unresolved toxicity is present at the End of Treatment visit.

Arms: arm 1: Tipifarnib 600 mg, po, bid daily on days 1-7 and 15-21 of 28-day treatment cycles for up to 24 months
Interventions: intervention 1: Tipifarnib
Intervention descriptions: intervention 1: Tipifarnib 600 mg will be administered until progression

Protocol documents:
Prot_SAP_000.pdf: 
 
Confidencial 
 
 
 
 
 
 
 
 
 Official Title: “An Open Label Phase II Study of Tipifarnib in Advanced Squamous  
Non-small Cell Lung Cancer with HRAS mutations”  
 
NCT Number: NCT03496766 
 
Document Dates: Protocol Version 4.0: 15 July 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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An Open Label Phase II Study of Tipifarnib in Advanced 
Squamous Non-small Cell Lung Cancer with HRAS mutations 
 
THOMAS: Tipifarnib in Advanced Squamous NSCLC with HRAS 
MutAtionS 
 
 
Study Sponsor: Fundación GECP 
EudraCT Number: 2017-004822-13 
Sponsor code: GECP 17/04 
Kura code: KO-IST-003 
Version 4.0 
 
 
 


 
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Contacts 
 
TRIAL CHAIRS 
Principal Investigator 
 
Study Coordinator 
 
Dr. Luis Paz Ares, PhD 
 
Dr. Santiago Ponce, PhD  
Oncology Service 
H. Universitario 12 de Octubre 
Av. Cordoba, s/n,  
28041 Madrid 
Tel: +34 91 469 23 13 
Fax: : +34 91 460 33 10 
Email: lpazaresr@seom.org  
Email: sponceaix@gmail.com  
Seguridad y Regulación 
(Safety and Regulatory 
Affairs) 
Coordinating office of the 
Fundación GECP 
Avenida Meridiana 358, 6ªplanta 
08027 Barcelona 
Tel. 93 430 20 06 
Fax. 93 419 17 68 
Email: 
pharmacovigilance.slcg@gecp.org 
Coordinating office of the 
Fundación GECP 
 
Monitoring team 
Monitor/CRA 
 
 
 
 
 
Lead CRA 
 
 
 
 
 
Clinical Operations 
Manager 
Teresa Baz 
Avenida Meridiana 358, 6ªplanta 
08027 Barcelona 
Tel. 93 430 20 06 
Fax. 93 419 17 68 
Email: tbaz@gecp.org  
Ana Verdú 
Avenida Meridiana 358, 6ªplanta 
08027 Barcelona 
Tel. 93 430 20 06 ext: 208 
Fax. 93 419 17 68 
Email: averdu@gecp.org 
Eva Pereira 
Avenida Meridiana 358, 6ªplanta 
08027 Barcelona 
Tel. 93 430 20 06 
Fax. 93 419 17 68 
Email: epereira@gecp.org 
 


 
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Protocol Signature Page 
 
 
An Open Label Phase II Study of Tipifarnib in Advanced Squamous 
Non-small Cell Lung Cancer with HRAS mutations 
THOMAS: Tipifarnib in Advanced Squamous NSCLC with HRAS mutations 
 
Sponsor code: GECP 17/04 
 
Approved by: 
 
 
Signature 
 
 
 
 
 
Dr. Luis Paz Ares 
Principal investigator 
 
Signature 
 
 
 
 
Dr. Santiago Ponce 
Study coordinator 
 
Signature 
 
 
 
 
Dr. Mariano Provencio 
President Fundación GECP 


 
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Principal Investigator Protocol Signature Page 
 
 
Study Title: “An Open Label Phase II Study of Tipifarnib in Advanced Squamous Non-small Cell Lung Cancer 
with HRAS mutations” THOMAS 
 
Sponsor protocol code: GECP 17/04 
 
EudraCT Number: 2017-004822-13 
 
Protocol version: v.4.0, 15th July 2019 
 
 
As principal investigator of this site, I hereby confirm that: 
I have read the protocol and agree that it contains all necessary details for conducting this trial. I will 
conduct the trial as outlined in the following protocol and in compliance with GCP, and will apply due 
diligence to avoid protocol deviations.  
I will provide copies of the protocol and all drug information relating to pre-clinical and prior clinical 
experience furnished to me by the Fundación GECP, to all physicians responsible to me who participate in 
this trial. I will discuss this material with them to assure that they are fully informed regarding the drug 
and the conduct of the trial.  
I agree to keep accurate records on all patient information including patient's informed consent 
statement, drug shipment and return forms, and all other information collected during the trial for a 
minimum period of 25 years according to the new Royal Decree 1090/2015 approved in Spain. 
 
 
Name of Principal Investigator: ___________________________________ 
 
 
Institution’s name and place: _____________________________________  
 
 
 
 
 
 
 
Signature                                                                                    Date 


 
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1 
SYNOPSIS 
 
TITLE: An Open Label Phase II Study of Tipifarnib in Advanced Squamous Non-small Cell Lung 
Cancer with HRAS mutations 
SPONSORS: Fundación GECP  
PROTOCOL NUMBER: THOMAS (GECP 17/04) 
KURA CODE: KO-IST-003 
STUDY SITES: 30 centers in Spain 
PHASE OF DEVELOPMENT: Phase II 
STUDY PERIOD: This trial is planned to initiate enrolment in the first half of 2017. It is estimated 
that it may require approximately 3 years to complete all its study objectives. 
OBJECTIVES: 
Primary Objective: To determine the antitumor activity in terms of objective response rate (ORR) 
of tipifarnib in subjects with locally advanced unresectable or metastatic, relapsed and/or 
refractory, squamous non-small cell lung cancer (SQ-NSCLC) with HRAS mutations. This objective 
will be evaluated in the treatment phase of the study.  
Secondary Objective 1:  To determine the frequency of HRAS mutations in squamous non-small 
cell lung cancer (SQ-NSCLC).  This objective will be evaluated in the pre-screening phase of the 
study. 
Secondary Objective 2:  Safety and tolerability of tipifarnib in subjects with locally advanced 
unresectable or metastatic, relapsed and/or refractory, squamous non-small cell lung cancer (SQ-
NSCLC) with HRAS mutations.  This objective will be evaluated in the treatment phase of the 
study. 
Exploratory Objective 1:  To explore the antitumor activity in terms of progression free survival 
(PFS) and duration of response (DOR) of tipifarnib in subjects with locally advanced unresectable 
or metastatic, relapsed and/or refractory, squamous non-small cell lung cancer (SQ-NSCLC) with 
HRAS mutations.  This objective will be evaluated in the treatment phase of the study. 
Exploratory Objective 2: To explore the identification of biomarkers potentially related to 
tipifarnib activity in tumor tissue and/or cell free DNA.  This objective will be evaluated in the 
treatment phase of the study. 
 


 
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STUDY DESIGN: 
This Phase II study consists of 2 parts: 1) pre-screening phase and 2) treatment phase.   
The pre-screening phase will investigate the presence of HRAS mutations in subjects with a 
histologically or cytologically confirmed diagnosis of squamous non-small cell lung cancer (SQ-
NSCLC). Subjects may participate in the pre-screening phase at initial diagnosis or following prior 
lines of therapy for SQ-NSCLC.   
The treatment phase will investigate the antitumor activity in terms of ORR of tipifarnib in 
subjects with locally advanced squamous non-small cell lung cancer (SQ-NSCLC) with HRAS 
mutations and for whom there is no curative therapy available. Subject enrolment may proceed 
with information available on tumor HRAS status previously generated during the pre-screening 
phase, but all subjects must consent to provide tumor slides (or tumor tissue block) from a prior 
diagnostic biopsy for a retrospective testing of RAS gene status, including T81C polymorphism, 
and other potential biomarkers at a central facility. 
Tipifarnib will be administered at a starting dose of 600 mg, po, bid daily on days 1-7 and 15-21 
of 28-day treatment cycles. In the absence of unmanageable toxicities, subjects may continue to 
receive tipifarnib treatment for up to 24 months in the absence of disease progression and 
unmanageable toxicity. Treatment may continue beyond 24 months if there is documented 
evidence of continued clinical benefit.  
Tumor assessments will be performed at screening and approximately every 8 weeks for the first 
6 months (cycles 2, 4, 6) and then every 12 weeks (cycles 9, 12, 15, etc.) until disease progression, 
starting at the end of Cycle 2. Additional tumor assessments may be conducted if deemed 
necessary by the Investigator or for a confirmation of an objective response. Subjects who 
discontinue tipifarnib treatment for reasons other than disease progression must continue tumor 
assessments until disease progression, withdrawal of subject’s consent to study procedures or 
initiation of another anticancer therapy. 
Determination of objective tumor response will be performed by the Investigator according to 
the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 (Appendix II). Electronic copies of 
tumor images may be de-identified of subject’s personal information at the clinical sites and 
collected by the Sponsor to undergo an external independent radiological review if the sponsor 
deems it necessary for the final assessment of treatment efficacy. Subjects with a solitary site of 
disease who have experienced a response may be considered for surgical resection. Subjects with 
a best response of a partial response and residual disease after salvage surgery will be eligible to 
continue on study therapy. Information on the duration of response to the last prior therapy will 
be collected. 


 
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Upon disease progression, subjects will be followed approximately every 12 weeks for survival 
until either death or 24 months after accrual in the subject’s study cohort has been completed, 
whichever occurs first. Information on subsequent anticancer therapy will be collected.  
All subjects will be followed-up for safety during treatment and for approximately 30 additional 
days after treatment discontinuation (or until immediately before the administration of another 
anticancer treatment). Additional safety follow up may be conducted if unresolved toxicity is 
present at the End of Treatment visit. 
NUMBER OF SUBJECTS PLANNED: It is anticipated that approximately 2000 subjects will be 
enrolled in the pre-screening phase and up to 18 evaluable study subjects in the treatment phase.  
SUBJECT SELECTION:  
Inclusion Criteria 
 
For inclusion of a subject in the pre-screening phase, all of the following inclusion criteria must 
be fulfilled: 
1. Subject is at least 18 years of age. 
2. Subject has a histologically or cytologically confirmed diagnosis of squamous non-small 
cell lung cancer (SQ-NSCLC). 
3. Subject has consented to provide either a blood sample, tumor slides or tumor tissue 
blocks (including a fresh biopsy if no archival material is available) for testing of HRAS 
gene tumor status, including mutations, estimated amplification and T81C polymorphism 
status.  
4. Written and voluntary informed consent for the pre-screening phase understood, signed 
and dated. 
For inclusion of a subject in the treatment phase, all of the following inclusion criteria must be 
fulfilled: 
1. Subject has a histologically or cytologically confirmed diagnosis of squamous non-small 
cell lung cancer (SQ-NSCLC) for which there is no curative therapy available. 
2. Subject has relapsed (progressive disease) or is refractory to one or more prior therapies. 
In the case of therapy received in the adjuvant or neo-adjuvant setting, relapse must have 
occurred within 12 months to be considered prior therapy. Subject may have received 
prior immunotherapy. 


 
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3. Subject has a tumor that carries a missense HRAS mutation. HRAS status may have been 
assessed either in blood, primary tumor tissue, recurrent or metastatic disease. 
4. Subject has consented to provide tumor slides (or tumor tissue blocks) for biomarker 
evaluation. Before enrolment the site must confirm the availability of the tumor sample. 
If there is no sample available, the trial chair must be contacted for approval. If enrolment 
in the treatment portion of the study has taken place based on HRAS mutant status as 
assessed using a blood sample, tumor tissue must be sent before starting cycle 2 of 
treatment, and It will be used in part for confirmation of HRAS mutant tumor status. 
Confirmation of HRAS mutant status in tumor tissue is required for continuation of 
treatment. If HRAS mutation is not confirmed in tumor but is clearly positive in blood, the 
trial chair will be contacted for approval and the treatment could be maintained. All 
treated subjects will be evaluated for safety. 
5. Subject has measurable disease according to RECIST v1.1. 
6. At least 2 weeks since the last systemic therapy regimen prior to enrolment. Subjects 
must have recovered to NCI CTCAE v. 4.03 < Grade 2 from all acute toxicities (excluding 
Grade 2 toxicities that are not considered a safety risk by the Sponsor and Investigator) 
or toxicity must be deemed irreversible by the Investigator. 
7. At least 2 weeks since last radiotherapy. If radiation was localized to the only site of 
measurable disease, there must be documentation of disease progression of the 
irradiated site. Subjects must have recovered from all acute toxicities from radiotherapy. 
Subjects may be on a daily dose of corticosteroids (≤ 20mg prednisone or equivalent), as 
part of their management from prior radiotherapy. 
8. ECOG performance status of 0 or 1. 
9. Acceptable liver function:  
a. Bilirubin  1.5 times upper limit of normal (x ULN); does not apply to subjects with 
Gilbert’s syndrome diagnosed as per institutional guidelines. 
b. AST (SGOT) and ALT (SGPT)  3 x ULN; if liver metastases are present, then  5 x ULN 
is allowed. 
10. Acceptable renal function with serum creatinine  1.5 x ULN or a calculated creatinine 
clearance ≥ 60 mL/min using the Cockcroft-Gault or MDRD formulas. 
11. Acceptable hematologic status: 
a. ANC  1000 cells/μL. 


 
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b. Platelet count  75,000/μL. 
c. Hemoglobin  9.0 g/dL. 
12. Female subjects must be: 
a. Of non-child-bearing potential (surgically sterilized or at least 2 years post-
menopausal); or 
If of child-bearing potential, subject must use an adequate method of contraception 
consisting of two-barrier method or one barrier method with a spermicide or 
intrauterine device. Both females and male subjects with female partners of child-
bearing potential must agree to use an adequate method of contraception for 2 weeks 
prior to screening, during, and at least 4 weeks after last dose of trial medication. 
Female subjects must have a negative serum or urine pregnancy test within 72 hours 
prior to start of trial medication. 
b. Not breast feeding at any time during the study. 
13. Written and voluntary informed consent for the treatment phase understood, signed and 
dated. 
Exclusion Criteria 
The subject will be excluded from participating in the pre-screening phase if any of the following 
criteria are met: 
1. 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.  
2. The subject has legal incapacity or limited legal capacity. 
3. 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. 
The subject will be excluded from participating in the treatment phase if any of the following 
criteria are met: 
1. Ongoing treatment with an anticancer agent not contemplated in this protocol. 
2. Prior treatment (at least 1 full treatment cycle) with an FTase inhibitor. 
3. Any history of clinically relevant coronary artery disease or myocardial infarction within 
the last 3 years, New York Heart Association (NYHA) grade III or greater congestive heart 


 
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failure, cerebro-vascular attack within the prior year, or current serious cardiac 
arrhythmia requiring medication except atrial fibrillation. 
4. Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and 
well controlled for at least 4 weeks prior to Cycle 1 Day 1).  
5. Non-tolerable > Grade 2 neuropathy or evidence of emerging or rapidly progressing 
neurological symptoms within 4 weeks of Cycle 1 Day 1. Non-tolerable grade 2 toxicities 
are defined as those with moderate symptoms that the patient is not able to endure for 
the conduct of instrumental activities of daily life or that persists ≥ 7 days. 
6. Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1, 
without complete recovery.  
7. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. 
Known infection with HIV, or an active infection with hepatitis B or hepatitis C. 
8. Subjects who have exhibited allergic reactions to tipifarnib or structural compounds 
similar to tipifarnib or to the drug product excipients. This includes hypersensitivity to 
imidazoles, such as clotrimazole, ketoconazole, miconazole and others in this drug class.  
Patients with hypersensitivity to these agents will be excluded from enrolment. 
9. Required use of concomitant medications classified as strong inhibitors or inducers of 
cytochrome P450 3A4 (CYP3A4, Table 4) or UDP-glucuronosyltransferase (UGT).   
10. 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.  
11. The subject has legal incapacity or limited legal capacity. 
12. 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: 
Descriptive statistics are planned for the pre-screening phase.  The sample size was determined 
based on the expected frequency of HRAS mutations in SQ-NSCLC (~2%). In order to identify up 
to 18 evaluable subjects that could enroll into the treatment phase, approximately 2000 subjects 
will be enrolled in the pre-screening phase.   
Up to 18 evaluable subjects will be enrolled in the treatment phase using a two-stage design 
(Simon, 1989). Evaluable subjects are those that have HRAS missense mutant status in a tissue 


 
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sample, have an available baseline scan, and have received at least one daily administration (2 
doses) of tipifarnib. Seven evaluable study subjects will be enrolled for the first stage; the study 
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 two-stage study, the study is considered as failure 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 study at the 
end of first stage is 0.48 if the true ORR is 10% or less while the probability of terminating the 
study at the end of first stage is 0.13 if the true ORR is 30%.   
Summary statistics will be provided for other endpoints. 
 
 
 
 
 


 
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Table 1: Schedule of Activities 
Activity 
PRE-
SCREENING 
PHASE 
Screening 
TREATMENT PHASE 
End of 
Treatment 
Visit5 
Follow Up 
Visit6 
Follow Up 
Contact6 
D1 
(± 2d)3 
D8 
(± 2d)3 
D15 
(± 2d)3 
D22 
(± 5d)4 
ICF for pre-screening,  
Inclusion/exclusion 
criteria evaluation 
X 
 
 
 
 
 
 
 
 
HRAS mutation testing1  
X 
 
 
 
 
 
 
 
 
ICF for treatment phase, 
Inclusion / exclusion 
criteria evaluation, 
Collection of HRAS 
mutation information 
 
X 
 
 
 
 
 
 
 
Medical History, including 
HPV status16, outcome 
from the last prior 
therapy and duration of 
response 
 
X 
 
 
 
 
 
 
 
Concomitant meds and AE 
assessment2 
 
X 
X 
X 
X 
 
X 
 
 
ECOG performance status 
 
X 
X 
X 
X 
 
X 
 
 
Complete physical exam 
 
X 
 
 
 
 
X 
 
 
Symptom based physical 
exam 
 
 
X 
X 
X 
 
 
 
 
Weight and vital signs 
(temperature, blood 
pressure, heart rate) 
 
X 
X 
 
 
 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
Hematology7 
 
X8 
X9 
 
X 
 
X 
 
 
Blood chemistry7 
 
X8 
X9 
 
X 
 
X 
 
 
Coagulation7 
 
X8 
 
 
 
 
X 
 
 
Urinalysis7,10 
 
X8 
 
 
 
 
X 
 
 
Tumor blocks or slides  for 
biomarkers11 
X 
X 
X 
 
 
 
 
 
 
Cell free DNA15 
 
 
X 
 
 
 
 
 
 
Pregnancy test 
 
X 
X 
 
 
 
X 
 
 
Tumor assessment (CT 
scan or MRI)12  
 
X 
 
 
 
X 
X 
X 
 
Tipifarnib administration13 
 
  
X 
 
X 
X14 
 
 
 
Collection of survival and 
anticancer treatment 
information 
 
 
 
 
 
 
 
X 
X 


 
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1. A blood sample must be sent to evaluate HRAS mutation. If the result is positive tumor sample is required 
for confirmation of HRAS. The positive result of these tests are required for subject enrolment 
2. Assessed throughout the course of the treatment and approximately 30 days after treatment 
discontinuation. Additional assessments may be performed until AE resolution or the adverse event is 
deemed irreversible by the Investigator. 
3. The visit at Day 1 of Cycle 2 and beyond can take place +/- 2 days if deemed necessary due to scheduling 
conflicts. The ± 2 days window is instituted to facilitate the scheduling of the visit, but should not affect 
dosing schedule. Subjects will be dosed using the 1-week on, 1-week off schedule independent of the visit. 
Visits on day 8 and 15 will be performed only in cycles 1, 2 and 3.  
4. Day 22 (± 5 days) is to occur every even cycle for the first 6 months (Cycles 2, 4, 6) and then every 12 weeks 
(Cycles 9, 12, 15, etc.) until disease progression or subject’s End of Treatment visit. 
5. An End of Treatment visit will be conducted within 30 days (30 +/- 7 days) from the last dose of tipifarnib 
or immediately before the initiation of any other anticancer therapy. 
6. On-site visits every 2-3 months will be required only if tumor assessments are conducted. 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 24 months after accrual in the subject’s study cohort has been 
completed, whichever occurs first. Information on survival and subsequent anticancer therapy may be 
collected by phone. 
7. Fasting for chemistry testing is not required. Laboratory tests may need to be conducted on additional 
time points if deemed necessary by the Investigator. Samples will be analyzed locally at the clinical site or 
its reference laboratory. Laboratory assessments may be repeated if values are borderline to inclusion 
level or may change due to best supportive care measures. 
8. During screening, hematology, chemistry, coagulation and urinalysis must be done within 14 days prior to 
first administration of study drug on Day 1 of Cycle 1.   
9. Screening laboratory tests do not need to be repeated on Cycle 1 Day 1 if they were conducted within 72 
hours prior to the first dose of tipifarnib. 
10. Macroscopic assessment of the amount of protein, glucose, white blood cells and blood will be conducted 
in the urine samples. If abnormalities are noted, these will be recorded and a microscopic urinalysis 
conducted and recorded. If at any time, the subject’s serum creatinine is ≥ Grade 2, then a serum 
chemistry, microscopic urinalysis including the measurement of protein, glucose, blood, and white blood 
cells will be conducted. If abnormalities are noted, then spot urine sodium, protein and creatinine should 
be performed to assess fractional sodium excretion (plasma creatinine x urine sodium / plasma sodium x 
urine creatinine) and urine protein/creatinine ratio (urine protein mg/urine creatinine mg ratio).  
11. Collection of available archival tumor tissues in paraffin embedded blocks or unstained slides. A minimum 
of 15 slides is requested. Subjects with fewer than 15 slides (or equivalent block) or no tumor available 
may be enrolled based on Trial Chair decision. The archival tumor tissue(s) can be gathered anytime within 
Cycles 1-2 if additional time is needed to locate the tissue blocks/slides, but time of actual tissue biopsies 
are always to be prior to any dosing of tipifarnib. Efforts should be made to collect these materials as early 
as possible. Biomarkers including HRAS status and T81C genetic polymorphism, will be assessed. The result 
of this assessment is not required for subject enrolment. Enrolment may proceed with the information on 
tumor HRAS status obtained during the pre-screening phase..  
12. Tumor assessments: Appropriate spiral CT scans (and bone scans for subjects with bone metastases) will 
be conducted at screening and Day 22 ± 5 days of every even cycle for the first 6 months (Cycles 2, 4, 6) 
and then every 12 weeks (Cycles 9, 12, 15, etc.) until disease progression or subject’s End of Treatment 


 
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visit. Scans at the End of Treatment visit will be performed if not done within the prior 8 weeks unless 
additional anticancer therapy has been initiated or if a tumor assessment is required for the confirmation 
of response. Subjects who discontinue treatment for reasons other than disease progression should 
continue tumor assessments until disease progression, withdrawal of subject’s consent or initiation of 
another anticancer therapy. If subjects are allergic to IV contrast, MRI scans or non-contrast CT may be 
used. The imaging schedule (every 8-12 weeks) should be maintained regardless of dosing delays or 
additional imaging assessments performed. Tumor scans will be reviewed by the clinical sites. Tumor 
assessments may be conducted locally for convenience; however, efforts should be made to decrease the 
variability of the assessments. An independent review of tumor scans may be planned if deemed necessary 
by the Sponsor for the assessment of the efficacy of tipifarnib. Copies of tumor images must be de-
identified of subject’s personal information at the clinical sites and provided to the Sponsor or its designee 
if an independent review is requested by the Sponsor. 
13. Tipifarnib starting at 600 mg, po, bid daily with food on days 1-7 and 15-21 of 28-day treatment cycles.  
14. Tipifarnib administration should occur if the Day 22 visit coincides with a dosing day (e.g. visit occurs on 
Days 17 - 21 of the current cycle). 
15. Cell free DNA sample is to be collected on Cycle 1 Day 1 (predose), Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 
Day 1 and Cycle 5 Day 1. 
16. HPV test is recommended but not mandatory. 


 
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2 TABLE OF CONTENTS 
Section 
                                                                                           
 
 
      Page 
1 
SYNOPSIS ............................................................................................................................. 6 
2 
TABLE OF CONTENTS ......................................................................................................... 16 
3 
ABBREVIATIONS ................................................................................................................ 20 
4 
INTRODUCTION ................................................................................................................. 22 
4.1 
Mechanism of Action ........................................................................................................ 22 
4.2 
Clinical Pharmacology ....................................................................................................... 23 
4.3 
Clinical Development ........................................................................................................ 24 
4.4 
Rationale for the Study ..................................................................................................... 25 
5 
OBJECTIVES ....................................................................................................................... 25 
5.1 
Primary Objectives and Endpoints .................................................................................... 25 
5.2 
Secondary Objectives and Endpoints ................................................................................ 26 
5.3 
Exploratory Objective and Endpoints ............................................................................... 26 
6 
SUBJECT SELECTION .......................................................................................................... 27 
6.1 
Inclusion Criteria ............................................................................................................... 27 
6.1.1 
Pre-screening Phase .......................................................................................................... 27 
6.1.2 
Treatment Phase ............................................................................................................... 27 
6.2 
Exclusion Criteria ............................................................................................................... 29 
6.2.1 
Pre-screening Phase .......................................................................................................... 29 
6.2.2 
Treatment Phase ............................................................................................................... 29 
7 
TRIAL DESIGN .................................................................................................................... 30 
7.1 
Study Design ...................................................................................................................... 30 
7.2 
Subject Identification and Replacement of Subjects ........................................................ 32 
7.3 
Assignment to Treatment Groups ..................................................................................... 33 
7.4 
Removal of Subjects from Treatment or Assessment ....................................................... 33 
7.5 
Premature Discontinuation of the Trial ............................................................................ 34 
7.6 
Definition of End of Study ................................................................................................. 35 
8 
TREATMENTS ..................................................................................................................... 35 


 
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8.1 
Investigational Product (IP) ............................................................................................... 36 
8.1.1 
Product Characteristics ..................................................................................................... 36 
8.1.2 
Storage and Labeling ......................................................................................................... 36 
8.2 
Treatment Administration ................................................................................................ 36 
8.3 
Treatment Assignment ...................................................................................................... 37 
8.4 
Dose Selection ................................................................................................................... 37 
8.5 
Dose Modification and Management of Toxicity .............................................................. 39 
8.6 
Treatment of Overdose ..................................................................................................... 44 
8.7 
Blinding.............................................................................................................................. 44 
8.8 
Treatment Compliance ...................................................................................................... 44 
8.9 
Investigational Product Accountability ............................................................................. 44 
8.10 
Return and Disposition of Clinical Supplies ....................................................................... 44 
8.11 
Prior and Concomitant Medications ................................................................................. 45 
8.12 
Non-permitted Treatments ............................................................................................... 46 
8.13 
Dietary or Other Protocol Restrictions .............................................................................. 47 
8.14 
Potential Effects on Reproduction and Development ...................................................... 47 
8.15 
Medical Care of Subjects after End of Trial ....................................................................... 48 
9 
EFFICACY AND SAFETY VARIABLES .................................................................................... 48 
9.1 
Efficacy Variables .............................................................................................................. 48 
9.2 
Assessment of Safety ........................................................................................................ 49 
9.3 
Adverse Events .................................................................................................................. 50 
9.4 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings ................. 51 
9.5 
Serious Adverse Event ....................................................................................................... 51 
9.6 
Events that Do Not Meet the Definition of an SAE ........................................................... 52 
9.7 
Events Not to Be Considered as AEs/SAEs ........................................................................ 52 
9.8 
Methods of Recording and Assessing Adverse Events ...................................................... 52 
9.9 
Adverse Event Reporting Period ....................................................................................... 53 
9.10 
Procedure for Reporting Serious Adverse Events ............................................................. 53 
9.11 
Safety Reporting to Health Authorities, Institutional Review Boards and Investigators .. 54 
9.12 
Monitoring of Subjects with Adverse Events .................................................................... 54 


 
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9.13 
Pregnancy and In Utero Drug Exposure ............................................................................ 55 
9.14 
Laboratory Assessments ................................................................................................... 55 
9.14.1 Blood Sample Collection for General Clinical Laboratory Assessments ........................... 55 
9.14.2 Urinalysis ........................................................................................................................... 56 
9.15 
Additional Variables .......................................................................................................... 56 
10 
STUDY PROCEDURES ......................................................................................................... 56 
10.1 
Pre-screening Phase .......................................................................................................... 56 
10.2 
Treatment Phase ............................................................................................................... 57 
10.2.1 Screening and Baseline Assessments ................................................................................ 57 
10.2.2 Day 1 of Cycle 1 ................................................................................................................. 58 
10.2.3 Day 1 (+/- 2 days) of Cycle 2 and Beyond .......................................................................... 58 
10.2.4 Day 8 (±2 days) of Cycles 1, 2 and 3. ................................................................................. 59 
10.2.5 Day 15 (±2 days) of Cycles 1, 2 and 3. ............................................................................... 59 
10.2.6 Day 22 (±5 days) of Cycles 2, 4, 6 and Cycles 9, 12, 15, etc. ............................................. 60 
10.2.7 End of Treatment Visit ...................................................................................................... 60 
10.2.8 Post Treatment Follow up ................................................................................................. 61 
10.2.9 Follow Up after Disease Progression ................................................................................ 61 
11 
STATISTICAL METHODS ..................................................................................................... 61 
11.1 
Populations ....................................................................................................................... 62 
11.1.1 Efficacy Analysis ................................................................................................................ 62 
11.1.2 Safety Analysis ................................................................................................................... 62 
11.2 
Endpoints .......................................................................................................................... 62 
11.2.1 Efficacy .............................................................................................................................. 62 
11.2.2 Safety and Tolerability ...................................................................................................... 63 
11.3 
Sample Size Determination ............................................................................................... 63 
11.4 
Changes in the Conduct of the Study or Planned Analyses .............................................. 64 
12 
ETHICAL AND REGULATORY ASPECTS ............................................................................... 64 
12.1 
Responsibilities of the Investigator ................................................................................... 64 
12.2 
Subject Information and Informed Consent ..................................................................... 65 
12.3 
Subject Identification and Privacy ..................................................................................... 66 


 
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12.4 
Emergency Medical Support and Subject Card ................................................................. 66 
12.5 
Clinical Trial Insurance and Compensation to Subjects .................................................... 67 
12.6 
Institutional Review Board/Independent Ethnic Committee ........................................... 67 
12.7 
Communication to Health Authorities .............................................................................. 67 
13 
TRIAL MANAGEMENT ........................................................................................................ 67 
13.1 
Case Report Form Management ....................................................................................... 67 
13.2 
Source Data and Subject Files ........................................................................................... 68 
13.3 
Investigator Site File and Archiving ................................................................................... 69 
13.4 
Monitoring, Quality Assurance and Inspection by Health Authorities ............................. 69 
13.5 
Changes to the Clinical Trial Protocol ............................................................................... 70 
13.6 
Clinical Trial Report ........................................................................................................... 70 
13.7 
Publication ........................................................................................................................ 70 
14 
References ......................................................................................................................... 70 
APPENDIX I: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS ........ 74 
APPENDIX II: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST VERSION 1.1) ......... 75 
APPENDIX III: NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION ..................................... 86 
APPENDIX IV: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V4.0 (CTCAE) ............ 86 
APPENDIX V: PROHIBITED MEDICATION LIST ................................................................................ 87 
APPENDIX VI: SAE FORM AND PREGNANCY FORM........................................................................ 89 
 
TABLES 
Table 1: Schedule of Activities ....................................................................................................... 13 
Table 2: Tipifarnib dose levels........................................................................................................ 39 
Table 3: Summary of Dose Modifications for Treatment Related Toxicities ................................. 42 
Table 4: Strong Inhibitors or Inducers of CYP3A4 .......................................................................... 87 
Table 5: Sensitive substrates of CYP3A4 ........................................................................................ 88 
 
 
 


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


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


 
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4 INTRODUCTION 
Beginning in 1997, tipifarnib was the first specific inhibitor of farnesyl transferase (FTase) to enter 
clinical studies and has been evaluated in over 70 clinical oncology and hematology studies.  
Brief information on tipifarnib is presented in this section; more extensive information is 
provided in the Investigator’s Brochure (Tipifarnib Investigator’s Brochure, Edition 15, January 
2019).  
4.1 
Mechanism of Action 
The RAS family consists of three functional genes, HRAS, KRAS, and NRAS (reviewed in Cox and 
Der, 1997; Baines et al, 2011; Takashima and Faller, 2013). These genes are highly homologous 
and encode for four 21-kDa proteins: HRAS, the KRAS splice variants KI4ARAS and KI4BRAS, and 
NRAS, respectively. These proteins play a pivotal role in the transduction of cell growth-
stimulatory signals, and their mutation is known to lead to constitutive activation, resulting in 
uncontrolled cell proliferation. The high prevalence of mutated RAS genes, found in 30% of all 
human cancers, makes this pathway an attractive target for anticancer drug development.   
RAS targeting may be accomplished by multiple mechanisms. A promising way of interfering with 
RAS function is the inhibition of farnesyl transferase (FTase), the enzyme coupling an isoprenyl 
group to RAS proteins. Prenylation is essential for membrane localization and functional activity 
of RAS proteins. By inhibiting RAS farnesylation, a blockade of the RAS-mediated signal 
transduction pathway is accomplished, with attenuation of cell growth. Consequently, inhibition 
of RAS signaling using highly potent and selective farnesyl transferase inhibitors (FTase) was 
proposed as an effective therapeutic approach in multiple oncology indications (Cox and Der, 
1997; Baines et al, 2011; Takashima and Faller, 2013).  
Tipifarnib is a selective nonpeptide inhibitor of FTase. Isoprenylation by geranylgeranyl 
transferase type 1 is not sensitive to inhibition by tipifarnib. The farnesyl moiety is a 15-carbon 
unsaturated isoprene polymer derived from the mevalonate pathway of cholesterol synthesis. 
The farnesyl binding site is located in the alpha subunit of FTase whereas its beta subunit 
recognizes CAAX motifs in proteins. Tipifarnib inhibits FTase by interacting with its CAAX binding 
site. In vitro, the concentration resulting in 50% of maximum inhibition (IC50) values for isolated 
human FTase depends on the nature of its substrate, ranging from 0.86 nM for lamin B, a nuclear 
protein, to 7.9 nM for KRAS.  
Mean total plasma concentrations of tipifarnib over a 12-hour interval resulting from a single 
600-mg dose are markedly higher than those required to inhibit farnesylation. The unbound 
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Tipifarnib inhibits FTase activity in human peripheral blood lymphocytes isolated from study 
subjects after doses as low as 100 mg bid. Inhibition of FTase is reversible within 3 to 7 days upon 
discontinuation of tipifarnib administration.  
The correlative biology of FTase inhibition by tipifarnib has been studied extensively. The 
antitumor mechanism of action of tipifarnib is context-dependent and appears to include 
angiogenesis inhibition, induction of apoptosis, and direct anti-proliferative effects (End et al, 
2001). 
4.2 
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 FTase activity in human peripheral blood lymphocytes isolated from study 
subjects after doses as low as 100 mg bid.  Following a single 600 mg dose, both total and 
unbound plasma concentrations of tipifarnib over a 12-hour interval exceed those required to 
inhibit farnesylation.  Inhibition of FTase is reversible within 3 to 7 days upon discontinuation of 
tipifarnib administration.  
Increases in tipifarnib bioavailability by 18% to 34% have been consistently observed after its 
administration with food and therefore, tipifarnib has been administered with food throughout 
most of its clinical development program. 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 
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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.  
4.3 
Clinical Development 
Tipifarnib was the first specific inhibitor of FTase to enter clinical studies. The clinical 
development of tipifarnib began in 1997 and consisted of over 70 clinical oncology and 
hematology studies.  
Several efficacy trials of tipifarnib in subjects with nonhematological malignancies have been 
reported, including those in subjects with advanced breast cancer, metastatic pancreatic cancer, 
melanoma, small cell lung cancer (SCLC), myelodysplastic syndromes (MDS), multiple myeloma, 
urothelial tract transitional cell carcinoma, colorectal cancer and non-small cell lung cancer 
(NSCLC) (Adjei et al, 2003; Cohen et al, 2003; Johnston et al, 2003; Alsina et al, 2004; Heymach et 
al, 2004; Kurzrock et al, 2004; Rao et al., 2004; Rosenberg et al, 2005; Hong et al, 2011; Gajewski 
et al, 2012). In the study in 76 subjects with advanced breast cancer, 9 partial responses and 9 
cases of stable disease (of at least 24 weeks’ duration) were observed. In a phase II study of 
tipifarnib in subjects with metastatic transitional cell carcinoma of the urothelial tract (n=34), two 
responses were observed (6%) in subjects with no prior chemotherapy treatment and a total of 
13 study subjects achieved disease stabilization. Objective responses were also observed in 
subjects with differentiated thyroid (DTC, including follicular thyroid cancer) and medullary 
thyroid cancer (MTC) in combination with the multi-kinase inhibitor sorafenib. MTC partial 
response rate was 38% (five of 13) whereas the DTC partial response rate was 4.5% (one of 22). 
Median progression-free survival for all 35 subjects in the study was 18 months (Hong et al, 2011). 
Of note, a high prevalence of HRAS mutations have been reported in RET-negative sporadic 
medullary thyroid carcinomas. Somatic H-RAS mutations were detected in 14 of 25 (56.0%) of 
RET-negative sporadic MTC whereas only 1 of 40 (2.5%) RET-positive sporadic MTC had an HRAS 
mutation (Moura et al, 2011). However, a high frequency of HRAS mutation in RET-negative MTC 
has not been observed in other studies (Schulten et al, 2011). 
Promising activity of tipifarnib in an unselected patient population was reported in poor-risk 
acute myeloid leukemia or MDS, in which a 33% response rate (eight complete responses, two 


 
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partial responses) was initially seen. Patients were dosed at 600 mg twice daily for 21 days. In a 
second phase II trial in subjects with MDS, tipifarnib showed activity in 3 of 27 patients, resulting 
in two complete remissions and one partial remission. The drug was administered at a dose of 
600 mg twice daily for 4 weeks, followed by 2 weeks of rest. Subsequent phase III studies in acute 
myeloid leukemia and MDS failed to confirm a clinical benefit derived from tipifarnib treatment 
in these indications. 
4.4 
Rationale for the Study 
Initial studies of tipifarnib were conducted without a selection of treatment subjects based on 
their tumor molecular characteristics. Preclinical data indicate that tumor models carrying HRAS 
mutations are highly sensitive to FTase inhibitor. The reason for this selectivity is potentially the 
fact that, contrary to KRAS and NRAS, HRAS protein does not undergo geranylgenarylation. 
Geranylgenarylation allows membrane localization and signal transduction of KRAS and NRAS in 
a setting of FTase inhibition, overcoming the effect of FTase inhibitors. In HRASG12V +/+, p53 -/- 
mouse cells, incubation with tipifarnib at concentrations of 25 nM for 48 hours resulted in 
complete loss of pERK and pMEK (Kura Oncology Inc., data on file). Likewise, HRASG12V +/+, p53 -/- 
anaplastic thyroid tumors in mice treated with tipifarnib 80 mg/kg bid for 14 days, underwent 5 
regressions out of 9 animals with no significant loss in body weight noted (Dr. James Fagin, 
MSKCC). Similar results were observed in other HRAS mutant tumor models. For example, in a 
patient HRASQ61R adeno-squamous lung cancer-derived mouse xenograft model, a 4-week 
tipifarnib treatment of 80 mg/kg, bid resulted in regression or complete tumor growth inhibition 
in 2 out of 3 animals (Kura Oncology Inc. data on file).  These experiments strongly suggested that 
tipifarnib may be particularly active against tumors carrying HRAS mutations. Consistent with this 
hypothesis, the present study will include only subjects with tumors that carry missense HRAS 
mutations. Indications in which a relatively high incidence of HRAS mutations have been detected 
include thyroid cancer as well as HNSCC, urothelial carcinomas and salivary gland malignancies 
(cBIO Portal and COSMIC).  
The rationale for the selection of the dose and treatment regimen is provided in section 9.4. 
5 OBJECTIVES 
5.1 
Primary Objectives and Endpoints 
Primary Objective: To determine the antitumor activity in terms of objective response rate (ORR) 
of tipifarnib in subjects with locally advanced unresectable or metastatic, relapsed and/or 


 
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refractory, squamous non-small cell lung cancer (SQ-NSCLC) with HRAS mutations.  This objective 
will be evaluated in the treatment phase of the study.   
Primary endpoint: Response assessments according to RECIST 1.1.   
5.2 
Secondary Objectives and Endpoints 
Secondary Objective 1:  To determine the frequency of HRAS mutations in squamous non-small 
cell lung cancer (SQ-NSCLC).  This objective will be evaluated in the pre-screening phase of the 
study. 
Secondary Endpoint 1: Molecular analyses of tumor and/or cell free DNA samples. 
Secondary Objective 2: Safety and tolerability of tipifarnib in subjects with locally advanced 
unresectable or metastatic, relapsed and/or refractory, squamous non-small cell lung cancer (SQ-
NSCLC) with HRAS mutations. This objective will be evaluated in the treatment phase of the 
study.   
Secondary Endpoint 2: Treatment-emergent adverse events (TEAE) and SAEs evaluated 
according to NCI CTCAE v.4.03.   
5.3 
Exploratory Objective and Endpoints 
Exploratory Objective 1:  To explore the antitumor activity in terms of progression free survival 
(PFS) and duration of response (DOR) of tipifarnib in subjects with locally advanced unresectable 
or metastatic, relapsed and/or refractory, squamous non-small cell lung cancer (SQ-NSCLC) with 
HRAS mutations. This objective will be evaluated in the treatment phase of the study.   
Exploratory Endpoints 1: PFS and DOR according to RECIST 1.1. 
Exploratory Objective 2: To explore the identification of biomarkers potentially related to 
tipifarnib activity in tumor tissue and/or cell free DNA. This objective will be evaluated in the 
treatment phase of the study.   
Exploratory Endpoints 2: Molecular analyses of archival tissue samples. 


 
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6 SUBJECT SELECTION 
6.1 
Inclusion Criteria 
6.1.1 Pre-screening Phase 
For inclusion of a subject in the pre-screening phase, all of the following inclusion criteria must 
be fulfilled: 
1. Subject is at least 18 years of age. 
2. Subject has a histologically or cytologically confirmed diagnosis of squamous non-small 
cell lung cancer (SQ-NSCLC). 
3. Subject has consented to provide either a blood sample, tumor slides or tumor tissue 
blocks (including a fresh biopsy if no archival material is available) for testing of HRAS 
gene tumor status, including mutations, estimated amplification and T81C polymorphism 
status.  
4. Written and voluntary informed consent for the pre-screening phase understood, signed 
and dated. 
6.1.2 Treatment Phase 
For inclusion of a subject in the treatment phase, all of the following inclusion criteria must be 
fulfilled: 
1. Subject has a histologically or cytologically confirmed diagnosis of squamous non-small 
cell lung cancer (SQ-NSCLC) for which there is no curative therapy available. 
2. Subject has relapsed (progressive disease) or is refractory to one or more prior therapies. 
In the case of therapy received in the adjuvant or neo-adjuvant setting, relapse must have 
occurred within 12 months to be considered prior therapy.  Subject may have received 
prior immunotherapy. 
3. Subject has a tumor that carries a missense HRAS mutation. HRAS status may have been 
assessed either in primary tumor tissue, recurrent or metastatic disease. 
4. Subject has consented to provide tumor slides (or tumour tissue blocks) for biomarker 
evaluation. Before enrolment the site must confirm the availability of the tumor sample. 
If there is no sample available, the trial chair must be contacted for approval. If enrolment 
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assessed using a blood sample, tumor tissue must be sent before starting cycle 2 of 
treatment, and It will be used in part for confirmation of HRAS mutant tumor status. 
Confirmation of HRAS mutant status in tumor tissue is required for continuation of 
treatment. If HRAS mutation is not confirmed in tumor but is clearly positive in blood, the 
trial chair will be contacted for approval and the treatment could be maintained. All 
treated subjects will be evaluated for safety. 
5. Subject has measurable disease according to RECIST v1.1. 
6. At least 2 weeks since the last systemic therapy regimen prior to enrolment. Subjects 
must have recovered to NCI CTCAE v. 4.03 < Grade 2 from all acute toxicities (excluding 
Grade 2 toxicities that are not considered a safety risk by the Sponsor and Investigator) 
or toxicity must be deemed irreversible by the Investigator. 
7. At least 2 weeks since last radiotherapy. If radiation was localized to the only site of 
measurable disease, there must be documentation of disease progression of the 
irradiated site. Subjects must have recovered from all acute toxicities from radiotherapy. 
Subjects may be on a daily dose of corticosteroids (≤ 20mg prednisone or equivalent), as 
part of their management from prior radiotherapy. 
8. ECOG performance status of 0 or 1. 
9. Acceptable liver function:  
a. Bilirubin  1.5 times upper limit of normal (x ULN); does not apply to subjects with 
Gilbert’s syndrome diagnosed as per institutional guidelines. 
b. AST (SGOT) and ALT (SGPT)  3 x ULN; if liver metastases are present, then  5 x ULN is 
allowed. 
10. Acceptable renal function with serum creatinine  1.5 x ULN or a calculated creatinine 
clearance ≥ 60 mL/min using the Cockcroft-Gault or MDRD formulas. 
11. Acceptable hematologic status: 
a. ANC  1000 cells/μL. 
b. Platelet count  75,000/μL. 
c. Hemoglobin  9.0 g/dL. 
12. Female subjects must be: 
a. Of non-child-bearing potential (surgically sterilized or at least 2 years post-
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If of child-bearing potential, subject must use an adequate method of contraception 
consisting of two-barrier method or one barrier method with a spermicide or 
intrauterine device. Both females and male subjects with female partners of child-
bearing potential must agree to use an adequate method of contraception for 2 weeks 
prior to screening, during, and at least 4 weeks after last dose of trial medication. 
Female subjects must have a negative serum or urine pregnancy test within 72 hours 
prior to start of trial medication. 
b. Not breast feeding at any time during the study. 
13. Written and voluntary informed consent for the treatment phase understood, signed and 
dated. 
6.2 
Exclusion Criteria 
6.2.1 Pre-screening Phase 
The subject will be excluded from participating in the pre-screening phase if any of the following 
criteria are met: 
1. 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.  
2. The subject has legal incapacity or limited legal capacity. 
3. 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. 
6.2.2 Treatment Phase 
The subject will be excluded from participating in the treatment phase if any of the following 
criteria are met: 
1. Ongoing treatment with an anticancer agent not contemplated in this protocol. 
2. Prior treatment (at least 1 full treatment cycle) with an FTase inhibitor. 
3. Any history of clinically relevant coronary artery disease or myocardial infarction within 
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failure, cerebro-vascular attack within the prior year, or current serious cardiac 
arrhythmia requiring medication except atrial fibrillation. 
4. Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and 
well controlled for at least 4 weeks prior to Cycle 1 Day 1).  
5. Non-tolerable > Grade 2 neuropathy or evidence of emerging or rapidly progressing 
neurological symptoms within 4 weeks of Cycle 1 Day 1. Non-tolerable grade 2 toxicities 
are defined as those with moderate symptoms that the patient is not able to endure for 
the conduct of instrumental activities of daily life or that persists ≥ 7 days. 
6. Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1, 
without complete recovery.  
7. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. 
Known infection with HIV, or an active infection with hepatitis B or hepatitis C. 
8. Subjects who have exhibited allergic reactions to tipifarnib or structural compounds 
similar to tipifarnib or to the drug product excipients. This includes hypersensitivity to 
imidazoles, such as clotrimazole, ketoconazole, miconazole and others in this drug class.  
Patients with hypersensitivity to these agents will be excluded from enrolment. 
9. Required use of concomitant medications classified as strong inhibitors or inducers of 
cytochrome P450 3A4 (CYP3A4, Table 4) or UDP-glucuronosyltransferase (UGT).   
10. 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.  
11. The subject has legal incapacity or limited legal capacity. 
12. 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. 
7 TRIAL DESIGN 
7.1 
Study Design 
This Phase II study consists of 2 parts: 1) pre-screening phase and 2) treatment phase.   
The pre-screening phase will investigate the presence of HRAS mutations in subjects with a 
histologically or cytologically confirmed diagnosis of squamous non-small cell lung cancer (SQ-


 
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NSCLC).  Subjects may participate in the pre-screening phase at initial diagnosis or following prior 
lines of therapy for SQ-NSCLC.   
The treatment phase will investigate the antitumor activity in terms of ORR of tipifarnib in 
subjects with locally advanced squamous non-small cell lung cancer (SQ-NSCLC) with HRAS 
mutations and for whom there is no curative therapy available. Subject enrolment may proceed 
with information available on tumor HRAS status previously generated during the pre-screening 
phase of the study, but all subjects must consent to provide tumor slides (or tumor tissue block) 
from a prior diagnostic biopsy for a retrospective testing of RAS gene status, including T81C 
polymorphism, and other potential biomarkers at a central facility. 
Up to 18 evaluable subjects will be enrolled in the treatment phase using a two-stage design 
(Simon, 1989). Seven evaluable study subjects will be enrolled for the first stage; the study 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 two-stage study, the study is 
considered as failure 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%.   
Only consented subjects who meet all the eligibility criteria will be enrolled in the study. All 
screening evaluations will be completed within 4 weeks (28 days) of Cycle 1 Day 1. Any screening 
evaluation, including disease status, will need to be repeated if performed more than 4 weeks 
from Cycle 1 Day 1.  
Eligible subjects will receive tipifarnib administered at a starting dose of 600 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 
are described in Section 8.5. Unless otherwise contraindicated, subjects should be advised to be 
appropriately hydrated during the course of the study (e.g. drinking at least 8 glasses of 
water/day). 
In the absence of emerging unmanageable toxicity, subjects may continue tipifarnib treatment 
in the absence of disease progression and unmanageable toxicity. Treatment may continue 
beyond 24 months upon agreement by the Investigator and Sponsor. 
Tumor assessments will be performed at screening and approximately every 8 weeks for the first 
6 months (cycles 2, 4, 6) and then every 12 weeks (cycles 9, 12, 15, etc.) until disease progression, 
starting at the end of Cycle 2. Additional tumor assessments may be conducted if deemed 
necessary by the Investigator or for a confirmation of an objective response.  


 
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Determination of objective tumor response will be performed by the Investigator according to 
the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Electronic copies of tumor images 
may be de-identified of subject’s personal information at the clinical sites and collected by the 
Sponsor to undergo an external independent radiological review if the sponsor deems it 
necessary for the final assessment of treatment efficacy. Subjects with a solitary site of disease 
who have experienced a response may be considered for surgical resection. Subjects with a best 
response of a partial response and residual disease after salvage surgery will be eligible to 
continue on study therapy. Information on the duration of response to the last prior therapy will 
be collected. 
Upon disease progression, all subjects in the study cohort will be followed approximately every 
12 weeks for survival and the use of subsequent therapy until either death or 24 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 12 weeks).  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. 
7.2 
Subject Identification and Replacement of Subjects 
All screened subjects will be given a unique screening number that will be used to identify the 
subject throughout the entire study. Each subject will be assigned only one screening number. 
Screening numbers must not be re-used for different subjects.  
After the HRAS analysis, if positive and if patient meets all inclusion/exclusion criteria, the subject 
will be included in the data base (Case report form, CRF) of the study that will assign the final 
registration number of the subject. Also, the screening number will be recorded in the CRF. 
Subjects who do not receive at least one dose of tipifarnib will be replaced.  


 
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7.3 
Assignment to Treatment Groups 
This is a nonrandomized study. All eligible subjects enrolled in the treatment phase will be 
assigned to receive tipifarnib 600 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.   
7.4 
Removal of Subjects from Treatment or Assessment 
Subjects may withdraw their consent to participate in this study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. A 
subject’s participation in the study may also be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. Every effort should be made to 
complete, whenever possible, the tests and evaluations listed for the End of Treatment visit. The 
Sponsor must be notified of all subject withdrawals as soon as possible. The Sponsor also reserves 
the right to discontinue the study at any time for either clinical research or administrative reasons 
and to discontinue participation by an individual Investigator or site for poor enrolment or 
noncompliance. 
Overall, the reasons for which the Investigator or Sponsor may withdraw a subject from study 
treatment include, but are not limited to, the following: 
• Subject experiences disease progression 
• Subject experiences unacceptable toxicity 
• Subject requires more than 2 dose reductions 
• Subject experiences toxicity that is deemed by the Investigator to be no longer safe for 
the subject to continue therapy 
• Subject requests to withdraw from the study treatment 
• Subject requires or has taken medication prohibited by the protocol 
• Subject is unwilling or unable to comply with the study requirements 
• Subject withdraws consent to collect health information 
• Subject was erroneously admitted into the study or does not meet entry criteria 
• Subject is lost to follow-up 
• Subject becomes pregnant 


 
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Subjects will return for an End of Treatment visit within approximately 30 days after the last 
administration of the study drug (or sooner if another anticancer therapy is to be initiated). If a 
subject fails to return for scheduled visits, a documented effort must be made to determine the 
reason. If the subject cannot be reached by telephone after 2 attempts, a certified letter should 
be sent to the subject (or the subject’s legally authorized representative, if appropriate) 
requesting contact with the Investigator. This information should be recorded in the study 
records.  
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. This trial has two consents forms, one per pre-screening phase and 
another per treatment phase. 
Both consents must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial (both phases). 
The initial informed consent forms, any subsequent revised written informed consent forms and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this information 
will be provided and documented via a revised consent form or addendum to the original consent 
form that captures the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form templates at the 
protocol level.   
The informed consent forms will adhere to IRB/ERC requirements, applicable laws and 
regulations and Sponsor requirements. 
7.5 
Premature Discontinuation of the Trial 
This trial may be discontinued prematurely in the event of any of the following: 
• New information leading to a judgment of unfavorable risk-benefit of tipifarnib becomes 
available, e.g. due to: Evidence of inefficacy of tipifarnib in HRAS mutant tumors, 
occurrence of significant previously unknown adverse reactions or unexpectedly high 
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findings in the HRAS mutant tumor patient population. Evidence of inefficacy may arise 
from this trial or from other trials; unfavorable safety findings may arise from clinical or 
non-clinical examinations, e.g. toxicology. 
• Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical 
reasons. 
• Poor enrolment of subjects making completion of the trial within an acceptable time 
frame unlikely.  
• Discontinuation of development of tipifarnib by the Sponsor.  
• Request by a Health Authority. 
Health Authorities and IRBs/IECs will be informed about the discontinuation of the trial in 
accordance with applicable regulations. In the case of premature discontinuation of the study, 
the investigations scheduled for the End of Treatment assessment should be performed and the 
appropriate eCRF section completed. 
7.6 
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 trial completes the last Follow-up assessment 
no later than 24 months after the last study subject is enrolled in the study. Provisions will be 
made for the continuation of study treatment in patients who demonstrate sustained objective 
response or disease stabilization and manageable toxicity beyond the end of the study, e.g. a 
single patient treatment protocol. 
8 TREATMENTS 
Subjects enrolled in the treatment phase will receive tipifarnib as monotherapy in this study. In 
the absence of unacceptable tipifarnib related emergent toxicity or disease progression, subjects 
may receive treatment with tipifarnib for up to 24 months at the discretion of the Investigator. 
Treatment beyond 24 months may continue upon agreement of the Investigator and the 
Sponsor.  The Sponsor or its designee will provide the study site with a supply of tipifarnib 
sufficient for the completion of the study. 
All study subjects will be also eligible to receive best supportive care (BSC) defined as any 
standard supportive measures that are not considered a primary treatment of the disease under 
study, including the use of growth factors (i.e. GCSF) for myelosuppression. BSC will be provided 
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8.1 
Investigational Product (IP) 
Tipifarnib is a small molecule being developed as a potent, selective inhibitor of FTase for the 
treatment of cancer and other malignancies. 
8.1.1 Product Characteristics 
Tipifarnib will be provided in bottles containing film-coated, compressed, oral tablet containing 
100mg or 300mg of active substance. Each tablet strength has the same qualitative composition 
and a dose proportional quantitative composition. The tablets contain tipifarnib and the 
following 
inactive 
ingredients: 
lactose 
monohydrate, 
maize 
starch, 
hypromellose, 
microcrystalline cellulose, crospovidone, colloidal anhydrous silica, and magnesium stearate. The 
100mg and 300mg tablets are white. The film coatings contain hypromellose, titanium dioxide, 
lactose monohydrate, polyethylene glycol, and triacetin. Further information can be obtained 
from the current version of the Investigator’s Brochure. 
8.1.2 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. 
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 the Fundación GECP monitor, as instructed. 
Tipifarnib should be stored at controlled room temperature 15º C to 30º C. All study supplies 
must be kept in a restricted access area. 
8.2 
Treatment Administration 
Tipifarnib will be administered with food at a starting dose of 600 mg, po, bid daily on days 1-7 
and 15-21 of 28-day treatment cycles.  
The first study dosing (Cycle 1 Day 1) will take place in the study clinic. Tipifarnib will be 
administered orally with a meal in the morning and again approximately 12 hours later at 
approximately the same times each treatment day. Tablets should be swallowed whole with a 
glass of water 250 mL) and should not be chewed or crushed unless the Investigator deems it 


 
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necessary. Use of percutaneous endoscopic gastrostomy tubes is allowed at the judgment of the 
Investigator. If a dose is vomited or partially vomited, it should not be replaced with a new dose. 
Subjects may use proton pump inhibitors or H2 antagonists during the treatment portion of this 
study. However, subjects should be instructed to use antacids (magnesium or aluminium 
containing products) at least 2 hours before or after intake of oral study drug. 
On Cycle 1 Day 1, the site will provide tipifarnib to the subject from bulk supplies. Subjects will 
be provided with diaries with instructions to record the date and time of each dose and asked to 
bring the diaries and tablet bottles to each clinic visit for subject compliance and drug 
accountability review by the site staff.   
8.3 
Treatment Assignment 
Treatment will be conducted in an open label manner. The eCRF will assign a subject number 
identifier for each subject that is enrolled into the study. Study sites cannot start dosing the 
subject without receiving the assigned subject number.  
8.4 
Dose Selection 
In the majority of its phase II program, tipifarnib was given orally at a dose of 300 mg bid daily 
for 21 days, followed by 1 week of rest, in 28-day treatment cycles (21-day schedule). This 
regimen was employed in a prior version of this protocol. Under that protocol, a first subject was 
enrolled who presented with an advanced metastatic salivary gland tumor with a single HRAS 
mutation (Chen et al., 2015). The lack of effectiveness of the 21-day schedule in this patient and 
the hematological toxicity observed (grade 4 thrombocytopenia) prompted a review of the data 
generated with other tipifarnib dosing regimens as follows.  
The effect of higher dose levels given at intermittent schedules was tested in several phase 1 
studies, including a 5-day bid dosing followed by 9-day rest (5-day schedule; Zujewski et al., 2000) 
and two trials investigating a 7-day bid dosing followed by 7-day rest (7-day schedule; Lara et al., 
2005; Kirschbaum et al., 2011). In the 5-day schedule phase 1 trial in patients with non-
hematological malignancies, doses from 25 to 1300 mg bid were explored. No MTD was 
identified. Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 
fatigue in 4 of 6 patients treated with 1300 mg bid. Fatigue, that was not dose-limiting, was 
observed at the prior dose level (800 mg bid). Of note, myelosuppression which was the most 
common toxicity in the 21-day schedule (45% at 300 mg bid, Tipifarnib Investigator’s Brochure 
2015), was limited with the 5-day schedule and included a grade 3 neutropenia in a patient with 


 
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a prior history of myelosuppression treated with 50 mg bid and a grade 2 thrombocytopenia in a 
patient treated at the 1300 mg bid dose level. No objective responses were noted. 
In the first of the 7-day schedule studies (Lara et al., 2005), the starting dose was 300 mg bid with 
300 mg dose escalations to a maximum planned dose of 1800 mg bid. Two of 6 patients with non-
hematological tumors in dose level 3 (900 mg bid) developed grade 3 fatigue attributable to study 
drug, and 600 mg bid on alternate weeks was identified as the recommended phase II dose. There 
were no objective responses but 4 out of 21 patients, 3 of whom had NSCLC, remained on study 
for at least 1 year with stable disease (12, 13, 16 and 17 months). Five grade 3 events of 
myelosuppression (out of 21 patients) were described by the authors (doses not indicated) that 
were not considered DLTs and hematological toxicity was described as moderate and 
manageable. 
The second 7-day schedule study was conducted in patients with relapsed/refractory AML 
(Kirschbaum et al., 2011). Tipifarnib was administered bid on days 1–7 and days 15–21 of 28-day 
cycles at doses up to 1600 mg bid (Kirschbaum et al., 2011). At the 400 mg bid dose level, a grade 
5 hepatorenal failure occurred, potentially related to the study drug. There were no additional 
DLTs reported at 600, 800 or 1000 mg bid dose levels. At the 1200 mg bid dose level, a grade 3 
creatinine elevation was seen in one patient out of 6 treated. At the 1400 mg bid dose level, one 
patient experienced a grade 4 hypotension and a rising grade 2 creatinine that were dose limiting, 
and a second patient had a rising grade 2 creatinine that resulted in treatment discontinuation 
and was therefore considered dose limiting. At the 1600 mg dose level, grade 3 liver function 
tests and a rising grade 2 creatinine were dose limiting, and in a second patient, a rapidly rising 
creatinine was seen and treatment stopped. As a result, the 1200 mg bid dose was established 
as the MTD and 7 additional patients treated. Sixteen patients were treated at the 1000mg and 
1200 mg dosing levels, with 3 of them experiencing complete responses. No formal responses 
were seen among patients treated at the lower dose levels. 
Based on these data, the tipifarnib regimen to be investigated in the current study was 
modified to a starting dose of 900 mg, po, bid on days 1-7 and 15-21 of 28-day treatment 
cycles. Preliminary data from KO-TIP-001 indicate a tolerability that is broadly similar to the 
safety profile observed of other tipifarnib regimens in prior clinical studies which administered 
tipifarnib daily in a 21-day on, 7 days off treatment cycle schedule. The most common AES of 
tipifarnib including hematological events, gastrointestinal disturbances (nausea, vomiting and 
diarrhea) and fatigue have been monitorable and manageable with protocol defined 
assessments and management of toxicity guidance.  Dose reduction to 600 mg has been able to 
reduce tipifarnib-related toxicity and several subjects have maintained their response and 
continued on treatment for over 1 year.    


 
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Given these preliminary observations and in discussion with study investigators, the starting dose 
has been reduced to 600 mg, po, bid on days 1-7 and 15-21 of 28-day treatment cycles. In the 
absence of unmanageable toxicities, subjects may continue to receive tipifarnib treatment for up 
to 24 months in the absence of disease progression and unmanageable toxicity. Stepwise 300 mg 
dose reductions to control treatment-related, treatment-emergent toxicities are also included in 
this protocol amendment. Treatment may continue beyond 24 months upon agreement of the 
Investigator and Sponsor. 
8.5 
Dose Modification and Management of Toxicity 
All subjects will begin treatment with tipifarnib at a starting dose of 600 mg bid in alternating 
weeks.  If treatment-related, treatment-emergent AEs are observed meeting criteria for dose 
modification detailed further in this section, the dose level reductions summarized in Table 2 
will be used. 
Table 2: Tipifarnib dose levels 
Dose Level 
Alternate Week Schedule 
Doses in mg (am + pm) 
Starting Dose 
600 + 600 
-1 
300 + 600* 
-2 
300 + 300 
*Depending on subject preference, the 600 mg dose may be taken in the morning or in the evening, as long as the 
total daily dose is 900 mg, i.e. 600 mg can be taken in the morning or evening with 300 mg taken for the other 
scheduled dose time.  Tipifarnib should always be taken with a meal. 
If treatment-related treatment-emerging CTCAE grade 4 non-hematological toxicity is observed, 
treatment with tipifarnib will be permanently discontinued. 
If treatment-related treatment-emerging CTCAE > grade 3 hematological or grade 3 non-
hematological toxicity is observed that cannot be managed with supportive care measures, 
treatment with tipifarnib will be interrupted until recovery to < grade 2. If recovery requires 
more than 4 weeks, treatment is to be discontinued. Upon recovery, tipifarnib may be restarted 
at the original dose or at the next lower dose level (see Table 2) at the discretion of the 
investigator.  If grade 3 or 4 toxicity recurs, subsequent dose reductions may be conducted 
according to Table 2. 
 


 
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If treatment-related treatment-emerging CTCAE grade 2 renal toxicity is observed that cannot 
be managed with supportive care measures (including hydration and correction of electrolyte 
abnormalities, if appropriate), treatment with tipifarnib will be interrupted until recovery to < 
grade 1.  Upon recovery to < grade 1, the subject may restart tipifarnib at their current dose 
level. 
If treatment-related treatment-emerging CTCAE grade 2 renal toxicity recurs or if grade 3 renal 
toxicity is observed that cannot be managed with supportive care measures, treatment with 
tipifarnib will be interrupted until recovery to < grade 1. Additional treatment may be given at 
the next lower dose level (see Table 2) upon subject’s recovery from toxicity. If grade 2 or 3 
renal toxicity recurs, a subsequent dose reduction may be conducted. Reduced doses due to 
renal toxicity will not be re-escalated.   
Treatment with tipifarnib should also be interrupted until recovery to grade 2 tolerable or better 
if treatment-related treatment-emergent CTCAE grade 2 intolerable neurological toxicity is 
observed. Additional treatment may be given at the next lower dose level (see Table 2) upon 
subject’s recovery from toxicity. If grade 2 intolerable neurological toxicity recurs, a subsequent 
dose reduction may be conducted. Reduced doses due to neurological toxicity will not be re-
escalated.  The occurrence of grade 3 neurological toxicity will result in permanent 
discontinuation of treatment. 
Unless otherwise indicated (e.g. dosing discontinuation), reduced doses may be re-escalated to 
the original dose at the judgement of the investigator. However, patients who experience serious 
adverse events or a recurrence of ≥ grade 3 toxicity deemed to be related to tipifarnib will not 
have their dose re-escalated following dose reduction. In addition, patients experiencing more 
than one dose delay of ≥ 14 days will not have their dose re-escalated.   
  
Asymptomatic laboratory findings will not be considered dose limiting unless otherwise 
determined by the Investigator. A summary of dose modifications is presented in  


 
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Table 3. 
 
 


 
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Table 3: Summary of Dose Modifications for Treatment Related Toxicities 
Adverse Event 
Management 
Tipifarnib Dosing 
Grade 4 Non-
Hematological 
Discontinue tipifarnib permanently 
> Grade 3 Hematological 
or Grade 3 Non-
Hematological 
Manage with BSC, including 
RBC or platelet transfusion. 
If not manageable, 
interrupt tipifarnib 
treatment until recovery to 
grade 2 or better. 
If recovery requires more 
than 4 weeks, treatment is 
to be discontinued.  
Upon recovery to < grade 2, 
re-start tipifarnib at current 
dose or at the next lower 
dose level (see Table 2) at 
the judgement of the 
investigator.  
If the same toxicity recurs, 
upon recovery to < grade 2, 
re-start tipifarnib at the 
next lower dose level (see 
Table 2). If grade 3 
thrombocytopenia recurs, 
consider additional cycles at 
original dose at the 
judgement of the 
investigator 
Grade 2 Renal 
Manage with BSC, including 
hydration and correction of 
electrolyte abnormalities, if 
appropriate.  
Upon recovery to < grade 1, 
re-start tipifarnib at current 
dose. 
Grade 2 Recurrent or 
Grade 3 Renal 
Manage with BSC, including 
hydration and correction of 
electrolyte abnormalities, if 
appropriate. If not 
manageable, interrupt 
tipifarnib treatment until 
Upon recovery to < grade 1, 
re-start tipifarnib at the 
next lower dose level (see 
Table 2).  
If grade 2 or 3 renal toxicity 
recurs, upon recovery to < 


 
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In exceptional circumstances, dosing delays or skipping of dosing for reasons other than the 
management of toxicity will be allowed at the judgement of the investigator as long as 50% of 
the total dose is maintained in a given cycle. 
Upon restarting tipifarnib following a treatment interruption, the cycle and dosing day are to be 
defined by the following:  
• If a dose delay/interruption occurs and resolves within a cycle, dosing picks up where it 
left off.   
o For example, if a subject’s treatment is held on Day 3, subject recovers 14 days 
later (nominal Day 17 in the cycle) and resumes tipifarnib treatment, the subject 
is considered to be dosing on Day 3 of the same cycle. 
• If the delay goes beyond the cycle (> nominal day 28 of that cycle), upon recovery, the 
subject should be started at Day 1 of the next cycle.   
o For example, if a subject’s treatment is held on Day 3, subject recovers 30 days 
later (nominal Day 33 in the cycle) and resumes tipifarnib treatment, the subject 
is considered to be dosing on Day 1 of the next cycle. 
 
recovery to grade 1 or 
better 
grade 1, re-start tipifarnib 
at the next lower dose level 
(see Table 2). 
Grade 2 non-tolerable 
Neurological  
Manage with BSC. If not 
tolerable, interrupt 
tipifarnib treatment until 
recovery to grade 2 
tolerable or better 
Upon recovery to grade 2 
tolerable or better, re-start 
tipifarnib at the next lower 
dose level (see Table 2).  
If grade 2 intolerable 
neurological toxicity recurs, 
upon recovery to grade 2 
tolerable or better, re-start 
tipifarnib at the next lower 
dose level (see Table 2). 
Grade 3 Neurological  
Discontinue tipifarnib permanently 


 
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8.6 
Treatment of Overdose 
An overdose is defined as any dose greater than 20% over the daily tipifarnib dose. Any overdose 
must be recorded in the trial medication and adverse event sections of the eCRF. There is no 
known antidote for tipifarnib. In the event of overdose of tipifarnib, subjects should receive 
appropriate advice and supportive medical care by the Investigator or his/her designee and be 
followed-up accordingly. 
For monitoring purposes, any case of overdose – whether or not associated with an AE (serious 
or non-serious) – must be reported to the Sponsor in an expedited manner. 
8.7 
Blinding 
This is an open label study with no placebo or comparators. 
8.8 
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 Drug accountability 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. 
8.9 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates and 
quantities) of IP received, subjects to whom IP is dispensed (subject by subject specific 
accounting), and IP lost or accidentally or deliberately destroyed.  
8.10 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 


 
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the Sponsor’s designated clinical trial monitor. The Investigator or designee must provide an 
explanation for any destroyed or missing study drug or study materials. 
Study drug may be destroyed on site, per the site’s standard operating procedures, but only after 
the Sponsor or its designee has been notified and granted approval for drug destruction. All study 
drug destroyed on site must be documented. 
Documentation must be provided to the Sponsor or its designee and retained in the Investigator’s 
study files. If a site is unable to destroy study drug appropriately, the site can return unused study 
drug to the Sponsor or its designee at the end of the study. 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 current clinical trial law. 
8.11 Prior and Concomitant Medications 
All prescription and over-the-counter medications taken by a subject within 28 days before the 
first study drug administration will be recorded in the eCRF. In particular, subjects will be asked 
about the use of agents that may affect the mevalonate pathway including statins (e.g. 
atorvastatin, simvastatin, rosuvastatin, pravastatin), bisphosphonates (e.g. pamidronate, 
risedronate, ibandronate, etidronate, alendronate) and nutritional agents (e.g. coenzyme Q₁₀, 
ubiquinone). 
Supportive care medications considered necessary for the subject’s safety and well-being may be 
given at the discretion of the Investigator. Any concomitant medications added or discontinued 
during the study should be recorded on the eCRF. 
BSC will be provided by the clinical study sites according to local guidelines and standard 
practices. 
Furthermore, the following treatments are allowed during the trial: 
• Correction of electrolyte deficiency. 
• Radiotherapy for pain control against non-target lesions as long as it does not influence 
bone marrow function. 
• Total tumor resection in responding subjects who have become candidates for curative 
resection. 
• Subjects that has been enrolled with asymptomatic or controlled brain metastases and 
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for the brain metastasis during the study may have their treatment interrupted to receive 
a course of cranial radiation and restart trial medication after a recovery period of at least 
1 week. High dose corticosteroids may be employed for the management of cranial 
radiation but must be tapered off before resuming treatment. 
• Hematopoietic growth factors and transfusions of blood or blood products in subjects 
who are experiencing hematological toxicity in accordance with standard institutional 
practice. However, such supportive care should not be used prior to hematological 
findings unless absolutely clinically necessary and after discussion with the Sponsor or 
designee’s medical monitor.  
• Antiemetic therapy in a subject experiencing gastrointestinal symptoms in accordance 
with standard clinical practice.  If a subject experiences vomiting or nausea, prophylactic 
antiemetic medications may be administered with subsequent treatment in accordance 
with standard clinical practice. 
• Concurrent use of bisphosphonates as well as Thyroid-Stimulating Hormone (TSH) 
suppressive therapy.  
8.12 Non-permitted Treatments 
Use of the following medications and therapies is not allowed during the trial: 
• Investigational agents other than tipifarnib. 
• Any other anticancer therapy, including radiation or surgery, for the primary disease 
under study with the exceptions of palliative treatment of non-target lesions and 
treatment of residual disease in study subjects who have experienced a partial response 
during the study. 
• High dose systemic corticosteroids or any other immunosuppressive drugs except: 
o Glucocorticosteroid treatment administered with a daily dose of ≤ 20 mg 
prednisone or equivalent,  
o Single doses for the management of treatment-related AEs or for premedication 
of BSC agents. 
o Short course (≤ 7 days, including tapering) high dose systemic steroids for the 
treatment of upper airway obstruction associated with HNSCC 
• Strong inhibitors or inducers of CYP3A4 or UGT beginning at least 14 days prior to Cycle 
1 Day 1 and during the subject’s participation in the tipifarnib treatment portion of this 


 
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study.  See Table 4 for a list of medications classified as strong inhibitors or inducers of 
CYP3A4.  If continued concomitant therapy is needed, subjects should be transitioned to 
a medicine that is not a strong inhibitor or inducer of CYP3A4 or UGT. 
• Sensitive substrates of CYP3A4 beginning Cycle 1 Day 1 and during the subject’s 
participation in the tipifarnib treatment portion of this study.  See Table 5 for a list of 
medications classified as sensitive CYP3A4 substrates. If continued concomitant therapy 
is needed, subjects should be transitioned to a medicine that is not a sensitive substrate 
of CYP3A4. 
• 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 trial and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration and indication of each drug. 
If the administration of a non-permitted concomitant drug becomes necessary during the trial, 
e.g., because of AEs or disease progression, the subject in question will be withdrawn from the 
trial, and the subject’s data which will have been obtained before the withdrawal may be used 
for safety and efficacy evaluations. 
8.13 Dietary or Other Protocol Restrictions 
No dietary restrictions related to tipifarnib are required. 
8.14 Potential Effects on Reproduction and Development 
Male and female fertility and reproductive capacity has been shown to be impaired in rats and 
additional details can be found in the Tipifarnib Investigator’s Brochure.  
In light of the observations in nonclinical testing, both female subjects and male subjects with 
female partners of child-bearing potential must agree to use a highly effective method of 
contraception for 2 weeks prior to screening, during, and at least 4 weeks after last dose of trial 
medication.  Female subjects of child-bearing potential must have a negative serum or urine 
pregnancy test within 72 hours prior to start of trial medication. 
Additionally, since tipifarnib could induce toxicity of male reproductive organs and cause 
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wishing to preserve their fertility following tipifarnib treatment.  Additionally, if the participant 
in the study is male, then the following items will be discussed with the subject: 
• Prevention of pregnancy in a female partner 
• Prevention of exposure of a partner to semen by any means (not just intercourse) 
• Prevention of the possible exposure of a pregnant female to the study drug from semen. 
• Informing their partner of the potential for harm to an unborn baby. The partner should 
know that if pregnancy occurs, she should promptly notify her personal doctor. 
• Acceptable methods of birth control for male subjects while participating in this study 
and for 4 weeks after the last dose of the study drug: 
o Abstinence (no sex) 
o Condom plus spermicidal agent (foam gel/cream/film/suppository) 
 
8.15 Medical Care of Subjects after End of Trial 
After a subject has completed the trial or has withdrawn from the study, standard treatment will 
be administered, if required, in accordance with the trial site’s standard of care and generally 
accepted medical practice and according to the subject’s individual medical needs. 
9 EFFICACY AND SAFETY VARIABLES 
Table 1 summarizes the study required evaluations. 
9.1 
Efficacy Variables 
Radiological and/or physical assessments of the tumor lesions will be made at screening (4 weeks 
before the first study drug administration), and approximately every 8 weeks for the first 6 
months (cycles 2, 4, 6) and then every 12 weeks (cycles 9, 12, 15, etc.) until disease progression, 
starting at the end of Cycle 2. Additional tumor assessments may be conducted if deemed 
necessary by the Investigator or for a confirmation of an objective response.  Subjects who 
discontinue treatment for reasons other than disease progression must continue tumor 
assessments until disease progression, withdrawal of their consent to study procedures or 
initiation of another anticancer therapy. Efficacy assessments may also be conducted at 
treatment discontinuation (End of Treatment visit) if the reason for the treatment termination is 
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treatment discontinuation (assessment must be conducted before additional anti-tumor therapy 
is started). Scans at the End of Treatment visit will be also conducted if required to confirm 
response to treatment. 
Lesions to be included in the tumor assessments should follow RECIST v1.1 criteria (Appendix II). 
Spiral CT scan with a contrast agent is the preferred imaging method. Tumor assessment with 
spiral CT scans of the abdomen, pelvis and chest plus other relevant evaluations, e.g. bone scans, 
should be performed as appropriate. Subjects with contrast allergy may use non-contrast CT or 
MRI, whichever is required to adequately assess all disease.  
Objective response (complete response and partial response) as determined by the subject’s best 
tumor response, duration of response, and time to progression will be assessed using RECIST 
criteria version 1.1. Confirmation of response is required. 
In addition to Investigator’s tumor response assessment, a central independent review tumor 
response assessment may be performed if the Sponsor deems it necessary for the final 
assessment of the efficacy of the treatment. If an independent radiological review were to be 
conducted, reviewers will be blinded to the Investigator’s efficacy assessments. The Sponsor, in 
consultation with the investigators, may initiate this independent review at any time during the 
trial. In that case, an independent review committee charter would be generated to provide the 
specific procedures that would be filed with IRBs/IECs and regulatory authorities prior to their 
initiation. 
Upon disease progression, all subjects will be followed approximately every 12 weeks for survival 
and the use of subsequent therapy until either death or 24 months after accrual in the subject’s 
study cohort has been completed, whichever occurs first. Information on survival and subsequent 
anticancer therapy may be collected by phone.  
9.2 
Assessment of Safety 
Adverse events will be graded according to the NCI CTCAE v 4.03 (Appendix IV). Adverse events 
will be summarized by relationship to trial drug, severity and grade. The safety profile of the IPs 
will be assessed through the recording, reporting and analyzing of baseline medical conditions, 
adverse events, physical examination findings including vital signs and laboratory tests. 
Comprehensive assessment of any apparent toxicity experienced by the subject will be 
performed throughout the course of the trial, from the time of the subject’s signature of 
informed consent. Trial site personnel will report any adverse event (AE), whether observed by 
the Investigator or reported by the subject. 


 
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9.3 
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 
• Grade 5: Death related to AE. Note: Death (Grade 5 as defined by NCI-CTCAE version 4.03) 
is mainly regarded as an outcome, to be documented as described below. 
According to the Sponsor’s convention, if a severity/intensity of Grade 4 or 5 is applied to an AE, 
then the Investigator must also report the event as a serious adverse event (SAE; see definition 
below) as per Section 9.10. 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. 


 
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Investigators must also systematically assess the causal relationship of AEs to the IPs, other 
medicinal products using the following definitions. Decisive factors for the assessment of causal 
relationship of an AE to the trial treatments include, but may not be limited to, temporal 
relationship between the AE and the trial treatments, known side effects of the trial treatments, 
medical history, concomitant medications and procedures, course of the underlying disease, trial 
procedures. 
Relatedness of an AE will be evaluated as follows: 
• Not related: Not suspected to be reasonably related to the IPs. AE could not medically 
(pharmacologically/clinically) be attributed to the IPs under trial in this clinical trial 
protocol. A reasonable alternative explanation must be available. 
• Related: Suspected to be reasonably related to the IPs. AE could medically 
(pharmacologically/clinically) be attributed to the IPs under trial in this clinical trial 
protocol. 
9.4 
Abnormal Laboratory Findings and Other Abnormal Investigational 
Findings 
Abnormal laboratory findings and other abnormal investigational findings (e.g. on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead 
to treatment discontinuation or are considered otherwise medically important by the 
Investigator. If an abnormality fulfills these criteria, the identified medical condition (e.g. anemia, 
increased ALT) must be reported as the AE rather than the abnormal value itself. 
9.5 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening. NOTE: The term “life-threatening” in this definition refers to an event 
in which the subject is at risk of death at the time of the event; it does not refer to an 
event that hypothetically might cause death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is otherwise considered as medically important. 


 
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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. 
9.6 
Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (e.g. an 
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered as SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (e.g., undesirable effects of any administered 
treatment) must be documented and reported as SAEs. 
9.7 
Events Not to Be Considered as AEs/SAEs 
Medical conditions are present at the initial trial visit that do not worsen in severity or frequency 
during the trial are defined as Baseline Medical Conditions, and are NOT to be considered AEs. 
Progression of underlying disease is not an AE and therefore not an SAE per se, rather an efficacy 
end-point, unless deemed to be causally related to administration of IPs. However, if adverse 
signs or symptoms occur in association with disease progression then these should be recorded 
as AEs and reported as SAEs if meeting any seriousness criteria. 
9.8 
Methods of Recording and Assessing Adverse Events 
At each trial visit, the subject will be queried on changes in his/her condition. During the reporting 
period of the trial any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the Investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the 
eCRF. Among these AEs, all serious AEs must be additionally documented and reported using the 
appropriate section of the eCRF. It is important that each AE report include a description of the 


 
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event, its duration (onset and resolution dates (/times “/times” to be completed when it is 
important to assess the time of AE onset relative to the recorded treatment administration 
time)), its severity, its relationship with the trial treatment, any other potential causal factors, 
any treatment given or other action taken (including dose modification or discontinuation of the 
IPs) and its outcome. In addition, serious cases should be identified and the appropriate 
seriousness criteria documented. Specific guidance can be found in the eCRF completion and 
monitoring conventions provided by the Sponsor. 
9.9 
Adverse Event Reporting Period 
The adverse event reporting period for safety surveillance begins when the subject is included 
into the trial (date of first signature of informed consent) and continues through the trial’s post-
treatment follow-up period, defined as 30 days from the final administration of the trial 
treatment or immediately before initiation of any other anticancer therapy, whichever comes 
first. 
9.10 Procedure for Reporting Serious Adverse Events 
 
Only the SAEs occurred after the signature of the IC general of the study will be notified to the 
pharmacovigilance office of the Fundación GECP (SLCG/GECP). The events that fulfill SAE criteria 
that occurred after the signature of the screening IC do not need to be notified. 
If applicable, SAEs must be collected that relate to any protocol-specified procedure (e.g., a 
follow-up skin biopsy).  The investigator should report any SAE that occurs after these time 
periods that is believed to be related to study drug or protocol-specified procedure.  
Any SAE, whether related or not related to study drug, and pregnancies, must be reported by 
completing the eCRF section “SAE Initial”, or in case that is not possible by sending the completed 
SAE Form (see Appendix V) within 24 hours of awareness by fax (+ 34 93 419 17 68) to the 
Fundación 
GECP 
(SLCG/GECP) 
pharmacovigilance 
office 
or 
by 
email 
to 
pharmacovigilance.slcg@gecp.org. 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be completed within 24 hours using the same 


 
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procedure used for transmitting the initial SAE report, completing the eCRF section “SAE Follow 
up”.  
All SAEs should be followed to resolution or stabilization. 
9.11 Safety Reporting to Health Authorities, Institutional Review Boards and 
Investigators 
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
Spanish clinical regulation via Eudravigilance within the timelines specified in GCP. The 
Investigator must comply with any applicable site-specific requirements related to the reporting 
of SAEs (and in particular deaths) involving his/her subjects to the IRB/IEC that approved the trial. 
In accordance with ICH GCP guidelines, the Sponsor will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the trial or alter the IRB/IEC’s 
approval/favorable opinion to continue the trial.” In particular and in line with respective 
regulations, the Sponsor will inform the Investigator of AEs that are both serious and unexpected 
and are considered to be related to the administered product (“suspected unexpected serious 
adverse reactions”, SUSARs). The 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. 
9.12 Monitoring of Subjects with Adverse Events 
Any AE that occurs during the course of a clinical trial and is considered to be possibly related to 
the IP must be monitored and followed up by the Investigator until stabilization or until the 
outcome is known, unless the subject is documented as “lost to follow-up”. Reasonable attempts 
to obtain this information must be made and documented. It is also the responsibility of the 
Investigator to ensure that any necessary additional therapeutic measures and follow-up 
procedures are performed. The Sponsor will actively follow-up and collect information on any AE 
that occurs during the course of a clinical trial, however while this activity will continue for any 


 
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serious AEs until stabilization or until the outcome is known, it will be discontinued at the time 
of database lock for non-serious AEs. 
9.13 Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator as related to trial treatment (e.g., resulting from 
a drug interaction with a contraceptive medication) are considered as adverse events. However, 
all pregnancies with an estimated conception date during the study safety period must be 
recorded by convention in the AE page/section of the e-CRF. The same rule applies to pregnancies 
in female subjects and in female partners of male subjects. The Investigator must notify the 
Sponsor in an expedited manner of any pregnancy using the Pregnancy Notification Form 
(Appendix V), which must be reported within 24 hours of awareness by fax (+ 34 93 419 17 68) 
to 
the 
Fundación 
GECP 
(SLCG/GECP) 
pharmacovigilance 
office 
or 
by 
email 
to 
pharmacovigilance.slcg@gecp.org.Investigators must actively follow up, document and report on 
the outcome of all these pregnancies, even if the subjects are withdrawn from the trial. The 
Investigator must notify the Sponsor of these outcomes using the Pregnancy Report Form, and. 
Any abnormal outcome must be reported in an expedited manner, while normal outcomes must 
be reported within 45 days from delivery using the Pregnancy Notification form. 
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor must be notified without delay 
and the subject must be followed as mentioned above. 
9.14 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 9.9). 
9.14.1 Blood Sample Collection for General Clinical Laboratory Assessments 
Blood samples will be collected for the following clinical laboratory tests: 
• Serum Chemistry: Glucose, Blood Urea Nitrogen (or Uric Acid), Creatinine, Sodium, 
Potassium, Chloride, Calcium, Magnesium, Phosphorus, Total Protein, Albumin, Total 
Bilirubin, Alkaline Phosphatase, ALT, AST, Gamma-Glutamyltransferase, Lactate 
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• Hematology: White Blood Cell Count, Red Blood Cell Count, Hemoglobin, Hematocrit, 
Platelet Count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils 
• Coagulation profile: APTT, PT/INR 
9.14.2 Urinalysis 
Macroscopic assessment of the amount of protein, glucose, white blood cells and blood will be 
conducted. If abnormalities are noted, these will be recorded and a microscopic analysis 
conducted and recorded. If at any time, the subject’s serum creatinine is ≥ Grade 2, then a serum 
chemistry, microscopic urinalysis including the measurement of protein, glucose, blood, white 
blood cells will be conducted. If abnormalities are noted, then spot urine sodium, protein and 
creatinine should be performed to assess fractional sodium excretion (plasma creatinine x urine 
sodium / plasma sodium x urine creatinine) and urine protein/creatinine ratio (urine protein 
mg/urine creatinine mg ratio).  
9.15 Additional Variables 
Additional variables to be examined as a part of this study include somatic mutations in archival 
tumor tissue. These biomarkers include but are not limited to members of the RAS family.  
10 STUDY PROCEDURES 
10.1 Pre-screening Phase 
A signed ICF for the pre-screening phase of this study 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 may be performed at any time prior to subject 
enrolment into the pre-screening phase of the study: 
• Signed informed consent form (ICF)/ patient informed consent (PIC) 
• Evaluation of the inclusion and exclusion criteria for the pre-screening phase 
• Collection of blood for cell-free DNA for HRAS mutation testing and if positive result 
collection of tumor (archival or fresh biopsy) 
• Collection of available archival tumor tissues in paraffin embedded blocks or unstained 
slides. A minimum of 15 slides is requested. Subjects with fewer than 15 slides (or 
equivalent block) or no tumor available may be enrolled based on Trial Chair decision. The 
archival tumor tissue(s) can be gathered anytime within Cycles 1-2 if additional time is 


 
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needed to locate the tissue blocks/slides, but time of actual tissue biopsies are always to be 
prior to any dosing of tipifarnib. Efforts should be made to collect these materials as early 
as possible. Biomarkers including HRAS status and T81C genetic polymorphism, will be 
assessed. The result of this assessment is not required for subject enrolment. Enrolment 
may proceed with the information on tumor HRAS status obtained during the pre-screening 
phase.   
If the subject meets all eligibility criteria for the pre-screening phase, the study site will request 
an assigned screening number using the Sponsor or designee.  
10.2 Treatment Phase 
10.2.1 Screening and Baseline Assessments 
A signed ICF for the treatment phase of this study must be obtained before any study-specific 
baseline assessment are performed and should be documented in the subject’s medical chart. 
The following evaluations and procedures will be performed within 28 days prior to the first study 
drug administration (Cycle 1 Day 1): 
• Signed informed consent form (ICF)/ patient informed consent (PIC) 
• Medical history (including demographics, HPV status, prior cancer therapy and any 
ongoing adverse events). NOTE: HPV test is recommended but not mandatory. 
• Collection of HRAS mutation data 
• Concomitant medications 
• Radiological assessments: CT (preferentially with contrast) or MRI scans of chest, 
abdomen and pelvis (the method used for a subject [CT or MRI] must be the same 
throughout the study) 
 
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 height, weight, vital signs (blood pressure, 
pulse, temperature) 
• ECOG performance status (Appendix I). 
• Hematology 


 
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• Chemistry (fasting not required) 
• Coagulation 
• Urinalysis   
• Serum/urine pregnancy test for females of child-bearing potential only 
If the subject meets all eligibility criteria after the screening visit(s), the study site will request an 
assigned subject number using the eCRF.  
10.2.2 Day 1 of Cycle 1 
Assessments prior dosing (Cycle 1 Day 1 only): The following assessments will be conducted 
before the first dose of tipifarnib on Day 1 of Cycle 1. Laboratory tests will not need to be 
repeated in Cycle 1 Day 1 if they were previously conducted at screening within 3 days prior to 
tipifarnib administration on Day 1: 
• ECOG performance status  
• Symptom based physical examination  
• Collection of weight and vital signs (blood pressure, pulse and temperature) 
• Hematology  
• Chemistry (fasting not required) 
• Serum/urine pregnancy test for females of child-bearing potential only 
• Concomitant medications 
• Assessment of adverse events 
• Sampling for cell-free DNA collection 
Subjects will be administered the first dose of tipifarnib (600mg), with food. 
Subjects will continue to self-administer tipifarnib twice a day (approximately every 12 hours, 
same time every morning and evening, with food) on days 1 – 7 and days 15 – 21 in 28-day 
treatment cycles (i.e. alternating week schedule). The interval between dosing should not be less 
than 8 hours. 
10.2.3 Day 1 (+/- 2 days) of Cycle 2 and Beyond 
Subjects will administer themselves their morning dose of tipifarnib with food prior to initiating 
the following procedures: 


 
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• ECOG performance status  
• Symptom based physical examination  
• Collection of weight and vital signs (blood pressure, pulse and temperature) 
• Hematology  
• Chemistry (fasting not required)  
• Serum/urine pregnancy test for females of child-bearing potential only 
• Concomitant medications 
• Assessment of adverse events  
• Sampling for cell-free DNA collection on Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 and 
Cycle 5 Day 1 
In addition to the above procedures, the clinical site will conduct a drug accountability on the 
returned empty bottles and unused medications. 
Subjects will administer themselves their evening dose of tipifarnib using the supplies provided 
by the study site.  
10.2.4 Day 8 (±2 days) of Cycles 1, 2 and 3.  
If required by the dosing schedule, subjects will administer themselves their morning dose of 
tipifarnib with food prior to the following procedures: 
• Symptom based physical examination 
• Concomitant medications 
• Assessment of adverse events 
If required by the dosing schedule, subjects will administer themselves their evening dose of 
tipifarnib using the supplies provided by the study site.  
10.2.5 Day 15 (±2 days) of Cycles 1, 2 and 3.  
If required by the dosing schedule, subjects will administer themselves their morning dose of 
tipifarnib with food prior to the following procedures: 
• Symptom based physical examination 
• Hematology  


 
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• Chemistry (fasting not required)  
• Concomitant medications 
• Assessment of adverse events 
If required by the dosing schedule, subjects will administer themselves their evening dose of 
tipifarnib using the supplies provided by the study site.  
10.2.6 Day 22 (±5 days) of Cycles 2, 4, 6 and Cycles 9, 12, 15, etc. 
If required by the dosing schedule, subjects will administer themselves their morning dose of 
tipifarnib with food prior to the following procedures: 
•  Tumor radiological assessments: CT (with contrast) or MRI scans of chest, abdomen and 
pelvis (the method used for a subject (CT or MRI) must be the same throughout the study).  
If required by the dosing schedule, subjects will administer themselves their evening dose of 
tipifarnib using the supplies provided by the study site.  
10.2.7 End of Treatment Visit 
The following assessments will occur approximately 30 days (+/- 7 days) after the last 
administration of study drug or immediately before the administration of another anti-cancer 
drug, whichever takes place first: 
• Complete physical examination  
• Collection of weight and vital signs (blood pressure, pulse and temperature) 
• ECOG performance status. 
• Hematology 
• Chemistry (fasting not required) 
• Coagulation 
• Urinalysis 
• Pregnancy test in women of childbearing potential 
• Tumor radiological assessments for subjects who have not previously demonstrated 
disease progression in the study unless completed within the previous 4 weeks: CT (with 
contrast) or MRI scans of chest, abdomen and pelvis (the method used for a subject (CT 


 
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or MRI) must be the same throughout the study). Tumor assessments may also be 
undertaken for a confirmation of objective response. 
• Assessments of adverse event and concomitant medications. 
• Conduct drug accountability on the returned empty bottles and unused medications. 
10.2.8 Post Treatment Follow up 
If the reason for the discontinuation was other than disease progression, tumor assessments will 
continue to be performed after treatment discontinuation in approximately 8 week intervals until 
progression. 
The tumor assessments to be conducted at these visits are: 
• Tumor radiological assessments: CT (with contrast) or MRI scans of chest, abdomen and pelvis 
(the method used for a subject (CT or MRI) must be the same throughout the study).  
Assessments of adverse events and concomitant medications may also be conducted if adverse 
events were not resolved at the time of the End of Treatment visit. 
10.2.9 Follow Up after Disease Progression 
Upon disease progression, all subjects will be followed approximately every 12 weeks for survival 
and the use of subsequent therapy until either death or 24 months after accrual in the subject’s 
study cohort has been completed, whichever occurs first. Information on survival and subsequent 
anticancer therapy may be collected by phone.  
11 STATISTICAL METHODS  
This section outlines the statistical analysis strategy and procedures for the study. Specific details 
of the primary and key secondary analyses will be provided in the Statistical Analysis Plan (SAP). 
If, after the study has begun, but prior to the final analysis, important changes are made to the 
protocol that affect principal features of the primary or key secondary analyses, then the protocol 
and/or SAP will be amended, as appropriate. Any other changes made to the planned analyses 
after the protocol and SAP have been finalized, along with an explanation as to when and why 
they occurred, will be listed in the Clinical Study Report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR. 


 
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11.1 Populations 
11.1.1 Efficacy Analysis 
The FAS population will serve as the primary population for the analysis of tumor response and 
other efficacy-related data. Subjects will be excluded for FAS for the following reasons: 
• No baseline data 
• Failure to receive at least one dose of tipifarnib 
• No post-baseline endpoint data subsequent to at least 1 dose of study drug 
A supportive analysis using the Per-Protocol population will be performed for the tumor response 
analysis. The Per-Protocol population excludes subjects due to important deviations from the 
protocol that may substantially affect the results of the primary analysis, such as not taking at 
least 80% of the intended dose in cycle 1. The final determination on protocol violations, and 
thereby the composition of the Per-Protocol population, will be made prior to locking the clinical 
database and final analysis and will be documented in a separate memorandum.  
11.1.2 Safety Analysis 
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data. The 
ASaT population consists of all enrolled subjects who receive at least one dose of tipifarnib. At 
least one laboratory or vital sign measurement obtained subsequent to at least one dose of study 
drug is required for inclusion in the analysis of a specific safety parameter. To assess change from 
baseline, a baseline measurement is also required. 
11.2 Endpoints 
11.2.1 Efficacy 
The efficacy endpoints are listed in section 5.  Up to 18 subjects will be enrolled in the treatment 
phase of this study. The primary endpoint is overall response rate (ORR) at 6 months, which will 
be compared to historical control via exact binomial test in comparison to historical control ORR 
10%. Binary response endpoints will be summarized by counts and percents of subjects. 
Traditional 90% confidence intervals for TRUE underlying rates will also be computed and 
reported. 
Correlation of responses with biomarkers will be assessed via comparisons of distributions of 
biomarkers among various categories of the response endpoints, to be defined in the SAP.  


 
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Additional categories of response may be defined and assessed based on the observed data 
during exploratory analyses. 
Summary statistics will be provided for other endpoints. 
11.2.2 Safety and Tolerability  
11.2.2.1 Subject Adherence 
Number of treatment cycles per subject will be summarized by numbers and percents of subjects 
who received each number of treatment cycles. 
11.2.2.2 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.  
11.2.2.3 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. 
11.2.2.4 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. 
11.3 Sample Size Determination 
No statistical testing is planned for the pre-screening phase. The sample size was determined 
based on the expected frequency of HRAS mutations in SQ-NSCLC (2%). In order to identify up to 
18 evaluable subjects that could enroll into the treatment phase, approximately 2000 subjects 
will be enrolled in the pre-screening phase.   
Up to 18 evaluable subjects will be enrolled in the treatment phase using a two-stage design 
(Simon, 1989). Seven evaluable study subjects will be enrolled for the first stage; the study will 


 
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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 two-stage study, the study is considered as failure 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 study at the 
end of first stage is 0.48 if the true ORR is 10% or less while the probability of terminating the 
study at the end of first stage is 0.13 if the true ORR is 30%.   
11.4 Changes in the Conduct of the Study or Planned Analyses 
Only the Sponsor, upon consultation with the principal Investigator may modify the protocol. The 
Sponsor will issue a formal protocol amendment to implement any changes. The only exception 
is when an Investigator considers that a subject’s safety is compromised without immediate 
action. In these circumstances, immediate approval of the chairman of the IRB/IEC must be 
sought, and the Investigator should inform the Sponsor and the full IRB/IEC within 2 working days 
after the emergency has occurred. 
The IRBI/EC must review and approve all protocol amendments. Protocol amendments that have 
an impact on subject risk or the study objectives, or require revision of the ICF, must receive 
approval from the IRB/IEC prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to subjects, the ICF will be amended and approved by the Sponsor and the IRB/IEC, and all active 
subjects must again provide informed consent. 
12 ETHICAL AND REGULATORY ASPECTS 
12.1 Responsibilities of the Investigator 
The Investigator is responsible for the conduct of the trial at their site. They will ensure that the 
trial is performed in accordance with the clinical trial protocol and with the ethical principles that 
have their origin in the Declaration of Helsinki, as well as with the ICH Note for Guidance on Good 
Clinical Practice (ICH Topic E6 (R2), June 2017) and applicable regulatory requirements. In 


 
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particular, the Investigator must ensure that only subjects who have given their informed consent 
are included into the trial. 
12.2 Subject Information and Informed Consent 
An unconditional prerequisite for a subject’s participation in the trial is their written informed 
consent. The subject’s written informed consent to participate in the trial must be given before 
any trial-related activities are carried out. The separate informed consent will be performed for 
those subjects who receive treatment beyond DLT in the safety run-in period. 
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 (R2), June 2017), and the ethical principles that have their origin in 
the Declaration of Helsinki, the Investigator will prepare the informed consent form and other 
written information to be used in obtaining informed consent from the trial subjects. The 
Investigator should cooperate with the sponsor for preparation of aforementioned written 
information. 
Before the consent may be obtained, the potential subject (or the potential subject’ legally 
acceptable representative) should be provided with sufficient time and opportunity to be 
accessed to the details of clinical trial and to decide if they would participate in the trial. All the 
queries related to the trial from the potential subject or legally acceptable representative should 
be answered by the Investigator or collaborators. 
In addition to providing this written information to a potential subject, the Investigator or his/her 
designate will inform the subject verbally of all pertinent aspects of the trial. The language used 
in doing so must be chosen so that the information can be fully and readily understood by lay 
persons. 
Depending on local regulations, a person other than the Investigator may inform the subject and 
sign the Informed Consent Form. Where the information is provided by the Investigator, the 
Informed Consent Form must be signed and personally dated by the subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived by the Investigator so that the forms can be retrieved at any time for 
monitoring, auditing and inspection purposes. A copy of the signed and dated information and 
Informed Consent Form should be provided to the subject prior to participation. 


 
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Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor and be submitted again to the IRB/IEC for review and 
favorable opinion. The agreed, revised information will be provided to each subject in the trial 
for signing and dating. The Investigator will explain the changes to the previous version. 
12.3 Subject Identification and Privacy 
A unique subject number will be assigned to each subject at inclusion, immediately after 
informed consent has been obtained. This number will serve as the subject’s identifier in the trial 
as well as in the clinical trial database. 
The subject’s data collected in the trial will be stored under this number. Only the Investigator 
will be able to link the subject’s trial data to the subject via an identification list kept at the site. 
The subject’s original medical data that are reviewed at the site during source data verification 
by the Monitor, audits and Health Authority inspections will be kept strictly confidential. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing subject data. Subjects will be informed accordingly, and will be requested to give 
their consent on data handling procedures in accordance with national regulations. 
12.4 Emergency Medical Support and Subject Card 
Subjects enrolled in this clinical trial will be provided with Emergency Medical Support cards 
during their trial participation, which will be provided by the Sponsor or designee. The Emergency 
Medical Support card is based on the need to provide clinical trial subjects with a way of 
identifying themselves as participating in a clinical trial, and subsequently to give health care 
providers access to the information about this participation that may be needed to determine 
the course of the subject’s medical treatment. 
This service is designed to provide information to health care providers who are not part of the 
clinical trial. Clinical trial investigators, who are already aware of the clinical trial protocol and 
treatment, have other means of accessing the necessary medical information for the 
management of emergencies occurring in their subjects. 
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide their emergency contact information on the 
card for this purpose. If the Investigator is available when an event occurs, they will answer any 
questions. Any subsequent action will follow the standard processes established for the 
Investigators. 


 
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12.5 Clinical Trial Insurance and Compensation to Subjects 
Spanish legislation demands cover with a civil responsibility policy for subjects participating in a 
clinical trial. The sponsor of the study provides this in accordance with the current legal 
requirements. 
12.6 Institutional Review Board/Independent Ethnic Committee 
Prior to commencement of the trial at a given site, the clinical trial protocol will be submitted 
together with its associated documents (Investigator’s brochure, Subject Information and 
Informed Consent Forms) to the responsible IRB/IEC for its favorable opinion/approval. The 
written favorable opinion/approval of the IRB/IEC will be filed in the Investigator Site File, and a 
copy will be filed in the Trial Master File at the Sponsor. 
The trial must not start at a site before the Sponsor has obtained written confirmation of 
favorable opinion/approval from the concerned IRB/IEC. The IRB/IEC will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, 
and of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the trial, the clinical trial protocol version and the Subject 
Information and Informed Consent Form version reviewed should be provided. Where possible, 
copies of the meeting minutes should be obtained. 
Amendments to the clinical trial will also be submitted to the concerned IRB/IEC, before 
implementation in case of substantial changes. Relevant safety information will be submitted to 
the IRB/IEC during the course of the trial in accordance with national regulations and 
requirements. 
12.7 Communication to Health Authorities 
The clinical trial protocol and its amendments and any applicable documentation (e.g. 
Investigator’s Brochure, Subject Information and Informed Consent Form) will be submitted or 
notified to the Health Authorities. 
13 TRIAL MANAGEMENT 
13.1 Case Report Form Management 
The Investigator or designee will be responsible for entering trial data in the eCRFs that will be 
provided by the Sponsor or its designee. It is the Investigator’s responsibility to ensure the 


 
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accuracy of the data entered in the eCRFs. Database lock will occur once quality control and 
quality assurance procedures (if applicable) have been completed.  
13.2 Source Data and Subject Files 
The Investigator must keep a subject file (medical file, original medical records) on paper or 
electronically for every subject included in the trial. This file will contain the available 
demographic and medical information for the subject, and should be as complete as possible.  
In particular, the following data should be available in this file: 
• Subject’s full name 
• Date of birth 
• Gender 
• Height 
• Weight 
• Relevant medical history and concomitant diseases 
• Prior and concomitant therapies (including changes during the trial) 
• Trial identification  
• Date of subject’s inclusion into the trial (i.e. date of informed consent) 
• Subject identifier in the trial 
• Dates of the subject’s visits to the site 
• Any medical examinations and clinical findings predefined in the clinical trial protocol 
• All adverse events observed in the subject 
• Date of subject’s end of trial, and 
• Date of and reason for early withdrawal of the subject from the trial or from treatment, if 
applicable. 
It must be possible to identify each subject by using this subject file. Additionally, any other 
documents containing source data must be filed. This includes original printouts of data recorded 
or generated by automated instruments, CT scan images, ECG recordings, laboratory value 
listings, etc. Such documents must bear at least the subject identifier and the date when the 


 
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procedure was performed. Information should be printed by the instrument used to perform the 
assessment or measurement, if possible. Information that cannot be printed by an automated 
instrument will be entered manually. Medical evaluation of such records should be documented 
as necessary and the documentation signed and dated by the Investigator. 
The following information described in the eCRFs is regarded as the source data: 
• Any Investigator’s comments 
• Subject identifier 
• Information on AE (e.g. seriousness, severity, outcome, and causality to the IP) 
• Reason for providing concomitant medications and procedures (if applicable) 
• Assessment of antitumor effect including tumor measurements 
• Description about trial discontinuation 
13.3 Investigator Site File and Archiving 
The Investigator will be provided with an Investigator Site File upon initiation of the trial. This file 
will contain all documents necessary for the conduct of the trial and will be updated and 
completed throughout the trial. It must be available for review by the Monitor, and must be ready 
for audit by the Sponsor as well as for inspection by Health Authorities during and after the trial, 
and must be safely archived for at least 25 years (or per local requirements or as otherwise 
notified by the Sponsor) after the end of the trial. The documents to be thus archived include the 
Subject Identification List and the signed subject Informed Consent Forms. If archiving of the 
Investigator Site File is no longer possible at the site, the Investigator must notify the Sponsor. 
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per 
ICH GCP guidelines or ordinance of GCP, whichever is longer. In any case, the Investigator should 
ensure that no destruction of medical records is performed without the written approval of the 
Sponsor. 
13.4 Monitoring, Quality Assurance and Inspection by Health Authorities 
This trial will be monitored in accordance with the ICH Note for Guidance on Good Clinical 
Practice (ICH Topic E6 (R2), June 2017). The site Monitor will perform visits to the trial site at 
regular intervals. 


 
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The Sponsor, as well as Health Authorities, must be permitted to inspect all trial-related 
documents and other materials at the site, including the Investigator Site File, the completed 
CRFs, the IP(s), and the subjects’ original medical records/files. 
The clinical trial protocol, each step of the data captures procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity 
of the trial data. 
13.5 Changes to the Clinical Trial Protocol 
Changes to the clinical trial protocol will be documented in written protocol amendments. Major 
(substantial, significant) amendments will usually require submission to the Health Authorities 
and to the relevant IRB/IEC for approval or favorable opinion. In such cases, the amendment will 
be implemented only after approval or favorable opinion has been obtained. 
Minor (non-substantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and by the Investigator at the clinical study site. They will be submitted to the 
relevant IRB/IEC or to Health Authorities only where requested by pertinent regulations. 
Any amendment that could have an impact on the subject’s agreement to participate in the trial 
requires the renewal of the subject’s informed consent prior to implementation. 
13.6 Clinical Trial Report 
After completion of the trial, a clinical trial report according to ICH E3 will be generated by the 
Sponsor in consultation with the Principal Investigator. 
13.7 Publication 
Authorship on the final manuscript or publications or provisional extracts will be decided in 
accordance with the Fundación GECP publication and authorship guidelines. (PNT GECP: Política 
de publicaciones y autorías) 
None of the participants will present data to his center in isolation from the rest of the results of 
the study and will need to seek approval from the sponsor. 
14 References 
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15;103(10):2035-41 
Schulten HJ, Al-Maghrabi J, Al-Ghamdi K, Salama S, Al-Muhayawi S, Chaudhary A, Hamour O, 
Abuzenadah A, Gari M, Al-Qahtani M. Mutational screening of RET, HRAS, KRAS, NRAS, BRAF, 
AKT1, and CTNNB1 in medullary thyroid carcinoma. Anticancer Res. 2011 Dec;31(12):4179-83. 
Takashima A, Faller DV. Targeting the RAS oncogene. Expert Opin Ther Targets. 2013 
May;17(5):507-31 
Zujewski J, Horak ID, Bol CJ, Woestenborghs R, Bowden C, End DW, Piotrovsky VK, Chiao J, Belly 
RT, Todd A, Kopp WC, Kohler DR, Chow C, Noone M, Hakim FT, Larkin G, Gress RE, Nussenblatt 
RB, Kremer AB, Cowan KH. Phase I and pharmacokinetic study of farnesyl protein transferase 
inhibitor R115777 in advanced cancer. J Clin Oncol. 2000 Feb;18(4):927-41. 
 
 


 
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APPENDIX I: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
STATUS 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol1982;5:649-55. 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
 
 
 


 
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APPENDIX II: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST 
VERSION 1.1) 
Source: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45:228-247. 
 
DEFINITIONS 
 
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1). Changes 
in only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria. Note: Lesions are either measurable or non-measurable using the criteria 
provided below. The term “evaluable” in reference to measurability will not be used because it 
does not provide additional meaning or accuracy. 
 
 
 
Measurable Disease 
 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10mm). 
• 10 mm caliper measurement by clinical exam (when superficial). 
• 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
Non-measurable Disease 


 
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All other lesions (or sites of disease), including small lesions (longest diameter ≥ 10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable. 
 
Bone lesions: 
• Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above. 
• Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Lesions with prior local treatment: 
 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Trial protocols should detail the conditions under which 
such lesions would be considered measurable. 


 
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Target Lesions 
 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organ, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥ 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital, or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis ≥ 10 mm 
but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression 
in the measurable dimension of the disease. 
 
Non-target Lesions 
 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present”, “absent”, or in rare cases “unequivocal 
progression” (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g., “multiple enlarged 
pelvic lymph node” or “multiple liver metastases”). 


 
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GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
P10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical examination and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the trial. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, 
lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. As is described in Appendix II of the original 
source article cited above, when CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g., for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies 


 
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are obtained or to determine relapse in trials where recurrence following complete response or 
surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a subject to 
be considered in complete response. Because tumor markers are disease specific, instructions 
for their measurement should be incorporated into protocols on a disease specific basis. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent 
prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup has 
developed CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g., with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
 
RESPONSE CRITERIA 
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 


 
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Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the “sum” of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. Case short axis 
< 10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be included in 
the sum of target lesions. 
Target lesions that become “too small to measure”. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being “too small 
to measure”. When this occurs it is important that a value be recorded on the eCRF. 
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule 
will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well). This default value is derived from the 5 mm CT 
slice thickness (but should not be changed with varying CT slice thickness). The measurement of 
these lesions is potentially non-reproducible, therefore providing this default value will prevent 
false responses or progressions based upon measurement error. To reiterate, however, if the 
radiologist is able to provide an actual measure, that should be recorded, even if it is below 5 
mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions “fragment”, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
thisminstance should be the maximal longest diameter for the “coalesced lesion”. 
 
Evaluation of Non-target Lesions 
 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 


 
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Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also considered progression). 
When the patient also has measurable disease. In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the patient has only non-measurable disease. This circumstance arises in some phase III 
trials when it is not a criterion of trial entry to have measurable disease. The same general 
concept apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e., an increase in tumor burden representing an 
additional 73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from “trace” to “large”, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols 
as “sufficient to require a change in therapy”. If “unequivocal progression” is seen, the subject 
should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so, therefore the increase must be substantial. 
 
New Lesions 
 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 


 
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unequivocal: i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the patient’s baseline lesions show partial or complete response. For example, necrosis of 
a liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the subject 
who has visceral disease at baseline and while on trial has a CT or MRI brain ordered which reveals 
metastases. The subject’s brain metastases are considered to be evidence of PD even if he/she 
did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible “new” disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
b) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-
up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT 
scans are needed to determine if there is truly progression occurring at that site (if so, the date 
of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the study drug 
treatment until the end of treatment taking into account any requirement for confirmation. On 
occasion a response may not be documented until after the end of therapy so protocols should 
be clear if post-treatment assessments are to be considered in determination of best overall 
response. 


 
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Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The subject’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of 
new lesions. Furthermore, depending on the nature of the trial and the protocol requirements, 
it may also require confirmatory measurement. Specifically, in non-randomized trials where 
response is the primary endpoint, confirmation of PR or CR is needed to deem either one the 
“best overall response”. 
The best overall response is determined once all the data for the patient is known. Best response 
determination in trials where confirmation of complete or partial response IS NOT required: Best 
response in these trials is defined as the best response across all time points (for example, a 
subject who has SD at first assessment, PR at second assessment, and PD on last assessment has 
a best overall response of PR). When SD is believed to be best response, it must also meet the 
protocol specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best time point response, the subject’s best response depends on the subsequent 
assessments. For example, a subject who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same subject lost tofollow-
up after the first SD assessment would be considered inevaluable. 
 
 
See text for more details. 
 
Note: When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it bebased on increase in size of the nodes. As noted earlier, this means that 
subjects with CR may not have a total sum of “zero” on the eCRF. 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, 
in most trials it is reasonable to consider a subject with time point responses of PR-NE-PR as a 
confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping trial therapy. 


 
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Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar to 
a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/ sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
at the next scheduled assessment, progression is confirmed, the date of progression should be 
the earlier date when progression was suspected. 
 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
 
Confirmation 
 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e., in 
randomized trials (phase II or III) or trials where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response 
confirmation may increase the importance of central review to protect against bias, in particular 
in trials which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 to 8 weeks) that is defined in the trial protocol. 
 
Duration of Overall Response 


 
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The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
 
Duration of Stable Disease 
 
Stable disease is measured from the start of the treatment (in randomised trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If 
the proportion of subjects achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between two measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account many 
parameters including disease types and stages, treatment periodicity, and standard practice. 
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between trials are to be made. 
 
 
 


 
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APPENDIX III: NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION 
 
 
 
 
APPENDIX IV: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V4.0 
(CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 
 


 
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APPENDIX V: PROHIBITED MEDICATION LIST 
Reference: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteract
ionslabeling/ucm093664.  Accessed 2019-03-22. 
Table 4: Strong Inhibitors or Inducers of CYP3A4  
The following medications may not be taken from at least 14 days prior to the start of tipifarnib 
treatment and throughout the tipifarnib treatment portion of KO-TIP-001. 
Strong Inhibitors 
Strong Inducers 
boceprevir 
carbamazepine 
clarithromycin 
enzalutamide 
cobicistat 
mitotane 
conivaptan 
phenytoin 
dasabuvir 
rifampin 
danoprevir 
St. John’s wort 
diltiazem 
 
elvitegravir 
 
grapefruit juice (high-dose or double strength preparations 
only) 
 
idelalisib 
 
indinavir 
 
itraconazole 
 
ketoconazole 
 
lopinavir 
 
nefazodone 
 
nelfinavir 
 
ombitasvir 
 
paritaprevir 
 
posaconazole 
 
ritonavir 
 
saquinavir 
 
telaprevir 
 
tipranavir 
 
troleandomycin 
 


 
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voriconazole 
 
Table 5: Sensitive substrates of CYP3A4  
The following medications may not be taken during the tipifarnib treatment portion of KO-TIP-
001. 
alfentanil 
lovastatin 
avanafil 
lurasidone 
budesonide 
maraviroc 
buspirone 
midazolam 
conivaptan 
naloxegol 
darifenacin 
nisoldipine 
darunavir 
quetiapine 
dasatinib 
saquinavir 
dronedarone 
sildenafil 
ebastine 
simvastatin 
eletriptan 
sirolimus 
eplerenone 
tacrolimus 
everolimus 
ticagrelor 
felodipine 
tipranavir 
ibrutinib 
tolvaptan 
indinavir 
triazolam 
lomitapide 
vardenafil 
 
 
 


 
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APPENDIX VI: SAE FORM AND PREGNANCY FORM 
 
SAE Form 
 
 
  
 
 
Pregnancy Form