Clinical trial NCT02418000
Conditions: AML MDS CMML
Sponsor: Spirita Oncology, LLC
Start date: 2015-04-10; Completion date: 2017-06-08
Enrollment: 27 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1/2a dose-escalation study of E6201, a dual mitogen-activated protein kinase/extracellular-signal regulated kinase 1 (MEK1) and FMS-like tyrosine kinase 3 (FLT3) inhibitor, in subjects with advanced hematologic malignancies with documented FLT3 and/or rat sarcoma (Ras) mutations. The Phase1 portion of the study will be a safety run-in (up to 30 subjects) to establish a recommended Phase 2 dose (RP2D). The Ph. 2a portion of the study will evaluate three specific patients groups: Cohort 1 will enroll patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) without prior exposure to a FLT3 inhibitor; Cohort 2 will enroll patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) with prior exposure to a FLT3 inhibitor; Cohort 3 will enroll patients with relapsed or refractory AML with a confirmed Ras mutation and no FLT3 mutation.

Detailed description:
Phase 1 (Safety Run-In): Following Screening, a total of up to 30 subjects in up to 5 dose cohorts to establish the RP2D. The safety run-in phase will be a standard 3+3 cohort design.

Phase 2a (Expansion): Once the Phase 1 Safety Run-In portion of the study is complete and an RP2D is established, additional subjects will be enrolled into the Phase 2 Expansion portion in three cohorts. Cohort 1 will enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) without prior exposure to a FLT3 inhibitor. Cohort 2 will enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) with prior exposure to a FLT3 inhibitor. Cohort 3 will enroll up to 10 patients with relapsed or refractory AML with a confirmed Ras mutation and no FLT3 mutation. Cohort 1 and 2 of the Expansion Phase will incorporate a Simon 2-stage optimal design. Subjects with AML enrolled in the Phase 1 portion of the study at the RP2D will count towards the Phase 2a accrual for the appropriate cohort.

Subjects will receive E6201 weekly or bi-weekly on a 28-day schedule, with the schedule and dose level established in the Safety Run-In portion of the study. Disease assessments, including analysis of blood and bone marrow samples, will be performed at the end of Cycles 1 and 3 and every 2 cycles thereafter. Disease assessments may be made at other time points at the discretion of the Investigator.

Subjects who demonstrate clinical benefit (objective response or stable disease) will be allowed to continue therapy with E6201 until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in the patient's condition that prevents further study participation.

During the study, ECGs will be performed, blood will be collected for hematology, serum chemistry, pharmacokinetics and pharmacodynamics assessments, and bone marrow will be collected for the assessment of disease response and mutational status.

Arms: arm 1: E6201 240 mg/m\^2 administered IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) arm 2: E6201 320 mg/m\^2 administered IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) arm 3: E6201 160 mg/m\^2 administered IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) arm 4: E6201 240 mg/m\^2 administered IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) arm 5: E6201 320 mg/m\^2 administered IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22, and 25, repeated every 28 days (= 1 cycle)
Interventions: intervention 1: E6201
Intervention descriptions: intervention 1: Single Group Assignment

Protocol documents:
Prot_001.pdf: 
Protocol No. BSC-101-01 
Strategia Therapeutics, Inc. 
Confidential 
October 30, 2016 
1
Amendment 6
 
O 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
BSC-101-01 
Protocol Title: 
A Phase 1/2a study of E6201 for the 
treatment 
of 
advanced 
hematologic 
malignancies 
with 
FLT3 
and/or 
Ras 
mutations, including acute myeloid leukemia 
(AML), myelodysplastic syndrome (MDS) or 
chronic myelomonocytic leukemia (CMML) 
Study Chair: 
Gautam Borthakur, MD 
Department of Leukemia 
The University of Texas MD Anderson  
Cancer Center 
1515 Holcombe Blvd., Unit 428, FC 4.2006 
Houston, TX 77030-4009 
Telephone: (713) 563-1586 
Sponsor Contact: 
Teletha Gipson, MS, PhD 
Director, Clinical Operations 
Strategia Therapeutics, Inc. 
2 8 4 2 0  H a r d y  T o l l  R d . ,  S u i t e 1 1 0  
Spring, TX 77373 
Telephone: (713) 269-1272 
Email: Teletha.gipson@strategiatx.com 
 
Sponsor Medical Monitor: 
Linda J. Paradiso, DVM, MBA  
Chief Operating Officer 
Strategia Therapeutics, Inc.  
28420 Hardy Toll Rd., Suite 110 
Spring, TX 77373 
Telephone: (713) 898-8965 
Email: Linda.paradiso@strategiatx.com 
Original Protocol 
October 21, 2014 
Amendment 1 
December 19, 2014 
Amendment 2 
Amendment 3 
Amendment 4 
Amendment 5 
Amendment 6 
April 7, 2015 
August 26, 2015 
January 21, 2016 
May 5, 2016 
October 30, 2016 
 


Protocol No. BSC-101-01 
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INVESTIGATOR SIGNATURE PAGE 
I have reviewed the above-titled protocol and agree that it contains all the information 
necessary to conduct the study as required. I will conduct the trial in accordance with the 
principles of the International Conference on Harmonisation (ICH) Good Clinical 
Practice, the Declaration of Helsinki and the applicable U.S. Food and Drug 
Administration (FDA) regulations. 
I will maintain as confidential all written and verbal information provided to me by the 
Sponsor, including but not limited to, the protocol, case report forms, investigator’s 
brochure, material supplied at investigator meetings, minutes of teleconferences, etc. 
Such material will only be provided as necessary to site personnel involved in the 
conduct of the trial, the Institutional Review Board (IRB) or local regulatory authorities. 
I will obtain written informed consent from each prospective trial subject or each 
prospective trial subject’s legal representative prior to conducting any protocol-specified 
procedures. The Informed Consent Document (ICD) used will have the approval of the 
IRB. 
I will maintain adequate source documents and record all observations, treatments and 
procedures pertinent to trial subjects in their medical records. I will accurately complete 
and submit the electronic case report forms supplied by the Sponsor in a timely manner. I 
will ensure that my facilities and records will be available for inspection by 
representatives of Strategia Therapeutics, the IRB or local regulatory authorities. I will 
ensure that I and my staff are available to meet with representatives of Strategia 
Therapeutics during regularly-scheduled monitoring visits. 
I will notify the Medical Monitor within 24 hours of any serious adverse events.  Following 
this notification, a written report describing the serious adverse event will be provided to 
S t r a t e g i a  T h e r a p e u t i c s  as soon as possible, but no later than 5 days following 
the initial notification. 
 
 
 
 
 
 
Investigator’s Signature 
 
 
 
Date 
 
 
 
 
Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. BSC-101-01 
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SYNOPSIS 
 
Sponsor 
Strategia Therapeutics, Inc. 
Protocol Number 
BSC-101-01 
Name of Study Drug 
E6201 for Injection 
Protocol Title 
A Phase 1/2a study of E6201 for the treatment of 
advanced hematologic malignancies with FLT3 
a n d / o r  R a s  mutations, including acute myeloid 
leukemia (AML), myelodysplastic syndrome (MDS) 
or chronic myelomonocytic leukemia (CMML) 
Name of Active Ingredient 
(3S,4R,5Z,8S,11E)-14- 
(Ethylamino)-8,9,16-trihydroxy- 
3,4-dimethyl-3,4,9,10-tetrahydro- 
1H-2-benzoxacyclotetradecine- 
1,7(8H)-dione 
Phase of Development 
Phase 1/2a 
Primary Objective 
• 
Phase 1: To determine the safety and tolerability of E6201 in subjects with FLT3+ 
a n d / o r  R a s +  AML, MDS or CMML and to establish a recommended Phase 
2 dose (RP2D) 
• 
Phase 2a: To evaluate the overall response rates (ORR) in subjects who receive 
E6201 for the treatment of FLT3+ and/or Ras+ relapsed/refractory AML 
Secondary Objectives 
• 
To evaluate duration of response 
• 
To evaluate progression-free survival (PFS) 
• 
To evaluate overall survival (OS) 
• 
To evaluate the pharmacokinetics (PK) of E6201 
• 
To explore pharmacodynamic (PD) changes from baseline in signal transduction 
markers in blood or/and bone marrow: pERK, pFLT3 and pAKT 
• 
To explore quantitative changes from baseline in FLT3 internal tandem 
duplication (FLT3 ITD), FLT3 tyrosine kinase domain (TKD) and Ras+ allelic 
burden, FLT3 ligand and plasma inhibitory assay (PIA) for FLT3, and evaluate 
the correlation between FLT3 a n d  R a s +  allelic burden and objective 
response 
• 
To determine the safety and tolerability of E6201 at the RP2D (Phase 2a) 


Protocol No. BSC-101-01 
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Methodology 
This is a Phase 1/2a, dose-escalation study of E6201, a dual MEK1 and FLT3 inhibitor, 
in subjects with advanced hematologic malignancies with documented FLT3 and/or 
Ras mutations. The Phase 1 portion of the study will be conducted as a safety run-
in in  up  t o 3 0 s ubjec t s  to establish a recommended Phase 2 dose (RP2D). 
The Phase 2a portion of the study will evaluate three specific patient groups: Cohort 1 will 
enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation 
(with or without a Ras mutation) without prior exposure to a FLT3 inhibitor, Cohort 2 will 
enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation 
(with or without a Ras mutation) with prior exposure to a FLT3 inhibitor, and Cohort 3 
will enroll up to 10 patients with relapsed or refractory AML with a 
confirmed Ras mutation and no FLT3 mutation. Cohorts 1 and 2 of the 
expansion phase will incorporate a Simon 2-stage optimal design. 
A total of up to N= 92 subjects will be enrolled in the study.  
Major selection criteria are: age ≥ 18 years with confirmed diagnosis of FLT3+ and/or 
Ras+ higher-risk MDS/CMML (Phase 1 only), or relapsed or refractory AML with a FLT3 
and/or Ras mutation. In the absence of rapidly-progressing disease, ≥ 3 weeks after 
prior cancer treatment for the disease under study, with the exception of 
hydroxyurea to control peripheral blast counts allowed during the first 2 cycles. 
Subjects must have recovered from all acute toxicities (≤ Grade 1), have adequate 
renal and hepatic function, and no known history of significant cardiac disease. 
Phase 1 (Safety Run-In): Following Screening, a total of up to 30 subjects in up to 5 
dose cohorts will be enrolled to establish the RP2D. The safety run-in phase will be a 
standard 3+3 cohort design. 
Dose Level 1: 240 mg/m2 weekly Days 1, 8, 15 and 22, repeated every 28 days (=1 
cycle) 
Dose Level 2: 320 mg/m2 weekly Days 1, 8, 15 and 22, repeated every 28 days 
Dose Level 3: 160 mg/m2 twice weekly Days 1, 4, 8, 11, 15,18, 22 and 25, repeated every 
28 days (=1 cycle) 
Dose Level 4: 240 mg/m2 twice weekly Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated 
every 28 days (=1 cycle) 
Dose Level 5: 320 mg/m2 twice weekly Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated 
every 28 days 
In the first cohort, the dose of E6201 will be 240 mg/m2, administered as an intravenous 
(IV) infusion over 2 hours once weekly (Dose Level 1), on Days 1, 8, 15 and 22 of a 28- 
day schedule (=1 cycle). A minimum of 3 subjects will be treated. If 1 of 3 subjects 
experiences DLT during Cycle 1, the cohort will be expanded to 6. If ≥ 2 of 6 subjects 
experiences DLT by Day 28, no dose escalation to Dose Level 2 will occur. However, if 0 
of 3 or ≤ 1 of 6 subjects treated at Dose Level 1 experience DLT by Day 28, dose 
escalation will proceed to the next cohort, 320 mg/m2 weekly (Dose Level 2), 
administered by IV infusion over 2 hours on Days 1, 8, 15 and 22 of a 28-day schedule. 
A minimum of 3 subjects will be treated at this dose level. If 1 of 3 subjects treated at 
Dose Level 2 experiences DLT during Cycle 1, the cohort will be expanded to 6 subjects. 
If ≥ 2 of 6 subjects experience DLT by Day 28, no further dose escalation will occur. 
However, if 0 of 3 or ≤ 1 of 6 subjects treated at Dose Level 2 experience DLT by Day 
28, dose escalation will proceed to the next dose cohort, 160 mg/m2 administered as 


Protocol No. BSC-101-01 
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Methodology (continued) 
an IV infusion over 2 hours twice weekly (Dose Level 3), on Days 1, 4, 8, 11, 15, 18, 22 
and 25 of a 28-day schedule (=1 cycle). A minimum of 3 subjects will be treated at this 
dose level. If 1 of 3 subjects treated at Dose Level 3 experiences DLT during Cycle 1, 
the cohort will be expanded to 6 subjects. If ≥ 2 of 6 subjects experience DLT by Day 28, 
no further dose escalation will occur.  
However, if 0 of 3 or ≤ 1 of 6 subjects treated at Dose Level 3 experiences DLT by Day 
28, dose escalation will proceed to the next dose cohort, 2 4 0  mg/m2 administered as 
an IV infusion over 2 hours twice weekly (Dose Level 4), on Days 1, 4, 8, 11, 15, 18, 
22 and 25 of a 28-day schedule. A minimum of 3 subjects will be treated at this dose 
level. If 1 of 3 subjects treated at Dose Level 4 experiences DLT during Cycle 1, the 
cohort will be expanded to 6 subjects. If ≥ 2 of 6 subjects experience DLT by Day 28, 
no further dose escalation will occur. 
However, if 0 of 3 or ≤ 1 of 6 subjects treated at Dose Level 4 experiences DLT by Day 
28, dose escalation will proceed to the next dose cohort, 320 mg/m2 administered as an IV 
infusion over 2 hours twice weekly (Dose Level 5), on Days 1, 4, 8, 11, 15, 18, 22 and 25 
of a 28-day schedule. A minimum of 3 subjects will be treated at this dose level. If 1 of 3 
subjects treated at Dose Level 5 experiences DLT during Cycle 1, the cohort will be 
expanded to 6 subjects. If there are ≤ 1 of 6 subjects with DLT at Dose Level 5, this dose 
(320 mg/m2 twice weekly) will be declared the MTD and RP2D. If, however, ≥ 2 of 6 
subjects experiences DLT, then either 320 mg/m2 weekly (Dose Level 2) or 240 mg/m2 
twice weekly (Dose Level 4) will be declared the MTD and RP2D based on additional 
factors (e.g., PK and PD parameters). 
Dose-limiting toxicity will be defined as any  one of  the following events: prolonged 
myelosuppression (as defined by the National Cancer Institute [NCI] criteria specific for 
leukemia, i.e., marrow cellularity <  5%  at  ≥  6 weeks from  start  of  therapy without 
evidence of leukemia); ≥ Grade 3 non-hematologic toxicity (excluding Grade 3 nausea, 
vomiting or diarrhea that is adequately controlled with supportive care and resolves to ≤ 
Grade 2 within 48 hours, or Grade 3 electrolyte disturbances responsive to correction 
within 24 hours); ≥ Grade 3 liver function tests (LFTs) lasting > 7 days; treatment  
interruption >  14 days due to toxicity; or other important medical event. 
Phase 2a (Expansion): Once the Phase 1 Safety Run-In portion of the study is complete 
and an RP2D is established, additional subjects will be enrolled into the Phase 2 
Expansion portion in three cohorts. Cohort 1 will enroll up to 26 patients with relapsed or 
refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) without 
prior exposure to a FLT3 inhibitor. Cohort 2 will enroll up to 2 6  patients with relapsed 
or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) with 
prior exposure to a FLT3 inhibitor. Cohort 3 will enroll up to 10 patients with relapsed or 
refractory AML with a confirmed Ras mutation and no FLT3 mutation. Cohorts 1 and 2 of 
the Expansion Phase will incorporate a Simon 2-stage optimal design. Subjects with 
AML enrolled in the Phase 1 portion of the study at the RP2D will count towards the 
Phase 2a accrual for the appropriate cohort. 
During the study, a Safety Review Committee (SRC), consisting of the actively recruiting 
investigators, the Medical Monitor and Strategia Therapeutics will review data from 
each cohort on an ongoing basis.  
Subjects will receive E6201 weekly or bi-weekly on a 28-day schedule, with the schedule 
and dose level established during the safety run-in portion of the study. Disease 
assessments, including analysis of blood and bone marrow aspirates, will be performed at 
the end of Cycles 1 and 3 and every 2 cycles thereafter. Disease assessments may be  


Protocol No. BSC-101-01 
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Protocol Number 
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Methodology (continued)  
made at other time points at the discretion of the Investigator.  
Subjects who demonstrate clinical benefit (objective response or stable disease) will be 
allowed to continue therapy with E6201 until progression of disease, observation of 
unacceptable adverse events, intercurrent illness or changes in the patient’s condition that 
prevents further study participation. 
Subjects will be instructed to contact their study doctor for ophthalmic evaluation should 
they experience disturbances in their vision. 
ECGs will be taken within 28 days prior to Cycle 1, and Days 1 and 15 of each cycle, 
pre-dose, 5 minutes following the end of the infusion, 2, 4 and 24 hours post-infusion, 
and at the End-of-Study visit. 
Blood for hematology and serum chemistry will be collected within 28 days prior to Cycle 
1 Day 1, on Days 1, 8, 15 and 22 of Cycle 1, on Day 1 of each subsequent cycle and at 
the End-of-Study visit. 
Blood samples for PK assessment of E6201 concentrations will be collected on Cycle 1 
Days 1 and Day 15, and Cycle 2 Day 1 pre-dose, 5 minutes following the end of the 
infusion, 2, 4, 8 and 24 hours post-infusion. 
Blood samples for PD assessment will be collected at Cycle 1, Days 1 and 15 and Cycle 
2 Day 1, pre-dose, 4 and 24 hours post-infusion. 
Bone marrow will be collected pre-study, at the end of Cycle 1, every 2 cycles thereafter, 
and at disease relapse/progression, unless the peripheral blood absolute blast count is ≥ 
5.0 x 109 cells/L, to assess mutational status and potentially PD markers. 
Number of Subjects and Centers 
Phase 1: Up to 30 subjects are planned for the Safety Run-in portion of the study. 
Phase 2a: Up to 26 subjects are planned for Cohort 1 of the Expansion portion, 26 
subjects for Cohort 2 and up to 10 subjects for Cohort 3 (total N=62), for a total of up to 92 
subjects. 
The study will be conducted at The University of Texas M.D. Anderson Cancer Center 
with Gautam Borthakur, M.D. serving as Study Chair. Additional clinical sites include 
Moffitt Cancer Center (Kendra Sweet, MD), Health ONE Cares (Michael Maris, MD) and 
Methodist Hospital, San Antonio (Jose Cruz, MD). Additional sites may be added to 
complete study enrollment in a timely manner. 
Duration of Study 
The accrual phase for the Phase 1 Safety Run-in portion is expected to be 24 – 27 
months. The expected accrual for the Phase 2a Expansion portion is expected to be 12 
months, for a total accrual period of 36 – 39 months. With the last subject followed for up 
to 6 months, a total study duration of 4 2 – 4 5  months is anticipated. The anticipated 
accrual rate for the Phase 2a portion is 4 – 6 subjects per month across all sites. 


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Protocol Number 
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Inclusion Criteria 
• 
Males and females ≥ 18 years of age 
• 
Phase 1: Subjects with confirmed relapsed or refractory AML with a documented 
FLT3 and/or Ras mutation, or age ≥ 60 years with newly diagnosed FLT3+ and/or 
Ras+ AML and not eligible for standard induction chemotherapy, or FLT3+ and/or 
Ras+, higher-risk MDS/CMML (defined as ≥ 10% marrow blasts or ≥ 5% peripheral 
blood blasts or Revised International Prognostic Scoring System [IPSS-R] score ≥ 
3.5), and relapsed or refractory to prior therapy 
• 
Phase 2: Subjects with confirmed relapsed or refractory AML with a documented 
FLT3 and/or Ras mutation, or age ≥ 60 years with newly diagnosed FLT3+ and/or 
Ras+ AML and not eligible for standard induction chemotherapy 
• 
At least 3 weeks beyond the last cancer treatment for the disease under 
study, major surgery and recovered from all acute toxicities (≤ Grade 1) by first 
dose of study drug (C1D1). Hydroxyurea used to control peripheral blast counts 
is permitted during the first 2 cycles. 
• 
Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 2 
(Appendix A) 
• 
Adequate renal and hepatic function: 
• 
Serum creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance ≥ 45 
mL/minute per the Cockcroft-Gault formula (Appendix B) 
• 
Total bilirubin ≤ 2 times the upper limit of normal (ULN) unless due to Gilbert’s 
disease or thought to be due to underlying AML 
• 
ALT and AST ≤ 5 times ULN 
• 
Negative serum pregnancy test within 14 days prior to the first dose of study therapy 
for women of child-bearing potential (WCBP), defined as a sexually mature woman 
who has not undergone a hysterectomy or who has not been naturally post- 
menopausal for at least 24 consecutive months (i.e., who has had menses any time 
in the preceding 24 consecutive months). Sexually active WCBP and male subjects 
must agree to use adequate methods to avoid pregnancy (oral, injectable, or 
implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier 
contraceptive with spermicide; or vasectomized partner) throughout the study and for 
28 days after the completion of study treatment. 
• 
Ability to provide written informed consent 


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Protocol Number 
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Exclusion Criteria 
• 
History of clinically significant cardiac impairment, congestive heart failure (CHF) 
New York Heart Association (NYHA) Class III or IV, unstable angina, or myocardial 
infarction during the previous 6 months, or serious cardiac arrhythmia (Appendix C) 
• 
QT interval corrected for rate (QTc) > 450 msec for males and > 460 msec for 
females on the electrocardiogram (ECG) obtained at Screening using Fridericia 
method for QTc calculation (average of 3 readings) 
• 
Concomitant medication(s) that may cause QTc prolongation or induce Torsades de 
Pointes with the exception of anti-microbials used as standard of care to prevent or 
treat infections and other such drugs that are considered by the Investigator to be 
essential for the care of the patient (Appendix D). However, if such medications are 
deemed to be necessary during the study, more intensive ECG monitoring will be 
added during the period of concomitant drug administration. 
• 
Presence of active central nervous system (CNS) leukemia. Subjects adequately 
treated for CNS leukemia documented by 2 consecutive cerebrospinal fluid samples 
negative for leukemia cells are eligible. Subjects with no history of CNS leukemia will 
not be required to undergo cerebrospinal fluid sampling for eligibility. 
• 
Known positive for human immunodeficiency virus (HIV), hepatitis B virus surface 
antigen (HBsAg), or hepatitis C virus (HCV) 
• 
Active, uncontrolled infection 
• 
Known hypersensitivity to any study drug component 
• 
History of another malignancy; Exception: Patients disease-free for 2 years or treated 
in situ carcinoma 
• 
Any other medical intervention or other condition which, in the opinion of the Principal 
Investigator, could compromise adherence to study requirements or confound the 
interpretation of study results 
• 
Pregnancy or lactation 


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Protocol Number 
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Criteria for Evaluation 
Safety 
Safety will be assessed through the monitoring of adverse events (AEs), clinical 
laboratory parameters (hematology and serum chemistry), vital sign measurements, 
ECGs and physical examinations. Adverse events will be classified according to the 
Medical Dictionary for Regulatory Affairs (MedDRA) and graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 4.03. 
Efficacy 
Efficacy assessment for AML will be performed using a modification of the 
recommendations 
of 
the 
International Working 
Group 
(IWG) 
for 
Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards 
for Therapeutic Trials in Acute Myeloid Leukemia. Efficacy assessments for subjects 
with MDS or CMML will be performed using a modification of the IWG Response Criteria 
in Myelodysplasia. 
Pharmacokinetics 
Pharmacokinetic determinations of E6201 in plasma will be made. 
Pharmacodynamics 
Levels of pERK, pFLT3, pAKT, FLT3 ITD, FLT3 TKD and Ras+ allelic burden, FLT3 ligand 
and plasma inhibitory assay (PIA) for FLT3, will be measured in blood and/or bone 
marrow samples collected from each subject. Additional markers or mutation analysis will 
be undertaken, if needed. 
Investigational Product 
E6201 for Injection is a natural product analog and novel inhibitor of FMS-like tyrosine 
kinase-3 (FLT3) and mitogen-activated protein kinase/extracellular-signal regulated 
kinase kinase-1 (MEK1). It is a sterile white lyophilized powder containing 60 mg of E6201 
formulated in cyclodextrin to improve E6201 solubility in water.  E6201 for Injection is 
packaged in a 15-mL or 20-mL capacity Type I glass vial with a bromobutyl rubber 
stopper and an aluminum cap. Reconstituted and diluted E6201 solutions should be 
stored refrigerated (2 to 8°C) and protected from light before administration. 
Reference therapy None 
Statistical Methods 
Efficacy Endpoints and Analyses 
The primary endpoint will be the proportion of patients who achieve an objective response 
(OR) as best response within 3 cycles of treatment with E6201. Each Phase 1 dose 
cohort will be analyzed independently; each Phase 2a disease cohort will be analyzed 
independently. The number and percentage of subjects with an OR will be 
summarized. For secondary endpoints, duration of response, PFS and OS curves will be 
estimated using the Kaplan-Meier product-limit estimates. 


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Statistical Methods (continued) 
Pharmacokinetic Endpoint Analyses 
Mean plasma concentrations of E6201 will be determined in blood samples collected 
before administration of E6201 and at multiple time points after administration of E6201. 
Because plasma concentrations will be determined at a limited number of time points 
during the study, a complete pharmacokinetic profile of E6201 at each dose level will not 
be possible. Limited pharmacokinetic analyses will be performed. 
Pharmacodynamic Endpoint Analyses 
Changes from baseline in levels of pERK, pFLT3, pAKT, FLT3 ITD, FLT3 TKD and Ras+ 
allelic burden, FLT3 ligand and PIA for FLT3, and will be measured in blood and/or 
bone marrow samples collected from each subject at multiple points during the study. 
Changes from baseline in pERK and pFLT3 will be measured in bulk and progenitor 
cells. Correlation between FLT3 and Ras+ allelic burden, pharmacokinetics and clinical 
response will be assessed. 
Changes from baseline in PD parameters for each cohort will be summarized using
descriptive statistics, including number of patients (N), mean, standard deviation (SD),
minimum, median, maximum range, and coefficient of variation (CV). Additional or other
genomic changes may be evaluated. 
Safety Endpoints and Analyses 
Safety endpoints for adverse events (AEs) include the following: incidence of all 
treatment-emergent AEs (TEAEs) and all serious AEs (SAEs); by severity, relationship 
to study medication, Grade 3 and 4 TEAEs, discontinuation of subjects from study due to 
AEs or death. Safety endpoints for AEs, clinical laboratory tests, vital signs, physical 
examinations and ECGs will be specified in the statistical analysis plan. Safety 
summaries will be provided by each cohort independently, and for the combined safety 
population representing all cohorts. 
 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION 
18 
1.1. 
Oncogenic Growth Stimulatory Pathways in Hematologic Malignancies 
18 
1.2. 
Single Agent Clinical Activity of Kinase Inhibitors Targeting FLT3 or MEK in 
Hematologic Malignancies 
18 
1.3. 
Hypothesis and Rationale for Dual Pathway Inhibition in Hematologic Malignancies
 
18 
1.4. 
E6201, a Dual MEK1/FLT3 Inhibitor to Overcome Resistance to Single-Pathway 
Inhibitors 
19 
1.4.1. In Vitro and In Vivo Pharmacology of E6201 
19 
1.4.2. Safety Pharmacology 
23 
1.4.3. Pharmacokinetics and Metabolism 
23 
1.4.4. Nonclinical Toxicology 
24 
1.5. 
E6201 for Injection Clinical Experience 
24 
1.5.1. Phase 1 Study in Advanced Melanoma (E6201-A001-102) 
24 
1.5.2. Phase 1/2a Study in Advanced Hematologic Malignancies (BSC-101-01) 
26 
1.5.3. Rationale for Phase 1/2a Study of E6201 in FLT3+ and/or Ras+ AML 
27 
2. 
STUDY OBJECTIVES 
27 
2.1. 
Primary Objective 
27 
2.2. 
Secondary Objectives 
27 
3. 
INVESTIGATIONAL PLAN 
28 
3.1. 
Overall Study Design 
28 
3.2. 
Number of Subjects and Centers 
30 
3.3. 
Duration of Study 
31 
3.4. 
Criteria for Termination of the Study 
31 
4. 
STUDY POPULATION 
31 
4.1. 
Inclusion Criteria 
31 
4.2. 
Exclusion Criteria 
32 
4.3. 
Molecular Characterization of Mutational Status 
33 
4.4. 
Discontinuation of Subjects 
33 
4.4.1. Procedures for Withdrawal 
33 
4.4.2. Replacement of Study Subjects 
34 
5. 
STUDY TREATMENT 
34 
5.1. 
E6201 Study Drug Description 
34 
5.2. 
Study Drug Preparation and Administration 
34 
5.3. 
Treatment Duration 
34 


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5.4. 
Dosing Delays and Modifications Due to Toxicity 
35 
5.4.1. Toxicity Grading Criteria 
35 
5.4.2. Definitions of Dose-Limiting Toxicity 
35 
5.4.3. Dose Modifications and Dose Reductions 
35 
5.4.4. Schedule Adjustments for Toxicity 
36 
5.5. 
Supportive Care Guidelines 
36 
5.6. 
Concomitant Medications and Therapies 
36 
5.6.1. Permitted Medications 
36 
5.6.2. Prohibited Medications 
37 
5.7. 
Packaging and Labeling 
37 
5.8. 
Shipping and Storage 
37 
5.9. 
Study Drug Accountability 
37 
6. 
STUDY PROCEDURES 
37 
6.1. 
Screening Procedures 
37 
6.2. 
Requirements During Treatment Cycle 1 
38 
6.2.1. Cycle 1, Day 1 
38 
6.2.2. Cycle 1, Day 8 (+/-1 day) 
38 
6.2.3. Cycle 1, Day 15 (+/-1 day) 
39 
6.2.4. Cycle 1, Day 22 (+/-1 day) 
39 
6.2.5. End of Cycle 1 (Day 28 +/- 3 days) 
39 
6.3. 
Requirements During Treatment Cycles After Cycle 1 (Cycles 2, 3, 4, etc.) 
40 
6.3.1. Day 1 (+/- 1 day) 
40 
6.3.2. Day 8 (+/-1 day) 
40 
6.3.3. Day 15 (+/-1 day) 
40 
6.3.4. Day 22 (+/-1 day) 
41 
6.3.5. End of Cycle 3 (Day 28 +/- 3 days) and Every 2 Cycles Thereafter 
41 
6.4. 
At Relapse or Progression of Disease 
41 
6.5. 
End of Study (28 Days After Last Dose of Study Medication +/- 5 days) 
41 
6.6. 
Long-Term Follow-Up 
42 
7. 
DESCRIPTION OF ASSESSMENTS 
42 
7.1 
Safety Assessments 
42 
7.1.1. Adverse Event Definition 
42 
7.1.2. Serious Adverse Event 
42 
7.1.3. Unexpected Adverse Event 
43 
7.1.4. Adverse Event Reporting Period 
43 


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7.1.5. Recording of Adverse Events 
43 
7.1.6. Adverse Event Reporting 
44 
7.1.7. Adverse Event and Serious Adverse Event Follow-Up 
45 
7.1.8. Ongoing Safety Evaluation 
46 
7.1.9. Clinical Laboratory Tests 
46 
7.1.10. 
Vital Sign Measurements 
46 
7.1.11. 
Physical Examinations 
46 
7.1.12. 
Electrocardiograms 
47 
7.2. 
Efficacy Assessments 
47 
7.2.1. Criteria for Evaluation of Response and Progression 
47 
7.2.2. Disease Response Criteria 
47 
7.2.3. Efficacy Endpoints 
49 
7.2.4. Pharmacokinetic Endpoints 
50 
7.2.5. Pharmacodynamic Endpoints 
50 
8. 
STATISTICAL METHODOLOGY 
50 
8.1. 
Determination of Sample Size 
50 
8.2. 
Analysis Populations 
51 
8.3. 
Statistical Analysis Methods 
51 
8.3.1. Safety Analyses 
51 
8.3.2. Efficacy Analyses 
52 
8.3.3. Pharmacokinetic Endpoint Analysis 
52 
8.3.4. Pharmacodynamic Endpoint Analysis 
53 
9. 
STUDY MANAGEMENT 
53 
9.1. 
Data Management 
53 
9.2. 
Monitoring 
53 
9.3. 
Audits and Inspections 
53 
9.4. 
Amendments 
54 
9.5. 
Record Keeping 
54 
9.5.1. 
Health Insurance Portability Accountability Act of 1996 
54 
9.5.2. 
Financial Disclosure 
54 
9.5.3. 
Access to Original Records 
54 
9.5.4. 
Retention of Study Documents 
54 
10. 
ADMINISTRATIVE STRUCTURE OF THE STUDY 
54 
11. 
REFERENCES 
56 
 


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LIST OF TABLES 
Table 1. AML Cell Lines Examined .........................................................................................19 
Table 2. IC50 of E6201 in Multiple Types of AML Cells .........................................................20 
Table 3. Treatment-Emergent Adverse Events Considered by Investigators to be Probably 
Related to E6201 in the Dose Escalation Part of Study E6201-A001-102 .............................25 
Table 4. Dose-Limiting Toxicities of E6201 Administered by Intravenous Infusion ............25 
Table 5. TEAEs Related to E6201 Administered at 320 mg/m2 ............................................26 
Table 6. Treatment-Emergent Serious Adverse Events Related to E6201 Administered at 
320 mg/m2 over 60 minutes ....................................................................................................26 
Table 7. E6201 Dose Modification Guidelines for General Adverse Events .......................35 
Table 8. E6201 Dose Modification Guidelines for QTc Prolongation ...................................36 
Table 9. Reporting Guidelines for Adverse Events ...............................................................45 
Table 10. Clinical Laboratory Parameters ..............................................................................46 
 
LIST OF FIGURES 
Figure 1. Chemical Structure and Mechanism of Action of E6201 ......................................19 
Figure 2. E6201 Exerts Cytotoxic Effects in AML Cells with FLT3 or N-Ras Mutations ......20 
Figure 3. E6201 Induces Apoptosis in FLT3-ITD-mutated Primary AML Cells Ex vivo ........21 
Figure 4. E6201 Enhanced Cytotoxicity in N-Ras Mutated Leukemia Cells ........................21 
Figure 5. E6201 Modulation of Apoptosis Via Signaling Proteins and Bcl-2 .......................22 
Figure 6. E6201 Blocks Leukemia Progression in a MOLM13 Murine Xenograft Model ......22 
Figure 7. E6201 Reduces Leukemia Cell Infiltration in Progression ...................................23 
 
LIST OF APPENDICES 
Appendix A. Eastern Cooperative Group (ECOG) Performance Status Scale .....................58 
Appendix B. Cockcroft-Gault Formula for Calculation of Creatinine Clearance .................59 
Appendix C. New York Heart Association (NYCA) Classification for Heart Failure NYHA 
Classification - The Stages of Heart Failure ..........................................................................60 
Appendix D. Drugs Known to Prolong QT Interval or Induce Torsades de Pointes ............61 
Appendix E. Schedule of Study Procedures .........................................................................65 
Appendix F. Ethical Standards ...............................................................................................67 
Appendix G. Investigator Obligations ....................................................................................69 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase 
BUN 
Blood urea nitrogen 
C 
Centigrade 
CFR 
Code of Federal Regulations 
Cmax 
Peak concentration 
CML 
Chronic myelocytic leukemia 
CMML 
Chronic myelomonocytic leukemia 
CNS 
Central nervous system 
CR 
Complete remission 
Cri 
Complete remission with incomplete blood count recovery 
CRF 
Case report form 
CTCAE 
Common terminology criteria for adverse events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
dL 
Decaliter 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FLT3 
FMS-like tyrosine kinase-3 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
HbsAg 
Hepatitis B surface antigen 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICD 
Informed consent document 


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Abbreviation 
Definition 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IPSS-R 
Revised International Prognostic Scoring System 
IRB 
Institutional Review Board 
ITD 
Internal tandem duplication 
IV 
Intravenous 
IWG 
International Working Group 
Kg 
Kilogram 
L 
Liter 
LDH0 
Lactate dehydrogenase 
m2 
Meters squared 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
Mitogen-activated protein kinase 
Mg 
Milligram 
mL 
Milliliter 
µ 
Micro 
M 
Molar 
MTD 
Maximum tolerated dose 
N 
Number 
NCI 
National Cancer Institute 
NOAEL 
No adverse effect level 
NOG 
Non-obese diabetic gamma null 
NYHA 
New York Heart Association 
OR 
Objective response 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Pharmacodynamic, progressive disease 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PIA 
Plasma inhibitory assay 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PR 
Partial remission 
QTc 
QT interval corrected for rate 
RBC 
Red blood cell 


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Abbreviation 
Definition 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SD 
Standard deviation, stable disease 
SRC 
Safety Review Committee 
T1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
TKD 
Tyrosine kinase domain 
TKI 
Tyrosine kinase inhibitor 
Tmax 
Time to peak concentration 
U 
Units 
UDS 
Unscheduled DNA synthesis 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WCBP 
Woman of child-bearing potential 
 
 


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1. INTRODUCTION 
 
1.1. 
Oncogenic Growth Stimulatory Pathways in Hematologic 
Malignancies 
Survival of acute myeloid leukemia (AML) and other malignant cells is dependent to 
variable degrees on mutational activation of oncogenic pathways. This is evidenced by 
clinical activity of single-agent FLT3 inhibitors observed in patients carrying FMS-like 
tyrosine kinase 3 (FLT3) mutations (30% of AML) and of mitogen-activated protein 
kinase (MEK) inhibitors in patients carrying either K or N-Ras mutations (~25 – 40% of 
AML).
1-4 Constitutive phosphorylation and subsequent activation of FLT3 is observed in 
patients carrying either internal tandem duplication (ITD) or point (D835) mutation in the 
FLT3 gene. AML associated with FLT3 mutation, in particular the FLT3 internal tandem 
duplication (ITD) mutation, is associated with poor overall prognosis and event-free 
survival in a group of relatively younger patients with AML.
5-8
 
The Ras/Raf signaling pathway signals through the downstream signal transducers MEK1 
and ERK and is relevant in FLT3 mutated AML. Activation of this pathway as evidenced 
by ERK phosphorylation is present constitutively and more importantly is seen in AML 
cells of patients failing FLT3 inhibitor therapy even when FLT3 phosphorylation remains 
suppressed (data from MDACC). Activating Ras mutations are also encountered in 10-
15% of patients with AML. While the direct clinical association between Ras mutations 
and clinical outcome in AML is not as clearly documented as with FLT3 mutations, clinical 
data clearly show that ERK phosphorylation, a downstream mediator of Ras signaling, in 
AML cells is linked to poor clinical outcome in patients with AML.9 
 
1.2. 
Single Agent Clinical Activity of Kinase Inhibitors Targeting FLT3 or 
MEK in Hematologic Malignancies 
Kinase inhibitors targeting FLT3 or MEK have shown clear clinical activity, including 
complete remissions, in patients with AML harboring relevant activating mutations. A 
phase 2 study of quizartinib (AC220) in patients with relapsed/refractory AML associated 
with FLT3-ITD mutation showed a composite CR rate of 45% and partial remission (PR) 
rate of 24%.
2 Trametinib (GSK1120212) demonstrated a CR/CRp rate of 25% in patients 
with relapsed/refractory AML and myelodysplastic syndrome (MDS) associated with Ras 
mutation.
3 Unfortunately the remissions in patients with AML and MDS receiving selective 
tyrosine kinase inhibitors (TKIs) are relatively short-lasting.10,11 Furthermore, 
cells 
resistant to FLT3-ITD inhibitors sorafenib and quizartinib can acquire resistant point 
mutations of FLT3 in the tyrosine kinase domain in addition to the ITD mutation.12 
 
1.3. 
Hypothesis and Rationale for Dual Pathway Inhibition in 
Hematologic Malignancies 
Responses to agents that act on single signaling pathways are of relatively short duration, 
suggesting emergence of resistance which may be mediated through parallel activation 
of multiple signaling pathways9,13 and which may be overcome by simultaneous targeting 
of multiple signaling pathways. Because activation of parallel signaling pathways can 
contribute to development of resistance to FLT3 inhibitors, we hypothesize that 
simultaneous inhibition of both the FLT3 and MEK signaling pathways will provide a 
mechanism to overcome resistance that occurs via activation of parallel growth 
stimulatory and survival pathways. 
 


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1.4. 
E6201, a Dual MEK1/FLT3 Inhibitor to Overcome Resistance to 
Single-Pathway Inhibitors 
E6201 is a natural product analog that inhibits both MEK1 and FLT3. This dual inhibition 
activity is anticipated to provide a mechanism to overcome resistance that occurs via 
activation of parallel growth stimulatory and survival pathways. The chemical structure 
and mechanism of action of E6201 are depicted in Figure 1. 
 
 
 
 
 
Figure 1. Chemical Structure and Mechanism of Action of E6201 
1.4.1.  In Vitro and In Vivo Pharmacology of E6201 
E6201 is a dual MEK1/FLT3 inhibitor with activity against both targets reportedly in the 
low nanomolar range. E6201 shows identical affinity and residence time for active and 
inactive forms of MEK1. While affinity for FLT3 is lower, the residence time for FLT3 is 
11-fold higher than for MEK1, thus making this compound an effective inhibitor for both 
MEK1 and FLT3. 
To verify the hypothesis that concomitant pathway inhibition could achieve longer lasting 
antitumor activity, E6201 was tested in a series of studies described below.14 
E6201 was tested against AML cell lines (including FLT3-inhibitor resistant cells), primary 
AML patient samples, and in a murine AML model. The AML cell lines examined in this 
study are depicted in Table 1. 
Table 1. AML Cell Lines Examined 
 
 
E6201 inhibited cell growth and induced apoptosis in AML cells with FLT3 ITD mutations 


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(including sorafenib-resistant cells harboring ITD plus N676D/Y842C point mutations) at 
nanomolar concentrations, and showed 600- to 1000-fold more selective activity against 
cells with FLT3-ITD mutations than those with FLT3-Wild Type (WT), with IC50 of 0.003, 
0.005 and 0.002 µM against Ba/F3-ITD, FLT3-ITD mutant MOLM13 and MV4-11 cells, 
respectively, compared to 3.18 µM in Ba/FLT3-WT cells. Notably, dual FLT3-WT/RAS 
mutant OCI/AML3 cells, with high basal p-ERK level and with resistance to most 
chemotherapeutic agents, were sensitive to E6201, with IC50 = 0.037 µM (Table 2). 
Table 2. IC50 of E6201 in Multiple Types of AML Cells 
 
 
 
 
Apoptosis was determined via FACS analysis by measuring annexin V-positivity at 72 
hours. The IC50 of E6201 was sub-micromolar in all 5 FLT3-ITD mutant primary AML 
samples, which included one with FLT3-ITD/RAS dual mutation (Figures 2 and 3). 
 
 
Figure 2. E6201 Exerts Cytotoxic Effects in AML Cells with FLT3 or N-Ras Mutations 
 
 
 


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Figure 3. E6201 Induces Apoptosis in FLT3-ITD-mutated Primary AML Cells Ex vivo 
Consistent with its MEK1 inhibitory activity, E6201 was more active against NRAS 
mutant MV4-11 cells than its NRAS-WT isogenic counterpart (Figure 4). 
 
 
Figure 4. E6201 Enhanced Cytotoxicity in N-Ras Mutated Leukemia Cells  
by Suppression of Pim-1 and Mcl 
Mechanistically, E6201 markedly suppressed p-FLT3 and p-ERK in all tested FLT3 
mutant AML cell lines and in N-Ras mutant OCI/AML3 cells. 
 
In addition, decreased Bcl-xL and Mcl-1 levels (green arrows) and increased cleaved- 
caspase-3 (red boxes) were observed in all FLT3 mutant cell lines after treatment with 
E6201 for 1 hour (left panel) and 24 hours (right panel) (Figure 5). 
*N-Ras mutation 
**K-Ras mutation 


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Figure 5. E6201 Modulation of Apoptosis Via Signaling Proteins and Bcl-2 
Non-obese diabetic gamma null (NOG) mice bearing xenografts of MOLM13-Luc-GFP 
(FLT3-ITD mutated) cells were treated with E6201 intravenously (IV) on a twice weekly 
schedule from Day 5 after leukemia cell injection until Day 21. Bioluminescence imaging 
revealed profound reductions in tumor burden and leukemia cell infiltration in groups 
receiving E6201 at 20 or 40 mg/kg versus vehicle control; 3.1x106, 2.7x106 versus 
5.6x106 photons/sec, respectively (p<0.01). The bioluminescence imaging was confirmed 
by immunohistochemistry with an anti-luciferase antibody in spleen and bone marrow 
specimens (Figure 6). 
 
 
 
 
 
 
 
 
 
Figure 6. E6201 Blocks Leukemia Progression in a MOLM13 Murine Xenograft Model 
Leukemia cell infiltration was markedly reduced in bone marrow, spleen, liver and lungs 
starting on Day 9 after the first E6201 dose (Day 5 and 14 shown below in Figure 7). 
 
(20 mg/kg) 
(40 mg/kg) 
Quantity of Bioluminescence Imaging 
Immunohistochemistry (IHC) 
Anti-luciferase Antibody 
Spleen 
Bone Marrow 


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Figure 7. E6201 Reduces Leukemia Cell Infiltration in Progression  
in Murine Xenograft Model with MOLM13 Cells 
E6201 has been extensively studied in preclinical IND-enabling studies performed by 
Eisai Pharmaceuticals. An Investigator’s Brochure is available that describes these studies 
in more detail.15 
1.4.2. Safety Pharmacology 
In vivo studies of E6201 administered as a 30-minute intravenous infusion at doses up to 
60 mg/kg in rats had no effects on the central nervous system (CNS) or on respiratory 
function. In dogs, doses of E6201 up to 30 mg/kg (in 18% – 30% Captisol formulation) 
administered as a 30-minute intravenous infusion showed no effects on heart rate (HR), 
blood pressure (BP) or electrocardiogram (ECG) parameters. The maximum observed 
plasma concentration (Cmax) was estimated to be 16169.24 ng/mL in the male rat and 
8988.10-15269.67 ng/mL in dogs. 
In a 5-minute infusion in anesthetized dogs, both vehicle (30% Captisol) and E6201 (6- 
30 mg/kg in 30% Captisol) exhibited effects on cardiopulmonary function, including 
increases in mean BP, systolic left ventricular pressure, left ventricular end-diastolic 
pressure, mean right atrial pressure, mean pulmonary artery pressure, pulmonary artery 
wedge pressure, and cardiac output. These effects were attributed to the physiochemical 
properties of Captisol (high osmolality and viscosity) and were not observed after 30- 
minute intravenous infusion, except for a 36.5% increase in cardiac output observed with 
E6201 at 30 mg/kg in 30% Captisol solution, compared to vehicle alone (30% Captisol). 
Doses of E6201 up to 18 mg/kg in 18% Captisol solution administered as a 30-minute 
intravenous infusion had no effects on cardiopulmonary function. 
1.4.3. Pharmacokinetics and Metabolism 
After oral or intravenous administration, the PK of E6201 in mice, rats, and rabbits was 
characterized by moderately extensive distribution, rapid clearance (CL) and elimination. 
No gender differences were found in either rat (up to 60 mg/kg) or dog (30 mg/kg) 
toxicokinetic studies after intravenous dosing. In in vitro studies, E6201 did not inhibit or 
induce the major human cytochrome P450 (CYP) isoenzymes. 
 


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1.4.4. Nonclinical Toxicology 
1.4.4.1. 
Single-Dose Toxicity in Rats and Dogs 
Doses up to 60 mg/kg E6201 in Captisol solution administered as single intravenous 
(IV)bolus injections to rats produced pulmonary toxicity. Decreased activity and/or ptosis 
were observed at doses of 20 or 60 mg/kg E6201, which disappeared within 1 day. The 
incidence of mortality was 1/40 (2.5%) and 4/76 (5.3%) at 20 and 60 mg/kg, respectively. In 
animals 
with 
severe 
clinical 
signs, 
histopathological 
findings 
of perivascular 
edema/hemorrhage and alveolar edema were observed, with death due to acute 
pulmonary edema. No degenerative changes in the alveoli or cardiac histopathological 
findings were observed. These effects were obviated by changing the mode of 
administration from a bolus injection to a 30-minute infusion; E6201 is thought to have 
little direct effect itself on the lung. In a single intravenous bolus toxicity study in dogs (6, 
18, or 30 mg/kg doses), E6201-related clinical signs were limited to transient decreased 
activity and abnormal gait at 30 mg/kg. In a PK study, gastrointestinal toxicity and 
deteriorating physical condition were observed at 30 mg/kg. 
1.4.4.2. 
Repeat-Dose Toxicity in Rats and Dogs 
In repeat-dose IV toxicity studies in rats and dogs (every 7 days over a 15-day period), 
no E6201-related effects were observed in rats, while limited clinical signs of transient 
tremors, salivation and emesis were observed in dogs at doses ≥18 mg/kg without any 
clinical pathological or histopathological correlates. E6201 (10 or 30 mg/kg) administered 
intravenously once a day for 4 days to male and female Beagle dogs resulted in no 
deaths, no test article-related abnormal clinical signs, no toxicologically significant changes 
in body weights, food consumption, hematology, blood chemistry, or macroscopic 
pathology. 
1.4.4.3. 
Genotoxicity 
E6201 was negative in the reverse mutation assay in bacteria (Ames test) and in the in 
vivo rat micronucleus and unscheduled DNA synthesis (UDS) tests. The genotoxic risk of 
E6201 in humans is, therefore, considered low. 
1.4.4.4. 
Reproductive and Developmental Toxicity 
E6201 was positive in studies of maternal and fetal toxicity. The NOAEL for maternal 
toxicity and embryo-fetal development in pregnant rats and rabbits was 6 mg/kg. In rats, 
the no adverse effect level (NOAEL) for maternal toxicity was 6 mg/kg and 2 mg/kg for 
reproduction and early embryo development. Therefore, precautions will be taken to 
avoid pregnancy in the proposed clinical study. 
 
1.5. 
E6201 for Injection Clinical Experience 
Eisai Co., Ltd. was developing E6201 for Injection for patients with cancer and E6201 
topical cream for dermatologic indications. The information summarized below is for 
E6201 for Injection. Please refer to the Investigator’s Brochure for more information.15 
1.5.1. Phase 1 Study in Advanced Melanoma (E6201-A001-102) 
The safety and tolerability of E6201 for Injection was investigated by Eisai Co., Ltd. In 
Protocol E6201-A001-102, a Phase 1, multicenter, open-label, dose-escalation, safety, 
pharmacokinetic and pharmacodynamic study in subjects with advanced melanoma. The 
study, which is now closed to enrollment, had 2 parts: Part A (Dose Escalation) and Part B 
(Expansion). A total of 25 subjects with advanced solid tumors were enrolled in Part A and 


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30 subjects with BRAF-mutated melanoma or wild-type melanoma were enrolled in Part B 
for a total of 55 subjects. 
1.5.1.1. 
Most Frequently Observed Adverse Events 
In the dose escalation portion of the study, the primary endpoint was determination of 
the maximum tolerated dose (MTD) of E6201. Twenty-five subjects received E6201 in 
dosing cohorts of 20, 40, 80, 160, 320, 400 and 480 mg/m2 E6201 administered by 
intravenous infusion over 30 minutes once a week on Days 1, 8, and 15 of a 28-day 
cycle. Treatment-emergent adverse events considered by the Investigator to be probably 
related to E6201 are listed in Table 3. Two subjects had serious adverse events (SAEs) 
considered by the Investigator to be possibly or probably related to study medication. 
Table 3. Treatment-Emergent Adverse Events Considered by Investigators to be Probably Related 
to E6201 in the Dose Escalation Part of Study E6201-A001-102 
 
MedDRA 
Preferred Term 
E6201 Dose Level (mg/m2) 
20 
(N=4) 
n (%) 
40 
(N=3) 
n (%) 
80 
(N=3) 
n (%) 
160 
(N=3) 
n (%) 
320 
(N=7) 
n (%) 
400 
(N=1) 
n (%) 
480 
(N=4) 
n (%) 
Total 
(N=25) 
n (%) 
QTc prolonged 
0 
0 
0 
0 
1 (14) 
0 
2 (50) 
3 (12) 
Amnesia 
0 
0 
0 
0 
0 
0 
1 (25) 
1 (4) 
Confusional state 
0 
0 
0 
0 
0 
0 
1 (25) 
1 (4) 
Disorientation 
0 
0 
0 
0 
0 
1 (100) 
0 
1 (4) 
Dizziness 
0 
0 
0 
0 
0 
1 (100) 
0 
1 (4) 
Feeling abnormal 
0 
0 
0 
0 
0 
0 
1 (25) 
1 (4) 
Nausea 
1 (25) 
0 
0 
0 
0 
0 
1 (4) 
Tinnitus 
0 
0 
0 
0 
0 
0 
1 (25) 
1 (4) 
1.5.1.2. 
Dose-Limiting Toxicities 
Based on DLT data, summarized in Table 4, the MTD of E6201 was determined to be 
320 mg/m2 when administered by intravenous infusion over 30 minutes once a week on 
Days 1, 8, and 15 of a 28-day cycle. 
Table 4. Dose-Limiting Toxicities of E6201 Administered by Intravenous Infusion  
over 30 Minutes Once a Week 
Patient 
Number 
E6201 Dose Level 
at DLT Onset (mg/m2) 
Adverse Event 
(Investigator Term) 
CTC Grade 
10011019 
320 
QTc Prolongation 
2 
10011014 
480 
QTc Prolongation 
3 
10011015 
480 
Confusion 
4 
 
Thirty (30) patients were enrolled in the dose expansion portion of the study, with 27 
receiving E6201 at 320 mg/m2 by one-hour intravenous infusion once weekly. No DLTs 
were observed in this group of patients. 
1.5.1.3. 
Adverse and Serious Adverse Events at 320 mg/m2 
Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) 


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considered by the Investigator to be related to E6201 when administered at 320 mg/m2 
once weekly in the Phase I study are summarized in Tables 5 and 6, respectively. 
Table 5. TEAEs Related to E6201 Administered at 320 mg/m2 
 
MedDRA Preferred Term 
Total n (%) (N=34 Subjects) 
QTc prolonged 
1 (2.7)* 
Nausea 
3 (8.1) 
Vomiting 
2 (5.4) 
Rash 
1 (2.7) 
Constipation 
1 (2.7) 
Fatigue 
1 (2.7) 
Hypokalemia 
1 (2.7) 
Neutrophil count decreased 
1 (2.7) 
Skin hyperpigmentation 
1 (2.7) 
* observed in the dose-escalation portion of the Phase I study in which E6201 was administered by infusion 
over 30 minutes; not observed with 60-minute infusion 
Table 6. Treatment-Emergent Serious Adverse Events Related to E6201 Administered at 320 mg/m2 
over 60 minutes 
 
MedDRA Preferred Term 
Total n (%) (N=34 Subjects) 
Uncontrolled hypertension 
1 (2.7) 
The SAE of uncontrolled hypertension developed during Cycle 2 and resolved without 
treatment. 
1.5.1.4. 
Pharmacokinetic Profile of E6201 
The pharmacokinetic profiles of E6201 and its major metabolite ER-813010 were 
determined in blood samples collected on Days 1 and 15 of Cycle 1 from patients with 
advanced solid tumors enrolled in the dose escalation portion of the Phase I study. The 
PK data for the 7 dosing cohorts in which E6201 was administered by intravenous 
infusion over 30 minutes at doses ranging from 20 to 480 mg/m2, indicate that E6201 
undergoes extensive distribution and fast elimination that is independent of dose. E6201 
exposure (AUC0-∞) increased with increasing dose up to 320 mg/m2 and was comparable 
at doses above 320 mg/m2. Mean Cmax and AUC0-∞ were similar between Day 1 and Day 
15 at comparable doses of E6201. ER-813010, the isomeric metabolite of E6201, 
represented 9.5% to 44.9% of the parent compound. Urinary clearance is a minor route 
of elimination for E6201. For further pharmacokinetic details, please refer to the 
Investigator’s Brochure.12 
1.5.2. Phase 1/2a Study in Advanced Hematologic Malignancies (BSC-101-
01) 
The Phase 1/2a, dose-escalation study of E6201 in patients with advanced hematologic 
malignancies with documented FLT3 and/or Ras mutations is ongoing. As of December 
21, 2015, a total of 5 patients had been treated at 240 mg/m2 weekly (Cohort 1) and 5 
patients had been treated at 320 mg/m2 weekly (Cohort 2) for a total of 10 subjects.  
The most frequently reported AEs across all doses in ≥ 2 subjects (≥ 20%) include QTc 
prolongation, decreased appetite, fatigue, intracranial hemorrhage, sepsis, hypokalemia, 
acute respiratory failure and sinusitis reported in 2 subjects (20%) each. Febrile 


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neutropenia and cellulitis were reported in 3 subjects each (30%). E6201-related AEs 
include QTc prolongation in 1 subject in the 240 mg/m2 dose group (Grade 3) and in 1 
subject in the 320 mg/m2 dose group (Grade 2) when E6201 was administered over a 1 
hour infusion. Both cohorts were expanded to N=6 each, the infusion time lengthened to 
2 hours via Amendment 4 to the study protocol and no further events have occurred. 
1.5.3. Rationale for Phase 1/2a Study of E6201 in FLT3+ and/or Ras+ AML 
In contrast to patients with chronic myeloid leukemia (CML), the remissions in patients 
with AML and MDS receiving tyrosine kinase inhibitors (TKIs) are relatively short-lasting. 
Because activation of parallel signaling pathways can contribute to development of 
resistance to FLT3 and MEK inhibitors, it is hypothesized that simultaneous inhibition of 
both the FLT3 and MEK signaling pathways with E6201, a dual inhibitor of MEK1 and 
FLT3, will provide a mechanism to overcome resistance that occurs via activation of 
parallel growth stimulatory and survival pathways. 
E6201 has not caused ophthalmic changes in the 55 patients treated in the E6201- 
A001-102 study at doses of 20 – 480 mg/m2 weekly or twice weekly, and 1 of these 
patients remain on E6201 for ≥ 5 years at a dose of 320 mg/m2/week x 3 weeks q 28 
days. However, other MEK inhibitors have caused ocular toxicities including retinal vein 
occlusion, retinal pigment epithelial detachment, uveitis, and iritis, and these findings are 
believed to be related to the drug class. Since E6201 is a MEK1 and FLT3 inhibitor, 
patients should contact their study doctor for an ophthalmologic evaluation if they 
experience visual disturbances. 
2. STUDY OBJECTIVES 
 
2.1. 
Primary Objective 
Phase 1: To determine the safety and tolerability of E6201 in subjects with 
FLT3+ and/or Ras+ AML, MDS or CMML and to establish a recommended 
Phase 2 dose (RP2D) 
Phase 2a: To evaluate the overall response rates (ORR) in subjects who 
receive E6201 for the treatment of FLT3+ and/or Ras+ relapsed/refractory AML 
 
2.2. 
Secondary Objectives 
• To evaluate duration of response 
• To evaluate progression-free survival (PFS) 
• To evaluate overall survival (OS) 
• To assess the pharmacokinetics (PK) of E6201 
• To explore pharmacodynamics (PD) changes from baseline in signal 
transduction markers in blood or/and bone marrow: pERK, pFLT3 and pAKT 
• To explore quantitative changes from baseline in FLT3 internal tandem 
duplication (FLT3 ITD), FLT3 tyrosine kinase domain (TKD) and Ras+ allelic 
burden, FLT3 ligand and plasma inhibitory assay (PIA) for FLT3, and evaluate 
the correlation between FLT3 and Ras+ allelic burden and objective response 
• To determine the safety and tolerability of E6201 at the RP2D (Phase 2a) 
 
 


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3. INVESTIGATIONAL PLAN 
 
3.1. 
Overall Study Design 
This is a Phase 1/2a, dose-escalation study of E6201, a dual MEK1 and FLT3 inhibitor, in 
subjects with advanced hematologic malignancies with documented FLT3 and/or Ras 
mutations. The Phase 1 portion of the study will be conducted as a safety run-in in  
u p  t o  3 0 s ubj ec t s  to establish a recommended Phase 2 dose (RP2D). 
The Phase 2a portion of the study will evaluate three specific patient groups: Cohort 1 will 
enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation 
(with or without a Ras mutation) without prior exposure to a FLT3 inhibitor, Cohort 2 will 
enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation (with 
or without a Ras mutation) with prior exposure to a FLT3 inhibitor, and Cohort 3 will 
enroll up to 10 patients with relapsed or refractory AML with a confirmed Ras mutation and 
no FLT3 mutation. Cohorts 1 and 2 of the expansion phase will incorporate a Simon 2-
stage optimal design. 
A total of up to N=92 subjects will be enrolled in the study. 
Major selection criteria are: age ≥ 18 years with confirmed diagnosis of FLT3+ and/or 
Ras+ higher-risk MDS/CMML (Phase 1 only), or relapsed or refractory AML with a FLT3 
and/or Ras mutation. In the absence of rapidly-progressing disease, ≥ 3 weeks after 
prior cancer treatment for the disease under study, with the exception of 
hydroxyurea to control peripheral blast counts allowed during the first 2 cycles. Subjects 
must have recovered from all acute toxicities (≤ Grade 1), have adequate renal and 
hepatic function, and no known history of significant cardiac disease. 
Phase 1 (Safety Run-In): Following Screening, a total of up to 30 subjects in up to 5 
dose cohorts will be enrolled to establish the RP2D. The safety run-in phase will be a 
standard 3+3 cohort design. 
Dose Level 1:  240 mg/m2 weekly Days 1, 8, 15 and 22, repeated every 28 days (=1 
cycle) 
Dose Level 2: 320 mg/m2 weekly Days 1, 8, 15 and 22, repeated every 28 days 
Dose Level 3: 160 mg/m2 twice weekly Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 
days 
Dose Level 4: 240 mg/m2 twice weekly Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated 
every 28 days (=1 cycle) 
Dose Level 5: 320 mg/m2 twice weekly Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated 
every 28 days 
In the first cohort, the dose of E6201 will be 240 mg/m2, administered as an intravenous (IV) 
infusion over 2 hours once weekly (Dose Level 1), on Days 1, 8, 15 and 22 of a 28-day 
schedule (=1 cycle). A minimum of 3 subjects will be treated. If 1 of 3 subjects 
experiences DLT during Cycle 1, the cohort will be expanded to 6. If ≥ 2 of 6 subjects 
experiences DLT by Day 28, no dose escalation to Dose Level 2 will occur. However, if 0 of 
3 or ≤ 1 of 6 subjects treated at Dose Level 1 experiences DLT by Day 28, dose 
escalation will proceed to the next cohort, 320 mg/m2 weekly (Dose Level 2), administered 
by IV infusion over 2 hours on Days 1, 8, 15, and 22 of a 28-day schedule. A minimum of 3 
subjects will be treated at this dose level. If 1 of 3 subjects treated at Dose Level 2 
experiences DLT during Cycle 1, the cohort will be expanded to 6 subjects. If ≥ 2 of 6 


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subjects experience DLT by Day 28, no further dose escalation will occur.  
However, if 0 of 3 or ≤ 1 of 6 subjects treated at Dose Level 2 experience DLT by Day 28, 
dose escalation will proceed to the next dose cohort, 160 mg/m2 administered as an IV 
infusion over 2 hours twice weekly (Dose Level 3), on Days 1, 4, 8, 11, 15, 18, 22 and 25 
of a 28-day schedule (=1 cycle). A minimum of 3 subjects will be treated at this dose level. 
If 1 of 3 subjects treated at Dose Level 3 experiences DLT during Cycle 1, the cohort 
will be expanded to 6 subjects. If ≥ 2 of 6 subjects experience DLT by Day 28, no further 
dose escalation will occur.  
However, if 0 of 3 or ≤ 1 of 6 subjects treated at Dose Level 3 experience DLT by Day 28, 
dose escalation will proceed to the next dose cohort, 240 mg/m2, administered as an IV 
infusion over 2 hours twice weekly (Dose Level 4), on Days 1, 4, 8, 11, 15, 18, 22 and 25 
of a 28-day schedule. A minimum of 3 subjects will be treated at this dose level. If 1 of 
3 subjects treated at Dose Level 4 experiences DLT during Cycle 1, the cohort will be 
expanded to 6 subjects. If ≥ 2 of 6 subjects experience DLT by Day 28, no further dose 
escalations will occur. 
However, if 0 of 3 or ≤ 1 of 6 subjects treated at Dose Level 4 experience DLT by Day 
28, dose escalation will proceed to the next dose cohort, 320 mg/m2 administered as 
an IV infusion over 2 hours twice weekly (Dose Level 5), on Days 1, 4, 8, 11, 15, 18, 22 
and 25 of a 28-day schedule. A minimum of 3 subjects will be treated at this dose level. 
If 1 of 3 subjects treated at Dose Level 5 experiences DLT during Cycle 1, the cohort 
will be expanded to 6 subjects. If there are ≤ 1 of 6 subjects with DLT at Dose Level 5, 
this dose (320 mg/m2 twice weekly) will be declared the MTD and RP2D. If, however, ≥ 2 
of 6 subjects experience DLT, then either 320 mg/m2 weekly (Dose Level 2) or 240 mg/m2 
twice weekly (Dose Level 4 ) will be declared the MTD and RP2D based on additional 
factors (e.g., PK and PD parameters). 
Dose-limiting toxicity will be defined as any  one of  the following events: prolonged 
myelosuppression (as defined by the National Cancer Institute [NCI] criteria specific for 
leukemia, i.e., marrow cellularity <  5%  at  ≥  6 weeks from  start  of  therapy without 
evidence of leukemia); ≥ Grade 3 non-hematologic toxicity (excluding Grade 3 nausea, 
vomiting or diarrhea that is adequately controlled with supportive care and resolves to ≤ 
Grade 2 within 48 hours, or Grade 3 electrolyte disturbances responsive to correction 
within 24 hours); ≥ Grade 3 liver function tests (LFTs) lasting > 7 days; ; treatment  
interruption > 14 days due to toxicity; or other important medical event. 
Phase 2a (Expansion): Once the Phase 1 Safety Run-In portion of the study is complete 
and an RP2D is established, additional subjects will be enrolled into the Phase 2 Expansion 
portion in three cohorts. Cohort 1 will enroll up to 26 patients with relapsed or refractory 
AML and confirmed FLT3 mutation (with or without a Ras mutation) without prior 
exposure to a FLT3 inhibitor. Cohort 2 will enroll up to 2 6  patients with relapsed or 
refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) with prior 
exposure to a FLT3 inhibitor. Cohort 3 will enroll up to 10 patients with relapsed or refractory 
AML and a confirmed Ras mutation with no FLT3 mutation. Cohorts 1 and 2 of the Expansion 
Phase will incorporate a Simon 2-stage optimal design. 
Subjects with AML enrolled in the Phase 1 portion of the study at the RP2D will count 
towards the Phase 2a accrual for the appropriate cohort. 
During the study, a Safety Review Committee (SRC), consisting of the actively recruiting 
investigators, the Medical Monitor and Strategia Therapeutics will review data from 
each cohort on an ongoing basis. 


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Subjects will receive E6201 weekly or bi-weekly on a 28-day schedule, with the schedule 
and dose level established in the safety run-in portion of the study. Disease 
assessments, including analysis of blood and bone marrow aspirates, will be performed at 
the end of Cycles 1 and 3 and every 2 cycles thereafter. Disease assessments may be 
made at other time points at the discretion of the Investigator. 
Subjects who demonstrate clinical benefit (objective response or stable disease) 
will be allowed to continue therapy with E6201 until progression of disease, observation 
of unacceptable adverse events, intercurrent illness or changes in the patient’s condition 
that prevents further study participation. 
Subjects will be instructed to contact their study doctor for ophthalmologic evaluation 
should they experience disturbances in their vision. 
ECGs will be taken within 28 days prior to Cycle 1, and Days 1 and 15 of each cycle, 
pre-dose, 5 minutes following the end of the infusion, 2, 4 and 24 hours post-infusion, 
and at the End-of-Study visit. 
Blood for hematology and serum chemistry will be collected within 28 days prior to Cycle 1 
Day 1, on Days 1, 8, 15 and 22 of Cycle 1, on Day 1 of each subsequent cycle and at the 
End-of-Study visit. 
Blood samples for PK assessment of E6201 concentrations will be collected on Cycle 1 
Days 1 and Day 15, and Cycle 2 Day 1 pre-dose, 5 minutes following the end of the 
infusion, 2, 4, 8 and 24 hours post-infusion. 
Blood samples for PD assessment will be collected at Cycle 1, Days 1 and 15 and Cycle 2 
Day 1, pre-dose, 4 and 24 hours post-infusion. 
Bone marrow will be collected pre-study, at the end of Cycle 1, every 2 cycles thereafter, 
and at disease relapse/progression, unless the peripheral blood absolute blast count is ≥ 
5.1 x 109 cells/L, to assess mutational status and potentially PD markers. 
Safety will be assessed through the monitoring of adverse events (AEs), clinical laboratory 
parameters (hematology and serum chemistry), vital sign measurements, ECGs and 
physical examinations. Adverse events will be classified according to the Medical 
Dictionary for Regulatory Affairs (MedDRA) and graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. 
Efficacy assessment for AML will be performed using a modification of the 
recommendations 
of 
the 
International 
Working 
Group 
(IWG) 
for 
Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards 
for Therapeutic Trials in Acute Myeloid Leukemia. Efficacy assessments for subjects with 
MDS or CMML will be performed using a modification of the IWG Response Criteria in 
Myelodysplasia. 
Pharmacokinetic determinations of E6201 in plasma will be made. 
Levels of pERK, pFLT3, pAKT, FLT3 ITD, FLT3 TKD and Ras allelic burden, FLT3 ligand 
and plasma inhibitory assay (PIA) for FLT3, will be measured in blood and/or bone marrow 
samples collected from each subject as pharmacodynamics endpoints and correlated with 
FLT3 and Ras+ allelic burden, pharmacokinetics and clinical response. 
 
3.2. 
Number of Subjects and Centers 
Phase 1: Up to 30 subjects are planned for the Safety Run-in portion of the study. 
Phase 2a: Up to 26 subjects are planned for Cohort 1 of the Expansion portion and 26 


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subjects for Cohort 2 (total N=52) and up to 10 subjects for Cohort 3. Therefore, up to 92 
total subjects are planned. 
The study will be conducted at The University of Texas M.D. Anderson Cancer Center 
with Gautam Borthakur, M.D. serving as Study Chair. Additional clinical sites include 
Moffitt Cancer Center (Kendra Sweet, MD), Health ONE Cares (Michael Maris, MD) 
and Methodist Hospital, San Antonio (Jose Cruz, MD). Additional sites may be added 
to complete the study in a timely manner. 
 
3.3. 
Duration of Study 
The accrual phase for the Phase 1 safety run-in portion is expected to be 24-27 months. 
The expected accrual for the Phase 2a Expansion portion is expected to be 12 months, 
for a total accrual period of 36-39 months. With the last subject follow up for up to 6 
months, a total study duration of 42-45 months is anticipated. The anticipated accrual rate 
is 4–6 subjects per month across all sites. 
 
3.4. 
Criteria for Termination of the Study 
If the sponsor, investigators, study monitor or regulatory officials discover conditions 
arising during the study that indicate that the study should be halted or that the study site 
should be terminated, this action may be taken after appropriate consultation between 
the sponsor and investigators. 
Conditions that may warrant termination include, but are not limited to, the following: 
• 
The discovery of an unexpected, serious, or unacceptable risk to subjects 
enrolled in the study 
• 
A decision on the part of the sponsor to suspend or discontinue testing, 
evaluation, or development of the product 
• 
Failure of an investigator to enroll subjects into the study at an acceptable rate 
• 
Failure of an investigator to comply with pertinent FDA regulations 
• 
Submission of knowingly false information from the study site to the sponsor, 
study monitor or the FDA 
• 
Insufficient adherence to protocol requirements 
Study termination and follow-up would be performed in compliance with the conditions 
set forth in 21 CFR 312.50 and 21 CFR 312.56. 
 
4. STUDY POPULATION 
 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to participate in the study: 
• 
Males and females ≥ 18 years of age 
• 
Phase 1: Subjects with confirmed relapsed or refractory AML with a documented 
FLT3 a n d / o r  R a s  mutation, or age ≥ 60 years with newly diagnosed FLT3+ 
a n d / o r  R a s +  AML and not eligible for standard induction chemotherapy, or 
FLT3+ and/or Ras+ higher-risk MDS/CMML (defined as ≥ 10% marrow blasts or ≥ 
5% peripheral blood blasts or Revised International Prognostic Scoring System 


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[IPSS-R] score16 ≥ 3.5), and relapsed or refractory to prior therapy 
• 
Phase 2: Subjects with confirmed relapsed or refractory AML with a documented 
FLT3 a n d / o r  R a s  mutation, or age ≥ 60 years with newly diagnosed FLT3+ 
and/or Ras+ AML and not eligible for standard induction chemotherapy 
• 
At least 3 weeks beyond the last cancer treatment for the disease under study, 
major surgery and recovered from all acute toxicities (≤ Grade 1) by first dose 
of study drug (C1D1). Hydroxyurea used to control peripheral blast counts is 
permitted during the first 2 cycles. 
• 
Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 2 
(Appendix A) 
• 
Adequate renal and hepatic function: 
• 
Serum creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance ≥ 45 
mL/minute per the Cockcroft-Gault formula (Appendix B) 
• 
Total bilirubin ≤ 2 times the upper limit of normal (ULN), unless due to 
Gilbert’s disease or thought to be due to underlying AML 
• 
ALT and AST ≤ 5 times ULN 
• 
Negative serum pregnancy test within 14 days prior to the first dose of study 
therapy for women of child-bearing potential (WCBP), defined as a sexually 
mature woman who has not undergone a hysterectomy or who has not been 
naturally post-menopausal for at least 24 consecutive months (i.e., who has had 
menses any time in the preceding 24 consecutive months). Sexually active 
WCBP and male subjects must agree to use adequate methods to avoid pregnancy 
(oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine 
device; barrier contraceptive with spermicide; or vasectomized partner) throughout 
the study and for 28 days after the completion of study treatment. 
• 
Ability to provide written informed consent 
 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
• 
History of clinically significant cardiac impairment, congestive heart failure (CHF) 
New York Heart Association (NYHA) Class III or IV, unstable angina, or myocardial 
infarction during the previous 6 months, or serious cardiac arrhythmia (Appendix 
C) 
• 
QT interval corrected for rate (QTc) > 450 msec for males and > 460 msec for 
females on the electrocardiogram (ECG) obtained at Screening using the 
Fridericia method for QTc calculation (average of 3 readings) 
• 
Concomitant medication(s) that may cause QTc prolongation or induce Torsades 
de Pointes with the exception of anti-microbials that are used as standard of care to 
prevent or treat infections and other such drugs that are considered by the 
Investigator to be essential for the care of the patient (Appendix D). However, if 
such medications are deemed to be necessary during the study, more intensive 
ECG monitoring will be added during the period of concomitant drug administration. 
• 
Presence of active central nervous system (CNS) leukemia. Subjects adequately 
treated for CNS leukemia documented by 2 consecutive cerebrospinal fluid samples 


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negative for leukemia cells are eligible. Subjects with no history of CNS leukemia 
will not be required to undergo cerebrospinal fluid sampling for eligibility. 
• 
Known positive for human immunodeficiency virus (HIV), hepatitis B virus surface 
antigen (HbsAg), or hepatitis C virus (HCV) 
• 
Active, uncontrolled infection 
• 
Known hypersensitivity to any study drug component 
• 
Any other medical intervention or other condition which, in the opinion of the 
Principal Investigator, could compromise adherence to study requirements or 
confound the interpretation of study results 
• 
Pregnancy or lactation 
 
4.3. 
Molecular Characterization of Mutational Status 
For sites with the ability to characterize the FLT3 and Ras mutational status (quantitative 
allelic burden) in a CLIA-certified laboratory setting, the local lab results may be used 
for Screening. For subjects whose mutational status is not known at the time of screening, 
a bone marrow or peripheral blood sample will be collected prior to enrollment. The subject 
may be enrolled only if mutational testing shows the presence of a FLT3 a n d / o r  R a s  
mutation. 
 
4.4. 
Discontinuation of Subjects 
4.4.1. Procedures for Withdrawal 
Any subject may be removed from study for the following reasons: 
• 
Subject withdrawal of the informed consent 
• 
Subject noncompliance 
• 
An increasing or unexpected pattern of unacceptable toxicity 
• 
Disease progression or confirmed loss of clinical response 
• 
Investigator judgment when the well-being and best interest of the subject is 
compromised 
Subjects experiencing unacceptable toxicity should be removed from the study once 
complete resolution of toxicity has been documented. Individual subjects may be 
discontinued from the study by the investigator or sponsor at any time if either determines 
that it is not in the best interest of the subject to continue. 
Any subject who becomes pregnant during the study must be discontinued from the 
study immediately, but should be followed through delivery or termination of the 
pregnancy. Subjects should also notify the investigator if they become pregnant within 28 
days following the last dose of study drug. Strategia Therapeutics also must be notified if a 
subject becomes pregnant on study. 
If a subject is discontinued from the study before completing the specified duration of 
treatment, they should be encouraged to complete the end-of-study assessments and to 
agree to report any serious adverse events for 28 days following the last dose of study 
drug. The date the subject is withdrawn and the primary reason for discontinuation will be 
recorded on the case report form (CRF). 


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4.4.2. Replacement of Study Subjects 
Subjects who are screened but do not receive E6201, and subjects treated in Cycle 1 who 
complete < 75% of their prescribed study drug treatment or do not complete C1D28 evaluation 
due to progression of disease, withdrawal of consent or non-DLT adverse events, will be 
replaced. 
 
5. STUDY TREATMENT 
 
5.1. 
E6201 Study Drug Description 
E6201 for Injection is a sterile white lyophilized powder containing 60 mg of E6201 
formulated in cyclodextrin to improve E6201 solubility in water.  
 
5.2. 
Study Drug Preparation and Administration 
E6201 will be provided directly from the Strategia Therapeutics drug distribution center. 
Each vial contains 60 mg of E6201 and will be reconstituted with 8.5 mL of Sterile Water 
for Injection to provide a solution of E6201 at a concentration of 6 mg/mL and a pH of 
approximately 4.5. Once the Sterile Water is added, gently swirl to mix and let sit until 
totally dissolved. This may take up to 30 minutes to go into solution. Each reconstituted 
vial will contain 10 mL of E6201 solution. 
After reconstitution, the appropriate number of vials may be combined as needed per 
dose calculation. The resulting solution will be diluted to 250 mL in 0.9% Sodium Chloride. 
Reconstituted and diluted E6201 solutions should be stored refrigerated (2 to 8°C) and 
protected from light before administration. E6201 solutions can be stored under 
refrigerated conditions (2 to 8°C) for up to 24 hours. Light protection is not required 
during the 2 hour (± 10 minutes) infusion time. However, E6201 should not be exposed 
to normal light for > 3 hours at room temperature. 
Subjects should be scheduled to begin study therapy following completion of Screening. 
E6201 will be administered at the dose level prescribed per cohort by IV infusion over 2 
hours (± 10 minutes) in normal saline. Subjects will receive E6201 weekly or twice 
weekly on a 28-day schedule, based on the dose cohort to which they have been assigned. 
In the absence of lengthy clinical experience, E6201 should be considered an irritant and 
precautions should be taken to avoid extravasation. With IV administration of E6201, 
extravasation may occur with, or without an accompanying stinging or burning sensation 
(even if blood returns on aspiration of the infusion needle). If any signs or symptoms of 
extravasation occur, the infusion should be immediately terminated and restarted in 
another vein. The application of ice over the site of extravasation for approximately 30 
minutes may be helpful in alleviating the local reaction. 
E6201 must not be given by intramuscular or subcutaneous route. 
 
5.3. 
Treatment Duration 
Treatment will continue until confirmation of disease progression, unacceptable toxicity, 
or subject decision to discontinue therapy. 
 
 
 


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5.4. 
Dosing Delays and Modifications Due to Toxicity 
5.4.1. Toxicity Grading Criteria 
Toxicity grading is based on NCI Common Terminology Criteria for Adverse Events Version 
4.03 (CTCAE v4.03); http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
5.4.2. Definitions of Dose-Limiting Toxicity 
A DLT is defined as any one of the following events: 
• 
Prolonged myelosuppression (as defined by the NCI criteria specific for 
leukemia, i.e., marrow cellularity < 5% at ≥ 6 weeks from start of therapy without 
evidence of leukemia) 
• 
≥ Grade 3 non-hematologic toxicity (excluding Grade 3 nausea, vomiting or 
diarrhea that is adequately controlled with supportive care and resolves to ≤ 
Grade 2 within 48 hours, or Grade 3 electrolyte disturbances responsive to 
correction within 24 hours) 
• 
≥ Grade 3 liver function tests (LFTs) lasting > 7 days 
• 
Treatment interruption > 14 days due to toxicity 
• 
Other important medical event 
5.4.3. Dose Modifications and Dose Reductions 
Patients who experience a DLT may continue treatment at the next lower dose level until 
disease progression or unacceptable toxicity. 
Adverse events considered for dose reduction should not include the events assessed 
by the investigator as exclusively related to underlying disease or other medical 
condition or concomitant treatment. 
The dose modification guidelines for general adverse events are outlined in Table 
7. Provisions are not made for dose levels below 160 mg/m2. If 160 mg/m2 weekly is 
determined to be unsuitable based on DLT as defined above, E6201 will be permanently 
discontinued. 
Table 7. E6201 Dose Modification Guidelines for General Adverse Events 
 
Dose Modifications for Weekly Dosing Schedule 
Dose Level 
Modified Dose Level -1 
Modified Dose Level -2 
240 mg/m2 weekly 
160 mg/m2 weekly 
- 
320 mg/m2/weekly 
240 mg/m2 weekly 
160 mg/m2/weekly 
Dose Modifications for Twice Weekly Dosing Schedule 
Dose Level 
Modified Dose Level -1 
Modified Dose Level -2 
160 mg/m2 twice weekly 
160 mg/m2 weekly 
- 
240 mg/m2 twice weekly 
160 mg/m2 twice weekly 
160 mg/m2 weekly 
320 mg/m2 twice weekly 
240 mg/m2 twice weekly 
160 mg/m2 twice weekly 
 
Dose modifications for QTc prolongation are defined in Table 8 below. 


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Table 8. E6201 Dose Modification Guidelines for QTc Prolongation 
QTc Criteria 
E6201 Dose 
QTc greater than 500 msec or ≥ 60 msec from 
baseline on at least 2 separate ECGs 
Withhold until recovery to baseline, then 
resume at reduced unit dose (50%) 
QTc interval prolongation with signs/symptoms 
of life-threatening arrhythmia 
Permanently discontinue 
 
5.4.4. Schedule Adjustments for Toxicity 
• 
Dosing delays are permitted for DLT and clinically-significant toxicities. Once 
a DLT has resolved to ≤ Grade 1, the patient may resume treatment. The 
dose level must be reduced to the next lower dose level when treatment is re- 
initiated following a delay for drug-related toxicity unless otherwise specified. 
For a dose delay that occurs for a reason other than DLT, a dose reduction is 
not mandatory when resuming treatment. 
• 
The maximum delay allowed between treatment cycles is 2 weeks. If toxicity 
has not resolved after 2 weeks of delay, the Medical Monitor should be 
contacted to discuss permission for resuming treatment after a longer delay 
for patients who are experiencing clinical benefit. 
• 
There will 
be no dose adjustment 
for myelosuppression unless the 
myelosuppression meets the definition for DLT as described above. 
 
5.5. 
Supportive Care Guidelines 
• 
Medications may be administered for the management of symptoms 
associated with the administration of E6201, as required. 
• 
Prophylactic pre-medication will not be used routinely. Adequate treatment for 
nausea and/or vomiting and diarrhea is permitted during Cycle 1. After Cycle 
1, prophylaxis of nausea and/or vomiting and diarrhea is permitted. 
• 
Granulocyte stimulating growth factors (e.g., G-CSF or GM-CSF) are not 
allowed during Cycle 1 except for the following situations (defined as DLT): 
any ≥ Grade 3 neutropenia lasting ≥ 6 weeks from start of study drug, in the 
setting of < 5% marrow cellularity without evidence of leukemia. After Cycle 
1, use of granulocyte growth factors are allowed for prophylaxis or 
management of neutropenia. 
• 
Erythropoiesis-stimulating agents, transfusions, etc. are permitted for 
management of hematologic toxicities. 
 
5.6. 
Concomitant Medications and Therapies 
5.6.1. Permitted Medications 
All medications and other treatments taken by subjects 4 weeks before and throughout 
the study period will be recorded in the CRF module. Any changes in documented, 
permitted concomitant medications being taken at the beginning of the clinical trial or 
added during the time the patient is participating in this study (through the End of Study 


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Visit) must be recorded in the CRF module. 
Hydroxyurea to control peripheral blast counts is permitted during the first 2 cycles. 
If a concomitant medication that is known to prolong QTc cannot be avoided, perform an 
additional ECG before first dose of QTc prolongation medication, and another one upon 
completion of the first dose of QTc prolongation medication (oral medications, approximately 
2 hours after first dose; IV medications, at end of infusion), if start of QTc prolongation 
medication is outside specified ECG study days. 
5.6.2. Prohibited Medications 
Concurrent anti-tumor therapy of any kind or any other investigational agent is prohibited. 
Concomitant medication(s) that may cause QTc prolongation or induce Torsades de 
Pointes are prohibited, with the exception of anti-microbials that are used as standard of 
care to prevent or treat infections and other such drugs that are considered by the 
Investigator to be essential for the care of the patient. However, if such medications are 
deemed to be necessary during the study, more intensive ECG monitoring will be added 
during the period of concomitant drug administration. See Appendix D for a list of drugs 
that may cause QTc prolongation or induce Torsades de Pointes. 
 
5.7. 
Packaging and Labeling 
E6201 for Injection is packaged in a 15-mL or 20-mL capacity Type I glass vial with a 
bromobutyl rubber stopper and an aluminum cap for IV administration. The study drug 
vials will be labeled with strength and other information as per local regulatory requirements. 
 
5.8. 
Shipping and Storage 
E6201 for Injection is demonstrated to be stable when stored in the defined container 
closure system. E6201 for Injection should be stored refrigerated at 2 to 8 °C and protected 
from light. 
 
5.9. 
Study Drug Accountability 
The investigator must maintain accurate records of receipt of study drug, dispensing 
information, and the prompt return or destruction of unused supplies. A drug 
accountability log will be supplied to each clinical site for purposes of recording study 
drug dispensation for the study and will be monitored by Sponsor personnel. If the site 
has an electronic study drug accountability form that is in keeping with institutional 
practice and the form collects the same information as the form supplied by the Sponsor, 
this form may be substituted for the Sponsor’s drug accountability form. 
Unused or unexpired E6201 for Injection will be destroyed per institutional policy. 
 
6. STUDY PROCEDURES 
See Schedule of Study Procedures in Appendix E. 
 
6.1. 
Screening Procedures 
The following evaluations are to be performed within 28 days of study treatment to 
determine subject eligibility 
• 
Administration of informed consent 


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• 
Medical history, physical examination and vital signs 
• 
ECOG Performance Status 
• 
Height and weight 
• 
The following laboratory tests: 
• 
Hematology 
• 
Serum Chemistry 
• 
Beta HCG pregnancy test for WCBP 
• 
12-lead ECG (in triplicate) 
• 
Collection of bone marrow for mutational analysis and PD assessment 
• 
Review of concomitant medications 
 
6.2. 
Requirements During Treatment Cycle 1 
6.2.1. Cycle 1, Day 1 
• 
Abbreviated physical examination 
• 
Vital signs 
• 
ECOG Performance Status 
• 
Weight 
• 
The following lab tests 
• 
Hematology, if not performed within previous 24 hours 
• 
Serum chemistry, if not performed within previous 24 hours 
• 
Study drug administration (also on Day 4 for subjects in twice weekly cohorts) 
• 
12-lead ECG, pre-dose, at 5 minutes after the infusion ends (± 5 minutes), and 
at 2, 4 (± 15 minutes) and 24 hours (± 2 hours) post-infusion (each reading in 
triplicate) 
• 
Collection of blood samples for PK determinations pre-dose, at 5 minutes 
after the infusion ends (± 5 minutes), and at 2, 4 hours (± 15 minutes), 8 (±1 
hour) and 24 (± 2 hours) hours post-infusion 
• 
Collection of blood samples for PD determinations pre-dose, 4 hours (± 15 
minutes) and 24 hours ( ±  2  h o u r s )  post-infusion 
• 
Review of concomitant medications 
• 
Assessment of adverse events 
• 
Assessment for survival 
6.2.2. Cycle 1, Day 8 (+/-1 day) 
• 
Vital signs 
• 
The following lab tests: 
• 
Hematology 


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• 
Serum Chemistry 
• 
Study drug administration (also on Day 11 for subjects in twice weekly cohorts) 
• 
Review of concomitant medications 
• 
Assessment of adverse events 
• 
Assessment for survival 
6.2.3. Cycle 1, Day 15 (+/-1 day) 
• 
Vital signs 
• 
The following lab tests: 
• 
Hematology 
• 
Serum Chemistry 
• 
Study drug administration (also on Day 18 for subjects in twice weekly cohorts) 
• 
12-lead ECG, pre-dose, at 5 minutes after the infusion ends (± 5 minutes), and 
at 2, 4 (± 15 minutes) and 24 hours (± 2hours) post-infusion (each reading in 
triplicate) 
• 
Collection of blood samples for PK determinations pre-dose, at 5 minutes 
after the infusion ends (± 5 minutes), and at 2, 4 hours (± 15 minutes), 8 (± 1 
hour) and 24 hours (± 2 hours) post-infusion 
• 
Collection of blood samples for PD determinations pre-dose, 4 hours (± 15 
minutes) and 24 hours ( ±  2  h o u r s )  post-infusion 
• 
Review of concomitant medications 
• 
Assessment of adverse events 
• 
Assessment for survival 
6.2.4. Cycle 1, Day 22 (+/-1 day) 
• 
Vital signs 
• 
The following lab tests: 
• 
Hematology 
• 
Serum Chemistry 
• 
Study drug administration (also on Day 25 for subjects in twice weekly cohorts) 
• 
Review of concomitant medications 
• 
Assessment of adverse events 
• 
Assessment for survival 
6.2.5. End of Cycle 1 (Day 28 +/- 3 days) 
• 
Bone marrow aspirate or biopsy for response and PD assessments, unless 
peripheral blood absolute blast count is ≥ 5.0 x 109 cells/L 
• 
Disease assessment for response 


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• 
Review of concomitant medications 
• 
Assessment of adverse events 
• 
Assessment for survival 
 
6.3. 
Requirements During Treatment Cycles After Cycle 1 (Cycles 2, 3, 4, 
etc.) 
6.3.1. Day 1 (+/- 1 day) 
• 
Abbreviated physical examination 
• 
Vital signs 
• 
ECOG Performance Status 
• 
Weight 
• 
The following lab tests (+/- 3 days) 
• 
Hematology 
• 
Serum chemistry 
• 
Study drug administration (also on Day 4 for subjects in twice weekly cohorts) 
• 
12-lead ECG, pre-dose, at 5 minutes after the infusion ends (± 5 minutes), and 
at 2, 4 (± 15 minutes) and 24 hours (± 2 hours) post-infusion (each reading in 
triplicate) 
• 
Collection of blood samples for PK determinations pre-dose, at 5 minutes 
after the infusion ends (± 5 minutes), and at 2, 4 (± 15 minutes), 8 ( ±  1  
h o u r )  and 24 hours ( ±  2  h o u r s )  post-infusion (Cycle 2 only) 
• 
Collection of blood samples for PD determinations pre-dose, 4 hours (± 15 
minutes) and 24 hours (±  2  h o ur s) post-infusion (Cycle 2 only) 
• 
Review of concomitant medications 
• 
Assessment of adverse events 
• 
Assessment for survival 
6.3.2. Day 8 (+/-1 day) 
• 
Study drug administration (also on Day 11 for subjects in twice weekly cohorts) 
• 
Review of concomitant medications 
• 
Assessment of adverse events 
• 
Assessment for survival 
6.3.3. Day 15 (+/-1 day) 
• 
12-lead ECG, pre-dose, at 5 minutes after the infusion ends (± 5 minutes), and 
at 2, 4 (± 15 minutes) and 24 hours (± 2 hours) post-infusion (each reading in 
triplicate). 
• 
Study drug administration (also on Day 18 for subjects in twice weekly cohorts) 
• 
Review of concomitant medications 


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• 
Assessment of adverse events 
• 
Assessment for survival 
6.3.4. Day 22 (+/-1 day) 
• 
Study drug administration (also on Day 25 for subjects in twice weekly cohorts) 
• 
Review of concomitant medications 
• 
Assessment of adverse events 
• 
Assessment for survival 
6.3.5. End of Cycle 3 (Day 28 +/- 3 days) and Every 2 Cycles Thereafter 
• 
Bone marrow aspirate or biopsy for response and PD assessments, unless 
peripheral blood absolute blast count is ≥ 5.0 x 109 cells/L 
• 
Disease assessment for response 
• 
Review of concomitant medications 
• 
Assessment of adverse events 
• 
Assessment for survival 
 
6.4. 
At Relapse or Progression of Disease 
• 
Bone marrow aspirate or biopsy for response status and PD assessment, 
unless peripheral blood absolute blast count is ≥ 5.0 x 109 cells/L 
• 
Disease assessment for response 
• 
Review of concomitant medications 
• 
Assessment of adverse events 
• 
Assessment for survival 
 
6.5. 
End of Study (28 Days After Last Dose of Study Medication +/- 5 
days) 
• 
Physical examination 
• 
Vital signs 
• 
ECOG Performance Status 
• 
Weight 
• 
The following lab tests 
• 
Hematology 
• 
Serum chemistry 
• 
12-lead ECG (in triplicate) 
• 
Review of concomitant medications 
• 
Assessment of adverse events 
• 
Assessment for survival 


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6.6. 
Long-Term Follow-Up 
Long-term follow-up will consist of a clinic visit or telephone call to assess survival every 3 
months for up to 6 months. 
 
7. DESCRIPTION OF ASSESSMENTS 
 
7.1 Safety Assessments 
7.1.1. Adverse Event Definition 
An adverse event (AE) includes any noxious, pathological, or unintended change in 
anatomical, physiological, or metabolic functions as indicated by physical signs, 
symptoms, and/or laboratory changes occurring whether or not temporally associated 
with study drug administration and whether or not considered related to study drug. This 
definition includes an exacerbation of pre-existing medical conditions or events, 
intercurrent illnesses, hypersensitivity reactions, drug interactions, or clinically significant 
laboratory findings. 
 
An AE does not include the following: 
• 
Medical or surgical procedures, e.g., tooth extraction, transfusion, surgery (The 
medical condition that leads to the procedure is to be recorded as an AE.) 
• 
Pre-existing conditions or procedures present or detected at the start of the study 
that do not worsen 
• 
Hospitalization for elective surgeries or for other situations in which an untoward 
medical event has not occurred 
• 
Abnormal laboratory value, unless it is clinically significant 
• 
Overdose of study drug or concomitant medication unaccompanied by 
signs/symptoms (If sign/symptoms occur, the final diagnosis should be recorded as 
an AE.) 
• 
Pregnancy by itself, unless a complication occurs during pregnancy leading to 
hospitalization; in this case (The medical condition that leads to the hospitalization 
is to be recorded as the AE.) 
• 
A significant worsening of the disease under investigation which is captured as 
an efficacy parameter in this study and, thus, is not to be recorded as an AE. 
7.1.2. Serious Adverse Event 
A serious adverse event (SAE) is defined as an adverse event that results in any of the 
following outcomes: 
• 
Death 
• 
Life-threatening, i.e., immediate risk of death from the event as it occurred; (This 
does not include an adverse event that, had it occurred in a more serious form, 
might have caused death.) 
• 
Persistent or substantial disability/incapacitation 
• 
Results in or prolongs an existing inpatient hospitalization 


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• 
Congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based on medical judgment, they may 
jeopardize the subject or may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. 
7.1.3. Unexpected Adverse Event 
An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed; 
or, is not consistent with the risk information described in the protocol or elsewhere. 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the Investigator’s Brochure referred only to elevated hepatic enzymes 
or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the Investigator’s Brochure listed only 
cerebral vascular accidents. 
 
"Unexpected," as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the Investigator’s Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the investigational therapy, but are not 
specifically mentioned as occurring with the investigational therapy. 
7.1.4. Adverse Event Reporting Period 
The adverse event reporting period begins from the date of the first dose of study drug to 
28 days following the last dose of study drug. 
7.1.5. Recording of Adverse Events 
Each AE should be recorded in standard medical terminology on the AE CRF module. 
Whenever possible, the AE should be evaluated and reported as a diagnosis rather than 
as individual signs or symptoms. For example, cough, runny nose, sneezing, sore throat, 
and head congestion should be reported as ‘upper respiratory infection’. If a definitive 
diagnosis is not possible, the individual signs and symptoms should be recorded. Dates of 
start (onset) and stop (recovery), action taken, and outcome will be recorded in the AE CRF 
module. 
 
All clinically significant abnormal changes in laboratory parameters will be recorded as 
an AE on the AE module, with the following exceptions: clinically significant abnormal 
laboratory changes determined to be related to the study condition and concomitant 
conditions, e.g., diabetes, of which the investigator was previously aware and that have 
not worsened. 
 
The investigator will evaluate all AEs with regard to maximum intensity and relationship to 
study drug, as follows. 
7.1.5.1. 
Maximum Intensity 
Maximum intensity should be assigned using one of the severity grades as outlined in 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE v4.03); if the AE is not specifically listed in CTCAE v4.03, use the following 
grades: 
• 
Grade 1: mild 


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• 
Grade 2: moderate 
• 
Grade 3: severe 
• 
Grade 4: life-threatening or disabling 
• 
Grade 5: death 
 
7.1.5.2. 
Relationship to Study Drug 
The degree of certainty with which an AE is attributed to study drug (or alternative 
causes, e.g., natural history of the underlying diseases, concomitant therapy, etc.) will be 
determined by how well the event can be understood in terms of known pharmacology of 
the study drug and/or reactions of similar nature previously observed with study drug. 
Each AE will be assigned one of the following five categories: 
• 
Not related: There is not a temporal relationship to the study drug (e.g., too early, 
too late), or there is a reasonable causal relationship to another drug, concurrent 
illness, or circumstance. 
• 
Unlikely related: There is a temporal relationship to study drug, but there is not a 
reasonable causal relationship between the time of study drug administration and 
the AE (i.e., it is doubtful the AE is related to the study drug); could be reasonably 
explained by other factors, including underlying disease, complications, concomitant 
drugs, or concurrent treatment. 
• 
Possibly related: There is a reasonable temporal sequence from time of study 
drug administration (e.g., occurred in a time frame relevant to study drug dose); or 
for which the possibility of the study drug being the causative factor (e.g., 
existence of similar reports attributed to the study drug; reactions attributable to 
the pharmacological effect) could not be excluded, although other factors such as 
underlying disease, complications, concomitant drugs, or concurrent treatment 
are presumable. 
• 
Probably related: There is a reasonable temporal sequence from time of study 
drug administration; and for which the possibility of factors other than the study 
drug administration, such as underlying disease, complications, concomitant drugs, 
or concurrent treatment, could not be excluded as the cause. 
• 
Definitely related: Follows a clear temporal sequence from time of study drug 
administration; could not be possibly explained by the known characteristics of 
the subject’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the subject; follows a response pattern known to be 
associated with study drug administration. 
7.1.6. Adverse Event Reporting 
Each AE is to be reported by the investigator as serious or non-serious according to the 
definitions above. This classification determines the regulatory reporting procedures to be 
followed as described in Table 9. 
 
 
 
 


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Table 9. Reporting Guidelines for Adverse Events 
 
Gravity of AE 
Reporting Time to 
Strategia Therapeutics  
Type of Report 
Serious 
Within 24 hours after the site 
becomes aware of the event 
Initial SAE Report 
Non-Serious 
Per AE CRF module 
Completed AE CRF Module 
 
Any SAE, regardless of relationship to investigational therapy that occurs within 28 days 
following the last dose of study drug must be reported to the Medical Monitor within 24 
hours after the site becomes aware of the event. The investigator is encouraged to 
discuss with the Medical Monitor any adverse experiences for which the issue of 
reportability is unclear or questioned. The initial report should be followed by submission of 
a more detailed SAE Report when follow-up information is available. 
If the SAE occurs more than 28 days after the last dose of study drug, SAEs should be 
reported only if considered related to E6201. In the event of subject death, the reason for 
death should be recorded as the SAE, with ‘death’ recorded as the outcome on the SAE 
CRF module. 
The SAE also will be recorded as an AE on the AE CRF module. Note: the SAE Report is 
different from the AE CRF. In areas of both forms where the same data are reported, the 
forms will be completed in a consistent manner. For example, the same term should be 
used for the AE on both forms, with the same start and stop dates, action taken, 
outcome, etc. A checkbox on the AE CRF module for whether the AE resulted in an 
SAE, will link the two types of report for a given event. 
An SAE Report should be prepared with as much available information concerning the 
event as possible so that a written report can be filed with the appropriate regulatory 
authorities. If causality cannot be determined definitively at the time of the SAE 
occurrence, it is important to notify Strategia Therapeutics within the timeline stated above, 
and to attribute the relationship as ‘Not Assessable’ (only applicable for the initial SAE 
Report). When new significant information is obtained and the outcome and attribution of 
the event is known, the investigator will communicate this in a follow-up SAE Report. 
This relevant information will be provided in a timely manner to allow reporting to regulatory 
authorities within the required reporting period. Any SAE follow-up information requested 
by Strategia Therapeutics, Inc. should be provided in a timely manner. 
As necessary, the SAE Report should be accompanied by relevant pages from the 
CRFs, e.g., medical history, AEs, concomitant medications. Additional information may 
be requested by Strategia Therapeutics in an expedited manner to ensure that the 
initial reporting of the SAE made to the regulatory authorities complies with the required 
time frame. Strategia Therapeutics may be required to collect and report additional 
information to the regulatory authorities in a follow-up report, containing a final evaluation 
of the event, including copies of hospital reports, autopsy reports, or other relevant 
information. 
7.1.7. Adverse Event and Serious Adverse Event Follow-Up 
All AEs and SAEs should be followed until resolution, return to baseline, or until the point it 
is deemed that further recovery is unlikely. All measures required for AE management and 
the ultimate outcome of the AE will be recorded in the source document and AE CRF 


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module. 
7.1.8. Ongoing Safety Evaluation 
A study safety evaluation will be conducted on a regular (monthly) basis by 
teleconference. Dose exposure, dose-limiting toxicity, AE/SAE profiles and clinical 
laboratory abnormalities, and other safety measures will be reviewed during each 
convened meeting. Subject accrual will not be interrupted during the regular scheduled 
safety evaluations. These discussions will be led by the Strategia Therapeutics Medical 
Monitor and Principal Investigator. 
7.1.9. Clinical Laboratory Tests 
Clinical laboratory tests include hematology, serum chemistry and bone marrow 
assessment (Table 10). 
 
Table 10. Clinical Laboratory Parameters 
 
Hematology 
Serum Chemistry 
Bone Marrow 
Aspirate/Biopsy 
Red blood cell count 
Serum creatinine 
Marrow blast percent 
Hemoglobin 
BUN 
Marrow cellularity percent 
Hematocrit 
Glucose (non-fasting) 
Cell line maturation 
White blood cell count 
Albumin 
Auer rods 
Differential: 
AST 
Dysplasia 
Neutrophils 
ALT 
Cytogenetic abnormalities 
ANC 
LDH 
Lymphocytes 
Total bilirubin 
Monocytes 
Total protein 
Eosinophils 
Alkaline phosphatase 
Basophils 
Calcium 
Platelets 
Phosphorus 
Blasts percent 
Magnesium 
Sodium 
Potassium 
Chloride 
Bicarbonate 
 
7.1.10. Vital Sign Measurements 
Vital sign measurements include temperature, blood pressure and pulse rate. Additional 
measurements may be obtained if clinically indicated. Any value considered clinically 
significant by the investigator will be recorded as an AE on the CRF. Clinically significant 
changes compared to baseline values should be followed until clinical resolution. 
7.1.11. Physical Examinations 
Complete physical examinations include the following body system evaluations: General 
Appearance, Skin, Musculo-skeletal, Eyes, Ears, Nose, Throat, Cardiovascular, Chest, 
Abdomen, Lymph Nodes, and Neurological.  Symptom-oriented (abbreviated) evaluations 
will be performed at study visits where indicated, and otherwise when clinically indicated. 
Weight will be measured at Screening, Day 1 of each treatment cycle, and the End of 
Study Visit. 


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7.1.12. Electrocardiograms 
12-lead ECGs will be performed at Screening, Days 1 and 15 of each cycle (pre-dose, 5 
minutes after end of infusion, and 2, 4 and 24 hours post-infusion) and at End of Study 
(in triplicate). 
 
7.2. 
Efficacy Assessments 
7.2.1. Criteria for Evaluation of Response and Progression 
Evaluation of response to treatment and determination of disease progression in patients 
with AML will be evaluated using criteria defined in Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia.17 Efficacy assessments for subjects with MDS or CMML will be made using 
the modified International Working Group Response Criteria in Myelodysplasia.18 
7.2.2. Disease Response Criteria 
7.2.2.1. 
Subjects with AML 
• 
Complete Remission (CR) 
The subject must be free of all symptoms related to leukemia and have an 
absolute neutrophil count > 1.0 x 109/L, platelet count ≥ 100 x 109/L, and 
normal bone marrow with < 5% blasts and no Auer rods 
• 
Complete Remission with Incomplete Blood Count Recovery (CRi) 
As per CR but with residual thrombocytopenia (platelet count <100 x 109/L) or 
residual neutropenia (absolute neutrophil count <1.0 x 109/L) 
• 
Partial Remission (PR) 
A ≥ 50% decrease in bone marrow blasts to 5 to 25% abnormal cells in the 
marrow; or CR with ≤ 5% blasts if Auer rods are present 
• 
Treatment Failure 
Treatment has failed to achieve CR, CRi, or PR. 
• 
Recurrence 
Relapse after confirmed CR: reappearance of leukemic blasts in peripheral 
blood or ≥ 5% blasts in the bone marrow not attributable, in the Investigator’s 
opinion, to any other cause (e.g., bone marrow regeneration after consolidation 
therapy), or appearance of new dysplastic changes. 
7.2.2.2. 
Subjects with High-Risk MDS or CMML 
• 
Complete Remission (CR) 
The subject must be free of all symptoms related to leukemia and have an 
absolute neutrophil count ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L, bone 
marrow ≤ 5% myeloblasts, with normal maturation of all cell lines, hemoglobin 
≥ 11g/dL, and no blasts in the peripheral blood 
• 
Partial Remission (PR) 
All CR criteria with ≥ 50% decrease in bone marrow blasts over pre-treatment 
(but still > 5%) 


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• 
Marrow CR 
In bone marrow, ≤ 5% myeloblasts and decrease by ≥ 50% over pre- treatment 
• 
Hematologic Improvement (HI) 
− 
Erythroid Response (HI-E) 
o Major Response 
◇ 
For subjects with pretreatment hemoglobin < 11 g/dL, > 2 g/dL 
increase in hemoglobin 
◇ 
For 
RBC 
transfusion-dependent 
subjects, 
transfusion 
independence 
 
o Minor Response 
◇ 
For subjects with pretreatment hemoglobin < 11 g/dL, 1 to 2 g/dL 
increase in hemoglobin 
◇ 
For RBC transfusion-dependent subjects, ≥ 50% decrease in 
transfusion requirements 
− Platelet Response (HI-P) 
o Major Response 
◇ 
For subjects with a pretreatment platelet count < 100 x 109/L, an 
absolute increase of ≥ 30 x 109/L 
◇ 
For platelet transfusion-dependent 
subjects, stabilization of 
platelet transfusion independence 
o Minor Response 
◇ 
For subjects with a pretreatment platelet count < 100 x 109/L, a ≥ 
50% increase in platelet count with a net increase > 10 x 109/L but < 
30 x 109/L 
− Neutrophil Response (HI-N) 
o Major Response 
◇ 
For absolute neutrophil count (ANC) < 1.5 x 109/L before therapy, 
≥ 100% increase or an absolute increase of ≥ 0.5 x 109/L, whichever 
is greater 
o Minor Response 
◇ 
For ANC < 1.5 x 109/L before therapy, ANC ≥ 100%, but absolute 
increase < 0.5 x 109/L 
• 
Progressive Disease 
Subject did not achieve PR, CR or marrow CR or is otherwise a non-
responder. 
• 
Relapse after CR or PR 
One or more of the following: 


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− 
Return to pretreatment bone marrow blast percentage 
− Decrement of ≥ 50% from maximum remission/response levels in 
granulocytes or platelets 
− 
Reduction in hemoglobin concentration by ≥ 2 g/dL or transfusion 
dependence. 
• 
Progression or Relapse after Hematologic Improvement 
One or more of the following: 
− 
A ≥ 50% decrement from maximum response levels in granulocytes or 
platelets 
− 
A reduction in hemoglobin concentration by ≥ 2 g/dL 
− 
Transfusion 
7.2.3. Efficacy Endpoints 
7.2.3.1. 
Primary Efficacy Endpoint 
To evaluate the proportion of subjects with objective response achieved within 3 cycles of 
treatment with E6201 in patients with relapsed/refractory AML and FLT3 a n d / o r  R a s  
mutation without or with prior exposure to a FLT3 inhibitor (Phase 2: Cohorts 1 and 2, 
respectively), or with a Ras mutation and no FLT3 mutation (Phase 2: Cohort 3), or in 
subjects with FLT3+ and/or Ras+ high-risk MDS or CMML. 
• 
Subjects with AML 
Objective responses for subjects with AML include complete remission (CR), 
complete remission with incomplete blood count recovery (CRi) and partial 
remission (PR), as defined above. 
• 
Subjects with MDS 
Objective responses for subjects with MDS include CR, PR and marrow CR, 
as defined above. 
• 
Subjects with CMML 
Objective responses for subjects with CMML include CR, PR and marrow 
CR, as defined above. 
7.2.3.2. 
Secondary Efficacy Endpoints 
To evaluate duration of response, progression-free survival and overall survival, as 
defined below: 
• 
Duration of Response: length of time from the first evidence of objective response 
(CR, CRi, PR) to the first objective evidence of progression 
• 
Progression-Free Survival: length of time from the date of first administration of 
study drug to the first objective evidence of disease progression or death, 
whichever is earlier 
• 
Overall Survival: length of time from the date of first administration of study drug to 
the date of death from any cause. 


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7.2.3.3. 
Timing of Assessments to Determine Objective Response 
Disease assessments will be made at the end of Cycles 1 and Cycle 3, and every 2 
cycles thereafter. Disease assessments may be made at other time points at the discretion 
of the Investigator. 
7.2.4. Pharmacokinetic Endpoints 
Mean plasma concentrations of E6201 will be determined in blood samples collected 
before administration of E6201 and at multiple time points after administration of E6201. 
Because plasma concentrations will be determined at a limited number of time points 
during the study, a complete pharmacokinetic profile of E6201 at each dose level will not be 
possible. Limited pharmacokinetic analyses will be performed. 
7.2.5. Pharmacodynamic Endpoints 
Levels of pERK, pFLT3, pAKT, FLT3 ITD allelic burden, FLT3 ligand and plasma PIA for 
FLT3 will be measured in blood and/or bone marrow samples collected from each 
subject at multiple points during the study. pERK and pFLT3 will be measured in bulk 
and progenitor cells. Correlation between FLT3 ITD allelic burden, pharmacokinetics and 
clinical response will be assessed. Additional markers, or other genomic changes, may 
be evaluated. 
Changes from baseline in PD parameters for each cohort will be summarized using 
descriptive statistics, including number of patients (N), mean, standard deviation (SD), 
minimum, median, maximum range, and coefficient of variation (CV). 
 
8. STATISTICAL METHODOLOGY 
 
8.1. 
Determination of Sample Size 
Phase 1: The sample size reflects requirements associated with a 3+3 design. A total of 3 
to 30 subjects are planned (3 to 6 subjects in each of 5 dose cohorts) with FLT3+ and/or 
Ras+ AML, MDS or CMML. 
Phase 2a, Cohort 1: The statistical objective for Cohort 1 in the dose expansion portion of 
the study is evaluation of the objective response (OR) rate within 3 cycles of treatment with 
E6201 in patients with AML and FLT3 mutation, or FLT3 plus Ras mutations, without prior 
exposure to a FLT3 inhibitor. We are testing H0: true OR rate ≤ 5% versus H1: true 
OR rate ≥ 25%. An objective response rate (OR) of 25% or greater is deemed clinically 
important. An OR of less than or equal to 5% is not clinically valuable. Rejecting the null 
hypothesis, which rules out the OR rate of less than or equal to 5%, demonstrates that 
the study drug is efficacious and warrants further testing. The null hypothesis (true OR 
rate ≤ 5%) will be tested with the alternative hypothesis (true OR ≥ 25%). Based on 
Simon’s 2-stage optimal design, eight (8) patients will be enrolled in Stage I. If there are 
zero (0) ORs in these 8 patients, the cohort will be terminated. If there is at least 1 OR 
in the first 8 patients, 18 additional patients will be enrolled in Stage II, for a total of 26 
evaluable patients. If there are at least 4 ORs in a total of N=26, the alternative hypothesis 
will be accepted. This design provides a type I error of 5% and power of 85% when the true 
OR rate is 25%. 
Phase 2a, Cohort 2: The statistical objective for Cohort 2 in the dose expansion portion of 
the study is evaluation of the objective response (OR) rate within 3 cycles of treatment with 
E6201 in patients with AML and FLT3 mutation, or FLT3 plus Ras mutations, with prior 


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exposure to a FLT3 inhibitor. We are testing H0: true OR rate = 0% versus H1: true 
OR rate ≥ 15%. An objective response rate (OR) of 15% or greater is deemed clinically 
important. An OR of equal to 0% is not clinically valuable. Rejecting the null hypothesis, 
which rules out the OR rate of less than or equal to 0%, demonstrates that the study drug 
is efficacious and warrants further testing. The null hypothesis (true OR rate = 0%) will be 
tested with the alternative hypothesis (true OR ≥ 15%). Based on Simon’s 2-stage optimal 
design, eleven (11) patients will be enrolled in Stage I. If there are zero (0) ORs in these 
11 patients, the cohort will be terminated. If there is at least 1 OR in the first 11 patients, 
15 additional patients will be enrolled in Stage II, for a total of 26 patients. If there are at 
least 2 ORs in a total of N=26, the alternative hypothesis will be accepted. This design 
provides a type I error of 5% and power of 80% when the true OR rate is 15% or greater. 
Phase 2a, Cohort 3: We will evaluate the objective response (OR) rate within 3 cycles of 
treatment with E6201 in up to 10 patients with AML and Ras mutation but no mutation in 
FLT3. A response rate of 20% in this patient population is considered clinically meaningful.  
 
8.2. 
Analysis Populations 
The full analysis set (FAS) includes all subjects who are administered any fraction of a 
dose of study medication. For a particular measure, the per-protocol set (PPS) includes 
those subjects in the FAS who have had a valid baseline and one or more post- 
treatment assessments for that measure of interest. 
The E6201 PK population consists of all subjects in the FAS who complete all PK 
assessments. 
The E6201 PD population consists of all subjects in the FAS who complete all PD 
assessments. 
 
8.3. 
Statistical Analysis Methods 
All data will be analyzed using Statistical Analysis System (SAS Version 9.3 or higher for 
Windows, SAS Institute, Cary, NC). Continuous variables will be summarized using 
number, mean, standard deviation, median, minimum, and maximum. Categorical 
variables will be summarized using number and frequencies. 
8.3.1. Safety Analyses 
8.3.1.1. 
Adverse Events 
All safety endpoints will be summarized using descriptive statistics and will be based on 
the FAS dataset. 
All AEs will be coded based on the Medical Dictionary for Regulatory Affairs (MedDRA; 
Version 15.0 or higher). An AE will be considered a treatment emergent adverse event 
(TEAE) if the onset is after the first dose of study drug or if the condition was present at 
baseline but worsened after the first dose. 
All AEs for each subject will be listed, including intensity grading, relationship to study 
drug, action taken and outcome. Subject listings of deaths, SAEs, and AEs leading to 
treatment discontinuation will be provided. Subject narratives will be provided for deaths, 
SAEs and other significant AEs. Summary tables will be prepared to examine TEAE 
severity and relationship to study treatment. 
AE summaries will be produced separately for each dose cohort and overall, and each 
disease cohort by dose and overall. All summaries will show, by subject group, dose 


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cohort and overall, the number and percentage of subjects experiencing at least 1 TEAE of 
each preferred term, arranged by system organ class, and the number of occurrences of 
the event. Separate summaries will be produced by relationship to study medication, by 
severity, and for those events with an incidence rate of at least 2% in any group or overall. 
SAEs will be summarized in a similar manner; overall, by relationship to study medication, 
and by severity. 
In addition to the above, summaries of the number and percentage of subjects 
discontinuing the study due to AEs and, due to death, will be presented. 
8.3.1.2. 
Laboratory Data 
Laboratory data will be listed by subject. Values above and below normal ranges will be 
indicated, and whether statistically significant. All laboratory values will be graded 
according to the NCI-CTCAE version 4.03 criteria. Laboratory data will be summarized by 
actual value and change from baseline using number of non-missing observations, mean 
standard deviation, median, minimum and maximum. In addition, shift tables and the 
incidence of Grade 3 or 4 laboratory values will be presented. 
8.3.1.3. 
Vital Signs 
Vital signs will be listed by subject. Values above and below normal ranges will be 
indicated as will clinical significance. Vital sign data will be summarized by actual value 
and change from baseline using number of non-missing observations, mean, standard 
deviation, median, minimum and maximum. 
8.3.1.4. 
Other Safety Data 
Data collected for physical examinations, ECGs and related measures will be listed. 
8.3.2. Efficacy Analyses 
8.3.2.1. 
Primary Efficacy Endpoint 
The primary endpoint is the proportion of patients treated at the RP2D who achieve an 
objective response (OR) within 3 cycles of treatment with E6201 (i.e., within 3 months). 
The proportion of subjects in each disease cohort treated at the RP2D will be 
summarized, and 90% confidence intervals will be provided. 
8.3.2.2. 
Secondary Efficacy Endpoints 
For secondary endpoints, duration of response, progression-free survival and overall 
survival curves will be estimated at the RP2D using the Kaplan-Meier product-limit 
estimates. Median and 90% confidence intervals of time-to-event will be estimated. 
Duration of response will be calculated from the time of first evidence of response (CR, 
CRi, PR) to the first objective evidence of disease progression. Progression-free survival 
will be calculated from the date of first dose of study drug to the date of first objective 
evidence of disease progression or death, whichever is earlier. Overall survival will be 
calculated from the date of first dose of study drug to the date of death due to any cause. 
Subjects who did not experience progression or death will be censored at the last follow- 
up time point. 
8.3.3. Pharmacokinetic Endpoint Analysis 
Mean plasma concentrations of E6201 will be determined at each time point for evaluation 
of dose-linearity. Because a limited number of plasma concentrations will be determined, 
full determination of routine pharmacokinetic parameters may not be possible. In addition 


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to mean plasma concentrations, as the data allow, additional pharmacokinetic analyses will 
be provided (trough levels, t1/2, Tmax, Cmax, AUC, etc.) 
8.3.4. Pharmacodynamic Endpoint Analysis 
Changes from baseline in levels of pERK, pFLT3, pAKT, FLT3 ITD, FLT3 TKD and Ras 
allelic burden, FLT3 ligand and PIA for FLT3 will be measured in blood and/or bone marrow 
samples collected from each subject. Correlation between FLT3 a n d Ra s allelic burden 
and clinical response will be assessed. Pharmacodynamic parameters will be 
summarized using descriptive statistics including the number of subjects, mean, standard 
deviation, minimum, median, maximum, range, and coefficient of variation.  
Any additional biomarkers collected or genomic changes evaluated will be summarized 
accordingly. 
 
9. STUDY MANAGEMENT 
 
9.1. 
Data Management 
The investigator is responsible for completing and maintaining adequate and accurate 
source documentation. Source documentation constitutes original records, which may 
include: progress notes, medication administration records, laboratory reports, ECG 
tracings, discharge summaries, CRF worksheets, etc. Data for this study will be submitted 
electronically. Access to the database will be provided following a brief on-line training 
session. Each user will receive a unique username and password, which should not be 
shared. The investigator must sign the investigator’s statement for each subject indicating 
that the data reported are accurate. See Appendix F for Ethical Standards to be followed 
during the study. 
 
9.2. 
Monitoring 
Strategia Therapeutics is responsible for ensuring the proper conduct of the study with 
regard to ethics, protocol adherence, site procedures, integrity of the data, and applicable 
laws and/or regulations. At regular intervals during the study and following completion of 
the study, the sponsor’s study monitors will contact the study site via visits to the 
site, telephone calls, and letters in order to review study progress, CRF completion 
and address any concerns or questions regarding the study conduct. During monitoring 
visits, the following aspects of study conduct will be carefully reviewed: informed consent of 
subjects, subject recruitment, subject compliance with the study procedures, source data 
verification, drug accountability, use of concomitant therapy by subjects, AE and SAE 
documentation and reporting, and quality of data. Records pertaining to these aspects 
are expected to be kept current. 
 
9.3. 
Audits and Inspections 
Strategia Therapeutics, a regulatory authority or an IRB may visit the study site at any 
time during the study or after completion of the study to perform audits or inspections. 
The purpose of a sponsor audit or regulatory inspection is to  systematically and 
independently examine all study-related activities and documents to determine whether 
these activities were conducted according to the protocol, GCP, ICH guidelines, and any 
other applicable regulatory requirements. Investigators should contact Strategia 
Therapeutics immediately if contacted by a regulatory agency about an inspection at their 
site. 


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9.4. 
Amendments 
Any amendments to the protocol will be prepared by Strategia Therapeutics. All 
amendments must be submitted to the prevailing IRB for approval prior to implementing 
the changes at each institution. In some instances, an amendment requires changes to 
the informed consent form, which also must be submitted for IRB approval prior to 
administration to subjects. If any changes to the CRFs are required, Strategia Therapeutics 
will issue supplemental or revised CRF pages. 
 
9.5. 
Record Keeping 
9.5.1. Health Insurance Portability Accountability Act of 1996 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited 
to, the Standards for Individually Identifiable Health Information, 45 CFR. Parts 160 and 
164 (the Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy 
Regulation). The investigator shall ensure that study subjects authorize the use and 
disclosure of protected health information in accordance with HIPAA Privacy Regulation 
and in a form satisfactory to the sponsor. See Appendix G for Investigator Obligations. 
9.5.2. Financial Disclosure 
The investigator shall provide to Strategia Therapeutics sufficient accurate financial 
information to allow Strategia Therapeutics to submit complete and accurate financial 
certification or disclosure statements to the FDA. The investigator shall promptly update 
this information if any relevant changes occur in the course of the study or for one year 
following completion of the study. 
9.5.3. Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original 
source documentation to ensure data integrity. “Original” in this context is defined as the 
first documentation of an observation and does not differentiate between hard copy and 
electronic records. 
9.5.4. Retention of Study Documents 
Study-related records must be retained for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These 
documents should be retained for a longer period, however, if required by applicable 
regulatory requirements or by an agreement with the sponsor. 
The investigator must not destroy any study-related records without receiving approval 
from the sponsor. The investigator must notify the sponsor in the event of accidental loss or 
destruction of any study records. If the investigator leaves the institution where the study 
was conducted, the sponsor must be contacted to arrange alternative record storage 
options. 
10. ADMINISTRATIVE STRUCTURE OF THE STUDY 
Strategia Therapeutics will be responsible for data management, statistical analyses, 
and clinical study report writing. Clinical monitors under the direction of Strategia 


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Therapeutics will be used to monitor the study. Clinical laboratory parameters will be 
assessed by local laboratories and results recorded in the CRF module. 
 
 


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11. REFERENCES 
1. Borthakur G, Kantarjian H, Ravandi F, Zhang W, Konopleva M, Wright JJ, et 
al. Phase I study of sorafenib in patients with refractory or relapsed acute 
leukemias. Haematologica;96(1):62-8. 
2. Cortes J, Perl AE, Smith CC, al e. A Phase II Open-Label, AC220 Monotherapy 
Efficacy Study in Patients with Refractory/Relapsed FLT3-ITD Positive Acute 
Myeloid Leukemia: Updated Interim Results. Blood;118:2576. 
3. Borthakur G, Kirschbaum MH, Foran JM, Kadia TM, Jabbour E, Boyiadzis M, 
et al. Phase I/II Trial of the MEK 1/2 inhibitor GSK1120212 (GSK212) in 
patients with relapsed/refractory meyloid malignancies: evidence of activity 
in patients with RAS mutation. J ClinOncol 2011:Abst 6506. 
4. Zhang W, Konopleva M, Shi YX, McQueen T, Harris D, Ling X, et al. Mutant 
FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer 
Inst 2008;100(3):184-98. 
5. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et 
al. The presence of a FLT3 internal tandem duplication in patients with acute 
myeloid leukemia (AML) adds important prognostic information to cytogenetic 
risk group and response to the first cycle of chemotherapy: analysis of 854 
patients from the United Kingdom Medical Research Council AML 10 and 
12 trials. Blood 2001;98(6):1752-9. 
6. Santos FP, Jones D, Qiao W, Cortes JE, Ravandi F, Estey EE, et al. Prognostic 
value of FLT3 mutations among different cytogenetic subgroups in acute myeloid 
leukemia. Cancer;117(10):2145-55. 
7. Kottaridis PD, Gale RE, Linch DC. Prognostic implications of the presence 
of FLT3 mutations in patients with acute myeloid leukemia. Leuk Lymphoma 
2003;44(6):905-13. 
8. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, et 
al. Analysis of FLT3-activating mutations in 979 patients with acute 
myelogenous leukemia: association with FAB subtypes and identification of 
subgroups with poor prognosis. Blood 2002;99(12):4326-35. 
9. Kornblau SM, Womble M, Qiu YH, Jackson CE, Chen W, Konopleva M, et 
al. Simultaneous activation of multiple signal transduction pathways confers 
poor prognosis in acute myelogenous leukemia. Blood 2006;108(7):2358-65. 
10. Borthakur G, Kantarjian H, Ravandi F, Zhang W, Konopleva M, Wright JJ, et 
al. Phase I study of sorafenib in patients with refractory or relapsed acute 
leukemias. Haematologica 2011;96(1):62-8. 
11. Cortes J, Foran J, Ghirdaladze D. AC220, a potent, selective, second generation 
FLT3 receptor tyrosine kinase(RTK) inhibitor, in a first-in-human (FIH) phase 
1 AML study. Blood 2009;114:636a. 
12. Moore AS, Faisal A, de Castro DG, Bavetsias V, Sun C, Atrash B, et al. Selective 
FLT3 inhibition of FLT3-ITD(+) acute myeloid leukaemia resulting in secondary 
D835Y mutation: a model for emerging clinical resistance patterns. Leukemia 
2012;26(7):1462-70. 
13. Milella M, Ricciardi MR, Gergamo P, al. e. Development of MEK inhibition 


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(MEK-1) based therapeutic strategies in acute myeloid leukemia. Blood 
2008;112:Abstr 860. 
14. Zhang W, Borthakur G, Gao C, Chen Y, Lan YS, Ruvolo V, Nomoto K, Zhao 
N, Konopleva M, Andreeff M. Activity assessment of E6201, a dual FLT3 and 
MEK inhibitor, in FLT3- or RAS-mutant acute myelogenous leukemia. Blood 
2013; Abstr 2683. 
15. E6201 for Injection Investigator’s Brochures, 2012 (v.6) and 2016 (v. 8). 
16. Greenberg PL, Tuechler H, Schantz J, Sanz G, Garcia-Manero G, Sole F, 
Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis 
A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak M, 
Krieger O, Luebbert M, Maciejewski J, Magalhaes SMM, Miyazaki Y, 
Pfellstocker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, 
van de Loosdrecht AA, Germing U, Haase D. Revised International Prognostic 
Scoring System for myelodysplastic syndromes. Blood 2012; 120(12):2454-65. 
17. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et 
al. Revised recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin 
Oncol 2003; 21(24):4642-9. 
18. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer 
SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore 
SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification 
of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood 2006; 108(2):419-425. 
 


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Appendix A. Eastern Cooperative Group (ECOG) Performance Status Scale 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
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 selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
* From ECOG, Robert Comis, MD, Group Chair 
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 


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Appendix B. Cockcroft-Gault Formula for Calculation of Creatinine Clearance 
 
Creatinine clearance must either be measured or estimated using the Cockroft-Gault 
formula, as outlined below. 
 
 


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Appendix C. New York Heart Association (NYCA) Classification for Heart Failure NYHA 
Classification - The Stages of Heart Failure 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, 
discomfort is increased. 


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Appendix D. Drugs Known to Prolong QT Interval or Induce Torsades de Pointes 
 
 
The last revision date: October 01, 2016 
 
 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Amiodarone 
Cordarone, Pacerone, 
Nexterone 
Antiarrhythmic 
Abnormal heart 
rhythm 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 3 
inhibitor 
Thrombocythemia 
Arsenic trioxide 
Trisenox 
Anticancer 
Cancer (leukemia) 
Astemizole (Removed 
from Market) 
Hismanal 
Antihistamine 
Allergic rhinitis 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Bacterial infection 
Bepridil (Removed 
from Market) 
Vascor 
Antianginal 
Angina Pectoris 
(heart pain) 
Chloroquine 
Aralen 
Antimalarial 
Malaria 
Chlorpromazine 
Thorazine, Largactil, 
Megaphen 
Antipsychotic / 
Antiemetic 
Schizophrenia, 
nausea, many others 
Cilostazol 
Pletal 
Phosphodiesterase 3 
inhibitor 
Intermittent 
claudication 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Bacterial infection 
Cisapride (Removed 
from Market) 
Propulsid 
GI stimulant 
Increase GI motility 
Citalopram 
Celexa, Cipramil 
Antidepressant, SSRI 
Depression 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Bacterial infection 
Cocaine 
Cocaine 
Local anesthetic 
Anesthesia (topical) 
Disopyramide 
Norpace 
Antiarrhythmic 
Abnormal heart 
rhythm 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Abnormal heart 
rhythm 
Domperidone (Only 
on Non US Market) 
Motilium, Motillium, Motinorm 
Costi, Nomit 
Antinausea 
Nausea, vomiting 
Donepezil 
Aricept 
Cholinesterase 
inhibitor 
Dementia (Alzheimer's 
Disease) 
CredibleMeds Known QTDrug List 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Dronedarone 
Multaq 
Antiarrhythmic 
Abnormal heart 
rhythm 
Droperidol 
Inapsine, Droleptan, Dridol, 
Xomolix 
Antipsychotic / 
Antiemetic 
Anesthesia (adjunct), 
nausea 
Erythromycin 
E.E.S., Robimycin, EMycin, 
Erymax, Ery-Tab, Eryc 
Ranbaxy, Erypar, Eryped, 
Erythrocin Stearate Filmtab, 
Erythrocot, E-Base, 
Erythroped, Ilosone, MY-E, 
Pediamycin, Zineryt, Abboticin, 
Abboticin-ES, Erycin, PCE 
Dispertab, Stiemycine, 
Acnasol, Tiloryth 
Antibiotic 
Bacterial infection, 
increase GI motility 
Escitalopram 
Cipralex, Lexapro, Nexito, 
Anxiset-E (India), Exodus 
(Brazil), Esto (Israel), Seroplex, 
Elicea, Lexamil, Lexam, Entact 
(Greece), Losita (Bangladesh), 
Reposil (Chile), Animaxen 
(Colombia), Esitalo (Australia), 
Lexamil (South Africa) 
Antidepressant, SSRI 
Depression (major), 
anxiety disorders 
Flecainide 
Tambocor, Almarytm, Apocard, 
Ecrinal, Flécaine 
Antiarrhythmic 
Abnormal heart 
rhythm 
Fluconazole 
Diflucan, Trican 
Antifungal 
Fungal infection 
Gatifloxacin 
(Removed from 
Market) 
Tequin 
Antibiotic 
Bacterial infection 
Grepafloxacin 
(Removed from 
Market) 
Raxar 
Antibiotic 
Bacterial infection 
Halofantrine 
Halfan 
Antimalarial 
Malaria 
Haloperidol 
Haldol (US & UK), Aloperidin, 
Bioperidolo, Brotopon, Dozic, 
Duraperidol (Germany), 
Einalon S, Eukystol, Halosten, 
Keselan, Linton, Peluces, 
Serenace, Serenase, 
Sigaperidol 
Antipsychotic 
Schizophrenia, 
agitation 


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O 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Ibutilide 
Corvert 
Antiarrhythmic 
Abnormal heart 
rhythm 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Bacterial infection 
Levomepromazine 
(Only on Non US 
Market) 
Nosinan, Nozinan, Levoprome 
Antipsychotic 
Schizophrenia 
Levomethadyl 
acetate (Removed 
from Market) 
Orlaam 
Opioid agonist 
Narcotic dependence 
Levosulpiride (Only 
on Non US Market) 
Lesuride, Levazeo, Enliva 
(with rabeprazole) 
Antipsychotic 
Schizophrenia 
Mesoridazine 
(Removed from 
Market) 
Serentil 
Antipsychotic 
Schizophrenia 
Methadone 
Dolophine, Symoron, Amidone, 
Methadose, Physeptone, 
Heptadon 
Opioid agonist 
Narcotic dependence, 
pain 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 
Bacterial infection 
Ondansetron 
Zofran, Anset, Ondemet, 
Zuplenz, Emetron, Ondavell, 
Emeset, Ondisolv, Setronax 
Antiemetic 
Nausea, vomiting 
Oxaliplatin 
Eloxatin 
Antineoplastic Agent 
Cancer 
Papaverine HCl (Intra-
coronary) 
none 
Vasodilator, Coronary 
Diagnostic adjunct 
Pentamidine 
Pentam 
Antifungal 
Fungal infection 
(Pneumocystis 
pneumonia) 
Pimozide 
Orap 
Antipsychotic 
Tourette's Disorder 
Probucol 
(Removed from 
Market) 
Lorelco 
Antilipemic 
Hypercholesterolemia 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 
Abnormal heart 
rhythm 
Propofol 
Diprivan,  Propoven 
Anesthetic, general 
Anesthesia 
Quinidine 
Quinaglute, Duraquin, Quinact, 
Quinidex, Cin-Quin, Quinora 
Antiarrhythmic 
Abnormal heart 
rhythm 


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O 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Roxithromycin (Only 
on Non US Market) 
Rulide, Xthrocin, Roxl-150, 
Roxo, Surlid, Rulide, Biaxsig, 
Roxar, Roximycinv, 
Roxomycin, Rulid, Tirabicin, 
Coroxin 
Antibiotic 
Bacterial infection 
Sevoflurane 
Ulane, Sojourn 
Anesthetic, general 
Anesthesia 
Sotalol 
Betapace, Sotalex, Sotacor 
Antiarrhythmic 
Abnormal heart 
rhythm 
Sparfloxacin 
(Removed from 
Market) 
Zagam 
Antibiotic 
Bacterial infection 
Sulpiride (Only on 
Non US Market) 
Dogmatil, Dolmatil, Eglonyl, 
Espiride, Modal, Sulpor 
Antipsychotic, atypical 
Schizophrenia 
Sultopride (Only on 
Non US Market) 
Barnetil,  Barnotil,  Topral 
Antipsychotic, atypical 
Schizophrenia 
Terfenadine 
(Removed from 
Market) 
Seldane 
Antihistamine 
Allergic rhinitis 
Thioridazine 
Mellaril, Novoridazine, Thioril 
Antipsychotic 
Schizophrenia 
Vandetanib 
Caprelsa 
Anticancer 
Cancer (thyroid) 


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Appendix E. Schedule of Study Procedures 
Study Activity 
Screeninga 
Treatment Cycle 1 
Treatment Cycles after Cycle 1 
Progression 
or Relapse 
End of 
Studyo 
Long- 
Term 
Follow- 
Upp 
Day 
1 
Day 
8l 
Day 
15l 
Day 
22l 
End of 
Cycle 1m 
Day 
1l 
Day 
8l 
Day 
15l 
Day 
22l 
End of 
Cycle 3m,n 
Signed ICD 
X 
Medical history 
X 
Physical 
examination 
X 
Xk 
Xk 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
ECOG 
Performance Status 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
Hematologyb 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryc 
X 
X 
X 
X 
X 
X 
X 
Beta-hCG for 
WCBP 
X 
12-lead ECGd 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone Marrow 
Aspirate/biopsye 
X 
X 
X 
X 
Disease 
Assessmentf 
X 
X 
X 
Peripheral blood for 
PK assessmentg 
X 
X 
C2 
Only 
Peripheral blood for 
PD assessmenth 
X 
X 
C2 
Only 
Bone marrow for 
PD assessmenti 
X 
X 
X 
X 
Administration of 
E6201j 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of 
survival 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


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a Screening to be performed within 28 days of Cycle 1, Day 1 
b Hematology collected at Screening, Cycle 1 Day 1 (only if not performed within the previous 24 hours), Days 8, 15 and 22, Day 1 of each subsequent cycle (within 3 days of Day 1 
of each subsequent cycle) and End of Study. See Table 9 for tests to be conducted at each time point. 
c Serum chemistry collected at Screening, Cycle 1 Day 1 (only if not performed within the previous 24 hours), Days 8, 15 and 22, Day 1 of each subsequent cycle (within 3 days of 
Day 1 of each subsequent cycle) and End of Study. See Table 9 for tests to be conducted at each time point. 
d ECGs performed in triplicate every cycle Day 1 and 15: pre-dose, 5 minutes after end of infusion (± 5 minutes), and 2, 4 (± 15 minutes) and 24 hours (± 2 hours) post-infusion. If on a 
concomitant medication known to prolong QTc, perform an additional ECG before first dose of QTc prolongation medication, and another one upon completion of the first dose of 
QTc prolongation medication (oral medications, approximately 2 hours after first dose; IV medications, at end of infusion), if start of QTc prolongation medication is outside specified 
ECG study days 
e Bone marrow aspirate/biopsy required at Screening; at end of Cycles 1 and 3, every 2 cycles thereafter, and at relapse/progression, unless peripheral blood absolute blast count is ≥ 
5.0 x 109 cells/L. See Table 9 for tests to be conducted at each time point. 
f Disease Assessment may include bone marrow assessment, hematology for blood counts, physical exams, etc. 
g Peripheral blood collected for PK assessment at Cycle 1, Day 1, Day 15 and Cycle 2 Day 1: pre-dose, 5 minutes after end of infusion (+/- 5 minutes), and 2, 4 hours (+/- 15 
minutes), 8 hours (+/- 1 hour) and 24 hours (+/- 2 hours) post-infusion. 
h Peripheral blood collected for PD assessment at Cycle 1, Day1, Day 15 and Cycle 2 Day 1: pre-dose, 4 hours (+/- 15 minutes) and 24 hours (+/- 2 hours) post-infusion. 
i Best effort should be made to collect bone marrow (aspirate or biopsy) for PD assessment at this visit. May be omitted if it would require a separate bone marrow collection 
procedure beyond that necessary for disease assessment and patient has a peripheral blood absolute blast count ≥ 5.0 x 109 cells/L. 
j Dose weekly IV over a 2 hour (± 10 minutes) infusion Day 1, 8, 15 and 22 each 28-day cycle, or twice weekly Day 1, 4, 8, 11, 15, 18, 22, 25 each 28-day cycle, based on assigned 
dose cohort 
k Abbreviated physical exam 
l Day 1, 8, 15, or 22 +/- 1 day. All visit procedures must be conducted on the scheduled visit day. Pre-dose procedures must be conducted prior to receipt of study drug dose.  
m Day 28 +/- 3 days 
n And every 2 cycles thereafter 
o End of Study visit should be 28 days from last dose of study medication (+/- 5 days) 
p Long-term follow-up for 6 months consists of clinic visits or telephone calls every 3 months to assess survival status 


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Appendix F. Ethical Standards 
Ethics and Regulatory Considerations 
This study will be conducted according to Good Clinical Practice (GCP), US 21 Code of Federal 
Regulations (CFR) Part 50, (Protection of Human Subjects), US 21 CFR Part 56 (Institutional 
Review Boards), International Conference on Harmonisation Guidance for Industry, E6 Good 
Clinical Practice: Consolidated Guidance, the Nuremberg Code, and the Declaration of 
Helsinki. 
General Instructions 
The U.S. Food and Drug Administration (FDA) regulates studies of drugs, biologics, and 
medical devices. Consequently, these studies are subject to GCP and FDA regulations and 
guidance issued by the FDA and are included in, but not limited to, the following parts of 
the CFR and guideline document: 
• 
21 CFR Part 11 – Electronic Records; electronic signatures 
• 
21 CFR Part 50 – Protection of Human Subjects 
• 
21 CFR Part 54 – Financial Disclosure 
• 
21 CFR Part 56 – Institutional Review Boards 
• 
21 CFR Part 312 – Investigational New Drug Application 
• 
FDA Guidance for Industry: Oversight of Clinical Investigations —A Risk-Based 
Approach to Monitoring, August 2013 
• 
FDA Guidance for IRBs, Clinical Investigators, and Sponsors, June 2010 
• 
FDA Guidance for Industry: Investigator Responsibilities – Protecting the Rights, 
Safety, and Welfare of Study Subjects, October 2009 
• 
FDA Guidance for Industry and Investigators: Safety Reporting Requirements for 
INDs and BA/BE studies, December 2012 
• 
Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance, 1996 
Copies of these materials are available from the sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper conduct 
of clinical trials that have been developed by the medical, scientific, and regulatory communities. 
They are not intended to impede or restrict clinical research. 
The ethical standards defined within GCP are intended to ensure that: 
• 
Human subjects are provided with an adequate understanding of the possible risks 
of their participation in the study, and that they have a free choice to participate or not; 
• 
The study is conducted with diligence and in conformance with the protocol in such 
a way as to insure the integrity of the findings; 
• 
The potential benefits of the research justify the risks. 
Strategia Therapeutics, Inc. is the Sponsor of the IND. The Sponsor is responsible for the 
following: 
• 
Selecting qualified investigators, 
• 
Providing investigators with the information they need to properly conduct an 


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investigation, 
• 
Ensuring proper monitoring of the investigation, 
• 
Ensuring that the study is conducted according to the general investigational plan 
and protocols contained in the IND, 
• 
Maintaining the IND, and 
• 
Ensuring that FDA and all participating investigators are properly informed of significant 
new information regarding adverse effects or risks associated with the drug being 
studied. 


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Appendix G. Investigator Obligations 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56, 
the study protocol and the final version of the subject informed consent form will be approved 
by the institutional review board (IRB) before enrollment of any subjects.  The opinion of the 
IRB will be dated and given in writing. A copy of the letter of approval from the IRB and 
a copy of the approved informed consent form will be received by the sponsor prior to 
shipment of study medication supplies to the investigator. 
The investigator will ensure that the IRB will be promptly informed of all changes in the research 
activity and of all unanticipated problems including risk to subjects. The investigator will 
also ensure that no changes will be made to the protocol without IRB approval. 
As a part of the IRB requirement for continuing review of approved research, the investigator 
will be responsible for submitting periodic progress reports to the IRB at intervals appropriate 
to the degree of subject risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every subject prior to clinical 
trial participation. The rights, safety, and well-being of the trial subjects are the most important 
considerations and should prevail over interests of science and society. 
As described in GCP guidelines and FDA regulations, study personnel involved in conducting 
this trial will be qualified by education, training, and experience to perform their respective 
task(s). A FDA Form 1572 will be collected, listing the principal investigator and sub- 
investigators involved in the study. Study personnel will not include individuals against whom 
sanctions have been invoked after scientific misconduct or fraud (e.g., loss of medical licensure, 
debarment). Quality assurance systems and procedures will be implemented to assure 
the quality of every aspect of the study. 
Protection of Human Subjects (21 CFR Part 50) 
Informed consent must be obtained from every subject before entry into a clinical study. It must 
be given freely and not under duress. Consent must be documented by use of an IRB- 
approved consent form and signed by the subject or the subject’s legally authorized 
representative. The Department of Health and Human Services suggests that when minors are 
involved, a parent or guardian should sign the consent form. If the minor is an adolescent, his 
signature should also be included. Non-English-speaking subjects must be presented with 
a consent form written in a language that they understand. A copy of the signed consent 
form must be given to the subject signing it. Another copy must be kept in the investigator’s 
files and made available to and FDA representatives upon request. If, for any reason, 
subject risk is increased as the study progresses, a revised, IRB-approved consent form 
must be signed by the subject. Before the study begins, a sample of the consent form 
must be provided to the sponsor for review. The FDA may reject otherwise scientifically valid 
studies if proper informed consent has not been obtained from all subjects. 
Only in the case of a life-threatening incident may an investigational product be used without 
prior signed consent. In such an emergency situation, separate certifications must be written 
both by a physician not participating in the study and by the investigator. The certifications, 
along with the protocol and informed consent, must be sent to the IRB within 5 working days. 
In this situation, the investigator may not administer any subsequent product to that subject 
until informed consent and IRB approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each subject prior to entry in the study. One 
copy of the signed informed consent document will be given to the subject, and another will 


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be retained by the investigator. Additionally, the participant must be allowed adequate 
time to consider the potential risks and benefits associated with his/her participation in the 
study. The signed and dated consent must be retained with the study records and a copy 
provided to each participant. 
In situations where the participant is not legally competent to provide consent (i.e., mentally 
incapacitated), written consent must be obtained from a parent, legal guardian, or legal 
representative. In these situations, the consent must be signed and dated by a witness. 
The informed consent document must have been reviewed and approved by the sponsor and 
by the investigator’s IRB prior to the initiation of the study. The document must contain the 
eight basic elements of informed consent and may contain the six additional elements 
described in 21 CFR Part 50. The attached Declaration of Helsinki-provides further details 
regarding the specific requirements for informed consent. Every consent form must include 
the following eight elements: 
• 
A statement that the study involves research, an explanation of the purpose of 
the research and the expected duration of the subject’s participation, a description 
of the procedures to be followed, and identification of any procedures that are 
experimental 
• 
A description of any reasonably foreseeable risks or discomforts to the subject 
• 
A description of any benefits to the subject or to others that may reasonably be expected 
from the research 
• 
A disclosure of appropriate alternative procedures or course of treatment, if any, 
that might be advantageous to the subject 
• 
A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and noting the possibility that the FDA and 
representatives may inspect the records 
• 
An explanation as to whether any compensation or medical treatments are available 
if injury occurs for research involving more than minimal risk. The explanation 
should involve a description of the compensation or treatment available, or a 
statement describing where further information may be obtained 
• 
An explanation of whom to contact for answers to pertinent questions about the research 
and the subject’s rights and whom to contact in the event of a research-related injury 
• 
A statement that participation is voluntary, that refusal to participate will involve 
no penalty or loss of benefits to which the subject is otherwise entitled, and that the 
subject may discontinue participation at any time without penalty or loss of benefits to 
which the subject is otherwise entitled. 
Additional Elements of Informed Consent 
When appropriate, one or more of the following elements of information shall also be included 
in the consent form: 
• 
A statement that the particular treatment or procedure may involve risks to the subject 
(or to the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable 
• 
Anticipated circumstances under which the subject’s participation may be terminated 
by the investigator without regard to the subject’s consent 


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• 
Any additional costs the subject may incur from participation in the research 
• 
The consequences of a subject’s decision to withdraw from the research and 
procedures for orderly termination of participation by the subject 
• 
A statement that significant new findings developed during the course of the research 
that may relate to the subject’s willingness to continue participation will be provided 
to the subject 
• 
The approximate number of subjects involved in the study 
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in order 
that informed consent be legally effective. Some states, such as California and Oregon, require 
further action on the investigator’s part concerning subject consent. 
Institutional Review Board (IRB) Ethic Review Committee (ERC) Review/Approval 
The protocol and informed consent for this study, including advertisements used to recruit 
participants, must be reviewed and approved by an appropriate IRB/ERC prior to enrollment 
of participants in the study. It is the responsibility of the investigator to assure that all aspects 
of the ethical review are conducted in accordance with the current Declaration of Helsinki, 
International Conference on Harmonization (ICH) Good Clinical Practices, and/or local laws, 
whichever provide the greatest level of protection. A letter documenting the IRB/ERC approval 
which specifically identifies the study/protocol and a list of the committee members must 
be received by the sponsor prior to initiation of the study. Amendments to the protocol will 
be subject to the same requirements as the original protocol. 
A progress report with a request for re-evaluation and re-approval will be submitted by 
the investigator to the IRB/ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the sponsor. 
When the sponsor provides the investigator with a Safety Report, the investigator must promptly 
forward a copy to the IRB/ERC. 
After completion or termination of the study, the investigator will submit a final report to 
the IRB/ERC and to the sponsor, if required. This report should include: deviations from the 
protocol, the number and types of participants evaluated, the number of participants who 
discontinued (with reasons), results of the study, if known, and significant AEs, including deaths 
Study Files 
The investigator is required to maintain complete and accurate study documentation in 
compliance with current Good Clinical Practice standards and all applicable federal, state, 
and local laws, rules, and regulations related to the conduct of a clinical study. 
Patient Confidentiality 
The anonymity of participating subjects must be maintained. Subjects will be identified by 
their initials and an assigned subject number on CRFs and other documents submitted to the 
clinical monitor. Documents that will be submitted to the clinical monitor and that identify 
the subject (e.g., the signed informed consent document) must be maintained in strict 
confidence by the principal investigator, except to the extent necessary to allow auditing by 
the FDA, the clinical monitor, or sponsor personnel. 


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Investigational Product Accountability 
The investigator or designee is responsible for accountability of the investigational product 
at the site. The investigator or designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and return to the sponsor or alternative 
disposition of any unused product. These records must include dates, quantities, 
batch/serial/lot numbers, and expiration dates (if applicable). 
The investigator should ensure that the investigational product is used only in accordance 
with the protocol. 

SAP_000.pdf: 
Strategia Therapeutics, Inc. 
   
BSC-101-01 
 
 
A Phase 1/2a study of E6201 for the treatment of advanced 
hematologic malignancies with FLT3 and/or Ras mutations, 
including acute myeloid leukemia (AML), myelodysplastic 
syndrome (MDS) or chronic myelomonocytic leukemia (CMML) 
    
 
Statistical Analysis Plan 
 
 
October 19, 2017 
 
 
Version 1.0 
 
 
 
 
 
 
 
 
Westat 
5615 Kirby Drive, Suite 710 
Houston, TX 77005 
 
 
CONFIDENTIAL 
 
 
 


Strategia Therapeutics Inc. 
BSC-101-01 
 
Westat                                                                                                                                        Page 2 of 16 
BSC10101_SAP_v1.0.docx 
 
Table of Contents 
 
1. 
Project Overview ........................................................................................................... 5 
1.1. Project Design ........................................................................................................... 5 
1.2. Objectives .................................................................................................................. 6 
1.2.1. Primary Objective .............................................................................................. 6 
1.2.2. Secondary Objectives ......................................................................................... 6 
1.3. Treatment(s) .............................................................................................................. 6 
1.3.1. Treatment Assignments ...................................................................................... 6 
1.3.2. Selection and Timing of Doses .......................................................................... 7 
1.4. Procedures ................................................................................................................. 8 
1.4.1. Subject Identification ......................................................................................... 8 
1.4.2. Randomization ................................................................................................... 8 
1.4.3. Blinding/Unblinding ........................................................................................... 8 
1.4.4. Replacement ....................................................................................................... 8 
1.4.5. Data Monitoring ................................................................................................. 8 
2. 
Statistical Analysis Considerations ............................................................................... 9 
2.1. Sample Size and Power ............................................................................................. 9 
2.2. Analysis Populations ................................................................................................. 9 
2.2.1. Intent-to-Treat (ITT) Population ...................................................................... 10 
2.2.2. Randomized Population ................................................................................... 10 
2.2.3. Per Protocol Population .................................................................................... 10 
2.2.4. Safety Population ............................................................................................. 10 
2.2.5. Screen Failure Population ................................................................................ 10 
2.3. Data Handling ......................................................................................................... 10 
2.3.1. Measurement Times ......................................................................................... 10 
2.3.1.1. Visit Windows ........................................................................................... 10 
2.3.1.2. Baseline Values ......................................................................................... 10 


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BSC10101_SAP_v1.0.docx 
2.3.2. Missing Data Conventions ............................................................................... 10 
2.3.3. Imputation of Incomplete Dates ....................................................................... 11 
2.4. Statistical Methods .................................................................................................. 11 
2.4.1. General Overview and Plan of Analysis .......................................................... 11 
2.4.2. Hypothesis Testing ........................................................................................... 11 
2.4.3. Modeling .......................................................................................................... 11 
2.4.4. Multiplicity Issues/Multiple Comparisons ....................................................... 11 
2.4.5. Project Center Effects ....................................................................................... 11 
2.4.6. Interim Analysis ............................................................................................... 11 
2.4.7. Pharmacokinetic and Pharmacodynamic Analyses .......................................... 12 
3. 
Statistical Analysis ...................................................................................................... 12 
3.1. Enrollment and Disposition of Subjects .................................................................. 12 
3.2. Baseline Characteristics .......................................................................................... 12 
3.2.1. Demographic .................................................................................................... 12 
3.2.2. Physical Characteristics .................................................................................... 12 
3.2.3. Disease Characteristics ..................................................................................... 13 
3.3. Analysis of Efficacy ................................................................................................ 13 
3.3.1. Primary Endpoints ............................................................................................ 13 
3.3.2. Secondary Endpoints ........................................................................................ 13 
3.3.3. Exploratory/Other Analyses ............................................................................. 13 
3.4. Analysis of Safety and Tolerability ......................................................................... 13 
3.4.1. Study Drug Administration .............................................................................. 13 
3.4.2. Adverse Events ................................................................................................. 13 
3.4.3. Clinical Laboratory Results .............................................................................. 14 
3.4.4. Vital Signs ........................................................................................................ 14 
3.4.5. Physical/Other Examinations ........................................................................... 14 
3.4.6. Treatment Discontinuation, Project Termination, and Death ........................... 14 
4. 
Proposed Summary Tables, Figures and Listings ....................................................... 14 


Strategia Therapeutics Inc. 
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BSC10101_SAP_v1.0.docx 
4.1. Mock Tables ............................................................................................................ 14 
4.1.1. Subject Disposition .......................................................................................... 14 
4.1.2. Demographics and Baseline Characteristics .................................................... 14 
4.1.3. Safety Summaries ............................................................................................. 14 
4.1.3.1. Study Drug Administration ....................................................................... 14 
4.1.3.2. Adverse Events Summaries ....................................................................... 15 
4.1.3.3. Laboratory Assessments ............................................................................ 15 
4.1.3.4. Other Safety Summaries ............................................................................ 15 
4.2. Mock Figures .......................................................................................................... 15 
4.3. Mock Listings .......................................................................................................... 15 
 
 


Strategia Therapeutics Inc. 
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BSC10101_SAP_v1.0.docx 
1.  Project Overview 
1.1. Project Design  
 
(Protocol Amendment #6). This is a Phase 1/2a, dose-escalation study of E6201, a dual MEK1 
and FLT3 inhibitor, in subjects with advanced hematologic malignancies with documented FLT3 
and/or Ras mutations. The Phase 1 portion of the study will be conducted as a safety run-in in up 
to 30 subjects to establish a recommended Phase 2 dose (RP2D). The Phase 2a portion of the study 
will evaluate three specific patient groups: Cohort 1 will enroll up to 26 patients with relapsed or 
refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) without prior 
exposure to a FLT3 inhibitor, Cohort 2 will enroll up to 26 patients with relapsed or refractory 
AML and confirmed FLT3 mutation (with or without a Ras mutation) with prior exposure to a 
FLT3 inhibitor, and Cohort 3 will enroll up to 10 patients with relapsed or refractory AML with a 
confirmed Ras mutation and no FLT3 mutation. Cohorts 1 and 2 of the expansion phase will 
incorporate a Simon 2-stage optimal design. A total of up to N= 92 subjects will be enrolled in the 
study. 
 
The accrual phase for the Phase 1 Safety Run-in portion is expected to be 24 – 27 months. The 
expected accrual for the Phase 2a Expansion portion is expected to be 12 months, for a total accrual 
period of 36 – 39 months. With the last subject followed for up to 6 months, a total study duration 
of 42 – 45 months is anticipated. The anticipated accrual rate for the Phase 2a portion is 4 – 6 
subjects per month across all sites. 
 
During the study, a Safety Review Committee (SRC), consisting of the actively recruiting 
investigators, the Medical Monitor and Boston Strategics will review data from each cohort on an 
ongoing basis. 
 
Subjects who demonstrate clinical benefit (objective response or stable disease) will be allowed to 
continue therapy with E6201 until progression of disease, observation of unacceptable adverse 
events, intercurrent illness or changes in the patient’s condition that prevents further study 
participation. Subjects will be instructed to contact their study doctor for ophthalmic evaluation 
should they experience disturbances in their vision. 
 
Safety will be assessed through the monitoring of adverse events (AEs), clinical laboratory 
parameters (hematology and serum chemistry), vital sign measurements, ECGs and physical 
examinations. Adverse events will be classified according to the Medical Dictionary for 
Regulatory Affairs (MedDRA) and graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. 
 
Efficacy assessment for AML will be performed using a modification of the recommendations of 
the International Working Group (IWG) for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. 
Efficacy assessments for subjects with MDS or CMML will be performed using a modification of 
the IWG Response Criteria in Myelodysplasia. 
 
Pharmacokinetic determinations of E6201 in plasma will be made. Levels of pERK, pFLT3, 
pAKT, FLT3 ITD allelic burden, FLT3 ligand and plasma inhibitory assay (PIA) for FLT3, will 
be measured in blood and/or bone marrow samples collected from each subject. Additional 
markers or mutation analysis will be undertaken, if needed. Details of the PK analysis will be 
outlined in a separate Pharmacokinetic Report Analysis Plan.  


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1.2. Objectives 
1.2.1. Primary Objective 
• 
Phase 1: To determine the safety and tolerability of E6201 in subjects with FLT3+ and/or 
Ras+ AML, MDS or CMML and to establish a recommended Phase 2 dose (RP2D) 
• 
Phase 2a: To evaluate the overall response rates (ORR) in subjects who receive E6201 
for the treatment of FLT3+ and/or Ras+ relapsed/refractory AML 
1.2.2. Secondary Objectives 
• 
To evaluate duration of response 
• 
To evaluate progression-free survival (PFS) 
• 
To evaluate overall survival (OS) 
• 
To evaluate the pharmacokinetics (PK) of E6201 
• 
To explore pharmacodynamic (PD) changes from baseline in signal transduction markers 
in blood or/and bone marrow: pERK, pFLT3 and pAKT 
• 
To explore quantitative changes from baseline in FLT3 internal tandem duplication 
(FLT3 ITD), FLT3 tyrosine kinase domain (TKD) and Ras+ allelic burden, FLT3 ligand 
and plasma inhibitory assay (PIA) for FLT3, and evaluate the correlation between FLT3 
and Ras+ allelic burden and objective response 
• 
To determine the safety and tolerability of E6201 at the RP2D (Phase 2a) 
1.3. Treatment(s) 
1.3.1. Treatment Assignments 
 
Phase 1 (Safety Run-In): Phase 1 (Safety Run-In): Following Screening, a total of up to 30 
subjects in up to 5 dose cohorts will be enrolled to establish the RP2D. The safety run-in 
phase will be a standard 3+3 cohort design. 
 
Dose Level 1: 240 mg/m2 weekly Days 1, 8, 15 and 22, repeated every 28 days (=1 cycle) 
Dose Level 2: 320 mg/m2 weekly Days 1, 8, 15 and 22, repeated every 28 days 
Dose Level 3: 160 mg/m2 twice weekly Days 1, 4, 8, 11, 15,18, 22 and 25, repeated every 28 
days (=1 cycle) 
Dose Level 4: 240 mg/m2 twice weekly Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 
28 days (=1 cycle) 
Dose Level 5: 320 mg/m2 twice weekly Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 
28 days 
 
Phase 2a (Expansion): Once the Phase 1 Safety Run-In portion of the study is complete and 
an RP2D is established, additional subjects will be enrolled into the Phase 2 Expansion 
portion in three cohorts. Cohort 1 will enroll up to 26 patients with relapsed or refractory 
AML and confirmed FLT3 mutation (with or without a Ras mutation) without prior exposure 
to a FLT3 inhibitor. Cohort 2 will enroll up to 26 patients with relapsed or refractory AML 
and confirmed FLT3 mutation (with or without a Ras mutation) with prior exposure to a FLT3 
inhibitor. Cohort 3 will enroll up to 10 patients with relapsed or refractory AML with a 
confirmed Ras mutation and no FLT3 mutation. Cohorts 1 and 2 of the Expansion Phase will 
incorporate a Simon 2-stage optimal design. Subjects with AML enrolled in the Phase 1 


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portion of the study at the RP2D will count towards the Phase 2a accrual for the appropriate 
cohort.  
1.3.2. Selection and Timing of Doses 
 
Phase 1 (Safety Run-In):  
In the first cohort, the dose of E6201 will be 240 mg/m2, administered as an intravenous (IV) 
infusion over 2 hours once weekly (Dose Level 1), on Days 1, 8, 15 and 22 of a 28- day 
schedule (=1 cycle). A minimum of 3 subjects will be treated. If 1 of 3 subjects experiences 
DLT during Cycle 1, the cohort will be expanded to 6. If ≥ 2 of 6 subjects experiences DLT 
by Day 28, no dose escalation to Dose Level 2 will occur. However, if 0 of 3 or ≤ 1 of 6 
subjects treated at Dose Level 1 experience DLT by Day 28, dose escalation will proceed to 
the next cohort, 320 mg/m2 weekly (Dose Level 2), administered by IV infusion over 2 hours 
on Days 1, 8, 15 and 22 of a 28-day schedule. A minimum of 3 subjects will be treated at this 
dose level. If 1 of 3 subjects treated at Dose Level 2 experiences DLT during Cycle 1, the 
cohort will be expanded to 6 subjects. If ≥ 2 of 6 subjects experience DLT by Day 28, no 
further dose escalation will occur. 
 
However, if 0 of 3 or ≤ 1 of 6 subjects treated at Dose Level 2 experience DLT by Day 28, 
dose escalation will proceed to the next dose cohort, 160 mg/m2 administered as an IV 
infusion over 2 hours twice weekly (Dose Level 3), on Days 1, 4, 8, 11, 15, 18, 22 and 25 of 
a 28-day schedule (=1 cycle). A minimum of 3 subjects will be treated at this dose level. If 1 
of 3 subjects treated at Dose Level 3 experiences DLT during Cycle 1, the cohort will be 
expanded to 6 subjects. If ≥ 2 of 6 subjects experience DLT by Day 28, no further dose 
escalation will occur. 
 
However, if 0 of 3 or ≤ 1 of 6 subjects treated at Dose Level 3 experiences DLT by Day 28, 
dose escalation will proceed to the next dose cohort, 240 mg/m2 administered as an IV 
infusion over 2 hours twice weekly (Dose Level 4), on Days 1, 4, 8, 11, 15, 18, 22 and 25 of 
a 28-day schedule. A minimum of 3 subjects will be treated at this dose level. If 1 of 3 subjects 
treated at Dose Level 4 experiences DLT during Cycle 1, the cohort will be expanded to 6 
subjects. If ≥ 2 of 6 subjects experience DLT by Day 28, no further dose escalation will occur. 
 
However, if 0 of 3 or ≤ 1 of 6 subjects treated at Dose Level 4 experiences DLT by Day 28, 
dose escalation will proceed to the next dose cohort, 320 mg/m2 administered as an IV 
infusion over 2 hours twice weekly (Dose Level 5), on Days 1, 4, 8, 11, 15, 18, 22 and 25 of 
a 28-day schedule. A minimum of 3 subjects will be treated at this dose level. If 1 of 3 subjects 
treated at Dose Level 5 experiences DLT during Cycle 1, the cohort will be expanded to 6 
subjects. If there are ≤ 1 of 6 subjects with DLT at Dose Level 5, this dose (320 mg/m2 twice 
weekly) will be declared the MTD and RP2D. If, however, ≥ 2 of 6 subjects experiences DLT, 
then either 320 mg/m2 weekly (Dose Level 2) or 240 mg/m2 twice weekly (Dose Level 4) 
will be declared the MTD and RP2D based on additional factors (e.g., PK and PD 
parameters). 
 
Dose-limiting toxicity will be defined as any one of the following events: prolonged 
myelosuppression (as defined by the National Cancer Institute [NCI] criteria specific for 
leukemia, i.e., marrow cellularity < 5% at ≥ 6 weeks from start of therapy without evidence 
of leukemia); ≥ Grade 3 non-hematologic toxicity (excluding Grade 3 nausea, vomiting or 
diarrhea that is adequately controlled with supportive care and resolves to ≤ Grade 2 within 
48 hours, or Grade 3 electrolyte disturbances responsive to correction within 24 hours); ≥ 


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Grade 3 liver function tests (LFTs) lasting > 7 days; treatment interruption > 14 days due to 
toxicity; or other important medical event. 
 
Phase 2a (Expansion):  
Subjects will be enrolled into the Phase 2 Expansion portion in three cohorts. Subjects will 
receive E6201 weekly or bi-weekly on a 28-day schedule, with the schedule and dose level 
established in the safety run-in portion of the study.  
 
As of July 17, 2017, this study was terminated due to lack of sufficient efficacy in the Phase 
1 dose escalation portion of the study. Therefore, the SAP will include patient listing data and 
dose cohort summary tables for the 28 patients enrolled in the study.  
1.4. Procedures 
1.4.1. Subject Identification  
 
Once study eligibility has been determined, a subject will be enrolled into the study and will 
be assigned a sequential Subject Identification number within each participating site. The 
identification number will consist of a 2-digit site number, 1-digit cohort number, and a 2 
digit subject number. The subject identification number will be assigned sequentially within 
the cohort. The cohort number will remain the same if a subject’s dose is increased or 
decreased. If a subject is replaced, the identification number will not be reassigned. 
1.4.2. Randomization 
 
Not Applicable 
1.4.3. Blinding/Unblinding 
 
This is an unblinded study. 
1.4.4. Replacement 
 
Subjects who are screened but do not receive E6201, and subjects treated in Cycle 1 who 
complete < 75% of their prescribed study drug treatment or do not complete C1D28 
evaluation due to progression of disease, withdrawal of consent or non-DLT adverse events, 
will be replaced. 
1.4.5. Data Monitoring 
 
Strategia Therapeutics is responsible for ensuring the proper conduct of the study with regard 
to ethics, protocol adherence, site procedures, integrity of the data, and applicable laws and/or 
regulations. At regular intervals during the study and following completion of the study, the 
sponsor’s study monitors will contact the study site via visits to the site, telephone calls, and 
letters in order to review study progress, CRF completion and address any concerns or 
questions regarding the study conduct. During monitoring visits, the following aspects of 
study conduct will be carefully reviewed: informed consent of subjects, subject recruitment, 
subject compliance with the study procedures, source data verification, drug accountability, 


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use of concomitant therapy by subjects, AE and SAE documentation and reporting, and 
quality of data. Records pertaining to these aspects are expected to be kept current. 
 
2. Statistical Analysis Considerations 
2.1. Sample Size and Power 
 
A total of up to 92 subjects will be enrolled in this study. 
 
Phase 1 (Safety Run-In): The sample size reflects requirements associated with a 3+3 design. A 
total of 3 to 30 subjects are planned (3 to 6 subjects in each of 5 dose cohorts) with FLT3+ and/or 
Ras+ AML, MDS or CMML. 
 
Phase 2a (Expansion):  
 
Cohort 1: The statistical objective for Cohort 1 in the dose expansion portion of the study is 
evaluation of the objective response (OR) rate within 3 cycles of treatment with E6201 in patients 
with AML and FLT3 mutation, or FLT3 plus Ras mutations, without prior exposure to a FLT3 
inhibitor. If there is at least 1 OR in the first 8 patients, 18 additional patients will be enrolled in 
Stage II, for a total of 26 evaluable patients. If there are at least 4 ORs in a total of N=26, the 
alternative hypothesis will be accepted. This design provides a type I error of 5% and power of 
85% when the true OR rate is 25%. 
 
Cohort 2: The statistical objective for Cohort 2 in the dose expansion portion of the study is 
evaluation of the objective response (OR) rate within 3 cycles of treatment with E6201 in patients 
with AML and FLT3 mutation, or FLT3 plus Ras mutations, with prior exposure to a FLT3 
inhibitor. Based on Simon’s 2-stage optimal design, eleven (11) patients will be enrolled in Stage 
I. If there are zero (0) ORs in these 11 patients, the cohort will be terminated. If there is at least 1 
OR in the first 11 patients, 15 additional patients will be enrolled in Stage II, for a total of 26 
patients. If there are at least 2 ORs in a total of N=26, the alternative hypothesis will be accepted. 
This design provides a type I error of 5% and power of 80% when the true OR rate is 15% or 
greater. 
 
Cohort 3: We will evaluate the objective response (OR) rate within 3 cycles of treatment with 
E6201 in up to 10 patients with AML and Ras mutation but no mutation in FLT3. A response rate 
of 20% in this patient population is considered clinically meaningful. 
2.2. Analysis Populations  
 
The full analysis set (FAS) includes all subjects who are administered any fraction of a dose of 
study medication. For a particular measure, the per-protocol set (PPS) includes those subjects in 
the FAS who have had a valid baseline and one or more post-treatment assessments for that 
measure of interest. 
 
The E6201 PK population consists of all subjects in the FAS who complete all PK assessments.  
The E6201 PD population consists of all subjects in the FAS who complete all PD assessments. 
Details of the analysis will be outlined in the Pharmacokinetic Report Analysis Plan.  
 


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2.2.1. Intent-to-Treat (ITT) Population  
 
This population will not be used in the analysis. 
2.2.2. Randomized Population  
 
Since this is not a randomized study, there is no randomized population. 
2.2.3. Per Protocol Population 
 
All efficacy endpoints will be initially based on the subjects receiving any fraction of a dose 
of study medication and having at least one post-baseline value (PPS) for a particular efficacy 
endpoint. For each efficacy endpoint, an assessment for any subject may be performed at a 
time point deemed appropriate by the investigator. 
2.2.4. Safety Population 
 
All safety endpoints will be based on the FAS dataset. 
2.2.5. Screen Failure Population  
 
This population will not be used in the analysis. 
2.3. Data Handling 
2.3.1. Measurement Times 
2.3.1.1. Visit Windows  
 
Visit windows will not be used. The visit time point entered on the case report forms 
will be used. Unscheduled assessments, if any, will be listed, but will not be included 
in tabulations by visit. 
2.3.1.2. Baseline Values  
 
The screening assessments are performed within 28 days of Cycle 1, Day 1, before the 
first dose of study medication. Unless otherwise mentioned, baseline will be the last 
observation before patients receive initially assigned dose.  Generally, this will be 
Cycle 1 Day 1 pre-dose measurements. If a pre-dose assessment is not performed on 
Cycle 1 Day 1, the immediate previous non-missing value, including screening, will 
be treated as baseline. If there are multiple baseline assessments, the most recent one 
will be flagged as the baseline value and will be used for statistical analysis 
(evaluations may occur on the same day as Study Day 1, prior to dosing).  
2.3.2. Missing Data Conventions 
 
Unless otherwise specified, missing data will be considered missing and will not be imputed.  


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2.3.3. Imputation of Incomplete Dates 
 
Imputation of partial dates may be performed during the data analysis and will be documented. 
For start date of Adverse Event (AE) or Concomitant Medication (CM) with a missing day, 
the imputed date is the first day of the month. For stop date of AE or CM with a missing day, 
the imputed date is the last day of the month. For start date with both missing day and missing 
month, the imputed date is the subject start study date if AE or CM start year is the same as 
study start year. Otherwise, the imputed start date is the first day of the year. For stop date 
with both missing day and missing month, the imputed date is the subject end of study date if 
AE or CM stop year is the same as the study end year. Otherwise, the imputed stop date is the 
last day of the year.   
2.4. Statistical Methods 
2.4.1. General Overview and Plan of Analysis 
 
All data will be analyzed using Statistical Analysis System (SAS Version 9.4 or higher for 
Windows, SAS Institute, Cary, NC). Continuous variables will be summarized using number, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized using frequencies and percentages.  
2.4.2. Hypothesis Testing 
 
No formal hypothesis tests are planned.  
2.4.3. Modeling  
 
Not Applicable in this study. 
2.4.4. Multiplicity Issues/Multiple Comparisons  
 
There is no planned Multiplicity Issues/Multiple Comparisons analysis for this study. 
2.4.5. Project Center Effects  
 
 
The study will be conducted at The University of Texas M.D. Anderson Cancer Center with 
Gautam Borthakur, M.D. serving as Study Chair. Additional clinical sites include Moffitt 
Cancer Center (Kendra Sweet, MD), Health ONE Cares (Michael Maris, MD) and Methodist 
Hospital, San Antonio (Jose Cruz, MD).  
2.4.6. Interim Analysis  
 
No formal interim analysis is planned. Appropriate safety listings and summary tables will 
be generated for Scientific Review Committee meetings and Development Safety Update 
Reports (DSURs). 


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2.4.7. Pharmacokinetic and Pharmacodynamic Analyses 
 
 
Pharmacokinetic and Pharmacodynamic data will be summarized in a separate report. 
 
3. Statistical Analysis 
 
Data will be presented for clinical review and interpretation. Categorical variables will be summarized 
using frequency counts and percentages. Continuous variables will be summarized using descriptive 
statistics (n, mean, SD, median, minimum, and maximum). All listings will be presented for the FAS 
population except for PK and PD data.  
3.1. Enrollment and Disposition of Subjects 
 
Enrolled individuals are referred to as “subjects”. Subjects with advanced hematologic 
malignancies with FLT3 and/or Ras mutations, including acute myeloid leukemia (AML), 
myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) will be 
included. 
 
Major selection criteria are: age ≥ 18 years with confirmed diagnosis of FLT3+ and/or Ras+ 
higher-risk MDS/CMML (Phase 1 only), or relapsed or refractory AML with a FLT3 and/or Ras 
mutation. In the absence of rapidly-progressing disease, ≥ 3 weeks after prior cancer treatment for 
the disease under study, with the exception of hydroxyurea to control peripheral blast counts 
allowed during the first 2 cycles. Subjects must have recovered from all acute toxicities (≤ Grade 
1), have adequate renal and hepatic function, and no known history of significant cardiac disease. 
 
 
The analyses of subject disposition will be performed on the FAS population for all subjects and 
by dose cohort. The number of subjects treated, completed study and those who terminated early 
from the study, along with their reasons for early termination, will be presented.  
3.2. Baseline Characteristics 
3.2.1. Demographic 
 
Summary statistics for demographic characteristics will be presented for subjects by dose 
cohort using the full analysis set (FAS) population. Tabulations will be performed for age, 
sex (male or female), ethnicity (Hispanic/Latino or other), and race (American Indian or 
Alaska Native, Black or African American, White, Asian, Native Hawaiian or Other Pacific 
Islander, Unknown, or other). Age will be calculated as the number of complete years 
between a subject’s date of birth and the date of screening visit. Demographic characteristics 
will be presented in listing for each subject.  
3.2.2. Physical Characteristics  
 
 
Physical characteristics will be presented in listing for each subject.  
 
 
 


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3.2.3. Disease Characteristics 
 
The baseline disease assessment (AML and MDS/CMML), prior FLT3 inhibitor exposure, 
prior cancer therapy, medical history findings, and major protocol deviations will be 
presented in listings for each subject. 
 
3.2.4. Concomitant Medications  
 
Prior and concomitant medications will be listed.  
3.3. Analysis of Efficacy  
3.3.1. Primary Endpoints 
 
No primary endpoints analysis will be provided.  
3.3.2. Secondary Endpoints 
 
No secondary endpoints analysis will be provided. 
3.3.3. Exploratory/Other Analyses 
 
Pharmacokinetic and pharmacodynamic analyses will be provided by an outside laboratory. 
3.4. Analysis of Safety and Tolerability  
3.4.1. Study Drug Administration 
 
The study drug exposure will be summarized by dose cohort. The study drug administration 
will be presented in listing for each subject.   
3.4.2. Adverse Events 
 
 
 
All AEs will be coded based on the Medical Dictionary for Regulatory Affairs (MedDRA; 
Version 17.0 or higher). An AE will be considered a treatment emergent adverse event 
(TEAE) if the onset is after the first dose of study drug or if the condition was present at 
baseline but worsened after the first dose. All other AEs will be considered preexisting 
events.  
 
All AEs for each subject will be listed, including Treatment Emergent status, intensity 
grading, relationship to study drug, action taken and outcome. Subject listings of deaths, 
serious TEAEs, and TEAEs leading to treatment discontinuation will be presented.  
 
TEAE summaries will be produced for each dose cohort for subjects in FAS population. All 
TEAE summaries will show the number and percentage of subjects experiencing at least 1 
TEAE for each preferred term, arranged by system organ class, and the number of unique 
occurrences of the event. Separate summaries will be produced by relationship to study 
medication and by severity. Subjects with multiple events will be counted only once per SOC 


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and preferred term. For each level of summarization, the event with the highest level of 
severity, grade, or strongest drug relationship will be presented. TEAEs with Grade 3 or 
Grade 4 and drug-related TEAES with Grade 3 or Grade 4 will be summarized. TEAEs 
leading to study drug interruption or discontinuation, and Serious TEAEs will be provided in 
separate listings. 
3.4.3. Clinical Laboratory Results 
 
Laboratory data will be listed for each subject using FAS population. Laboratory values will 
be graded according to the NCI-CTCAE version 4.03 criteria. Laboratory results will be 
summarized by dose cohort using number of non-missing observations, mean, standard 
deviation, median, minimum, and maximum. 
3.4.4. Vital Signs 
 
Vital sign measurements include temperature, blood pressure and pulse rate. Vital signs will 
be listed for each subject. Actual vital sign results will be summarized by dose cohort using 
number of non-missing observations, mean, standard deviation, median, minimum and 
maximum by dose cohort. 
3.4.5. Physical/Other Examinations  
 
Data collected for physical examinations, ECGs and related measures will be listed for each 
subject.  
3.4.6. Treatment Discontinuation, Project Termination, and Death 
 
 
The participants who discontinued (with reasons) and deaths will be listed.  
 
4. Proposed Summary Tables, Figures and Listings 
4.1. Mock Tables  
 
The following tables will be presented by dose cohort. 
4.1.1. Subject Disposition 
 
• 
Subject Disposition 
4.1.2. Demographics and Baseline Characteristics 
 
• 
Demographics and Baseline Characteristics 
4.1.3. Safety Summaries 
4.1.3.1. Study Drug Administration  
 
• 
Summary of Study Drug Exposure  


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4.1.3.2. Adverse Events Summaries 
 
• 
Summary of Treatment Emergent Adverse Events 
• 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
• 
Treatment Emergent Adverse Events by Severity  
• 
Treatment Emergent Adverse Events by Relationship to Study Drug 
• 
Grade 3 and Grade 4 Treatment Emergent Adverse Events by Relationship to 
Study Drug 
• 
Serious Treatment Emergent Adverse Events 
• 
Serious Treatment Emergent Adverse Events Related to Study Drug 
4.1.3.3. Laboratory Assessments 
 
• 
Hematology Laboratory Results by Visit 
• 
Chemistry Laboratory Results by Visit 
4.1.3.4. Other Safety Summaries 
 
• 
Summary of Vital Sign Results 
4.2. Mock Figures 
 
No figures will be presented in the analysis.  
4.3. Mock Listings 
 
• 
Inclusion Criteria Not Met 
• 
Exclusion Criteria Not Met 
• 
Protocol Violations/Deviations/Exemptions 
• 
Demographics 
• 
End of Treatment 
• 
End of Study 
• 
Baseline Disease Assessment (AML) 
• 
Baseline Disease Assessment (MDS/CMML) 
• 
Medical History 
• 
All Prior FLT3 Inhibitor Exposure and Prior Cancer Therapy 
• 
Physical Examination  
• 
Prior and Concomitant Medications 
• 
Study Drug Administration 
• 
Disease Response Assessment (AML) 
• 
Disease Response Assessment (MDS/CMML) 
• 
Bone Marrow Assessment (BMA) 
• 
Treatment Emergent Adverse Events (TEAE) 
• 
Serious Treatment Emergent Adverse Events 
• 
Treatment Emergent Adverse Events Leading to Dose Adjustment, Temporary Interruption, 
and Permanent Discontinuation of Study Drug 
• 
Treatment Emergent Adverse Events Leading to Permanent Discontinuation from Study 


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• 
Deaths 
• 
Hematology 
• 
Chemistry 
• 
Vital Signs 
• 
12-lead Electrocardiogram 
• 
Blood Transfusion 
• 
Other Procedures 
• 
Long Term Follow-up