Clinical trial NCT02323113
Conditions: Acute Myelogenous Leukemia
Keywords: Drug therapy
Sponsor: Calithera Biosciences, Inc
Start date: 2015-03-09; Completion date: 2018-08-15
Enrollment: 43 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the Phase 1b dose finding phase is to determine the safety, tolerability, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-659 in participants with relapsed or refractory AML. The purpose of the Phase 2 expansion phase is to evaluate preliminary efficacy of TAK-659 in relapsed or refractory AML as measured by overall response rate (ORR).

Detailed description:
The drug being tested in this study is TAK-659. TAK-659 is being tested to treat people who have relapsed or refractory acute myelogenous leukemia (AML). This study will be conducted in 2 phases. The first phase will determine a safe and well-tolerated dose of TAK-659 to be used in the second phase, and the second phase will look at response to treatment in people who take TAK-659.

The study will enroll approximately 106 participants (approximately 40 in the first phase and 66 in the second phase). There will be two separate cohorts during Phase 2 portion of the study, one for participants with FLT-3 internal tandem duplication (ITD) mutations and the other for FLT-3 wild-type participants.

Phase 1b:

• TAK-659 60 milligram (mg) tablet starting dose escalated in 20 mg or higher increments to a maximum tolerated dose or RP2D

Phase 2:

• TAK-659 tablet at the maximum tolerated dose or RP2D determined in Phase 1b.

All participants will be asked to take their prescribed tablets at the same time each day throughout the study.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is up to 24 months (12 months of treatment and 12 months of follow up) unless the treating physician believes the participant would continue to derive benefit from the study drug.

Arms: arm 1: TAK-659 tablets taken orally, once daily or twice daily on Days 1-28 in a 28 day cycle, for up to 12 cycles or until disease progression. Dosage of TAK-659 may increase in 20 mg increments using a 3 + 3 dose escalation design to determine a MTD and/or RP2D. arm 2: TAK-659, tablets taken orally, once daily or twice daily on Days 1-28 in a 28 day cycle, for up to 12 cycles or until disease progression. Dosage for this phase will be determined from results of Phase 1b MTD/RP2D.
Interventions: intervention 1: TAK-659
Intervention descriptions: intervention 1: TAK-659 tablets.

Protocol documents:
Prot_000.pdf: 



Title: An Open-Label, Phase 1b/2 Study Investigating Recommended Phase 2 Dose, Safety, 
Tolerability, and Preliminary Efficacy of TAK-659 in Adult Patients With Relapsed or Refractory 
Acute Myelogenous Leukemia (AML)
NCT Number: NCT02323113
Protocol Approve Date: 05 January 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TAK-659 
Clinical Study Protocol C34002 Amendment 02
1
CLINICAL STUDY PROTOCOL C34002 AMENDMENT 02
TAK-659
An Open-Label, Phase 1b/2 Study Investigating Recommended Phase 2 Dose, Safety, 
Tolerability, and Preliminary Efficacy of TAK-659 in Adult Patients With Relapsed or 
Refractory Acute Myelogenous Leukemia (AML)
Protocol Number:
C34002
Indication:
Relapsed and/or refractory AML
Phase:
1b/2
Sponsor:
Millennium Pharmaceuticals, Inc.
Therapeutic Area:
Oncology
Protocol History
Original
24 September 2014
Amendment 01
15 June 2015
Amendment 02
05 January 2018
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA USA 02139
Telephone:  +1 (617) 679-7000
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
2
Approved by:
Note:  If this document was approved electronically, the electronic approval signatures may 
be found at the end of the document.
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Subject to the Applicable Terms of U


TAK-659 
Clinical Study Protocol C34002 Amendment 02
3
Rationale for Amendment 02
The main reasons for Amendment 02 are to update the risks (and associated changes 
throughout), clarify twice daily (BID) dosing, and to remove the pS6 secondary endpoint.
Purposes for Amendment 02
This document describes the changes in reference to the protocol incorporating 
Amendment 02. The primary reason for this amendment is to update the original protocol to 
comply with Takeda standards and standard operating procedures.
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only. The purposes of this amendment are:
!
To replace signatories who were previously assigned to the protocol.
!
To update the proposed number of patients in the study.
!
To update language specifying inclusivity of the tyrosine kinase domain mutant 
populations. 
!
To clarify TAK-659 dosage can include BID dosing.
!
To remove the PD effects of TAK-659 (due to the removal of the pS6 sample) and the 
PD assessment from secondary endpoints, Schedule of Events, Overview of Study, and 
Study Design.
!
To update the dose escalation status of Study C34001 and specify the maximum 
tolerated dose (MTD) as 100 mg.
!
To allow for prior exposure to investigational FLT-3 inhibitors in the phase 2 portion 
of the study.
!
To add creatine phosphokinase (CPK) testing to the Schedule of Events.
!
To add cytomegalovirus (CMV) testing to the Schedule of Events. 
!
To update title of Assessment Schedule.
!
To specify time of day for BID dosing.
!
To remove specification that subsequent anticancer therapy should not be initiated 
before recovery from all treatment-emergent toxicities associated with TAK-659.
!
To update TAK-659 50% inhibition concentration.
!
To update information on the nonclinical experience of TAK-659.
!
To update information on the clinical experience of TAK-659.
!
To update details for the PK
.
!
To update the risks of TAK-659 in nonclinical and clinical studies.
!
To update the number of patients and study centers.
!
To update the study duration.
!
To update contraception methods.
!
To update laboratory values regarding lipase and amylase, and to exclude patients with 
moderate renal impairment.
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
4

To clarify exclusion criteria of systemic anticancer treatment.

To clarify exclusion criteria regarding use or consumption of substances (medication 
and supplements).

To update TAK-659 dose adjustments for nonhematologic toxicities.

To provide updates to concomitant medications and procedures.

To provide details on managing pneumonitis, edema, hypophosphatemia, enzyme 
elevations (including transaminase, amylase and lipase, and CPK elevations, in 
addition to lactate dehydrogenase elevations).

To provide updated details on managing infections.

To provide updated details on managing rash with or without pruritus.

To update temperature of storage conditions to make consistent with other protocols.

To update language for concomitant medications and procedures.

To update clinical laboratory evaluations to reflect addition of CMV testing.

To clarify PD population will be derived from the plasma inhibitory assay.

To remove the PD assessment from the PK analysis.

To update product complaint telephone number.

To add CRp, CRh, and CRc to the definition of a response for purposes of disease 
assessment. 
For specific examples of changes in text and where the changes are located, see 
Section 14.6.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
5
PROTOCOL SUMMARY
Study Title:  An Open-Label, Phase 1b/2 Study Investigating Recommended Phase 2 Dose, Safety, 
Tolerability, and Preliminary Efficacy of TAK-659 in Adult Patients With Relapsed or Refractory 
Acute Myelogenous Leukemia (AML)
Number of Patients:  
Phase 1b dose finding phase:  approximately 40 patients
Phase 2 expansion phase:  up to 66 based on a Simon’s 2-Stage design in both FLT-3 wild type (WT) 
and FLT-3-internal tandem duplication (ITD) mutant populations (inclusive of the tyrosine kinase 
domain [TKD] mutant populations) 
Study Objectives
Primary
!
Phase 1b dose finding phase:  to determine the safety, tolerability, and maximum 
tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-659 administered 
orally on a once daily (QD) or twice daily (BID) dosing schedule in patients with 
relapsed or refractory AML
!
Phase 2 expansion phase:  to evaluate preliminary efficacy of TAK-659 in relapsed or 
refractory AML as measured by overall response rate (ORR)
Secondary
!
To evaluate additional efficacy measures of TAK-659, such as duration of response 
(DOR), time to progression (TTP), mortality rate at 3 and 6 months, and overall survival 
(OS)
!
To evaluate differential efficacy of TAK-659 in patients with or without FLT-
3-ITD/TKD mutation
!
To characterize the plasma pharmacokinetics (PK) of TAK-659 in patients with relapsed 
or refractory AML
Exploratory
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applica
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
6
Overview of Study Design:  This study will include a phase 1b dose finding portion and a single-
arm phase 2 expansion portion in relapsed or refractory AML.
The starting dose for the phase 1b portion of this study (Study C34002) will be directed by the 
current Study C34001, the first-in-human (FIH) dose escalation study of TAK-659 in patients with 
advanced solid tumors and lymphoma.  The starting dose in Study C34002 will not exceed the 
highest dose determined to be safe in Study C34001 at the time Study C34002 starts.  A dose of 
60 mg QD was determined to be tolerable based on a 3+3 dose escalation schema after evaluation of 
6 patients.  Based on these data, the starting dose will be 60 mg QD for Study C34002. Since the 
initiation of Study C34002, dose escalation has been completed in Study C34001 with 100 mg QD 
determined as the MTD. In the expansion phase of the ongoing FIH study, lymphoma patients are 
being evaluated at 100 mg and early clinical activity has been observed in this population. In the 
Non Hodgkin Lymphoma population, the more relevant target for TAK-659 is SYK.  
A 3+3 dose escalation design will be used to determine the MTD of TAK-659 in AML.  Each 
28-day treatment cycle will be composed of 28 consecutive days of QD or BID TAK-659 treatment.  
Planned dose escalation will follow 20-mg increments of escalation (eg, from 60 mg to 80 mg QD or 
BID).  A more aggressive dose escalation (more than 20-mg increments but not exceeding 100% 
escalation), evaluation of alternative regimens, and expansion of an existing dose level up to 
12 evaluable patients are all permissible following discussions between the sponsor and the 
investigators based on evolving safety, tolerability, and PK data of TAK-659.  Dose escalation will 
continue until either MTD is reached or the RP2D (if different from MTD) has been determined 
based on safety, tolerability, PK, and preliminary efficacy data, if available.  At least 6 patients will 
be evaluated at RP2D (either the MTD or at a lower dose as determined) before making a decision to 
advance to the phase 2 expansion phase.  In the process of determining or refining RP2D, expansion 
of more than 1 dose level to at least 6 patients (up to a maximum of 12 evaluable patients per dose 
level) is permissible so that early signs of clinical activity can be assessed to a greater extent to assist 
dose selection.
The phase 2 expansion study in relapsed or refractory AML will be conducted using a Simon’s 
2-stage design.  The objectives of this phase 2 stage of the study are to evaluate longer-term safety 
and tolerability of TAK-659 administered at the RP2D and to detect any efficacy signal that warrants 
further development of TAK-659 in AML.  The primary measure of efficacy for the phase 2 portion 
will be the ORR, which will include complete response (CR), CR with incomplete platelet recovery 
(CRp), CR with incomplete hematologic recovery (CRi), CR with partial hematologic recovery 
(CRh), a composite complete remission (CRc defined as the sum of a patient achieving a CR, CRh, 
CRi, or CRp), and partial response (PR).  Nine and 15 response-evaluable patients will be enrolled 
initially in the FLT-3 WT and FLT-3 ITD/TKD mutant cohorts, respectively, during the first stage.  
Best response will be assessed by the end of Cycle 4 of TAK-659 treatment for the purpose of an 
interim analysis between Stage 1 and Stage 2.  The FLT-3 WT and FLT-3 ITD/TKD mutant cohorts 
will proceed to the second stage if 2 and 6 patients, respectively, respond to treatment (ORR).  
Other efficacy measures, such as DOR, TTP, and mortality rate will also be considered in the 
decision to expand the study to the second stage.  If the FLT-3 WT and/or FLT-3 ITD/TKD mutant 
cohort(s) proceed(s) to the second stage, a further 14 and 17 evaluable patients will be assessed in 
the 2 cohorts, respectively.  Best responses from both cohorts will be assessed individually and 
combined in an effort to understand the all-comer response rate.  Retrospective analysis will be 
performed to identify potential patient selection markers either based on levels of baseline activation 
or posttreatment modulation of FLT-3 and SYK, the 2 targets of TAK-659.  Analysis for mutations 
reported for AML will also be performed.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
7
Study Population:  Patients will be males and females age 18 years or older with 
histopathologically documented primary or secondary AML (excluding acute promyelocytic 
leukemia) as defined by World Health Organization (WHO) criteria, for whom no standard therapies 
are anticipated to result in a durable remission based on the opinion of the investigator, or who refuse 
standard therapies.  For the phase 2 portion of the study, patients must be refractory to or relapsed 
after no more than 2 prior chemotherapy regimens. Patients must have adequate organ function and 
an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.  Patients must not 
have clinically significant toxicity from prior chemotherapy, hematopoietic stem cell transplant 
(HSCT) within 60 days of the first dose of TAK-659, or clinically significant graft-versus-host 
disease requiring ongoing immunosuppressive therapy.
Duration of Study:  It is anticipated that this study will last for approximately 66 to 72 months, 
including 34 to 36 months in the phase 1b portion and 32 to 36 months in the phase 2 portion.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
8
STUDY OVERVIEW DIAGRAM (PHASE 2 DOSE EXPANSION)
Arm 1:
FLT-3 WT
Initial cohort of
15 patients
Initial cohort of
9 patients
Arm 2:
FLT-3 MUT
2nd cohort of
17 patients
2nd cohort of
14 patients
≥2/9 responders
≥6/15 responders
Abbreviations:  MUT = mutation; WT = wild type
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
9
SCHEDULE OF EVENTS
Schedule of Events for Dose Escalation (Phase 1b) [28-Day Cycles]
Screeninga
Cycle 1
Cycles 2, 3, 
and 4
Cycles 5, 
6, and 
beyond
EOSb 
(+10 days)
Survival
Follow-upc
Day 
1
Day 
2
Day 
8
Day 
15
Day 
16
Day 
22
Day 
1
Day 15
Day 1
Dosing
TAK-659 
administrationd
TAK-659 is dosed orally once or twice daily every day
Study Procedures
Informed consente
X
Inclusion/exclusion 
criteria
X
Demographics and 
disease characteristics
X
Complete medical 
historyf
X
X
Modified Charlson 
Comorbidity Index 
Assessments
Xg
Physical examinationf
X
X
X
X
X
X
X
X
X
Height
X
Weighth
X
X
X
X
X
Vital signsi
X
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
12-lead ECGj
X
X
X
X
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
10
Schedule of Events for Dose Escalation (Phase 1b) [28-Day Cycles]
Screeninga
Cycle 1
Cycles 2, 3, 
and 4
Cycles 5, 
6, and 
beyond
EOSb 
(+10 days)
Survival
Follow-upc
Day 
1
Day 
2
Day 
8
Day 
15
Day 
16
Day 
22
Day 
1
Day 15
Day 1
Monitoring of 
concomitant 
medications and 
procedures
Recorded from first dose of study drug through 28 days after the last dose of study drug or to the start of subsequent 
anticancer therapy, whichever occurs first
Adverse event 
reporting
Recorded from first dose of study drug through 28 days after the last dose of study drug or to the start of subsequent 
anticancer therapy, whichever occurs first
Serious adverse eventsk will be reported from signing of the informed consent form through 28 days after the last dose of study drug 
even if the patient starts nonprotocol therapy
Patient diary reviewl
X
X
X
X
X
X
X
X
Response Assessments
Bone marrow biopsy 
and aspirate for 
disease response 
monitoring
Xm
Xm
Xm
Samples/Laboratory Assessments
Pregnancy testn
X
X
X
X
Hematology/
Chemistryo,p
X
X
X
X
X
X
X
X
X
CPK testingo,p
X
X
X
X
X
X
X
X
X
Urinalysis (for 
hematuria and 
proteinuria 
evaluation)p,q
X
X
X
X
Ophthalmic Examr
X
Xr
Xr
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
11
Schedule of Events for Dose Escalation (Phase 1b) [28-Day Cycles]
Screeninga
Cycle 1
Cycles 2, 3, 
and 4
Cycles 5, 
6, and 
beyond
EOSb 
(+10 days)
Survival
Follow-upc
Day 
1
Day 
2
Day 
8
Day 
15
Day 
16
Day 
22
Day 
1
Day 15
Day 1
Blood sample for 
FLT-3 mutation 
analysist
X
Blood sample for 
plasma inhibitory 
assayv
X
X
Xv
Xv
Blood samples for 
PKz
X
X
X
X
Survival Follow Up 
Contact c
X
CMV testingaa
X
Abbreviations:  AML = acute myelogenous leukemia; CPK= creatine phosphokinase; CxDx = Cycle x, Day x; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EOS = End of Study; P-gp = P-glycoprotein; PK =pharmacokinetic(s).
Evaluations/laboratory assessments performed on visit days need to take place before dosing unless otherwise indicated.  On these days, patients 
should be instructed to hold dosing until relevant assessments have been completed.  
a Screening assessments are performed within 28 days before the Cycle 1, Day 1 dose.  Screening assessments performed no more than 3 days before Day 1 
will qualify as baseline assessments and need not be repeated, unless otherwise specified. 
b End of Study visit will occur 28 days (+ 10 days) after the last dose of study drug or before the start of subsequent anticancer therapy (other than 
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
12
Schedule of Events for Dose Escalation (Phase 1b) [28-Day Cycles]
Screeninga
Cycle 1
Cycles 2, 3, 
and 4
Cycles 5, 
6, and 
beyond
EOSb 
(+10 days)
Survival
Follow-upc
Day 
1
Day 
2
Day 
8
Day 
15
Day 
16
Day 
22
Day 
1
Day 15
Day 1
hydroxyurea) if that occurs sooner. 
c All patients, including those patients no longer on treatment, will be assessed for survival.  Patients who discontinue the study, regardless of reasons for 
discontinuation, will be followed for survival every month until death, loss to follow-up, or withdrawal of consent for further follow-up for up to 12 months 
after discontinuation of the study drug.  In addition, information on any subsequent anticancer therapies will be collected during the survival follow-up 
period.  For patients who achieve CR but discontinue study treatment while still in remission, disease progression based upon available local data will also 
be collected during the survival follow-up period.
d TAK-659 will be administered orally once or twice daily for 28-day cycles.  The option to modify the schedule of drug administration to include alternative 
schedules will be based on the review of the available PK, safety, and other clinical data by the investigators and the sponsor.
e Informed consent may be obtained before the Screening period (28 days before Cycle 1, Day 1 dosing).
f
The Cycle 1, Day 1 physical examination and medical history are not required if the screening physical examination was conducted and medical history 
obtained within 3 days before administration of the first dose of study drug (Cycle 1, Day 1).  Complete physical examinations will be performed during 
screening and will include a neurological exam.  Complete physical exams will also be performed on Day 1 of each cycle, and at the End of Study (EOS) 
visit.  Symptom- or finding-directed physical examination will be performed on Days 8, 15, and 22 of Cycle 1 and Day 15 of Cycles 2, 3, and 4.
g See Section 14.1 for Modified Charlson Comorbidity Index.
h Weight should be obtained at screening, on Day 1 predose of each cycle, and at EOS. 
i
Vital signs measurement (blood pressure, heart rate, and temperature) should be performed before dosing on visit days and as clinically indicated.  
j
In Cycle 1, single 12-lead ECGs will be performed as detailed in the AML Dose Escalation (Phase 1b) PK, PIA, and ECG Assessment Schedule.  For 
Cycle 2 and beyond, the ECGs will be performed only on Day 1 predose.
k Serious adverse event (SAE) reporting will include serious pretreatment events.  Only those SAEs that occur after the first dose of study drug will be 
collected in the eCRF.  However, all SAEs occurring after consent will be reported to the Millennium Department of Pharmacovigilance or designee (see 
Section 9.2).
l
The study center staff will check the patient drug diary versus the patient’s supply of TAK-659 tablets to assess compliance.
m Bone marrow biopsy and aspirate assessments of disease burden (blast counts), cytogenetics, and cellular composition by flow cytometry will be performed 
at screening.  In addition, bone marrow biopsies and/or aspirates will be collected to assess disease response between Days 22 and 28 of Cycles 1, 2, and 4, 
provided that the disease assessment is available before Day 1 of the following cycle.  Beyond Cycle 4, bone marrow biopsy and/or aspirate assessment will 
be performed as clinically indicated based on changes in peripheral blood counts, or when it is needed to establish either CR or disease progression.  Note 
that a bone marrow biopsy is required only at screening. Residual and/or additional bone marrow samples will be requested for biomarker analysis as well 
as confirmation of the FLT-3 mutation status.  See footnotes w, x, y and Section 7.4.15.1 for further details.
n
A serum pregnancy test will be performed for women of childbearing potential at screening.  A urine pregnancy test must be performed predose on Day 1 
of all cycles with negative results available before the first dose of TAK-659 may be administered for that cycle.  If a serum pregnancy test is performed 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
13
Schedule of Events for Dose Escalation (Phase 1b) [28-Day Cycles]
Screeninga
Cycle 1
Cycles 2, 3, 
and 4
Cycles 5, 
6, and 
beyond
EOSb 
(+10 days)
Survival
Follow-upc
Day 
1
Day 
2
Day 
8
Day 
15
Day 
16
Day 
22
Day 
1
Day 15
Day 1
within 3 days of dosing and the result is negative, the urine pregnancy test may be waived on Cycle 1, Day 1.  
o The hematology and chemistry blood samples for Cycle 1, Day 1 may be collected within 3 days before dosing to ensure patient eligibility on study Day 1.  
The percentage of leukemic blast cells should also be noted in the hematology panel. If screening clinical laboratory testing was performed within 3 days 
before the Cycle 1, Day 1 dose, it need not be repeated on Cycle 1, Day 1.  The percentage of leukemic blast cells should also be noted in the hematology 
panel. 
p Laboratory assessments can be conducted within - 3 days of the scheduled visit, with the exception of PK/plasma inhibitory assay assessments or unless 
otherwise noted.  Day 1 visits of Cycle 2 and beyond may be modified by up to 3 days due to extenuating circumstances (ie, inclement weather, holidays, 
vacations, or other administrative reasons).
q Urinalysis samples will be collected predose and analyzed at the site’s local laboratory.
r
An ophthalmic exam should be performed at screening, on Cycle 2, Day 1, on Cycle 7, Day 1, every 6 cycles thereafter (# 2 weeks), and at EOS.  See 
Section 7.4.14 for details.
s
t
A peripheral blood sample will be obtained at screening for confirmation of the FLT-3 mutation status by a central laboratory test designated by the 
sponsor.
u
 
 
v Blood specimens will be collected for assessment of the FLT-3 and potentially SYK inhibitory effects of TAK-659 in vitro by plasma inhibitory assay.  
Time points for this blood collection are predose on Cycle 1, Day 1, Cycle 2, Day 1, Cycle 1, Day 15, and Cycle 2, Day 15.
w Additional bone marrow aspirates (remaining aspirate material from the first pull or a second or third pull of bone marrow aspirate) and biopsy specimens 
(segments of the first core biopsy or additional core biopsies) after taking specimens for disease assessment (see footnote m) will be collected during 
screening for confirmation of the FLT-3 mutation status and exploratory biomarker studies.  Note that if a standard of care bone marrow biopsy and aspirate 
have already been performed on a patient within 28 days of Day 1 of Cycle 1, additional bone marrow biopsy and aspirate need not be repeated if results are 
available for disease assessment purposes. However, if the site has access to these samples and adequate residual material remains, these samples should be 
sent to the Sponsor-designated laboratory(ies).  See the Laboratory Manual for details about the sample collection and shipment procedures. If only one 
specimen (biopsy or aspirate) has already been performed within 28 days of Day 1 of Cycle 1, please discuss with study sponsor.
x If adequate residual material is available from bone marrow aspirates and/or biopsies collected for disease assessment (or as clinically indicated ) during the 
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
14
Schedule of Events for Dose Escalation (Phase 1b) [28-Day Cycles]
Screeninga
Cycle 1
Cycles 2, 3, 
and 4
Cycles 5, 
6, and 
beyond
EOSb 
(+10 days)
Survival
Follow-upc
Day 
1
Day 
2
Day 
8
Day 
15
Day 
16
Day 
22
Day 
1
Day 15
Day 1
study period (from first dose to 28 days after discontinuation of study treatment), these samples are requested to be sent to the Sponsor-designated 
laboratory(ies) for biomarker studies. See Section 7.4.15.1 for further details.
y At the time of relapse of any patient who had initially responded to TAK-659, bone marrow aspirate and/or biopsy materials will be collected for biomarker 
study. See Section 7.4.15.1 for further details.
z Blood specimens for PK plasma samples will be collected at time points specified in the AML Dose Escalation (Phase 1b) PK, PIA, and ECG Assessment 
Schedule.  Refer to the Laboratory Manual for detailed instructions on collection, processing, storing, and shipping of PK samples.
aa  Blood specimen will be collected during screening for a local polymerase chain reaction testing of CMV replication. The CMV viral load data will be 
entered in the eCRF. Further monitoring of CMV, if indicated, will follow the local standard practice.
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
15
AML Dose Escalation (Phase 1b) PK, PIA, and ECG Assessment Schedule:  Cycle 1 
Cycle 1
Day 1
Day 2 
(24 hours 
post Day 1 
dose 1 
hour)a,b
Day 15a,b
Day 16 (24 hours 
post Day 1 dose 
1 hour)a,b
Single ECG
PK
PIAc
PK
Single ECG
PK
PIA
PK
Predose (within 1 hour 
before dosing)
X
X
X
X
X
X
X
X
0.5 hour postdose 
(10 min)
X
X
1 hours postdose 
(10 min)
X
X
2 hours postdose 
(10 min)
X
X
3 hours postdose 
(30 min)
X
X
X
X
4 hours postdose 
(30 min)
X
X
8 hours postdose 
(30 min)
X
X
Abbreviations: AML = acute myelogenous leukemia; CXDY = Cycle X, Day 1; ECG = electrocardiogram; h = hour(s); min = minutes; PIA = plasma 
inhibitory assay; PK = pharmacokinetic.
When the timing of a PK, PIA, or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the 
collection of the blood samples. For BID dosing, PK, PIA, and ECG assessment schedule refers to the AM dose.
a Instruct the patient to arrive at the clinic without taking his/her study drug dose for that day.
b The timing of the visit should be planned so that the predose assessments occur at approximately the same time as the dosing time on the previous day(s).
c PIA samples are also obtained on Days 1 and 15 in Cycle 2 (see Schedule of Events for Dose Escalation (Phase 1b) [28-Day Cycles] footnote v).
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
16
Schedule of Events for AML Expansion Cohort (Phase 2) [28 Day Cycles]
Screeninga
Cycle 1 
Cycles 2, 3, 
and 4
Cycles 5, 6, and 
beyond
EOSb  (+ 10 
days)
Survival
Follow-upc
Day 
1
Day 
2
Day 
8
Day 
15
Day 
22
Day 1
Day 
15
Day 1
Dosing
TAK-659 
administrationd
TAK-659 is dosed orally once or twice daily every day
Study Procedures
Informed consente
X
Inclusion/exclusion 
criteria
X
Demographics and 
disease 
characteristics
X
Medical historyf
X
X
Modified Charlson 
Comorbidity Index 
Assessments
Xg
Physical 
examinationf
X
X
X
X
X
X
X
X
X
Height
X
Weighth
X
X
X
X
X
Vital signsi
X
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
12-lead ECGj
X
X
X
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
17
Schedule of Events for AML Expansion Cohort (Phase 2) [28 Day Cycles]
Screeninga
Cycle 1 
Cycles 2, 3, 
and 4
Cycles 5, 6, and 
beyond
EOSb  (+ 10 
days)
Survival
Follow-upc
Day 
1
Day 
2
Day 
8
Day 
15
Day 
22
Day 1
Day 
15
Day 1
Monitoring of 
concomitant 
medications and 
procedures
Recorded from first dose of study drug through 28 days after the last dose of study drug or to the start of subsequent 
anticancer therapy, whichever occurs first
Adverse event 
reporting
Recorded from first dose of study drug through 28 days after the last dose of study drug or to the start of subsequent 
anticancer therapy, whichever occurs first
Serious adverse eventsk will be reported from signing of the informed consent form through 28 days after the last dose of study drug 
even if the patient starts nonprotocol therapy
Patient diary reviewl
X
X
X
X
X
X
X
X
Response Assessments
Bone marrow biopsy 
and aspirate for 
disease response 
monitoring
Xm
Xm
Xm
Samples/Laboratory Assessments
Pregnancy testn
X
X
X
X
Hematology/
Chemistryo,p
X
X
X
X
X
X
X
X
X
CPK Testingo,p
X
X
X
X
X
X
X
X
X
Urinalysis (for 
hematuria and 
proteinuria 
evaluation)p,q
X
X
X
X
Ophthalmic Examr
X
Xr
Xr
X
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
18
Schedule of Events for AML Expansion Cohort (Phase 2) [28 Day Cycles]
Screeninga
Cycle 1 
Cycles 2, 3, 
and 4
Cycles 5, 6, and 
beyond
EOSb  (+ 10 
days)
Survival
Follow-upc
Day 
1
Day 
2
Day 
8
Day 
15
Day 
22
Day 1
Day 
15
Day 1
Blood sample for 
FLT-3 mutation
analysist
X
Blood sample for 
PKy
X
X
Survival Follow Up 
Contact c
X
CMV testingz
X
Abbreviations:  AML = acute myelogenous leukemia; CPK= creatine phosphokinase; CxDx = Cycle x, Day x; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EOS = End of Study; PK =pharmacokinetic(s)
Evaluations/laboratory assessments performed on visit days need to take place before dosing unless otherwise indicated.  On these days, patients 
should be instructed to hold dosing until relevant assessments have been completed.  
a Screening assessments are performed within 28 days before the Cycle 1, Day 1 dose.  Screening assessments performed no more than 3 days before Day 1 
will qualify as baseline assessments and need not be repeated, unless otherwise specified. 
b End of Study visit will occur 28 days (+ 10 days) after the last dose of study drug or before the start of subsequent anticancer therapy (other than 
hydroxyurea) if that occurs sooner. 
c
All patients, including those patients no longer on treatment, will be assessed for survival.  Patients who discontinue the study, regardless of reasons for 
discontinuation, will be followed for survival every month until death, loss to follow-up, or withdrawal of consent for further follow-up for up to 12 months 
after discontinuation of the study drug.  In addition, information on any subsequent anticancer therapies will be collected during the survival follow-up 
period.  For patients who achieve CR but discontinue study treatment while still in remission, disease progression based upon available local data, will also 
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
19
Schedule of Events for AML Expansion Cohort (Phase 2) [28 Day Cycles]
Screeninga
Cycle 1 
Cycles 2, 3, 
and 4
Cycles 5, 6, and 
beyond
EOSb  (+ 10 
days)
Survival
Follow-upc
Day 
1
Day 
2
Day 
8
Day 
15
Day 
22
Day 1
Day 
15
Day 1
be collected during the survival follow-up period.
d TAK-659 will be administered orally once or twice daily for 28-day cycles.  The option to modify the schedule of drug administration to include alternative 
schedules will be based on the review of the available PK, safety, and other clinical data by the investigators and the sponsor.
e Informed consent may be obtained before the Screening period (28 days before Cycle 1, Day 1 dosing).
f
The Cycle 1, Day 1 physical examination and medical history are not required if the screening physical examination was conducted and medical history 
obtained within 3 days before administration of the first dose of study drug (Cycle 1, Day 1).  Complete physical examinations will be performed during 
screening and will include a neurological exam.  Post screening physical exams will be symptom- or finding-directed.
g See Section 14.1 for Modified Charlson Comorbidity Index.
h Weight should be obtained at screening, on Day 1 predose of each cycle, and at EOS. 
i
Vital signs measurement (blood pressure, heart rate, temperature) should be performed before dosing on visit days and as clinically indicated.  
j
Single 12-lead ECGs will be performed at screening, predose on Day 1 of each cycle, and EOS.  When the timing of a blood sample coincides with the 
timing of ECG measurements, the ECG will be completed before the collection of the blood samples.
k Serious adverse event (SAE) reporting will include serious pretreatment events.  Only those SAEs that occur after the first dose of study drug will be 
collected in the eCRF.  However, all SAEs occurring after consent will be reported to the Millennium Department of Pharmacovigilance or designee (see 
Section 9).
l
The study center staff will check the patient drug diary versus the patient’s supply of TAK-659 tablets to assess compliance.
m Bone marrow biopsy and aspirate assessments of disease burden (blast counts), cytogenetics, and cellular composition by flow cytometry will be performed 
at screening.  In addition, bone marrow biopsies and/or aspirates will be collected to assess disease response between Days 22 and 28 of Cycles1, 2, and 4, 
provided that the disease assessment is available before Day 1 of the following cycle.  Beyond Cycle 4, bone marrow biopsy and/or aspirate assessment will 
be performed as clinically indicated based on changes in peripheral blood counts or when it is needed to establish either CR or disease progression.  Note 
that a bone marrow biopsy is required only at screening. Residual and/or additional bone marrow samples will be requested for biomarker analysis as well 
as confirmation of the FLT-3 mutation status. See footnotes v, w, x and Section 7.4.15.1 for further details.
n A serum pregnancy test will be performed for women of childbearing potential at screening.  A urine pregnancy test must be performed predose on Day 1 
of all cycles with negative results available before the first dose of TAK-659 may be administered for that cycle.  If a serum pregnancy test is performed 
within 3 days of dosing and the result is negative, the urine pregnancy test may be waived on Cycle 1, Day 1.  
o The hematology and chemistry blood samples for Cycle 1, Day 1 may be collected within 3 days before dosing to ensure patient eligibility on study Day 1.  
The percentage of leukemic blast cells should also be noted in the hematology panel.  If screening clinical laboratory testing was performed within 3 days 
before the Cycle 1, Day 1 dose, it need not be repeated on Cycle 1, Day 1.  The percentage of leukemic blast cells should also be noted in the hematology 
panel.
p
Laboratory assessments can be conducted within - 3 days of the scheduled visit, with the exception of PK/pharmacodynamic assessments or unless 
otherwise noted.  Day 1 visits of Cycle 2 and beyond may be modified by up to 3 days due to extenuating circumstances (ie, inclement weather, holidays, 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
20
Schedule of Events for AML Expansion Cohort (Phase 2) [28 Day Cycles]
Screeninga
Cycle 1 
Cycles 2, 3, 
and 4
Cycles 5, 6, and 
beyond
EOSb  (+ 10 
days)
Survival
Follow-upc
Day 
1
Day 
2
Day 
8
Day 
15
Day 
22
Day 1
Day 
15
Day 1
vacations, or other administrative reasons).
q Urinalysis samples will be collected predose and analyzed at the site’s local laboratory.
r
An ophthalmic exam should be performed at screening, on Cycle 2, Day 1, on Cycle 7, Day 1, every 6 cycles thereafter (# 2 weeks), and at EOS.  See 
Section 7.4.14 for details.
s
t
A peripheral blood sample will be obtained at screening for confirmation of the FLT-3 mutation status by a central laboratory test designated by the 
sponsor. 
u
 
v
Additional bone marrow aspirates (remaining aspirate material from the first pull or a second or third pull of bone marrow aspirate) and biopsy specimens 
(segments of the first core biopsy or additional core biopsies) after taking specimens for disease assessment (see footnote m) are required during screening 
for confirmation of the FLT-3 mutation status and exploratory biomarker studies.  See Section 7.4.15.1 for further details and the Laboratory Manual for 
details about the sample collection and shipment procedures. 
w If adequate residual material is available from bone marrow aspirates and/or biopsies collected for disease assessment (or as clinically indicated) during the 
study period (from first dose to 28 days after discontinuation of study treatment), these samples are requested to be  sent to the Sponsor-designated 
laboratory(ies) for biomarker studies. See Section 7.4.15.1 for further details.
x At the time of relapse of any patient who had initially responded to TAK-659, bone marrow aspirate and/or biopsy materials will be collected for biomarker 
study. See Section 7.4.15.1 for further details.
y Blood specimens for PK plasma samples will be collected at time points specified in the AML Dose Expansion (Phase 2) PK Schedule.  Refer to the 
Laboratory Manual for detailed instructions on collection, processing, storing, and shipping of PK samples.  
z  Blood specimen will be collected during screening for a local polymerase chain reaction testing of CMV replication. The CMV viral load data will be 
entered in the eCRF. Further monitoring of CMV, if indicated, will follow the local standard practice. 
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
Confidential
21
AML Dose Expansion (Phase 2) PK Schedule:  Cycle 1
Cycle 1
Day 1
Day 15a,b 
PKc
PKc
Predose (within 1 hour before dosing)
X
X
2-4 hours postdose 
X
X
Abbreviations: AML = acute myelogenous leukemia; CXDY = Cycle X, Day 1; h = hour(s); min = minutes; PK = pharmacokinetic. For BID dosing, PK 
schedule refers to the AM dose.
a Instruct the patients to arrive at the clinic without taking his/her study drug dose for that day.
b The timing of the visit should be planned so that the predose assessments occur at approximately the same time as the dosing time on the previous days.
c Residual plasma from PK samples collected at scheduled sampling time points in the expansion cohorts may be used for PIA assessments, if determined to 
be appropriate by the sponsor.
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
22
TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................24
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................25
1. BACKGROUND AND STUDY RATIONALE..............................................................28
1.1 Scientific Background ..............................................................................................28
1.1.1 Disease Under Treatment...................................................................................28
1.1.2 Study Drug ........................................................................................................29
1.2 Nonclinical Experience.............................................................................................29
1.3 Clinical Experience ..................................................................................................30
1.3.1 Ongoing Studies With TAK-659........................................................................30
1.4 Study Rationale ........................................................................................................32
1.5 Potential Risks and Benefits .....................................................................................35
1.5.1 Potential Risks From Nonclinical Studies...........................................................35
1.5.2 Potential Risks From Clinical Studies ................................................................35
2. STUDY OBJECTIVES ..................................................................................................36
2.1 Primary Objectives ...................................................................................................36
2.2 Secondary Objectives ...............................................................................................36
2.3 Exploratory Objectives .............................................................................................37
3. STUDY ENDPOINTS....................................................................................................37
3.1 Primary Endpoints....................................................................................................37
3.2 Secondary Endpoints................................................................................................38
3.3 Exploratory Endpoints..............................................................................................38
4. STUDY DESIGN...........................................................................................................39
4.1 Overview of Study Design........................................................................................39
4.2 Number of Patients...................................................................................................42
4.3 Duration of Study.....................................................................................................42
5. STUDY POPULATION.................................................................................................43
5.1 Inclusion Criteria......................................................................................................43
5.2 Exclusion Criteria.....................................................................................................45
6. STUDY DRUG..............................................................................................................47
6.1 Study Drug Administration.......................................................................................47
6.2 Definitions of Dose-Limiting Toxicity......................................................................48
6.3 Dose Escalation Rules ..............................................................................................49
6.4 Dose Modification Guidelines ..................................................................................52
6.4.1 General Principles..............................................................................................52
6.4.2 Intrapatient Dose Escalation...............................................................................54
6.4.3 Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................54
6.4.4 TAK-659 Dose Modification for Hematologic Toxicities...................................54
6.4.5 TAK-659 Dose Modification for Nonhematologic Toxicities .............................55
6.5 Concomitant Medications and Procedures ................................................................57
6.6 Precautions and Restrictions .....................................................................................59
6.7 Management of Clinical Events................................................................................60
Pneumonitis................................................................................................................60
Enzyme Elevations .....................................................................................................64
6.8 Blinding and Unblinding ..........................................................................................64
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Clinical Study Protocol C34002 Amendment 02
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6.9 Description of Investigational Agents.......................................................................64
6.10 Preparation, Reconstitution, and Dispensation ........................................................64
6.11 Packaging and Labeling..........................................................................................65
6.12 Storage, Handling, and Accountability....................................................................65
7. STUDY CONDUCT ......................................................................................................65
7.1 Study Personnel and Organizations...........................................................................65
7.2 Arrangements for Recruitment of Patients ................................................................65
7.3 Treatment Group Assignments .................................................................................65
7.4 Study Procedures......................................................................................................66
7.4.1 Informed Consent ..............................................................................................66
7.4.2 Patient Demographics ........................................................................................66
7.4.3 Medical History.................................................................................................66
7.4.4 Physical Examination.........................................................................................67
7.4.5 Patient Height and Weight .................................................................................67
7.4.6 Vital Signs .........................................................................................................67
7.4.7 Eastern Cooperative Oncology Group Performance Status.................................67
7.4.8 Pregnancy Test ..................................................................................................67
7.4.9 Concomitant Medications and Procedures..........................................................68
7.4.10 Adverse Events................................................................................................68
7.4.11 Enrollment .......................................................................................................68
7.4.12 Electrocardiogram............................................................................................68
7.4.13 Clinical Laboratory Evaluations.......................................................................69
7.4.14 Ophthalmic Exam ............................................................................................71
7.4.15 Disease Assessment .........................................................................................71
7.4.16 Biomarker Measurements.................................................................................74
7.4.17 Pharmacokinetic Measurements.......................................................................76
7.4.18 DNA Measurements.........................................................................................76
7.4.19 Modified Charlson Comorbidity Index Assessment..........................................77
7.5 Completion of Treatment..........................................................................................77
7.6 Follow-Up Period.....................................................................................................77
7.7 Completion of Study.................................................................................................78
7.8 Discontinuation of Treatment With Study Drug, and Patient Replacement................78
7.9 Withdrawal of Patients From Study..........................................................................79
7.10 Study Compliance ..................................................................................................80
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................80
8.1 Statistical Methods ...................................................................................................80
8.1.1 Determination of Sample Size............................................................................81
8.1.2 Randomization and Stratification .......................................................................81
8.1.3 Populations for Analysis ....................................................................................81
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................82
8.1.5 Demographic and Baseline Characteristics.........................................................82
8.1.6 Efficacy Analysis...............................................................................................82
8.1.7 Pharmacokinetics/Pharmacogenomics/Biomarkers.............................................83
8.1.8 Safety Analysis ..................................................................................................84
8.1.9 Interim Analysis.................................................................................................86
9. ADVERSE EVENTS .....................................................................................................86
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
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9.1 Definitions................................................................................................................86
9.1.1 Pretreatment Event Definition............................................................................86
9.1.2 Adverse Event Definition...................................................................................86
9.1.3 Serious Adverse Event Definition ......................................................................87
9.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.................................................................................................88
9.3 Monitoring of Adverse Events and Period of Observation.........................................89
9.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events..........89
10. ADMINISTRATIVE REQUIREMENTS .....................................................................90
10.1 Good Clinical Practice............................................................................................90
10.2 Data Quality Assurance ..........................................................................................90
10.3 Electronic Case Report Form Completion...............................................................90
10.4 Study Monitoring ...................................................................................................91
10.5 Ethical Considerations............................................................................................91
10.6 Patient Information and Informed Consent..............................................................91
10.7 Patient Confidentiality............................................................................................92
10.8 Investigator Compliance.........................................................................................92
10.9 On-site Audits ........................................................................................................92
10.10 Investigator and Site Responsibility for Drug Accountability................................92
10.11 Product Complaints ..............................................................................................93
10.12 Closure of the Study .............................................................................................93
10.13 Record Retention..................................................................................................94
11. USE OF INFORMATION............................................................................................94
12. INVESTIGATOR AGREEMENT................................................................................95
13. REFERENCES.............................................................................................................96
14. APPENDICES .............................................................................................................98
14.1 Modified Charlson Comorbidity Index ...................................................................98
14.2 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.........98
14.3 Cockcroft-Gault Equation.......................................................................................99
14.4 New York Heart Association Classification of Functional Capacity........................99
14.5 Prohibited CYP3A and P-gp Inducers and Inhibitors ............................................100
14.6 Amendment 02 Detailed Summary of Changes.....................................................102
LIST OF TABLES 
Table 6-1   
Planned Dose Levels...................................................................................52
Table 6-2   
TAK-659 Dose Adjustments for Nonhematologic Toxicities.......................56
Table 14-1   
Modified Charlson Comorbidity Index........................................................98
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
25
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ASH
American Society of Hematology
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve from zero to infinity
AUC
Area under the plasma concentration versus time curve over the dosing interval
BID
twice daily
BSA
body surface area
BUN
blood urea nitrogen
CD
compact disc
CI
confidence interval
CL/F
apparent clearance
CLL
chronic lymphocytic leukemia
Cmax
maximum (peak) plasma concentration
CMV
cytomegalovirus
CO2
carbon dioxide
CPK
creatine phosphokinase
CR
complete response 
CRc
composite complete remission
CRh
complete response  with partial hematologic recovery
CRi
complete response  with incomplete recovery of blood counts
CRO
contract research organization
CRp
complete response without platelet recovery
CYP
cytochrome P450
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
26
Abbreviation
Term
DOR
duration of response
EC50
Concentration producing half-maximal response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOS
End of Study (visit)
FDA
United States Food and Drug Administration
FIH
first-in-human
FL
follicular lymphoma
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
γ-glutamyl transferase
GI
gastrointestinal
GM-CSF
granulocyte macrophage-colony stimulating factor
GVHD
graft-versus-host disease
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HSCT
hematopoietic stem cell transplant
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
ITAM
immunoreceptor tyrosine-based activating motifs
ITD
internal tandem duplication
IV
intravenous; intravenously
IWG
International Working Group
LC/MS/MS
liquid chromatography tandem mass spectrometry
LDH
lactate dehydrogenase
MCL
mantle cell lymphoma
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation
Term
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non Hodgkin lymphoma
NYHA
New York Heart Association
ORR
overall response rate
OS
overall survival
PD
progressive disease
P-gp
P-glycoprotein
PJP
Pneumocystis jiroveci pneumonia
PK
pharmacokinetic(s)
PR
partial response 
PTR
peak-trough ratio
QD
quaque die; each day; once daily
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QTcB
Bazett’s corrected QT interval
QTcF
Fridericia’s corrected QT interval
Rac
accumulation ratio
RP2D
recommended phase 2 dose
RBC
red blood cell
SAE
serious adverse event
t1/2z
terminal disposition phase half-life
TKD
tyrosine kinase domain
tmax
first time to reach maximum (peak) plasma concentration
TTP
time to progression
ULN
upper limit of the normal range
WHO
World Health Organization
WT
wild type
CCI
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(millisec)
millise
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1.   
BACKGROUND AND STUDY RATIONALE
1.1   Scientific Background
1.1.1   
Disease Under Treatment
Acute myelogenous leukemia (AML) is a heterogeneous disorder of the hematopoietic 
progenitor cells of myeloid lineage, characterized by a block in differentiation and 
uncontrolled proliferation.  The majority of patients with AML are older than 60 years of 
age.  The median age at diagnosis is between 65 and 70 years [2], and approximately 35% of 
patients with newly diagnosed AML are 75 years of age or older [3]. AML as a family of 
heterogeneous malignancies can be categorized using the World Health Organization 
(WHO) classification system based on a combination of morphology, immunophenotype, 
genetics, and clinical features.  In addition to clinical risk factors such as age, performance 
status, and whether AML is associated with prior therapy or antecedent hematologic 
disorders, cytogenetic and molecular features have been found to have major prognostic 
importance.  For example, data suggest that the presence of FLT-3 gene mutations 
negatively impacts response to standard therapy and disease outcome. 
Treatment of AML requires initial induction chemotherapy with the goal of achieving 
complete remission (CR) with resolution of morphologically detectable disease and 
restoration of normal blood counts.  Intensive combination chemotherapy is the primary 
modality for induction therapy for AML.  Options usually include standard or high-dose 
cytarabine (also referred to as Ara-C) in combination with an anthracycline.  Most 
remissions require only a single course; however, approximately one-quarter to one-third of 
patients will require a second induction cycle to obtain a complete remission.
Post-remission therapy, with the aim of prolonging the initial CR and eradicating minimal 
residual disease, has traditionally entailed further chemotherapy, typically 2 to 4 courses of 
consolidation therapy, with or without subsequent prolonged lower dose maintenance 
therapy.  Disease reoccurs in the majority of patients, with only a small likelihood of 
potential cure after administration of “salvage” therapy.  Allogeneic stem cell 
transplantation has been used to overcome this problem, and showed a higher cure and 
disease control rate.  However, it is associated with a higher risk of treatment-related 
morbidity and mortality and is not appropriate for many patients.  In addition, patients who 
relapse within 6 months of initial chemotherapy do not do as well after allogeneic stem cell 
transplant as those with longer initial responses [4]. 
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The CR rate achieved after standard induction therapy is reported to be between 45% and 
60%.  However, the probability of remaining in remission 3 years after diagnosis is below 
10%, the median overall survival (OS) is between 5 and 10 months, and the 5-year survival 
rate is between 6% and 12% [2].  These already disappointing results are still likely to 
overestimate the efficacy of chemotherapy in elderly patients because most studies included 
only patients considered to be medically fit [2]. 
AML represents a significant unmet medical need.  Despite great progress made in the 
understanding of the molecular basis for the heterogeneity of the disease, the standard of 
care has not changed in decades.  There is a dire need for alternative or additional 
therapeutic options for patients with this deadly disease.
1.1.2   
Study Drug
TAK-659 is a reversible, potent, dual inhibitor of SYK and FLT-3 being developed for 
oncology indications, the pathogenesis of a subset of tumors being driven by SYK- and/or 
FLT-3-mediated signaling.  TAK-659 inhibits purified SYK and FLT-3 enzymes with 
concentrations producing 50% inhibition (IC50) of 3.2 and 4.6 nM, respectively.  In cultured 
human tumor cells, TAK-659 potently inhibited the growth of hematopoietic-derived cell 
lines, with a concentration producing half-maximal response (EC50) ranging from 11 to 
775 nM in sensitive cell systems (eg, T-cell lymphoblastoma, megakaryoblastoma, and 
AML).  In a broad kinase panel, TAK-659 demonstrated a more than 50-fold selectivity for 
SYK and FLT-3 over 290 other protein kinases screened.  
1.2   Nonclinical Experience
Detailed information regarding the nonclinical pharmacology and toxicology of TAK-659 
may be found in the Investigator’s Brochure (IB).
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1.3   Clinical Experience 
As of 05 September 2017, 181 patients have been dosed with TAK 659 in 4 ongoing studies, 
including 121 patients in the first-in-human (FIH) Study C34001 (advanced solid tumors 
and lymphoma), 32 patients in Study C34002 (R/R AML), 19 patients in Study C34003 
(advanced solid tumor), and 9 patients in Study C34005 (advanced NHL). Both the C34001 
and C34002 studies are evaluating TAK-659 as a single agent, while the C34003 and 
C34005 studies are evaluating TAK-659 in combination with nivolumab (C34003) and 
5 additional combination agents (C34005). Different data cutoff dates were used to provide 
the most current clinical information, given that the ongoing studies are in various stages of 
conduct. The most current safety and efficacy data for Study C34001 are from the 02 June 
2017 data cutoff date. The most current safety and efficacy data for Study C34002 are from 
the 24 May 2017 data cutoff date. In Study C34003, the TAK-659 dose has been evaluated 
across 3 dose levels of 60 mg, 80 mg, and 100 mg and the maximum tolerated dose (MTD) 
determination is pending. In Study C34005, TAK-659 is currently being evaluated at 60 mg 
with plans to escalate to 100 mg.
1.3.1 Ongoing Studies With TAK-659 
As of 05 September 2017, 181 patients have been dosed with TAK 659 in 4 ongoing studies, 
including 121 patients in the first-in-human (FIH) Study C34001, 32 patients in 
Study C34002, 19 patients in Study C34003, and 9 patients in Study C34005. 
Study C34001: As of 02 June 2017, the TAK-659 dose was escalated from 60 mg to 120 mg 
(60 mg [10 patients], 80 mg [4 patients], 100 mg [90 patients], and 120 mg [7 patients]). The 
MTD for patients with lymphoma and solid tumors has been determined to be 100 mg once 
daily (QD). Expansion cohorts for patients with lymphoma were opened in December 2015, 
and patients in the expansion phase of the study are treated at the MTD/recommended 
phase 2 dose (RP2D) of 100 mg. Of the 111 patients treated in this study (92 patients with 
lymphoma, including 5 patients with chronic lymphocytic leukemia [CLL] and 19 patients 
with solid tumors), 96 patients had discontinued from study by the June 2017 data cutoff 
date. The reasons for discontinuation included PD (45 patients), adverse events (AEs) 
(29 patients), symptomatic deterioration (13 patients), initiation of hematopoietic stem cell 
transplant (2 patients), protocol violation (1 patient), withdrawal by subject (1 patient), and 
other (5 patients).
Study C34002: As of 24 May 2017, 31 patients had enrolled. TAK-659 has been escalated 
from 60 mg QD to 160 mg QD, and an additional dose level of 80 mg BID is also being 
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evaluated. The MTD/RP2D has not yet been determined. Of the 31 patients treated in this 
study, 28 patients had discontinued from the study as of the May 2017 data cutoff date. 
The reasons for discontinuation included PD (5 patients), AEs (18 patients), symptomatic 
deterioration (2 patients), withdrawal by subject (1 patient), and other (2 patients).
The reported AEs were generally as expected on the basis of nonclinical toxicology findings 
of TAK 659 and the patient population being studied. As of 02 June 2017, the most common 
treatment-related AEs reported in Study C34001 (≥20% of patients) have been aspartate 
aminotransferase (AST) increased (49 patients [44%]), amylase increased (39 patients 
[35%]), lipase increased (31 patients [28%]), alanine aminotransferase (ALT) increased and 
diarrhea (28 patients each [25%]), blood creatinine phosphokinase (CPK) increased and 
hypophosphatemia (26 patients each [23%]), and fatigue (22 patients [20%]). 
The most common Grade 3 or greater treatment-related AEs (≥5% of patients) have been 
amylase increased (23 patients [21%]), hypophosphatemia (18 patients [16%]), lipase 
increased (15 patients [14%]), neutropenia (14 patients [13%]), CPK increased (13 patients 
[12%]), anemia and AST increased (7 patients each [6%]), and pneumonia (5 patients [5%]). 
Further investigations are required to determine the clinical significance of the laboratory 
abnormalities, many of which have been asymptomatic, such as amylase and lipase 
increased, AST and ALT increased, and blood CPK increased. In Study C34001, as of 
02 June 2017, there were 35 on-study deaths. Three of the AEs that led to death were 
considered treatment related (multi-organ failure following sepsis, disseminated varicella, 
and respiratory failure in the presence of Pneumocystis jiroveci pneumonia [PJP]; 
cytomegalovirus [CMV] and aspergillus infection; and right pneumothorax and renal 
failure).   
In Study C34001, as of 02 June 2017, 9 of 48 response-evaluable patients with DLBCL 
achieved a complete response (CR) and 4 achieved a partial response (PR). Seven of 
10 response-evaluable patients with indolent lymphomas responded (1 CR and 6 PRs). 
Two of 4 response-evaluable patients with CLL achieved a response (both PR). 
In Study C34002, as of 24 May 2017, there were 15 on-study deaths (one drug-related, 
multiple organ dysfunction syndrome). To date, the safety profile in Study C34002 appears 
to be similar to that of Study C34001. Early signs of antileukemic activity have been 
observed in a number of patients who have demonstrated significant reductions in both 
peripheral blast and bone marrow blast counts. Three patients have achieved objective 
response per IWG 2003 criteria (1 CR, 2 CRi) [15] as of the cutoff date. 
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1.4   Study Rationale
TAK-659 is a selective, potent, dual inhibitor of FLT-3 and SYK.
FLT-3 is a Class III receptor tyrosine kinase that is normally expressed only in 
hematopoietic stem and progenitor cells.  However, its expression has been found in the 
blasts of a majority of patients with AML.  Activating mutations of FLT-3, including 
internal tandem duplication (ITDs) within the juxtamembrane region of FLT-3 and point 
mutations in the FLT-3 activation loop, are observed in approximately 30% of AML 
patients.  These FLT-3 mutations, associated with early relapse after standard chemotherapy 
and poor survival, represent a critical prognostic factor for AML.  The ligand-independent 
and constitutive activation of FLT-3 resulting from these gain-of-function mutations, 
promotes proliferation and survival of AML blasts through the STAT5, RAS/MAPK, and 
PI3K/AKT pathways.  Therefore, FLT-3 is a rational drug target for AML.  Several FLT-3 
inhibitors have been explored clinically and potential therapeutic benefit in AML has been 
demonstrated. 
SYK is a non-receptor protein tyrosine kinase that is broadly expressed in hematopoietic 
cells.  SYK binds to phosphorylated immunoreceptor tyrosine-based activating motifs 
(ITAM) in key surface receptors in immune cells, including Fc, B cell, T cell, and certain 
natural killer cell receptors.  SYK functions normally to mediate ITAM signaling by 
coupling activated immunoreceptors to downstream signaling events that mediate diverse 
cellular responses, including proliferation, differentiation, phagocytosis, and survival.  The 
importance of SYK in hematological malignancies has been recognized in lymphoma, 
leukemia, and myelodysplastic syndrome (MDS).  For example, recurrent ITK-SYK 
translocations have been reported in peripheral T-cell lymphoma, and SYK-dependent tonic 
B-cell receptor signaling has been recognized as an important survival pathway in DLBCL.  
Clinical trials demonstrating that SYK inhibition could lead to tumor responses in patients 
with non-Hodgkin lymphoma and chronic lymphocytic leukemia, further established the 
relevance of SYK in B-cell malignancy. 
A role for SYK in myeloid malignancies was first suggested with the report of a fusion of 
TEL to SYK in a patient with MDS with t(9;12) (q22;p12).  Importantly, this TEL-SYK 
fusion transformed the interleukin-3 (IL-3)-dependent murine hematopoietic cell line Ba/F3 
to growth factor independence.  Additionally, AML was identified as another hematologic 
malignancy in which SYK plays an important role.  Genetic and pharmacological 
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inactivations of SYK have been shown to promote differentiation of AML cells and 
attenuate leukemia growth in vivo.
A recently published study suggested that SYK is a critical regulator of FLT-3 in AML.  
FLT-3 was found to be transactivated by SYK via direct binding [6].  Highly activated SYK 
was predominantly found in FLT-3-ITD-positive AML and FLT-3-ITD AML cells were 
more vulnerable to SYK suppression than their FLT-3 wild-type (WT) counterparts.  SYK 
overexpression was also found to promote resistance to FLT-3-ITD-targeted therapy in an 
in vivo FLT-3-ITD model of AML.
This study will evaluate the safety and efficacy of TAK-659 for the treatment of AML.  The 
study is designed to assess the efficacy of TAK-659 in both FLT-3-ITD and FLT-3 WT 
patient populations.  A retrospective analysis will also be performed to explore the 
contribution of FLT-3 and/or SYK inhibition to the level of clinical activity observed.
Rationale for Pharmacokinetic Assessments
In the AML Dose Escalation cohorts, blood will be collected during Cycle 1 using an 
intensive sampling schedule so as to permit the detailed characterization of the plasma 
pharmacokinetics (PK) of TAK-659. Specifically, serial plasma PK assessments will be used 
to characterize single- and repeat-dose concentration-time profiles of TAK-659, calculate 
PK parameters, evaluate the dose-exposure relationship, assess dose- and time-dependence 
of PK parameters, and contribute to the development of a population PK model for 
TAK-659. The PK sampling time points are derived from considerations of clinic 
practicality and patient convenience. Sampling will be conducted on Days 1, 2, 15, and 16 of 
Cycle 1 to allow evaluation of the accumulation of TAK-659 with QD or twice-daily (BID) 
dosing. 
In the AML Dose Expansion cohorts, blood will be collected during Cycle 1 (on Days 1 and 
15) to support population PK model development.
Plasma PK data collected in the AML Dose Escalation cohorts and the AML Dose 
Expansion cohorts may be used individually or in combination with data from other studies 
to explore the relationship between TAK-659 PK and pharmacodynamics effects, 
pharmacogenomics in drug metabolizing enzymes and/or transporters, electrocardiogram 
(ECG) parameters (eg, QTc), other safety parameters, and clinical response.
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predictive of safety issues and/or clinical response to TAK-659, and/or that account for 
clinically meaningful variability in drug exposure.  
1.5   Potential Risks and Benefits
Because TAK-659 has been administered to a total of only 181 patients as of 05 September 
2017, it is not currently possible to describe with certainty the potential adverse effects of 
the compound.
1.5.1 Potential Risks From Nonclinical Studies
Potential risks from nonclinical studies in dogs and rats include the following:

Lymphoid/hematopoietic effects that include lymphoid depletion and 
myelosuppression that are associated with thrombocytopenia, neutropenia, and 
reticulocytopenia. These findings may be associated with increased susceptibility to 
infection, bleeding, and anemia.

Epithelial effects on the intestinal tract, urinary tract, and lens. Intestinal effects 
included minimal-to-slight mucosal hemorrhaging. Urinary and renal tract effects 
included hyperplasia of transitional epithelium in the kidney and bladder, dilatation 
and hemorrhage in the renal pelvis that led to hematuria and proteinuria, and 
urolithiasis with possible ureter obstruction. Lens effects included epithelium 
hyperplasia leading to anterior axial opacity.

Reproductive system effects, including decreased spermatozoa and seminiferous 
tubule degeneration in the testis and corpora luteal necrosis in the ovaries.

Possible mutation of DNA.

Growth plate thickening and disorganization (not relevant to adults).

Lymphoid and hematopoietic effects and reproductive system effects are considered 
important potential risks.
1.5.2  Potential Risks From Clinical Studies
Potential risks based on clinical observations include the following:
On the basis of data from Study C34001, asymptomatic elevation in lipase was added as an 
important potential risk of TAK-659. In nonclinical studies, lipase was sporadically elevated 
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at high doses of TAK-659; however, there was no evidence of microscopic organ damage. 
In clinical studies to date, asymptomatic lipase or amylase elevations are reported commonly 
(≥10% of patients). Patients in Study C34002 will have frequent monitoring of lipase and 
amylase as outlined in the Schedule of Events.
Cases of pneumonitis have been reported in clinical studies with B-cell receptor (BCR) 
pathway kinase inhibitors, including TAK-659, and pneumonitis is considered an important 
potential risk of TAK-659. Pneumonitis and other pulmonary toxicities are being closely 
monitored in TAK-659 clinical studies.
There have been occurrences of opportunistic infections such as PJP in some patients who 
had fever. These patients had other underlying conditions that made them prone to 
infections. With the limited experience we have with TAK-659, we have not determined 
whether TAK-659 is directly associated with the occurrences of these infections.
Further details regarding the benefits and risks associated with TAK-659 may be found in 
the current version of the TAK-659 IB.
2.   
STUDY OBJECTIVES
2.1   Primary Objectives
The primary objectives are:

Phase 1b dose finding phase:  to determine the safety, tolerability, and MTD/ RP2D 
of TAK-659 administered orally on a QD or BID dosing schedule in patients with 
relapsed or refractory AML 

Phase 2 expansion phase:  to evaluate preliminary efficacy of TAK-659 in relapsed 
or refractory AML as measured by overall response rate (ORR)
2.2   Secondary Objectives
The secondary objectives are:

To evaluate additional efficacy measures of TAK-659, such as duration of response 
(DOR), time to progression (TTP), mortality rate at 3 and 6 months, and overall 
survival (OS)
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!
To evaluate differential efficacy of TAK-659 in patients with or without FLT-3-ITD 
mutation
!
To characterize the plasma PK of TAK-659 in patients with relapsed or refractory 
AML
2.3   Exploratory Objectives
3.   
STUDY ENDPOINTS
3.1   Primary Endpoints
The primary endpoints are:
!
Dose finding phase:  AEs, serious adverse events (SAEs), dose-limiting toxicities 
(DLTs) (Cycle 1), clinical laboratory values, and vital sign measurements.
!
Phase 2 dose expansion phase:  ORR (which will include CR, CR with incomplete 
platelet recovery [CRp], CR with incomplete hematologic recovery [CRi], CR with 
partial hematologic recovery [CRh], a composite complete remission [CRc defined 
as the sum of patient achieving a CR, CRh, CRi, or CRp], and PR).
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3.2   Secondary Endpoints
The secondary endpoints are:
!
DOR.
!
TTP.
!
Mortality rate at 3 and 6 months.
!
OS.
!
ORR, DOR, TTP, mortality rate at 3 and 6 months, and OS in FLT-3-ITD mutant 
versus WT populations.
!
Plasma PK parameters, including but not limited to maximum (peak) plasma 
concentration (Cmax), first time to reach maximum (peak) plasma concentration 
(tmax), area under the plasma concentration versus time curve over the dosing interval 
(AUC%), apparent clearance (CL/F), accumulation ratio (Rac), and peak-trough ratio 
(PTR).
3.3   Exploratory Endpoints
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4.   
STUDY DESIGN 
4.1   Overview of Study Design
This study is an open-label, multicenter, phase 1b/2, dose escalation, and expansion study of 
TAK-659 in adult patients with relapsed or refractory AML.  This study will include a 
phase 1b dose finding portion and single-arm phase 2 expansion portion.  The patient 
population will consist of adults previously diagnosed with primary or secondary AML for 
whom no standard therapies are anticipated to result in a durable remission based on the 
opinion of the investigator, or who refuse standard therapies.  For the phase 2 portion of the 
study, patients must be refractory to or relapsed after no more than 2 prior chemotherapy 
regimens.  
It is expected that approximately 40 patients will be enrolled in the phase 1b portion and up 
to 66 patients will be enrolled in the phase 2 portion of this study.  Once enrolled into the 
study, patients will be administered TAK-659 tablets (available in 20-, 60-, and 100-mg 
dosage strengths).  Each 28-day treatment cycle will be composed of 28 consecutive days of 
QD or BID TAK-659 treatment.  Patients, including those who achieve a CR, may receive 
TAK-659 until they experience disease progression.  
The starting dose for the phase 1b portion of this study (Study C34002) will be directed by 
the current Study C34001, the FIH dose escalation study of TAK-659 in patients with 
advanced solid tumors and lymphoma.  The starting dose in Study C34002 will not exceed 
the highest dose determined to be safe in Study C34001 at the time Study C34002 starts.  
A dose of 60 mg QD has been determined to be tolerable based on a 3+3 dose escalation 
schema after evaluation of 6 patients.  Based on these data, the starting dose will be 60 mg 
QD for Study C34002.  Since the initiation of Study C34002, dose escalation has been 
completed in Study C34001 with 100 mg QD determined as the MTD. In the expansion 
phase of the ongoing FIH study, lymphoma patients are being evaluated at 100 mg and early 
clinical activity has been observed in this population. In the NHL population, the more 
relevant target for TAK-659 is SYK.  
To determine the MTD of TAK-659 in AML, an approach using a 3+3 dose escalation 
design will be used as detailed in Section 6.3.  Planned dose escalation will follow 20-mg 
increments of escalation (eg, from 60 mg to 80 mg QD).  A more aggressive dose escalation 
(more than 20-mg increments but not exceeding 100% escalation), evaluation of alternative 
dosing regimens (eg, BID), and expansion of an existing dose level up to 12 evaluable 
patients are all permissible following discussions between the sponsor and the investigators 
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if supported by evolving safety, tolerability, and PK data.  Dose escalation will continue 
until either MTD is reached or the RP2D (if different from MTD) has been determined 
based on safety, tolerability, preliminary PK, PIA, and preliminary efficacy data, if 
available.  
At least 6 patients will be evaluated at RP2D (either the MTD or at a lower dose as 
determined) before making a decision to advance to the phase 2 dose expansion phase.  In 
the process of determining or refining RP2D, expansion of more than 1 dose level to at least 
6 patients (up to a maximum of 12 evaluable patients per dose level) is permissible so that 
early signs of clinical activity can be assessed to a greater extent to assist dose selection.
The phase 2 expansion study in relapsed or refractory AML will be conducted using a 
Simon’s 2-stage design (see Study Overview Diagram).  The primary objective of the 
phase 2 portion of the study is to detect an efficacy signal that warrants further development 
of TAK-659 in AML.  The primary measure of efficacy for the phase 2 portion will be the 
ORR, which will include CR, CRp, CRi, CRh, CRc, and PR.  Nine and 15 response-
evaluable patients will be enrolled initially in the FLT-3 WT and FLT-3 ITD/tyrosine kinase 
domain (TKD) mutant cohorts, respectively, during the first stage.  Best response will be 
assessed by the end of Cycle 4 of TAK-659 treatment for the purpose of an interim analysis 
between Stage 1 and Stage 2.  The FLT-3 WT and FLT-3 ITD/TKD mutant cohorts will 
proceed to the second stage if ∀2 and ∀6 patients respond to treatment (ORR), respectively.  
Other efficacy measures, such as DOR, TTP, and mortality rate will also be considered in 
the decision to expand the study to the second stage.  If the FLT-3 WT and/or FLT-3 
ITD/TKD mutant cohort(s) proceed(s) to the second stage, a further 14 and 17 evaluable 
patients, respectively, will be assessed in the 2 cohorts.  
Best responses from both cohorts will be assessed individually and combined in an effort to 
understand the all-comer response rate.  For patients with known FLT-3 mutational status 
based on local data, enrollment and cohort assignment could proceed using the local results.  
Upon enrollment, the FLT-3 mutational status will be verified using a sponsor-designated 
central testing laboratory.  The central laboratory data will be used as the default result and 
cohort reassignment will occur in the case of discrepant central versus local test results.  
Prospective FLT-3 mutational testing will be performed prior to enrollment for patients for 
whom local data are not available.
 
 
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
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AEs will be assessed, and laboratory values, vital signs, and ECGs will be obtained to 
evaluate the safety and tolerability of TAK-659.  Toxicity will be evaluated according to
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
version 4.03, effective date 14 June 2010 [9].  Dose-limiting toxicities (DLTs) are defined in 
Section 6.2.
Patients will be treated until either disease progression or occurrence of unacceptable study 
drug-related toxicities.  Patients may discontinue therapy at any time.  Patients will attend 
the End of Study (EOS) visit 28 days (+10 days) after receiving their last dose of study drug 
or before the start of subsequent anticancer therapy (other than hydroxyurea) if that occurs 
sooner.
Assessment of disease response will follow the criteria outlined in the Revised 
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 [10].  
Blood samples for determination of the plasma concentration of TAK-659 will be obtained 
from patients in the AML Dose Escalation cohorts and the AML Expansion cohorts.  These 
samples will be obtained during Cycle 1 at the time points specified in the Schedule of 
Events.
A plasma inhibitory assay [1] will be used to assess the FLT-3 and possibly SYK inhibitory 
effects of TAK-659 in vitro using plasma samples collected from patients exposed to TAK-
659 at different dose/exposure levels as indicated in the Schedule of Events.
CCI
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-659 
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Bone marrow biopsies and aspirates for disease response monitoring will be obtained as 
described in the Schedule of Events.  Residual and/or designated samples from bone marrow 
biopsies and aspirates collected for disease assessment will also be used for analysis of 
biomarkers.
4.2   Number of Patients
For the phase 1b portion, approximately 40 patients will be enrolled in this study from 
approximately 6 study centers in the United States.  For the phase 2 portion, up to 
66 patients will be enrolled in this study from approximately 10 to 15 global sites.  
Enrollment is defined as time of initiation of the first dose of study drug.
Patients who are withdrawn from treatment during Cycle 1 for reasons other than toxicity 
during the phase 1b portion of the study will be replaced.  Patients in the phase 2 portion of 
the study who are not evaluable for response will be replaced.
4.3   Duration of Study
Patients, including those who achieve a CR, may receive TAK-659 until they experience 
disease progression.  Patients will discontinue treatment if they have an unacceptable 
TAK-659–related toxicity.  The maximum duration of treatment, however, will be 
12 months unless it is determined that a patient would derive benefit from continued therapy 
beyond 12 months.
Patients will be followed for 28 days after the last dose of TAK-659 or to the start of 
subsequent anticancer therapy, whichever occurs first, to permit the detection of any delayed 
treatment-related AEs.  All patients, including those patients no longer on treatment, will be 
assessed for survival.  Patients who discontinue the study, regardless of reasons for 
discontinuation, will be followed for survival every month until death, loss to follow-up, or 
withdrawal of consent for further follow-up for up to 12 months after discontinuation of the 
study drug.  In addition, information on any subsequent anticancer therapies will be 
collected during the survival follow-up period.  For patients who achieve CR but discontinue 
study treatment while still in remission, disease progression based upon available local data 
will also be collected during the survival follow-up period. 
The final analyses for the clinical study report may be conducted after all patients enrolled in 
the study have had the opportunity to complete 4 cycles of treatment with TAK-659.
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It is anticipated that this study will last for approximately 66 to 72 months, including 34 to 
36 months in the phase 1b portion and 32 to 36 months in the phase 2 portion.
5.   
STUDY POPULATION
Patients will be males and females age 18 years or older with histopathologically 
documented primary or secondary AML (excluding acute promyelocytic leukemia) as 
defined by WHO criteria, for whom no standard therapies are anticipated to result in a 
durable remission based on the opinion of the investigator, or who refuses standard therapies 
(phase 1b and 2).  For the phase 2 portion of the study, patients must be refractory to or 
relapsed after no more than 2 prior chemotherapy regimens.  Patients must have adequate 
organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of 
0 to 1.  Patients must not have clinically significant toxicity from prior chemotherapy, 
hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of TAK-659, or 
clinically significant graft-versus-host disease requiring ongoing immunosuppressive 
therapy.
5.1   Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients 18 years or older.
2. Patients must have a histopathologically documented diagnosis of primary or 
secondary AML (excluding acute promyelocytic leukemia), as defined by WHO 
criteria (Jaffe et al, 2001), for whom no standard therapies are anticipated to result in 
a durable remission according to the clinical judgement of the principal investigator, 
or who refuses standard therapies (phase 1b and 2).
3. Patients for the phase 2 portion of the study must, in addition, meet the following:
a.
Patients must be refractory to or relapsed after no more than 2 prior 
chemotherapy regimens.  Re-induction with the same regimen or stem cell 
transplant will not be considered a separate regimen.
4. Eastern Cooperative Oncology Group performance status of 0 to 1 (refer to 
Section 14.2).
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5. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method 
of contraception and 1 additional effective (barrier) method, at the same time, 
from the time of signing the informed consent through 180 days after the last 
dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 180 days after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods for the female partner], withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used together.)
6. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that consent may 
be withdrawn by the patient at any time without prejudice to future medical care.
7. In the absence of rapid progressive disease, the interval from prior systemic 
anticancer treatment to time of TAK-659 administration should be at least 2 weeks 
for cytotoxic agents (other than hydroxyurea), or at least 5 half-lives for 
noncytotoxic agents, and patients have to have recovered from acute toxicities of 
these therapies.  Patients who are on hydroxyurea may be included in the study and 
may continue on hydroxyurea for the first 28 days while participating in this study. 
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8. Suitable venous access for the study-required blood sampling, including PK 
sampling and blood transfusion support.
9. Clinical laboratory values as specified in the following:  

Total bilirubin must be ≤1.5 the upper limit of normal (ULN).

Serum ALT and AST must be ≤2.5 the ULN.

Lipase ≤1.5 ULN and amylase ≤1.5 ULN with no clinical symptoms 
suggestive of pancreatitis or cholecystitis.

Creatinine clearance ≥60 mL/min either as estimated by the Cockcroft-Gault 
equation (See Section 14.3) or based on urine collection (12 or 24 hours).
5.2   Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Clinically active central nervous system leukemia.
2. Female patients who are lactating and breastfeeding or have a positive serum 
pregnancy test during the Screening period or a positive urine pregnancy test on Day 
1 before first dose of study drug.
3. Any serious medical or psychiatric illness, including drug or alcohol abuse, that 
could, in the investigator’s opinion, potentially jeopardize the safety of the patient or 
interfere with the objectives of the study.
4. Systemic anticancer treatment (including investigational agents) ≤21 days or ≤5 
their half-lives before the first dose of study treatment. (For example, if the 5 × the 
half-life is shorter than 21 days, 5 × half-life should be used as the washout period. 
However, a minimum of 10 days should elapse from prior therapy to initiating 
protocol therapy.) 
5. Persistent clinically significant toxicity from prior chemotherapy that is Grade 2 or 
higher by the NCI CTCAE (v4.03).
6. Receipt of HSCT within 60 days of the first dose of TAK-659; clinically significant 
graft-versus-host disease (GVHD) requiring ongoing immunosuppressive therapy 
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post HSCT at the time of screening (use of topical steroids for ongoing skin GVHD 
is permitted).
7. Active, systemic infection requiring intravenous (IV) antibiotic, antifungal, or 
antiviral therapy or other serious infection within 14 days before the first dose of 
study drug.
8. Major surgery within 14 days before the first dose of study drug and have not 
recovered fully from any complications from surgery.
9. Radiotherapy less than 2 weeks before the first dose of study treatment or have not 
recovered from acute toxic effects from radiotherapy.
10. Known human immunodeficiency virus (HIV) positive (testing not required).
11. Known hepatitis B surface antigen-positive, known or suspected active hepatitis C 
infection (testing not required).
12. Any of the following cardiovascular conditions: 
a) Acute myocardial infarction within 6 months before starting study drug;
b) Current history of New York Heart Association (NYHA) Class III or IV heart 
failure (see Section 14.4);
c) Evidence of current uncontrolled cardiovascular conditions including cardiac 
arrhythmias, angina, pulmonary hypertension, or electrocardiographic evidence 
of acute ischemia or active conduction system abnormalities;
d) Fridericia’s corrected QT interval (QTcF) > 450 milliseconds (msec) (males) or 
> 475 msec (females) on a 12-lead ECG during the Screening period; 
e) Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm 
and intervals that in the opinion of the investigator are considered to be clinically 
significant.
13. Known gastrointestinal (GI) disease or GI procedure that could interfere with the 
oral absorption or tolerance of TAK-659 including difficulty swallowing tablets; 
diarrhea > Grade 1 despite supportive therapy.
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14. Use or consumption of any of the following substances:
a) Medications or supplements that are known to be inhibitors of P-gp and/or strong 
reversible inhibitors of CYP3A within 5 times the inhibitor half-life (if a 
reasonable half-life estimate is known) or within 7 days (if a reasonable half-life 
estimate is unknown) before the first dose of study drug. In general, the use of 
these agents is not permitted during the study except for AE management (see 
Section 6.7 for details). See Appendix 14.5 for a nonexhaustive list of strong 
CYP3A reversible inhibitors and/or P-gp inhibitors based on the US Food and 
Drug Administration (FDA) Draft DDI Guidance.
b) Medications or supplements that are known to be strong CYP3A mechanism-
based inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 days or 
within 5 times the inhibitor or inducer half-life (whichever is longer) before the 
first dose of study drug. In general, the use of these agents is not permitted during 
the study except for AE management (see Section 6.7 for details). See Appendix 
14.5 for a nonexhaustive list of strong CYP3A mechanism-based inhibitors or 
strong CYP3A inducers and/or P-gp inducers based on the US FDA Draft DDI 
Guidance.
c) Grapefruit-containing food or beverages within 5 days before the first dose of 
study drug. Note that grapefruit-containing food and beverages are not permitted 
during the study.
15. White blood cell count 50,000/L; hydroxyurea may be used to control the level of 
circulating leukemic blast cell counts prior to study entry and, if needed, 
concomitantly while on TAK-659 treatment during the first 28 days of the study.  
Hydroxyurea can be used up to a maximum dose of 5 g/day.
6.   
STUDY DRUG
6.1   Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
prior to drug administration.  Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).
The study drug will be dosed continuously, QD or BID, in 28-day cycles.  The study drug 
should be taken on an empty stomach, at least 1 hour before and no sooner than 2 hours after 
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ingestion of food and/or beverages other than water.  Each tablet should be swallowed 
separately with a sip of water.  A total of approximately 8 ounces (240 mL) of water should 
be taken with the prescribed dose.  Patients should swallow the study medication whole. The 
study medication should not be chewed, crushed, or manipulated in any way before 
swallowing. Administration of the tablets will be guided by the dosing tables included in the
Pharmacy Manual.
Patients should be instructed to take their study medication at approximately the same time 
each day and to not take more than the prescribed dose at any time. On visit days, patients 
should be instructed to hold their dose until predose assessments are performed. For BID 
dosing, morning and evening doses should be approximately 12 hours apart. In the event 
that a patient fails to take the TAK-659 dose at their scheduled dosing time (6 hours of 
their scheduled dosing time for QD dosing; ±3 hours of their scheduled dosing time for BID 
dosing), that dose should be skipped and the patient must not make dose adjustments on that 
day or subsequent days to account for the missed dose, for example, by taking a double dose 
of TAK-659 on the following day. Patients should record any skipped doses in their dosing 
diary (see the Study Manual) and resume dosing at the next scheduled time with the 
prescribed dosage. 
If severe emesis prevents the patient from taking a TAK-659 dose, that dose will be skipped.  
If emesis occurs after study medication ingestion, patients should not re-dose following 
emesis and should record the time of the emesis in their dosing diary (see the Study 
Manual).  Patients should resume dosing at the next scheduled time with the prescribed 
dosage.
6.2   Definitions of Dose-Limiting Toxicity 
Toxicity will be evaluated according to the NCI CTCAE, version 4.03, effective 14 June 
2010 [9].  These criteria are provided in the Study Manual.  DLT will be defined as any of 
the following events that are considered by the investigator to be at least possibly related to 
therapy with TAK-659:

Prolonged myelosuppression with the persistence of Grade 4 neutropenia or 
≥Grade 4 thrombocytopenia in the absence of leukemia (blast count <5% in bone 
marrow) at least 42 days after the initiation of Cycle 1 therapy
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
Any Grade 3 or greater nonhematologic toxicity with the following exceptions:
o
Grade 3 nausea and/or emesis resolved to ≤ Grade 1 or baseline in a week after 
the use of an optimal antiemetic regimen based on standard practice.  The 
optimal antiemetic regimen is defined as an antiemetic regimen that employs 
both a 5-hydroxytryptamine 3 serotonin receptor (5-HT3) antagonist and a 
corticosteroid given in standard doses and according to standard schedules.
o
Grade 3 diarrhea that resolved to ≤ Grade 1 or baseline in a week after receiving 
the maximal supportive therapy based on standard practice.
o
Brief (1 week) Grade 3 fatigue.
o
Asymptomatic Grade 3 laboratory abnormalities that are considered to be not 
clinically significant.  The determination of the clinical significance will be made 
jointly by the investigators and the sponsor and documented in writing.

Failure to administer ≥75% of planned doses of the study drug due to TAK-659–
related or possibly related hematological (considered not related to leukemic 
infiltration) or nonhematologic toxicities.

Other TAK-659–related Grade 2 or greater nonhematologic toxicities that, in the 
opinion of the investigator, require a dose reduction or discontinuation of therapy 
with TAK-659.
Although DLTs may occur at any point during treatment, only DLTs occurring during 
Cycle 1 of treatment will necessarily influence decisions regarding dose escalation, 
expansion of a dose level, or evaluation of intermediate dose levels.  Patients will be 
monitored through all cycles of therapy for treatment-related toxicities.
6.3   Dose Escalation Rules 
A 3+3 dose escalation design will be used to determine the MTD of TAK‑659 in AML.  
The starting dose for the dose escalation portion of this study (Study C34002) will be 
directed by the current Study C34001, the FIH dose escalation study of TAK-659 in patients 
with advanced solid tumors and lymphoma.  The starting dose in Study C34002 will not 
exceed the highest dose evaluated to be safe in Study C34001.  A dose of 60 mg QD has 
been determined to be safe and tolerable based on the 3+3 dose escalation schema after 
evaluation of 6 patients. Based on these data, the starting dose will be 60 mg QD for Study 
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C34002 unless additional data from Study C34001 indicate a higher dose is safe. Since the 
initiation of Study C34002, dose escalation has been completed in Study C34001 with 100 
mg QD determined as the MTD.
Planned dose escalation will follow 20-mg increments of escalation (eg, from 60 mg to 
80 mg QD).  A more aggressive dose escalation (more than 20-mg increments but not
exceeding 100% escalation), evaluation of alternative regimens (e.g. BID), and expansion of 
an existing dose level up to 12 evaluable patients are all permissible following discussions 
between the sponsor and the investigators, if supported by evolving safety, tolerability, and 
PK data of TAK-659.  Dose escalation will continue until either MTD is reached or the 
RP2D, if different from MTD, has been determined based on safety, tolerability, preliminary 
PK, and preliminary efficacy data, if available.
The dose escalation plan, as specified in Table 6-1, is based on the starting dose of 60-mg 
TAK-659 QD, the dose thus far determined to be tolerable in Study C34001.  Escalation will 
be based on safety as determined in Cycle 1.  While the primary escalation schema is 
designed to determine a classical Cycle 1-based MTD, dose escalation may be halted at any 
time after consultation between the sponsor and investigators if cumulative toxicity beyond 
Cycle 1 indicates that a given dose exceeds a tolerable RP2D.  At least 6 patients will be 
evaluated at the MTD or RP2D before making a decision to advance to phase 2 dose 
expansion.  In the process of determining or refining RP2D, expansion of more than 1 dose 
level to at least 6 patients (up to a maximum of 12 evaluable patients per dose level) is 
permissible so that pharmacodynamic measures and early sign of clinical activity can be 
assessed to a greater extent to assist dose selection.
Escalation rules based on DLTs include: 
1. If 0 of 3 patients experiences DLT, dose escalation will proceed to the next higher
dose level at which 3 patients will be enrolled.
2. If 1 of 3 patients experiences DLT, 3 more patients will be enrolled at that same dose 
level.  
3. Escalation will continue if 1 of 6 patients experiences DLT.
4. If 2 or more patients in any dose level experience DLT, enrollment at that dose level 
will stop.  Following consultation between the sponsor and investigators, either the 
previous dose level will be considered the MTD (if 6 or more patients have been 
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studied at that dose level), the previous dose level will be expanded (if fewer than 
6 patients have been studied at that dose level), or a dose level intermediate between 
the current and the previous dose level will be evaluated.  
Figure 6-1 is a diagrammatic representation of these rules.
Figure 6-1   
Dose Escalation Algorithm
Enter 3 at
same dose
> 1 of 6 DLTs
Stop
MTD = Previous dose
1 of 6 DLT
Escalate to
next dose
0 DLTs
Enter 3
1 DLT
2-3 DLTs
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Table 6-1   
Planned Dose Levels
Dose Level
Dose (unit)
Starting dose not exceeding highest safe dose 
evaluated in Study C34001:
-2
20 mg
-1
40 mg
1
60 mg
2
80 mg
3
100 mga
a Alternative dose escalation, including changing escalation increments, evaluation of alternative 
regimens/schedules (e.g. BID), and expansion of existing dose levels up to 12 evaluable patients, is 
permissible following written confirmation of discussions between the sponsor and the investigators, if 
such measures are needed for adjustment based on evolving safety, tolerability, and PK data.
DLT-evaluable patients in each dose cohort will consist of patients who have met the 
minimal treatment and safety evaluation requirements of the study and/or who experience a 
DLT during Cycle 1.  The minimum treatment and safety evaluation requirements are met, 
if, in Cycle 1, the patient has been treated with TAK-659 for ≥21 days (receiving at least 
75% of planned doses of TAK-659 in Cycle 1) and observed for ≥28 days following the 
dose on Cycle 1, Day 1, and is considered to have sufficient safety data by both the sponsor 
and investigators to conclude a DLT did not occur.  Patients who do not meet these 
minimum requirements will be regarded as ineligible for inclusion as DLT-evaluable 
patients for the given dose cohort and may be replaced within the same cohort.  
6.4   Dose Modification Guidelines
6.4.1   
General Principles
Treatment cycles with TAK-659 are 28 days.  The patient will be evaluated weekly during 
Cycle 1, every other week during Cycles 2 to 4, and then every cycle thereafter for possible 
toxicities that may have occurred after previous doses.  Toxicities are to be assessed 
according to the NCI CTCAE, version 4.03.  All toxicities that occur during the study will 
be actively managed following the standard of care unless otherwise specified in the 
protocol.  Patients experiencing AEs attributed to TAK-659 may continue study treatment 
and maintain the same dose, or have doses of TAK-659 held or reduced, or permanently 
discontinue from the study.  Detailed dose modification guidelines are provided in 
Sections 6.4.4 and 6.4.5.  
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Patients who have the TAK-659 dose held due to treatment-related or possibly related AEs 
may resume study drug after resolution of the AE, but may either maintain the same dose 
level or have doses of TAK-659 reduced (dose reduction) by at least 1 dose level.  When a 
dose reduction occurs, the TAK-659 dose will be reduced to the next lower dose that either 
has been established as a safe dose during dose escalation, or is lower by a 20-mg increment 
(Table 6-1).  If initial dose adjustment does not provide sufficient relief, the dose of TAK-
659 can be further reduced if the treating physician considers that the patient is benefiting 
from study treatment and may benefit at a further reduced dose of TAK-659.  When a dose 
reduction of TAK-659 is required due to toxicity, no dose re-escalation will be permitted. 
If TAK-659 dosing is delayed for > 21 days for TAK-659–related or possibly related 
toxicities despite supportive treatment per standard clinical practice or more than 2 dose 
reductions are required in a patient, this patient should be considered to have study treatment 
discontinued, unless the treating physician considers that the patient may benefit from 
continued study treatment after resolution of AEs to ≤Grade 1, or baseline, or a level 
considered acceptable by the physician.  The patient will continue to be followed for 28 days 
for safety evaluation after the last administration of TAK-659.
Patients who experience a DLT (during escalation) or DLT-like toxicity (during phase 2 of 
the study) during the first cycle will, in general, require that treatment with TAK-659 be 
permanently discontinued.  If, in the opinion of the investigator and the sponsor (project 
clinician or designee), it is in the patient’s best interest to continue treatment with TAK-659, 
then the dose of TAK-659 will be reduced by at least 1 dose level when treatment resumes 
after recovery of the toxicity or toxicities in question to Grade 1 or to baseline values or to 
a level considered acceptable by the investigator.  This discussion will be documented in the 
study file.  However, if a patient requires a dose delay of > 21 days for such an event to 
resolve despite the best supportive care permissible per protocol, then the patient must be 
discontinued from the study.  The patient will be followed until resolution or stabilization of 
the event.  
For management of toxicities on study, dose modification guidelines should be closely 
followed.  However, based on evolving safety data of TAK-659 and/or individual patient 
cases, alternative dose modifications may be recommended after discussion between the 
investigator and the sponsor to maximize exposure of study treatment while protecting 
patient safety.
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6.4.2   
Intrapatient Dose Escalation 
Intrapatient dose escalation is not allowed in this protocol.
6.4.3   
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
TAK-659 is administered in continuous cycles; therefore, study drug should be administered 
continuously unless AEs occur that meet the dose modification criteria as outlined in the 
following.
6.4.4   
TAK-659 Dose Modification for Hematologic Toxicities
Blood counts should be regularly monitored during the study as specified in the Schedule of 
Events, and tested more frequently if clinically indicated based on local standard practice.  
Comparison to baseline values and AE grading based on CTCAE (v.4.03) will be 
performed.  When severe hematological AEs occur (Grade 4 events, febrile neutropenia, 
neutropenic infection, thrombocytopenia with signs of overt bleeding or clinically 
significant bleeding), close monitoring and medical management using supportive care if 
indicated will be given based on standard practice (See Section 6.7) while the study drug 
should be continued.  If these events persist despite supportive care (not resolved to 
Grade 1, or baseline, or a level considered acceptable by the investigator within 7 days), 
at the investigator’s discretion, bone marrow aspirate assessment will be performed to 
evaluate whether the prolonged myelosuppression is due to leukemic infiltration or disease 
progression.  If leukemic blasts are 5% in bone marrow and bone marrow aplasia is seen, 
the study drug should be continued for an additional 14 days with repeat bone marrow 
aspirate in the absence of peripheral hematologic recovery to assess marrow cellularity.  
In the absence of evidence for bone marrow recovery, the study drug should be withheld for 
up to 21 days.  
Clinical and laboratory re-evaluation should be repeated at least weekly or more frequently 
until recovery to Grade 1 or baseline or a level considered acceptable by the investigator.  
Upon recovery, TAK-659 may be reinitiated either at the same dose level or at a reduced 
dose level at the discretion of the investigator.  If no recovery occurs within 21 days (based 
on peripheral blood counts and/or repeat bone marrow aspirate) after the study drug hold 
(42 days in total after the first dose on Cycle 1, Day 1), the patient should discontinue study 
treatment, and if this occurs in Cycle 1, the patient will be considered to have had a DLT.  
The patient will continue to be followed until resolution or stabilization of the event, 
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initiation of another anti-leukemia therapy, or overt AML progression, whichever occurs 
first.
Based on each individual patient’s case, if according to the opinion of the investigator, an 
alternative dose management plan should be considered in the best interest of the patient, 
deviation from this general dose modification and discontinuation guideline is permissible 
upon discussion between the investigator and the sponsor.    
When a dose reduction of TAK-659 is required, no re-escalation of dose will be permitted.
6.4.5   
TAK-659 Dose Modification for Nonhematologic Toxicities
Please refer to Table 6-2 for dose held and dose reduction recommendations for 
nonhematologic toxicities.  When the dose of TAK-659 is withheld based on the following 
criteria (Table 6-2), clinical and laboratory re-evaluation should be repeated at least weekly 
or more frequently until the toxicity resolves to ≤Grade 1, or baseline, or a level considered 
acceptable by the investigator (must be Grade 2).  Upon recovery, TAK-659 may be 
reinitiated either at the same dose level or at a reduced dose level.  For events in which there 
are transient lab value abnormalities that, based on investigator assessment, are not clinically 
significant or related to disease and not the drug, continuation of therapy without following 
the dose modification guideline is permissible upon discussion with the sponsor. 
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Table 6-2   
TAK-659 Dose Adjustments for Nonhematologic Toxicities
Criteria
Action
Grade 3 nonhematologic toxicities with the 
exception of:

Grade 3 nausea, vomiting, and diarrhea 
resolved to ≤Grade 1 or baseline within 1 
week with optimal antiemetics and 
antidiarrheal following standard of care

Transient Grade 3 fatigue (lasting <1 week)

Asymptomatic lipase elevation (<Grade 4) 
in the absence of significant amylase 
elevation (<Grade 3) considered not dose 
limiting following agreement between 
sponsor and investigators

Asymptomatic amylase elevation (<Grade 
4) in the absence of lipase elevation 
(<Grade 3) considered not dose limiting 
following agreement between sponsor and 
investigators

Asymptomatic Grade 3 elevation of a single 
liver enzyme (AST or ALT) in the absence 
of significant bilirubin elevation (<Grade 3) 
considered not dose limiting following 
agreement between sponsor and 
investigators

Grade 3 hypophosphatemia resolved to 
Grade ≤1 or baseline within 72 hours with 
phosphate repletion

Other asymptomatic Grade 3 laboratory 
abnormalities that are considered to be not 
clinically significant, as determined jointly 
by the investigators and the sponsor 
Hold TAK-659 until resolution to ≤Grade 1 or baseline or 
a level considered acceptable by the investigator (must be 
≤Grade 2).

If resolved in ≤7 days, then maintain dose level.

If resolved in >7 days, then reduce dose by 1 
dose level.

If recurrence occurs, then reduce dose by 1 dose 
level.
For the exceptions listed, maintain the dose level (no dose 
hold required). 
Permanent discontinuation should be considered if the 
toxicities persist as ≥Grade 3 for more than 21 days 
despite temporary disruption of study drug.
Grade 4 nonhematologic toxicities with the 
exception of:

Asymptomatic Grade 4 lipase elevation in 
the absence of significant amylase elevation
(<Grade 3).

Asymptomatic Grade 4 amylase elevation in 
the absence of significant lipase elevation
(<Grade 3).

Asymptomatic Grade 4 elevation of a single 
liver enzyme (AST or ALT) in the absence 
of significant bilirubin elevation (<Grade 3).

Grade 4 hypophosphatemia resolved to 
≤Grade 1 or baseline value within 72 hours 
with phosphate repletion.

Other Grade 4 asymptomatic enzyme 
elevations not considered clinically 
significant following agreement between 
sponsor and investigator.
Consider permanently discontinuing TAK-659, except in 
the case where the investigator determines the patient is 
obtaining a clinical benefit and has discussed this with the 
project clinician or designee. Dose reduction of ≥1 dose 
level is required if study treatment resumes after 
resolution to ≤Grade 1 or baseline values.
For the exceptions, hold TAK-659 until resolution to 
≤Grade 1 or baseline values or to a level that is clinically 
acceptable as determined by Investigator (≤Grade 2), 
then:

If resolved in ≤7 days, maintain dose level.

If resolved in >7 days, reduce dose by 1 dose 
level.

If recurrence occurs, then reduce dose by 1 dose 
level.
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Grade 4 nonhematologic toxicities will, in general, require that treatment with TAK-659 be 
permanently discontinued.  If, in the opinion of the investigator and the sponsor (project 
clinician or designee), it is in the patient’s best interest to continue treatment with TAK-659, 
then the dose of TAK-659 will be reduced by at least 1 dose level when treatment resumes 
after recovery of the toxicity or toxicities in question to Grade 1or to baseline values or to 
a level considered acceptable by the investigator (must be ≤ Grade 2).  When a dose 
reduction of TAK-659 is required, no re-escalation of dose will be permitted.
Based on each individual patient’s case, if according to the opinion of the investigator, an 
alternative dose management plan is considered in the best interest of the patient, deviation 
from this general dose modification and discontinuation guideline is permissible upon 
discussion between the investigator and the sponsor.
6.5   Concomitant Medications and Procedures
During the study, patients will be instructed not to take any additional medications 
(including over-the-counter products and supplements) without prior consultation with the 
investigator. At each visit, the investigator will ask the patient about any new medications 
he/she is taking or has taken while on study. All concomitant medications (defined as any 
medication given during the study) and significant nondrug therapies, including physical 
therapy and blood transfusions, should be recorded from signing of the informed consent 
form (ICF) through 28 days after the last dose of study drug or the start of subsequent 
antineoplastic therapy, whichever occurs first. 
The following restrictions apply during the study:

Any antineoplastic therapy other than TAK-659 (with the exception of hydroxyurea 
for the first 28 days of study drug treatment).  This includes chronic use of 
corticosteroids at daily doses greater than the equivalent of 10 mg of prednisone as 
part of any anticancer treatment regimens.  If alternative therapy is required for 
treatment of the patient’s tumor, the patient should be removed from this study and 
the reason for removal recorded in the electronic case report form (eCRF).

Prophylactic use of myeloid growth factors (eg, granulocyte colony stimulating 
factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF]) in 
Cycle 1 during dose escalation.  Patients who experience severe and/or febrile 
neutropenia can be managed with growth factor support if needed in accordance with 
American Society of Clinical Oncology (ASCO) guidelines.
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
Concurrent systemic administration of TAK-659 with inhibitors or inducers of P-gp 
or strong inhibitors or inducers of CYP3A should be avoided in this study. In vitro 
studies indicate that TAK-659 is a substrate for P-gp and that, among CYP isozymes, 
TAK-659 is preferentially metabolized by CYP3A4/5. Refer to the list below and 
Appendix 14.5 for a nonexhaustive list of medications, supplements, and food 
products that are inhibitors or inducers of P-gp or strong inhibitors or inducers of 
CYP3A based on the US FDA draft guidance for DDI studies.

Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole

Antibiotics: azithromycin, clarithromycin, erythromycin, telithromycin

Antimycobacterials: rifabutin, rifampin, rifapentine

Antiepileptics: carbamazepine, phenobarbital, phenytoin, primidone

Antidepressant: nefazadone

Immunosuppressant: cyclosporine

Calcium channel blockers: diltiazem, felodipine, mibefradil, verampamil

Antiarrhythmics: amiodarone, dronedarone, quinidine

Antiplatelet: ticagrelor

Antilipid: avasimibe

Other cardiovascular: captopril, carvedilol,  ranolazine

Vasopressin antagonist: conivaptan

Food/Herbals/Supplements: grapefruit-containing food and beverages, St. John’s 
wort, quercetin
If a patient experiences an AE on study and TAK-659 dosing is temporarily interrupted 
because of that AE, the medications listed above and Appendix 14.5 may be used for AE 
management if there is no appropriate alternative treatment available per the investigator’s 
judgment.  This situation will be handled on a case by case basis, and requires discussion 
between the investigator and the medical monitor to assess the relative benefit and risk for a 
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given patient. The discussion will be documented in the study file. Patients should be closely 
monitored for potential toxicities.
Note that medications used to treat HIV or hepatitis C infection are not listed above or in 
Appendix 14.5 because patients with known HIV infection or known or suspected active 
hepatitis C infection are excluded from study participation. In addition, oncology 
medications are not listed because they are prohibited during the study. If a medication, 
supplement, or food/beverage is suspected or known to be a or P-gp inhibitor or inducer 
and/or strong CYP3A inhibitor or inducer, but is not on the list above or in Appendix 14.5, 
then its use must be discussed on a case-by-case basis with the medical monitor or designee 
to assess the relative benefit and risk. The discussion will be documented in the study file. 
Patients should be closely monitored for potential toxicities.
6.6   Precautions and Restrictions 
Patients should not drive, operate dangerous tools or machinery, or engage in any other 
potentially hazardous activity that requires full alertness and coordination if they experience 
sedation while enrolled in this study.
Patients are to be instructed to limit the use of alcohol while enrolled in this study. 
It is not known what effects TAK-659 has on human pregnancy or development of the 
embryo or fetus.  Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner.  
Nonsterilized female patients of reproductive age group and male patients should use 
effective methods of contraception through defined periods during and after study treatment 
as specified below.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method, at the same time, from the 
time of signing of the ICF through 180 days after the last dose of study drug, or
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
Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea 
are not acceptable methods of contraception. Female and male condoms should not 
be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and 
through 180 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)
6.7   Management of Clinical Events 
Therapies that are required to manage AEs and control cancer symptoms are allowed based 
on standard clinical practice, unless specifically excluded.  Supportive care agents, such as 
blood products (red blood cell [RBC] and platelet transfusions), antiemetics, and pain 
medications are permitted as needed per American Society of Hematology (ASH)/ASCO 
guidelines or local institutional practice.  However, these agents should not be used in this 
study in a manner that would either help establish eligibility for the study or support 
escalation of study drug dose during dose escalation.
Pneumonitis
Patients with serious lung events that do not respond to conventional antimicrobial therapy 
should be assessed for drug-induced pneumonitis after ruling out infectious causes and 
alternative etiologies. If pneumonitis is suspected, TAK-659 treatment should be interrupted 
and the patient treated per standard of care. If pneumonitis is moderate/severe, discontinue 
TAK-659. Patients should be monitored for respiratory signs and symptoms throughout 
treatment and be advised to promptly report respiratory symptoms.
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Nausea and/or Vomiting
This study allows prophylactic use of antiemetics as clinically indicated before dosing with 
the study drug.  Premedication with oral ondansetron as monotherapy administered without 
steroids is recommended.  However, different practices may be followed if they are based on 
institutional standard of care.  In addition, a patient who develops nausea and/or vomiting 
will be actively managed by employing optimal antiemetic treatment based on local standard 
practice.  An optimal antiemetic regimen is defined as one that employs both 5-HT3
antagonist and a corticosteroid given in standard doses and according to standard schedules.  
Diarrhea
Prophylactic antidiarrheals will not be used in this protocol before the first dose of study 
drug.  However, diarrhea should be managed according to clinical practice, including the 
administration of antidiarrheals once infectious causes are excluded.  Fluid intake should be
maintained to avoid dehydration.  Fluid deficit should be corrected before initiation of 
treatment and during treatment.
Edema (Including Periorbital)
Peripheral and periorbital oedema have been observed in patients treated with TAK-659. 
Management of the event, if it occurs, should follow the standard local practice and dose 
modification should proceed following the dose modification guideline in Table 6-2.
Anemia
Hemoglobin should be monitored regularly as outlined in the Schedule of Events, with 
additional testing obtained according to standard clinical practice.  Packed RBC transfusion 
is permitted, as necessary, per local institutional practice.  In general, RBC transfusion is 
recommended for all symptomatic patients with anemia or any asymptomatic patients with a 
hemoglobin ≤ 7 to 8 g/dL with the purpose of maintaining the hemoglobin between 8 and 
10 g/dL depending on patients’ age, symptoms, and comorbid conditions.  Each transfusion 
episode, including the type of transfusion (RBC), should be recorded.  Erythropoietic agent 
use at the investigator’s discretion is also allowed and should be administered according to 
institutional practice.  
Thrombocytopenia
Blood counts should be monitored regularly as outlined in the Schedule of Events with 
additional testing obtained according to standard clinical practice.  Platelet transfusion is 
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allowed to manage severe thrombocytopenia to prevent and minimize bleeding according to 
ASH/ASCO guidelines.  In general, platelet transfusion should be given prophylactically to 
patients with platelet counts < 10,000/L or to any patients with signs of overt bleeding, 
such as oral purpura.  Each transfusion episode, including the type of transfusion (platelets), 
should be recorded.
Neutropenia
Blood counts should be monitored regularly as outlined in the Schedule of Events with 
additional testing obtained according to standard clinical practice.  Myeloid growth factors 
(eg, G-CSF, GM-CSF) may be used to treat severe and/or febrile neutropenia according to 
ASCO guidelines.  However, it should be noted that growth factors are not used routinely in 
AML patients undergoing chemotherapy, and prophylactic use of myeloid growth factors 
should be avoided during the first cycle of dose escalation (See Section 6.5).
Prophylaxis Against Infection
The severe and prolonged period of neutropenia seen with therapy is frequently associated 
with neutropenic fevers and a high risk of infection with bacteria or fungi and viral 
reactivation.  To minimize the risk of infection, it is recommended that patients be placed on 
“neutropenic precaution”, with or without the addition of prophylactic antibiotics, 
antifungals, or antivirals.  In addition, patients should be screened for possible infectious 
foci (eg, dental status).
The components of “neutropenic precaution” may vary by institution but most commonly 
include:  a high efficiency particulate air-filtered room, a diet free of raw berries or 
vegetables grown in dirt, no sick visitors, and no smoking.  In addition, hand washing by all 
visitors and caregivers should be strictly enforced.
Consideration should be given to antibiotic, antifungal, and antiviral prophylaxis during 
therapy, particularly if the patient is more prone to developing neutropenia; however, the use 
of such agents should be at the discretion of investigators based on the local standard 
practice. Patients who develop neutropenic fever should be evaluated promptly and treated 
immediately with parental antibiotics tailored to the prominent organisms and resistance 
patterns of the institution.
Patients with lymphopenia and neutropenia may be more prone to developing infections, 
such as respiratory tract infections or pneumonia. Consider a diagnosis of opportunistic 
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infection including PJP in patients presenting with shortness of breath, cough, or fever. 
Prophylaxis for PJP may be initiated (either at baseline or during treatment) if clinically 
indicated. For older patients, patients with recent exposure to steroids or immunosuppressive 
agents, or patients who, in the investigator’s opinion, are more susceptible to opportunistic 
infection at baseline, PJP prophylaxis should be considered at the start of the study 
treatment. When steroids and/or any immunomodulatory agents need to be used to manage 
the AEs during the study, PJP prophylaxis should be considered when the study treatment 
resumes or is coadministered. Trimethoprim-sulfamethoxazole is recommended as the 
treatment of choice for PJP prophylaxis unless contraindicated. However, investigator 
discretion in selecting a more appropriate prophylaxis regimen for their patients is permitted. 
Myelosuppression can also be associated with reactivation of herpes zoster, CMV, herpes 
simplex and other viruses. Antiviral therapy such as acyclovir, gancyclovir, valacyclovir, or 
other antiviral agents may be initiated as clinically indicated. Testing of CMV replication by 
a local polymerase chain reaction (PCR) assay will be required at baseline, and further 
monitoring and prophylactic or preemptive therapy to asymptomatic patients, if indicated, 
should follow the institutional standard practice. The following agents should be considered 
for prophylaxis or preemptive treatment against CMV: ganciclovir intravenously (IV), 
valganciclovir (orally), foscarnet (IV), or cidofovir (IV). Duration of antiviral therapy 
generally is for at least 2 weeks until CMV is no longer detected by PCR.
Leukocytosis
For patients who develop symptoms of leukocytosis (WBC > 100,000/mm3) while on the 
study, TAK-659 treatment should be withheld until the leukocytosis symptoms are 
controlled.  Treatment of leukocytosis symptoms may include leukapheresis and 
hydroxyurea administration (concurrent use of hydroxyurea with the study drug is only 
permitted during the first 28 days of study treatment) per institutional guidelines.  When the 
WBC of the patient is < 50,000/mm3 and symptoms are improved, TAK-659 treatment may 
be restarted after consulting with the project clinician.
Fluid Deficit
Fluid deficit should be corrected before initiation of study drug and during treatment.
Rash With or Without Pruritus
Prophylactic measures should also be considered if a patient develops a rash (eg, using a 
thick, alcohol-free emollient cream on dry areas of the body).  In the case of rash, the use of 
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a topical or oral steroid (eg, prednisone ≤ 10 mg per day or equivalent) is permitted.  
Treatment with TAK-659 must be withheld in the event of Grade 3 or 4 rash. Refer to dose 
modification guideline in Table 6-2.
Hypophosphatemia
Hypophosphatemia has been observed in patients treated with TAK-659. Consider 
prophylaxis; otherwise refer to dose modification guideline in Table 6-2.
Enzyme Elevations 
Transaminase, Amylase and Lipase, and CPK Elevations
Elevations of the enzymes above have been observed. Events are generally asymptomatic 
and reversible with dose interruption. See dose modification guideline in Table 6-2.
Lactate Dehydrogenase Elevations
Lactate dehydrogenase (LDH) elevations have been observed in the majority of patients 
exposed to TAK-659. These elevations have been asymptomatic and the clinical 
significance is unknown. No doses have been interrupted due to increased LDH; however, 
LDH elevations have been observed to be reversible in patients who had TAK-659 
interrupted due to other reasons. 
6.8   Blinding and Unblinding
This is an open-label study.  
6.9   Description of Investigational Agents
TAK-659 has been formulated into immediate-release film-coated tablets for use in clinical 
studies via a common granulation process.  Three different tablet dosage strengths, 20, 60, 
and 100 mg, were formulated.  The formulation contains compendial excipients that include 
mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, and 
magnesium stearate.  Tablets were coated with Opadry® film coat.
6.10   
Preparation, Reconstitution, and Dispensation
Detailed instructions for the dispensing of TAK-659 immediate-release film-coated tablets 
are provided in the Pharmacy Manual.  
TAK-659 is an anticancer drug, and as with other potentially toxic compounds, caution 
should be exercised when handling TAK-659.
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6.11   
Packaging and Labeling
TAK-659 20-, 60- and 100-mg tablets will be packaged into round, white, high-density 
polyethylene (HDPE) bottles with induction seal, desiccant pack, and polypropylene child-
resistant caps.  Each bottle of TAK-659 will be labeled with either a single-panel or 
multilanguage label containing pertinent study information, country-specific requirements, 
and a caution statement. 
6.12   
Storage, Handling, and Accountability
TAK-659 tablets should be stored in the original dispensing bottles at room temperature of 
1°C to 25°C (33.8°F to 77°F). Drug supply must be kept in an appropriate, limited access, 
secure place until it is dispensed to the enrolled patients, returned to sponsor, or forwarded 
to the sponsor’s designee for destruction.  Drug supplies received at the clinical sites will be 
counted and reconciled before being returned to the sponsor.
7.   
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
7.1   Study Personnel and Organizations
The contact information for the project clinician for this study, the central laboratory and 
any additional clinical laboratories, the contract research organization (CRO) team, and 
other vendors may be found in the Study Manual.  A full list of investigators is available in 
the sponsor’s or CRO’s investigator database.
7.2   Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians.  If advertisements become 
part of the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).  It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.
7.3   Treatment Group Assignments 
This is a study that incorporates a phase 1b dose escalation and a phase 2 dose expansion at 
the MTD and/or RP2D.  In the Dose Escalation phase, AML patients will be assigned a 
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cohort based on the dose escalation rules described in Section 6.3.  In the dose expansion 
phase, AML patients will be assigned to a cohort as described in Section 4.1.  All patients 
will receive TAK-659.
7.4   Study Procedures
Patients will be evaluated at scheduled visits over the following study periods:  Screening, 
Treatment, and End of Study (EOS).  Evaluations during the Screening period are to be 
conducted within 28 days before administration of the first dose of study drug.  Procedures 
conducted during the Screening period that are performed within 3 days of Cycle 1, Day 1 
may also be used as the predose evaluation and do not need to be repeated, unless otherwise 
specified.  
Unless otherwise noted, evaluations during the Treatment period must occur before study 
drug administration at scheduled visits.  Tests and procedures should be performed on 
schedule for all visits.  The timing of PK and plasma inhibitory assay assessments is 
specified in the Schedule of Events and is not flexible.  Other laboratory assessments and 
procedures may occur within -3 days before the scheduled day, and Day 1 of Cycle 2 and 
beyond may be modified by up to 3 days due to extenuating circumstances (ie, inclement 
weather, holidays, vacations, or other administrative reasons).
Refer to the Schedule of Events for timing of assessments.  Additional details are provided 
as necessary in the sections that follow.
7.4.1   
Informed Consent
Each patient must provide written informed consent before any study-required procedures 
are conducted, unless those procedures are performed as part of the patient’s standard care.  
7.4.2   
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
7.4.3   
Medical History
During the Screening period, a complete medical history will be compiled for each patient.  
The history will emphasize the background and progress of the patient’s malignancy and 
include a description of prior therapies for it.  In addition, concomitant medications will be 
recorded as specified in Section 7.4.9.  Sites will be required to record any screening reports 
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on tumor cytogenetics and/or mutation assays (eg, FLT-3) performed as part of the standard 
of care.
7.4.4   
Physical Examination
A physical examination (PE) will be completed per standard of care at the times specified in 
the Schedule of Events.  During dose escalation, complete PEs will be performed at 
screening, Day 1 of each cycle of treatment, and EOS.  Symptom- or finding-directed PEs 
will be performed on Days 8, 15, and 22 of Cycle 1 and Day 15 of Cycles 2, 3, and 4.  
During the phase 2 expansion, complete PEs will be performed at screening only, and post 
screening PEs will be symptom or finding directed. 
Note:  Physical examinations at screening will include a neurological examination.
7.4.5   
Patient Height and Weight
Height will be measured only during screening (within 28 days before the first dose of 
TAK-659).
Weight will be measured during the times specified in the Schedule of Events. 
7.4.6   
Vital Signs 
Vital sign measurements include diastolic and systolic blood pressure, heart rate, and 
temperature, and will be assessed as specified in the Schedule of Events.  Blood pressure 
should be determined with the patient in a seated position after the patient has been sitting 
quietly for approximately 5 minutes.
7.4.7   
Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group performance status is to be assessed at the times 
specified in the Schedule of Events.
7.4.8   
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening.  
A urine pregnancy test will be performed predose on Day 1 of all cycles with negative 
results available before the first dose may be administered.  If the serum pregnancy test is 
performed within 3 days from the first dose and the result is negative, the urine pregnancy 
test on Cycle 1, Day 1 may be waived.
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7.4.9   
Concomitant Medications and Procedures
Concomitant medications and procedures will be recorded in the eCRF from the time of the 
first dose of study drug through 28 days after the last dose of study drug or to the start of 
subsequent anticancer therapy, whichever occurs first.  See Section 6.5 for a list of 
medications and therapies that should be avoided during the study unless otherwise 
specified. 
7.4.10   
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events.  Refer to Section 9 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.  
7.4.11   
Enrollment
A patient is considered to be enrolled in the study when the first dose of TAK-659 has been 
administered.
Procedures for completion of the enrollment information are described in the Study Manual.
7.4.12   
Electrocardiogram
12-lead ECGs will be performed and interpreted locally.  ECGs will be obtained at the time 
points specified in the Schedule of Events.  The ECG schedule is more intensive for patients 
enrolled in the dose escalation cohorts.  The time points for ECG collection may be revised 
based on emerging PK data, but the number of time points will not increase.
Unless otherwise specified by the Schedule of Events, scheduled ECGs should be performed 
predose and after the patient has rested quietly for at least 5 minutes in a supine position.  
When the timing of a PK, PIA, or safety laboratory blood sample coincides with the timing 
of ECG measurements, the ECG will be completed before the collection of the blood 
sample.  In some cases, it may be appropriate to repeat an abnormal ECG to rule out 
improper lead placement as contributing to the ECG abnormality.
Confirmation that the machine-estimates of the rate-corrected QT interval (milliseconds) of 
electrocardiograph (QTc) are accurate using the appropriate QT correction formula (QTcF, 
Bazett’s corrected QT interval [QTcB]) should be performed.  Estimates of QTc for study 
eligibility should use QTcF.  In the event that a QTc value confirmed by the qualified reader 
is >475 msec, an evaluation to determine etiology should be conducted.  If the prolonged 
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QTc finding can be corrected based on change in medication and/or correction of electrolyte 
abnormalities, and a repeat ECG meets eligibility requirements, the patient may enroll to the 
study upon review and agreement by the sponsor’s clinician.  
Following initiation of treatment, if a QTc value is confirmed by a qualified reader as > 
500 msec for any ECG, the following will occur: 

The sponsor’s clinician will be promptly notified.

TAK-659 should be held and an evaluation should be conducted to correct other 
possible causes (eg, electrolyte disturbance, concomitant medication).

A formal consult by a cardiologist should be considered.  Additional ECGs may be 
performed at intervals that the treating physician deems clinically appropriate until 
repeated QTc measurements fall or are below the threshold interval that triggered the 
repeat measurement.
The decision whether to reinitiate TAK-659 treatment with or without dose reduction and 
additional monitoring in those patients who had asymptomatic prolonged QTc > 500 msec 
(Grade 3) that has reverted to an acceptable interval, have previously tolerated TAK-659, 
and appear to have benefited from TAK-659 treatment with either disease control or 
response will be agreed to by the investigator and the sponsor’s clinician on a case-by-case 
basis. 
The ECGs performed should be reviewed by the investigator or his/her delegate before the 
patient leaves the clinic on visit days.
7.4.13   
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally.  Handling and shipment of clinical 
laboratory samples will be outlined in the Study and Laboratory Manuals.  Clinical 
laboratory evaluations will be performed as outlined in the following:
Clinical Chemistry, Hematology, Urinalysis, and Virology 
Blood samples for analysis of the following clinical chemistry and hematological parameters 
and urine samples for urinalysis will be obtained as specified in the Schedule of Events.
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Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (absolute neutrophil count [ANC])

Percentage of leukemic blast cells
Serum Chemistry

Blood urea nitrogen 
(BUN)

Creatinine

Bilirubin (total)

Urate

Lactate 
dehydrogenase 
(LDH)

γ-Glutamyl 
transferase (GGT)

Phosphate

Albumin

Alkaline phosphatase 
(ALP)

AST

ALT

Glucose 

Sodium

Potassium

Calcium

Chloride

Carbon dioxide 
(CO2)

Magnesium

Amylase

Lipase

Total protein

CPK
Urinalysis

Turbidity and Color

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult Blood

Nitrite

Urobilinogen

Glucose

Leukocytes
When creatinine clearance is estimated, the Cockroft-Gault formula will be employed as 
follows (see Appendix 14.3):
For female patients, the result of the formula above should be multiplied by 0.85. 
Virology 

CMV
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7.4.14   
Ophthalmic Exam
A slit lamp eye examination will be performed by an ophthalmologist at screening; on 
Cycle 2, Day 1; on Cycle 7, Day 1; every 6 Cycles thereafter (2 weeks); and at EOS.  
Based on the nonclinical toxicology findings with TAK-659 in rats, slit lamp examinations 
should focus on detecting any posttreatment changes in ocular lens.  Examination and 
photographing of the retina will be performed at baseline but not during the study unless it is 
clinically indicated.  Additional eye exams may also be performed, as required.  
Additionally, patients will be carefully monitored for eye complaints at each visit and 
instructed to report visual symptoms as soon as they occur.  
7.4.15   
Disease Assessment
Assessment of disease response will follow the criteria outlined in the Revised 
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 [10].  Investigators are encouraged to 
consult the reference for more detailed explanation of response criteria.
CR, CRi, CRp, CRh, CRc, and PR are defined using the following criteria:
CR:  A CR designation requires that the patient achieve the morphologic leukemia-
free state and have an ANC of more than 1000/µL and platelets of ≥100,000/µL.  
A morphologic leukemia-free state requires less than 5% blasts in an aspirate sample 
with marrow spicules and with a count of at least 200 nucleated cells.  There should 
be no blasts with Auer rods.  The peripheral blood should have no leukemic blasts. 
Hemoglobin concentration or hematocrit has no bearing on remission status, 
although the patient must be independent of transfusions.  There should be no 
residual evidence of extramedullary leukemia. 
CRi (complete response with incomplete recovery of blood counts):  After 
chemotherapy, some patients fulfill all of the criteria for CR except for residual 
neutropenia (<1000/µL) or thrombocytopenia (<100,000/µL).
CRp (complete response without platelet recovery): CRp satisfies all CR criteria
except platelets < 100,000/μL, but platelet transfusions are not necessary.
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CRh (complete response with partial hematologic recovery): CRh is defined as 
no evidence of peripheral blasts and partial recovery of peripheral blast counts 
including ANC above 500/µL and platelets above 50,000/µL.
CRc: A composite complete remission is defined as the sum of patient achieving a 
CR, CRh, CRi, or CRp.
PR:  This designation requires all of the hematologic values for a CR but with a 
decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow 
aspirate.  Thus, if the pretreatment bone marrow blast percentage was 50% to 100%, 
the percentage of blasts must decrease to a value between 5% and 25%; if the 
pretreatment blast percentage was 20% to less than 49%, they must decrease by at 
least half to a value of more than 5%.  A repeat bone marrow aspiration after several 
weeks may be required to distinguish between a PR and increased blasts caused by 
bone marrow regeneration.  A value of ≤5% blasts may also be considered a PR if 
Auer rods are present.
Response assessments above generally follow the standard criteria except patients who 
achieve a CR, CRh, CRi, CRp, or PR are not required to be transfusion independent. 
Progressive Disease
Because the IWG criteria for AML do not provide a standardized definition for progressive 
disease [10], in this protocol, progressive disease is defined as 1 of the following:

>50% increase in bone marrow blasts from baseline value 

>50% increase in circulating blasts from baseline value with absolute blast 
count >1000/mm3

Development of biopsy-proven extramedullary disease, or new sites of 
extramedullary leukemia
Note:  If the initial marrow blast percentage is too high to base progression on a 
>50% increase in bone marrow blasts, then peripheral blood criteria will be used.
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Investigators should note that some patients may benefit from continued treatment even 
though their bone marrow blast counts may fluctuate over the course of the first 4 cycles.  
These patients may experience transient increase in bone marrow blasts before 
demonstrating a significant blast reduction that meets response criteria as specified 
previously.  Therefore, patients may be allowed to remain on study, after discussion 
between the investigator and the project clinician, even if they meet the criteria for 
progressive disease based only on bone marrow blast counts.
7.4.15.1   Bone Marrow Biopsy and Aspirate Collection and Analysis
Bone marrow biopsy and aspirate collection at screening will be required to assess disease 
burden, cytogenetics, karyotype, and cellular composition by flow cytometry.  Additional 
bone marrow aspirates (remaining aspirate material from the first pull or a second or third 
pull of bone marrow aspirate) and biopsy specimens (segments of the first core biopsy or 
additional core biopsies) will also be required at screening for biomarker analysis 
(Section 7.4.16).  During phase 1b dose escalation, if a patient has already had a bone 
marrow biopsy and aspirate performed within 28 days of Day 1 of Cycle 1, this procedure 
need not be repeated if results for disease assessment are available.  If only one test (biopsy 
or aspirate) has already been performed within 28 days of Day 1 of Cycle 1, the site should 
discuss the case with the Millennium project clinician or delegate during eligibility 
determination.
However, during phase 2, bone marrow aspirate and biopsy is a screening (baseline) 
procedure needed for the purpose of enrollment into the trial for both disease assessment and 
biomarker studies. In particular, bone marrow aspirate is needed to confirm the FLT-3
mutation status in marrow blasts, and therefore essential for patient assignment to either the 
FLT-3-ITD or WT group. In cases for which the performance of this baseline procedure is 
difficult based on an individual patient’s condition and a bone marrow aspirate/biopsy test 
has been performed within 28 days from Day 1 of Cycle 1, the site is encouraged to discuss 
the case with the Millennium project clinician or delegate.  In this circumstance, the site is 
required to investigate whether adequate residual material from the last bone marrow 
aspirate/biopsy procedure remains available for collection and whether the tissue processing 
procedures for these remaining samples conform to the requirements of this trial for the 
purpose of biomarker evaluation. If so, these samples should be collected and sent to the 
Sponsor-designated laboratory(ies).  
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
Note that a bone marrow biopsy is required only at screening.  However, post
screening, a biopsy that allows more bone marrow tissue to be examined should be
performed (eg, when spicules are absent from the aspirate sample or a dry tap
occurs) per local institutional practice at the time of disease assessment.
In addition, bone marrow aspirate and/or biopsy specimens (if needed) will be collected to 
assess disease response between Days 22 and 28 at the end of Cycle 1, Cycle 2, and Cycle 4, 
provided that the disease assessment is available before Day 1 of the following cycle.  
Beyond Cycle 4, bone marrow aspirate and/or biopsy assessments (if needed) will be 
performed as clinically indicated based on changes in peripheral blood counts, or when it is 
needed to establish either CR or disease progression.  At any of these time points, if 
adequate residual material remains, it should be sent to the Sponsor-designated 
laboratory(ies) for exploratory biomarker studies.  
At the time of relapse in patients who have had initial response to TAK-659, bone marrow 
aspirates and/or biopsies will be collected for biomarker studies (Section 7.4.16).

If a bone marrow aspirate and/or biopsy is performed per standard of care based on
suspected progression, if adequate residual material remains, these samples should
be sent to the Sponsor-designated laboratory(ies) after discussion with the sponsor to
ensure the usability of the samples (whether conforming to the required tissue
processing procedures for this study).

If the patient has initially responded and subsequently shows clinical signs of relapse
but a bone marrow aspirate and/or biopsy have not been obtained, the site will collect
a bone marrow aspirate and/or biopsy at this time to assess disease. During the
procedure, additional bone marrow aspirates (remaining aspirate material from the
first pull or a second or third pull of bone marrow aspirate) and biopsy specimens
(segments of the first core biopsy or additional core biopsies) will be collected for
biomarker studies and sent to the Sponsor-designated laboratory(ies).
Details regarding the preparation, handling, and shipping of these samples are provided in 
the Laboratory Manual.
7.4.16   
Biomarker Measurements
This study will investigate the biomarker hypotheses of both response and 
treatment-emergent resistance.
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The following samples will be collected to facilitate these analyses:
!
The FLT-3 mutation status will be confirmed using a blood sample and/or bone
marrow aspirate collected at screening.
Sample shipping and handling instructions are provided in the Laboratory Manual. 
Remaining samples from each of the collections listed may be used, if appropriate, to 
support other biomarker analyses described in this section.  Based on the evolving data, it is 
at the sponsor’s discretion to determine when and to what extent the biomarker studies 
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described in this section (except for the FLT-3 mutation assay) will be performed so that the 
patients’ samples are used most appropriately in an attempt to generate informative data to 
the extent feasible.
7.4.17   
Pharmacokinetic Measurements
The primary aim of PK sampling in this study is to measure the plasma concentrations of 
TAK-659.  
 
 
  
Details on the collection, storage, processing, handling, and shipping of the PK samples are 
provided in the Laboratory Manual.
AML Dose Escalation Cohorts
Blood specimens for the determination of the plasma concentrations of TAK-659 will be 
obtained in Cycle 1 on Days 1, 2, 15, and 16.  The specimens obtained on Days 2 and 16 
should be obtained before the dosing of TAK-659 on those days (ie, they should be predose 
specimens).  Blood sampling will be performed at the times indicated in the AML Dose 
Escalation (Phase 1b) PK, PIA, and ECG Assessment Schedule.  The timing but not the 
number of PK blood samples may be changed if emerging data indicate that an alteration in 
sampling scheme is needed to better characterize the PK of TAK-659.
AML Expansion Cohorts
Blood specimens for the determination of the plasma concentrations of TAK-659 will be 
obtained in Cycle 1 on Days 1 and 15.  Blood sampling will be performed at the times 
indicated in the AML Dose Expansion (Phase 2) PK Schedule.  The timing but not the 
number of PK blood samples may be changed if emerging data indicate that an alteration in 
sampling scheme is needed to better characterize the PK of TAK-659. 
The remainder of the plasma PK samples from any sampling points in the expansion cohorts 
may be used to evaluate the FLT-3 and possibly SYK inhibitory effects of TAK-659 in vitro 
using a plasma inhibitory assay [1] (Section 7.4.16) if determined to be appropriate by the 
sponsor.
7.4.18   
DNA Measurements 
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7.4.19   
Modified Charlson Comorbidity Index Assessment
Patients will be assessed during screening using the Modified Charlson Comorbidity Index 
(Section 14.1).
7.5   Completion of Treatment
A patient will be considered to have completed treatment if he/she discontinues treatment 
for any of the reasons outlined in Section 7.8.
7.6
Follow-Up Period
All patients, including those patients no longer on treatment, will be assessed for survival.  
Patients who discontinue the study, regardless of reasons for discontinuation, will be 
followed for survival every month until death, loss to follow-up, or withdrawal of consent 
for further follow-up for up to 12 months after discontinuation of the study drug.  In 
addition, information on any subsequent anticancer therapies will be collected during the 
survival follow-up period.  For patients who achieve CR but discontinue study treatment 
while still in remission, disease progression based upon available local data will also be 
collected during the survival follow-up period.
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7.7   Completion of Study
Patients will be considered to have completed the study if:

They are followed until death before the end of the survival follow-up window (up to 
12 months after discontinuation of study drug for any reason)

They remain on study treatment free of disease progression at the close of the study 
at least 1 year after their first dose of study treatment 

They continue on to the follow-up for survival after discontinuation of the study drug 
and reach the end of the 12-month OS follow-up window

They discontinue study treatment while in CR and continue on to the follow-up for 
progression and either experience disease progression before the end of the 12-month 
follow-up period or reach the end of the follow-up period

The sponsor terminates the study
7.8   Discontinuation of Treatment With Study Drug, and Patient Replacement
Patients may be allowed to remain on study, after discussion between the investigator 
and the project clinician, even if they meet the criteria for progressive disease based 
only on bone marrow blast counts.    
Treatment with study drug may be discontinued for any of the following reasons: 

AE 

Protocol violation

Progressive disease:  as noted previously, patients with progressive disease may 
remain on study, after discussion between the investigator and the project clinician, 
if it is felt that they are deriving a clinical benefit from doing so.

Symptomatic deterioration (at investigator’s discretion) 

Unsatisfactory therapeutic response 

Initiation of hematopoietic stem cell transplant 
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
Study terminated by sponsor

Withdrawal by subject

Lost to follow-up

Other
Once study drug has been discontinued, all study procedures outlined for the End of Study 
visit will be completed as specified in the Schedule of Events.  The primary reason for study 
drug discontinuation will be recorded on the eCRF.
During the dose escalation phase, patients who are withdrawn from treatment during Cycle 1 
for reasons other than DLT will be replaced.  During the expansion phase, patients who do 
not meet the response-evaluable criteria will be replaced.
7.9   Withdrawal of Patients From Study 
A patient may be withdrawn from the study for any of the following reasons:

AE.

Protocol violation.

Progressive disease. 

Symptomatic deterioration (at investigator’s discretion).

Unsatisfactory therapeutic response. 

Initiation of hematopoietic stem cell transplant. 

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Other.
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The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
7.10   
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s).  The appropriate study personnel will 
maintain records of study drug receipt and dispensing.  Patients will be given a diary to 
record study drug dosing.  The dosing diary will provide supporting information, if 
necessary.  The study center staff will check the patient drug diary versus the patient’s 
supply of TAK-659 tablets to assess compliance.
Tests and procedures should be performed on schedule, but, unless otherwise specified, 
occasional changes are allowable within a 3-day window for holidays, vacations, and other
administrative reasons.  The timing of PK and plasma inhibitory assay assessments is 
specified in the Schedule of Events and is not flexible.  If extenuating circumstances prevent 
a patient from beginning treatment or completing a planned procedure or assessment within 
3 days of the scheduled time, the patient may continue the study at the discretion of the 
investigator and after consultation with the Millennium clinician or designee.
If a dose of TAK-659 is held for up to 21 days for reasons unrelated to toxicity, the patient 
may be discontinued from the study following a discussion between the investigator and the 
sponsor.  
8.   
STATISTICAL AND QUANTITATIVE ANALYSES
8.1   Statistical Methods
This study is noncomparative in nature, ie, formal statistical comparisons will not be 
performed.  Summary tabulations will be presented that will display the number of 
observations, mean, standard deviation, median, minimum, and maximum for continuous 
variables, and the number and percentage per category for categorical data.  A formal 
statistical analysis plan will be developed and finalized before database lock.
For the dose escalation cohort, statistical analyses will be primarily descriptive and graphical 
in nature.  No formal statistical hypothesis testing will be performed.  
For the AML expansion cohort, ORR in the response-evaluable population will be tabulated 
descriptively with 95% exact binomial confidence intervals (CIs).  Time-to-event data will 
be analyzed by the Kaplan-Meier method and results will be summarized by the 25th, 50th, 
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and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of censored 
observations, by FLT-3 WT and mutant populations.
8.1.1   
Determination of Sample Size
During the dose escalation phase, dose escalation will be conducted according to a standard 
3+3 dose escalation schema, and approximately 40 response-evaluable patients will be 
enrolled.  The MTD/RP2D cohort will have at least 6 patients.
The sample sizes for the AML expansion cohort are estimated using a one-sided test at a 
significance level of = 0.1 with power of 80%.  The FLT-3 WT cohort uses a null 
hypothesis of response rate ≤15%, versus an alternative hypothesis of response rate ≥35%.  
Based on a Simon 2-stage design and a 15% dropout rate, approximately 11 patients will be 
needed if the trial fails in the first stage, or 28 patients will be needed if the FLT-3 WT 
cohort succeeds in going to the second stage.  The mutant cohort uses a null hypothesis of 
response rate ≤30%, versus an alternative hypothesis of response rate ≥50%.  Based on a 
Simon 2-stage design and a 15% dropout rate, approximately 18 patients will be needed if 
the trial fails in the first stage, or 40 patients will be needed if the mutant cohort succeeds in 
going to the second stage.
8.1.2   
Randomization and Stratification  
For the dose escalation cohort, patients will be enrolled in successive dose cohorts.  During 
the expansion, patients will be enrolled in 2 different cohorts based upon their FLT-3 
mutation status as described in the Study Overview Diagram.  No randomization is planned 
for this study.
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:

Safety population:  Patients who receive at least 1 dose of TAK-659 will be used for 
all safety analyses.

Pharmacokinetic population:  Patients in the AML Dose Escalation cohorts who have 
sufficient dosing and PK data to reliably estimate 1 or more PK parameters will be 
used for PK analyses.
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
Pharmacodynamics population:  Patients with sufficient dosing in Cycle 1 and 
sufficient pharmacodynamics data derived from the Plasma Inhibitory Assay will be 
used for pharmacodynamics analyses.

Response-evaluable population:  Patients who receive at least 1 dose of study drug, 
have measurable disease at baseline, and 1 postbaseline disease assessment will be 
used for analyses of response.  

DLT-evaluable population:  the DLT-evaluable population is defined as all patients 
in the phase 1b portion of the study who either experience DLT during Cycle 1 or 
complete at least 75% of the planned doses of TAK-659 and have sufficient follow-
up data to allow the investigators and sponsor to determine whether a DLT occurred.  
8.1.4   
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations.  No 
imputation of values for missing data will be performed.  The relevance of missing sample 
data will be assessed.
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.
8.1.5   
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized, including gender, age, race, 
weight, height, body surface area (BSA), primary diagnosis, and other parameters as 
appropriate.  No inferential statistics will be carried out.
8.1.6   
Efficacy Analysis
Primary Efficacy
There is no primary efficacy endpoint for the dose escalation portion of the study.  This 
study is not intended to demonstrate differences in treatment outcomes among disease 
groups.  The primary endpoint for the AML expansion cohort is ORR.  ORR is defined as 
the number of CRs and PRs in the response-evaluable population.
Secondary Efficacy
There is no secondary efficacy endpoint for the dose escalation portion of the study.  The 
secondary efficacy endpoints for the AML expansion cohort are ORR in FLT-3 mutant and 
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FLT-3 WT populations, DOR, mortality rate at 3 and 6 months, and OS (by FLT-3 mutant 
cohort, FLT-3 WT cohort, and combined cohort).  DOR is defined as the time from the date 
of first documentation of a response to the date of first documented progressive disease.  
OS is defined as the time from the date of study entry to death.
8.1.7   
Pharmacokinetics/Pharmacogenomics/Biomarkers
Pharmacokinetic Analysis
The plasma concentrations of TAK-659 will be determined by validated liquid 
chromatography tandem mass spectrometry (LC/MS/MS) assay methods.
Plasma TAK-659 concentrations will be summarized by time postdose, grouped by dosing 
schedule, dose group, and dosing cycle and day.  Mean and individual plasma TAK-659 
concentration data will be plotted over time, grouped by dosing schedule, dose group, and 
dosing cycle and day.
Plasma PK data from the AML Dose Escalation cohorts will be used for the estimation of 
PK parameters in the PK-Evaluable Population.  Standard single-dose (Cycle 1, Day 1) and 
multiple-dose (Cycle 1, Day 15) plasma PK parameters will be estimated using 
noncompartmental methods.  Estimation of plasma PK parameters of the terminal 
disposition phase, such as terminal disposition phase half-life (t1/2z) and area under the 
plasma concentration versus time curve from zero to infinity (AUC) will depend on an 
adequate representation of the terminal disposition phase during the duration of PK 
sampling.  Plasma PK parameters will be summarized, grouped by dosing schedule, dose 
group, and dosing cycle and day.
Dose proportionality of TAK-659 plasma exposures will be evaluated by visual inspection 
of plots of individual PK parameter values versus dose.  If data permit, regression analysis 
using a power model will also be used to assess dose proportionality.
TAK-659 plasma concentration-time data collected in this study, together with data 
collected from other studies, may contribute to population PK analysis.  If applicable, the 
specifics of the population PK modeling approaches will be described separately in a 
population PK analysis plan, and the results will be reported separately from the clinical 
study report.
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8.1.8   
Safety Analysis
Safety evaluations will be based on the incidence, intensity, and type of AEs; and clinically 
significant changes in the patient’s vital signs, weight, and clinical laboratory results.  Safety 
variables will be tabulated and presented for the safety population.  Exposure to study drug 
and reasons for discontinuation of study treatment will be tabulated.
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 28 days after the last dose of study drug, or until the start of subsequent 
antineoplastic therapy, whichever occurs first, will be tabulated.  Treatment-emergent events 
will also include any AE that is considered by the investigator to be drug-related regardless 
of the start date of the event, or any event that is present at baseline but worsens in intensity 
or is subsequently considered by the investigator to be drug related.
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AEs will be tabulated according to the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary for the purpose of summarization.  AEs are to be tabulated 
using MedDRA system organ class, high-level term, and preferred term, and will include the 
following categories: 

Treatment-emergent AEs.

Drug-related treatment-emergent AEs.

Grade 3 or higher treatment-emergent AEs.

Grade 3 or higher drug-related treatment-emergent AEs.
The most commonly reported treatment-emergent AEs (ie, those events reported by 10% of 
all patients in the safety population) will be tabulated by the MedDRA preferred term.  
Tabulation also will be provided that enumerates AEs by maximum intensity.  Deaths, 
SAEs, and AEs resulting in study drug discontinuation will be tabulated. Clinical laboratory 
parameters will be summarized at each scheduled time point.  Shift tables will be produced 
for selected laboratory parameters. These tables will summarize the number of patients with 
each baseline NCI CTCAE grade and changes to the worst NCI CTCAE grade during the 
study.
Descriptive statistics for the actual values of vital signs and weight over time will be 
tabulated by scheduled time point.  
All concomitant medications collected from screening through the study period will be 
classified by preferred term according to the WHO drug dictionary.
Additional safety analyses may be determined at any time without prejudice to enumerate 
rates of toxicities and to further define the safety profile of study drugs.
Electrocardiogram Analysis
A summary of ECG abnormalities will be presented by visit.  ECG intervals (QT, QTcB, 
QTcF, PR, QRS, and heart rate) will be summarized at each scheduled time point, along 
with change from baseline to each post treatment time point.  
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8.1.9   
Interim Analysis
An interim analysis for futility stopping will be conducted to determine whether 
continuation of the AML expansion cohorts until study completion is warranted.  The 
investigator-assessed response rate will be used as the endpoint for the interim analysis.  The 
FLT-3 mutant and FLT-3 WT cohorts will be evaluated independently and could be subject 
to enrollment hold by individual cohort.  For the FLT-3 mutant cohort, the interim analysis 
will be performed when the first 15 response-evaluable patients have had the opportunity to 
complete up to 4 cycles of therapy or have discontinued therapy before 4 cycles.  If 6 or 
more responders are observed out of these initial 15 evaluable patients, patient enrollment 
will continue.  The number of evaluable patients needed in the second stage is 17.  For the 
FLT-3 WT cohort, the interim analysis will be performed when the first 9 response-
evaluable patients have had the opportunity to complete up to 4 cycles of therapy or have 
discontinued therapy before 4 cycles.  If 2 or more responders are observed out of these 
initial 9 evaluable patients, patient enrollment will continue.  The number of evaluable 
patients needed in the second stage is 14.
9.   
ADVERSE EVENTS
9.1   Definitions
9.1.1   
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has 
signed informed consent to participate in a study but before administration of any study 
medication; it does not necessarily have to have a causal relationship with study 
participation.
9.1.2   
Adverse Event Definition
AE means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product whether or not it is related to the 
medicinal product.  This includes any newly occurring event, or a previous condition that 
has increased in severity or frequency since the administration of study drug.
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An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.  
9.1.3   
Serious Adverse Event Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent.   
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse; any organism, virus, or infectious particle (eg, prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.  
In this study, intensity for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, Version 4.03, effective date 14 June 2010 [9].  Clarification should be 
made between a serious AE (SAE) and an AE that is considered severe in intensity (Grade 3 
or 4), because the terms serious and severe are NOT synonymous.  The general term severe
is often used to describe the intensity (severity) of a specific event; the event itself, however, 
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may be of relatively minor medical significance (such as a Grade 3 headache).  This is NOT 
the same as serious, which is based on patient/event outcome or action criteria described 
above, and is usually associated with events that pose a threat to a patient’s life or ability to 
function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  
For example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3
(severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
9.2   Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures will be recorded on the appropriate page of the eCRF (see Section 9.3 for the 
period of observation).  Any clinically relevant deterioration in laboratory assessments or 
other clinical finding is considered an AE.  When possible, signs and symptoms indicating a 
common underlying pathology should be noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 9.1) 
must be reported (see Section 9.3 for the period of observation) by the investigator to the 
Millennium Department of Pharmacovigilance or designee (contact information provided 
below).  This should be done by faxing the SAE Form within 24 hours after becoming aware 
of the event.  The SAE Form, created specifically by Millennium, will be provided to each 
clinical study site.  A sample of the SAE Form may be found in the Study Manual.  Follow-
up information on the SAE or serious pretreatment event may be requested by Millennium.  
SAE report information must be consistent with the data provided on the eCRF.
SAE Reporting Contact Information
Cognizant
US and Canada
Toll-Free Fax #:  1-800-963-6290
E-mail:  takedaoncocases@cognizant.com
All other countries (Rest of World)
Fax #:  1-202-315-3560
E-mail:  takedaoncocases@cognizant.com
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the condition 
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deteriorated in an unexpected manner during the trial (eg, surgery was performed earlier or 
later than planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of 
the event and the relationship of the event to study drug administration.  For serious 
pretreatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [9].  The criteria are provided in the 
Study Manual.
Relationship to study drug administration will be determined by the investigator responding 
yes or no to this question:  Is there a reasonable possibility that the AE is associated with the 
study drug?
9.3   Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:  

AEs will be reported from the first dose of study drug through 28 days after 
administration of the last dose of study drug and recorded in the eCRFs.    

Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the ICF up to first 
dose of study drug, but will not be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance or designee from the first dose of study drug through 28 days 
after administration of the last dose of study drug and recorded in the eCRF.  After 
this period, only related SAEs must be reported to the Millennium Department of 
Pharmacovigilance or designee.  SAEs should be monitored until they are resolved 
or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).  
9.4   Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
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drug.  The sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 9.2).  
The pregnancy must be followed for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor must also be contacted immediately by faxing a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee (see Section 9.2).  Every effort should be made to follow the pregnancy for the 
final pregnancy outcome.
10.   
ADMINISTRATIVE REQUIREMENTS
10.1   
Good Clinical Practice
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and the IB.
10.2   
Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient.  Study data will be entered into an eCRF by site personnel using a secure, validated, 
web-based electronic data capture (EDC) application.  Millennium will have access to all 
data upon entry in the EDC application.  
Study monitors will discuss instances of missing or uninterpretable data with the 
investigator for resolution.  Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF.
10.3   
Electronic Case Report Form Completion 
Millennium or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible.
eCRFs will be completed for each study patient.  It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
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The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible.  The audit trail entry will show the user’s 
identification information and the date and time of the correction.
Millennium, or a designee, will retain the eCRF data and corresponding audit trails.  A copy 
of the final archival eCRF in the form of a compact disk (CD) or other electronic media will 
be placed in the investigator’s study file.
10.4   
Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation.  During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements.  The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained.  
10.5   
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards.  The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the patients.  The study will 
be conducted only at sites where IRB/IEC approval has been obtained.  The protocol, IB, 
ICF, advertisements (if applicable), written information given to the patients (including 
diary cards), safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB/IEC by the investigator or the sponsor, as allowed by local 
regulations.
10.6   
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation.  
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The method of obtaining and documenting the informed consent and the contents of the 
consent must comply with the ICH-GCP and all applicable regulatory requirements.
10.7   
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.
10.8   
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by 
Millennium and given approval/favorable opinion by the IRB/IEC and the appropriate 
regulatory authority(ies).  Modifications to the protocol are not to be made without 
agreement of both the investigator and Millennium.  Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients. Millennium, 
or a designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Millennium, or a designee, if 
circumstances permit, to discuss the planned course of action.  Any departures from the 
protocol must be documented.
10.9   
On-site Audits
Regulatory authorities, the IEC/IRB, and/or Millennium may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection.  Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.
10.10   Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the trial site is the responsibility of the investigator.  
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to Millennium, or a designee (or disposal of 
the drug, if approved by Millennium) will be maintained by the clinical site.  Millennium or 
its designee will review drug accountability at the site on an ongoing basis.
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All material containing study drug will be treated and disposed of in accordance with 
governing regulations.
10.11   Product Complaints
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals 
who identify a potential product complaint situation should immediately contact PPD (see 
below) and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a 
Millennium Quality representative.
For Product Complaints:
Call Center
Phone 
E-mail
Fax
Hours
Monday-
Friday, 
9 AM–7 PM, 
ET
Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, an SAE form should be completed and sent to Cognizant (refer to Section 9.2).
10.12   Closure of the Study
Study participation by individual sites or the entire study may be prematurely terminated if, 
in the opinion of the investigator or Millennium, there is sufficient reasonable cause.  
Written notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:
!
Determination of unexpected, significant, or unacceptable risk to patients
!
Failure to enter patients at an acceptable rate
!
Insufficient adherence to protocol requirements
!
Insufficient, incomplete, and/or unevaluable data
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
Determination of efficacy based on interim analysis

Plans to modify, suspend or discontinue the development of the study drug
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded.  In the 
event that any access devices for the EDC application have been provided, these will be 
returned to Millennium once the site’s participation in the study has concluded.
10.13   Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s).  If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified.  
11.   
USE OF INFORMATION
All information regarding TAK-659 supplied by Millennium to the investigator is privileged 
and confidential information.  The investigator agrees to use this information to accomplish 
the study and will not use it for other purposes without consent from Millennium.  It is 
understood that there is an obligation to provide Millennium with complete data obtained 
during the study.  The information obtained from the clinical study will be used toward the 
development of TAK-659 and may be disclosed to regulatory authority(ies), other 
investigators, corporate partners, or consultants as required.
Upon completion of the clinical study and evaluation of results by Millennium, the hospital 
or institution and/or investigator may publish or disclose the clinical trial results pursuant to 
the terms contained in the applicable Clinical Trial Agreement.
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12.   
INVESTIGATOR AGREEMENT
I have read Protocol C34002 Amendment 02:  An Open-Label, Phase 1b/2 Study 
Investigating Recommended Phase 2 Dose, Safety, Tolerability, and Preliminary Efficacy of 
TAK-659 in Adult Patients With Relapsed or Refractory AML
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)
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13.   
REFERENCES
1.
Levis M, Brown P, Smith BD, Stine A, Pham R, Stone R, et al. Plasma inhibitory 
activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic 
response to FLT3 inhibitors. Blood 2006;108(10):3477-83.
2.
Kuendgen A, Germing U. Emerging treatment strategies for acute myeloid leukemia 
(AML) in the elderly. Cancer Treatment Reviews 2009;35(2):97-120.
3.
Laubach J, Rao AV. Current and emerging strategies for the management of acute 
myeloid leukemia in the elderly. Oncologist 2008;13(10):1097-108.
4.
Shipley JL, Butera JN. Acute myelogenous leukemia. Experimental Hematology 
2009;37(6):649-58.
5.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of 
Hodgkin and non-Hodgkin lymphoma: the Lugano classification. Journal of Clinical 
Oncology 2014;32(27):3059-68.
6.
Puissant A, Fenouille N, Alexe G, Pikman Y, Bassil CF, Mehta S, et al. SYK is a 
critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell 2014;25(2):226-
42.
7.
Benderra Z, Faussat AM, Sayada L, Perrot JY, Tang R, Chaoui D, et al. MRP3, 
BCRP, and P-glycoprotein activities are prognostic factors in adult acute myeloid 
leukemia. Clinical Cancer Research 2005;11(21):7764-72.
8.
Sudhindra A, Smith CC. FLT3 inhibitors in AML: are we there yet? Curr Hematol 
Malig Rep 2014;9(2):174-85.
9.
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. 
Department of Health and Human Services National Cancer Institute. 14 June 2010.
10.
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH. 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. Journal of Clinical Oncology 2003;21(24):4642-9.
11.
Cancer Genome Atlas Research N. Genomic and Epigenomic Landscapes of Adult 
De Novo Acute Myeloid Leukemia. New England Journal of Medicine 
2013;368(22):2059-74.
12.
Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal 
evolution in relapsed acute myeloid leukaemia revealed by whole-genome 
sequencing. Nature 2012;481(7382):506-10.
13.
Etienne A, Esterni B, Charbonnier A, Mozziconacci MJ, Arnoulet C, Coso D, et al. 
Comorbidity is an independent predictor of complete remission in elderly patients 
receiving induction chemotherapy for acute myeloid leukemia. Cancer 
2007;109(7):1376-83.
14.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
American Journal of Clinical Oncology 1982;5(6):649-55.
15.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.
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16.
The Criteria Committee of New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, 
Brown & Co; 1994.
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14.   
APPENDICES
14.1   
Modified Charlson Comorbidity Index
Table 14-1   Modified Charlson Comorbidity Index
Point
Comorbid Condition
1
Myocardial infarction
1
Congestive heart failure
1
Cerebrovascular disease
1
Ulcer
1
Hepatic disease (mild)
1
Diabetes (mild or moderate)
1
Pulmonary disease (moderate or severe)
1
Connective tissue disease
2
Diabetes (severe with end-organ damage)
2
Renal disease (moderate or severe)
2
Solid tumor (without metastases)
3
Hepatic disease (moderate or severe)
6
Solid tumor (with metastases)
Total score
Source:  From Etienne et al, 2007 [13]. 
14.2   
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status
Grade
Description
0
Normal activity.  Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work)
2
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours.
3
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair
5
Dead
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55 [14].
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14.3   
Cockcroft-Gault Equation
For male subjects:
Creatinine clearance = (140 age[years]) weight [kg]
OR
(140 age[years]) weight [kg]
72 (serum creatinine[mg/dL])
0.81 (serum creatinine[mol/L])
For female subjects:
Creatinine clearance = 0.85 (140 age[years]) weight [kg]
OR 0.85 (140 age[years]) weight [kg]
72 (serum creatinine[mg/dL])
0.81 (serum creatinine[mol/L])
Source:  Cockcroft DW, Gault MH.  Prediction of creatinine clearance from serum creatinine.  Nephron 
1976;16(1):31-41 [15].
14.4   
New York Heart Association Classification of Functional Capacity
The following table presents the New York Heart Association classification of cardiac 
disease.  
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure 
or the anginal syndrome may be present even at rest. If any 
physical activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 1994:253-256 
[16].
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14.5   
Prohibited CYP3A and P-gp Inducers and Inhibitors
Medication, Supplement, or Food Producta,b
Required Washout Period Prior to First Dose
Strong CYP3A Reversible Inhibitors and/or 
P-gp Inhibitors
amiodarone
azithromycin
captopril
carvedilol
cyclosporine
diltiazem
dronedarone
erythromycin
felodipine
ketoconazole
itraconazole
nefazodone
posaconazole
quercetin
quinidine
ranolazine
ticagrelor
verapamil 
voriconazole
5 times the inhibitor half-life (if a reasonable half-life 
estimate is known), or 7 days (if a reasonable half-life 
estimate is unknown) 
Strong CYP3A  Mechanism-Based Inhibitors 
clarithromycinc
conivaptanc
mibefradilcc,d
telithromycin
7 days, or 5 times the inhibitor half-life, whichever is 
longer
Grapefruit-containing foods and beverages
5 days
Strong CYP3A Inducers and/or P-gp 
Inducers
avasimibee
carbamazepine
phenobarbital
phenytoin
primidone
rifabutin
rifapentine
rifampin
St. John’s wort
7 days, or 5 times the inducer half-life, whichever is 
longer
a Note the list of strong CYP3A inhibitors or inducers and/or P-gp inhibitors or inducers is not exhaustive 
and is based on the FDA Draft DDI Guidance (Sources: fda.gov/downloads/Drugs/GuidanceCompliance 
RegulatoryInformation/Guidances/UCM292362.pdf and fda.gov/Drugs/DevelopmentApprovalProcess/ 
DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm). If a medication, supplement, or 
food/beverage is suspected or known to be a or P-gp inhibitor or inducer and/or strong CYP3A inhibitor 
or inducer, but is not on the list, then its use must be approved on a case by case basis by the Medical 
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Monitor after consultation with the Clinical Pharmacologist and assessment of the relative benefit and 
risk.
b Note that medications used to treat HIV or hepatitis C infection that are strong CYP3A inhibitors or 
inducers and/or P-gp inhibitors or inducers are not included in this list, as patients with known HIV 
infection or known or suspected active hepatitis C infection are excluded from study participation. The 
list also does not include oncology medications because they are prohibited during the study (with the 
exception of hydroxyurea for the first 28 days of study drug treatment).
c Also inhibitors of P-gp.
d Withdrawn from the US market due to safety reasons.
e Not marketed in the US.
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14.6  
Amendment 02 Detailed Summary of Changes
THE PRIMARY SECTION(S) OF THE PROTOCOL AFFECTED BY THE CHANGES IN 
AMENDMENT 02 ARE INDICATED.  THE CORRESPONDING TEXT HAS BEEN REVISED 
THROUGHOUT THE PROTOCOL.
Purpose:  To replace signatories who were previously assigned to the protocol.
The primary change occurs on the Signature Page:
Amended 
text now 
reads:
Purpose:  To update the proposed number of patients in the study.
The primary change occurs in the Protocol Summary:
Amended 
text now 
reads:
Phase 1b dose finding phase:  12 to 15approximately 40 patients
Sections that also contain this change are:
!
Section 4.1
!
Section 4.2
!
Section 8.1.1
Purpose:  To update language specifying inclusivity of the tyrosine kinase domain mutant populations.
The primary change occurs in the Protocol Summary:
Amended 
text now 
reads:
Phase 2 expansion phase:  up to 66 based on a Simon’s 2-Stage design in both FLT-3 wild 
type (WT) and FLT-3-internal tandem duplication (ITD) mutant populations (inclusive of 
the tyrosine kinase domain [TKD] mutant populations)
...
...in patients with or without FLT-3 ITD/TKD mutation
Section 4.1 also contains this change.
PPD
Property of Takeda: For Non-Commercial Use O
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
103
Purpose:  To clarify TAK-659 dosage can include BID dosing.
The primary change occurs in Protocol Summary:
Amended 
text now 
reads:

Phase 1b dose finding phase:  to determine the safety, tolerability, and maximum 
tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-659 administered 
orally on a once daily (QD) or twice daily (BID) dosing schedule in patients with 
relapsed or refractory AML 
Sections that also contain this change are:

Schedule of Events

Section 2.1

Section 4.1

Section 6.1

Section 6.3
Purpose:  To remove the PD effects of TAK-659 (due to the removal of the pS6 sample) and the 
PD assessment from the Protocol Summary, Secondary Endpoints, Schedule of Events, Overview of 
Study, and Study Design.
Deleted 
text from 
Protocol 
Summary:
To evaluate the pharmacodynamic (PD) effects of TAK 659 against FLT-3 and SYK 
signaling in circulating AML blasts
Deleted 
row in the 
Schedule 
of Events 
for Dose 
Escalation 
(Phase 1b) 
[28-Day 
Cycles] :
Blood samples for PDaa
With assessments at Screening, and Cycle 1, Day 1 and Day 3
Deleted 
footnote in 
the 
Schedule 
of Events 
for Dose 
Escalation 
(Phase 1b) 
[28-Day 
Cycles]:
aa Blood specimens for PD analysis will be collected at screening and at time points 
specified in the AML Dose Escalation (Phase 1b) PK, PD, and ECG Assessment 
Schedule.  
Schedule of Events for AML Expansion Cohort (Phase 2) [28 Day Cycles] also contains this change.
Deleted 
row in the 
Schedule 
of Events 
for AML 
Blood samples for PDz
With assessments at Screening, and Cycle 1, Day 1 and Day 3
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
104
Expansion 
Cohort 
(Phase 2) 
[28 Day 
Cycles]:
Deleted 
footnote in 
the 
Schedule 
of Events 
for AML 
Expansion 
Cohort 
(Phase 2) 
[28 Day 
Cycles]:
z Blood specimens will be collected at screening and at time points specified in AML 
Dose Expansion (Phase 2) PK, PD Schedule the to evaluate the pharmacodynamic effects 
of TAK-659 in AML blasts.
Deleted 
columns in 
AML 
Dose 
Escalation 
(Phase 1b) 
PK, PIA, 
and ECG
Assessmen
t Schedule
PD columns under Cycle 1, Day 1 and Day 15
AML Dose Expansion (Phase 2) PK Schedule also contains this change.
Deleted 
text in 
Section 
3.2:

PD effect measured as modulation of expression of pathway markers such as pS6 
in peripheral AML blasts
Amended 
text in 
Section 
4.1 now 
reads:
PD will be assessed in AML dose escalation and expansion cohorts by evaluating 
peripheral AML blast at the time points specified in the Schedule of Events.  In addition, 
aA plasma inhibitory assay will be used to assess the FLT-3 and possibly SYK inhibitory 
effects of TAK-659 in vitro using plasma samples collected from patients exposed to 
TAK-659 at different dose/exposure levels as indicated in the Schedule of Events.
Deleted text in 
Section 7.4.16:

Serial blood samples for the determination of PD effects of TAK-659 
will be collected at screening and during treatment as outlined in the 
Schedule of Events.  Expression levels of pS6 in AML blast cells will 
be examined.
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
105
Purpose:  To update the dose escalation status of Study C34001 and specify the MTD as 100 mg.
The primary change occurs in the Protocol Summary:
Amended 
text now 
reads:
The starting dose for the phase 1b portion of this study (Study C34002) will be directed 
by the current Study C34001, the first-in-human (FIH) dose escalation study of TAK-659 
in patients with advanced solid tumors and lymphoma.  The starting dose in Study 
C34002 will not exceed the highest dose determined to be safe in Study C34001 at the 
time Study C34002 starts.  Thus far in Study C34001, up to 120 mg once daily (QD) of 
TAK-659 has been evaluated in a total of 11 patients with advanced solid tumors and 
lymphoma, of whom 8 were evaluable for DLT.  A dose of 60 mg QD has beenwas
determined to be tolerable based on a 3+3 dose escalation schema after evaluation of 
6 patients.  Dose escalation is ongoing in Study C34001.  Based on these data, the starting 
dose will be 60 mg QD for Study C34002. Since the initiation of Study C34002, dose 
escalation has been completed in Study C34001 with 100 mg QD determined as the 
MTD. In the expansion phase of the ongoing FIH study, lymphoma patients are 
being evaluated at 100 mg and early clinical activity has been observed in this 
population. In the Non Hodgkin Lymphoma population, the more relevant target for 
TAK-659 is SYK.  , unless additional data from Study C34001 indicate a higher dose is 
safe.  A higher starting dose, if supported, will be communicated to investigators in 
writing at the time of protocol initiation.  
Sections that also contain this change are:

Section 4.1

Section 6.3
Purpose:  To allow for prior exposure to investigational FLT-3 inhibitors in the phase 2 portion of the 
study.
The primary change occurs in the Protocol Summary:
Amended 
text now 
reads:
For the phase 2 portion of the study, patients must be refractory to or relapsed after no 
more than 2 prior chemotherapy regimens and must not have prior exposure to any 
investigational FLT-3 inhibitors.  
Sections that also contain this change are:

Section 4.1

Section 5

Section 5.1
Purpose:  To add CPK testing to the Schedule of Events
The primary change occurs in the Schedule of Events for Dose Escalation (Phase 1b) [28-Day Cycles]:
Added row: 
CPK testingo,p to coincide with hematology/chemistry timepoints
Schedule of Events for AML Expansion Cohort (Phase 2) [28 Day Cycles] also contains this change.
Purpose:  To add CMV testing to the Schedule of Events.
The primary change occurs in the Schedule of Events for Dose Escalation (Phase 1b) [28-Day Cycles]:
Added row: 
CMV testingaa
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
106
To take place at Screening
With 
corresponding 
footnote:
aa  Blood specimen will be collected during screening for a local polymerase 
chain reaction testing of CMV replication. The CMV viral load data will be 
entered in the eCRF. Further monitoring of CMV, if indicated, will follow 
the local standard practice. 
The Schedule of Events for AML Expansion Cohort (Phase 2) [28 Day Cycles] also contains this 
change.
Purpose:  To update title of Assessment Schedule.
The primary change occurs in the AML Dose Escalation (Phase 1b) PK, PIA, and ECG Assessment 
Schedule:
Amended title 
now reads:
AML Dose Escalation (Phase 1b) PK, PIA, PD, and ECG Assessment 
Schedule: Cycle 1
Purpose:  To specify time of day for BID dosing.
The primary change occurs in the AML Dose Escalation (Phase 1b) PK, PIA, and ECG Assessment 
Schedule:
Amended 
Footnote 
now reads:
When the timing of a PK, PIA, or safety laboratory blood sample coincides with the 
timing of ECG measurements, the ECG will be completed before the collection of the 
blood samples. For BID dosing, PK, PIA, and ECG assessment schedule refers to 
the AM dose.
The Schedule of Events for AML Expansion Cohort (Phase 2) [28 Day Cycles] also contains this 
change.
This change also occurs in Section 6.1:
Amended 
text now 
reads:
Patients should be instructed to take their study medication at approximately the same 
time each day and to not take more than the prescribed dose at any time. On visit days, 
patients should be instructed to hold their dose until predose assessments are performed. 
For BID dosing, morning and evening doses should be approximately 12 hours 
apart. In the event that a patient fails to take the TAK-659 dose at their scheduled dosing 
time (6 hours of their scheduled dosing) time for QD dosing; ±3 hours of their 
scheduled dosing time for BID dosing), that dose should be skipped and the patient must 
not make dose adjustments on that day or subsequent days to account for the missed dose, 
for example, by taking a double dose of TAK-659 on the following day. Patients should 
record any skipped doses in their dosing diary (see the Study Manual) and resume dosing 
at the next scheduled time with the prescribed dosage.
Purpose:  To remove specification that subsequent anticancer therapy should not be initiated before 
recovery from all treatment-emergent toxicities associated with TAK-659.
The primary change occurs in the Schedule of Events for Dose Escalation (Phase 1b) [28-Day Cycles]:
Amended 
footnote 
b End of Study visit will occur 28 days (+ 10 days) after the last dose of study drug or 
before the start of subsequent anticancer therapy (other than hydroxyurea) if that occurs 
sooner.  Subsequent anticancer therapy should not be initiated before recovery from all 
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
107
now reads:
treatment-emergent toxicities associated with TAK-659.
Schedule of Events for AML Expansion Cohort (Phase 2) [28 Day Cycles] also contains this change.
Purpose:  To update TAK-659 50% inhibition concentration.
The primary change occurs in Section 1.1.2:
Amended 
text now 
reads:
TAK-659 inhibits purified SYK and FLT-3 enzymes with concentrations producing 50% 
inhibition (IC50) of 4.33.2 and 4.6 nM, respectively.  
Purpose:  To update information on the nonclinical experience of TAK-659.
The primary change occurs in Section 1.2:
Amended 
text now 
reads:
Detailed information regarding the nonclinical pharmacology and toxicology of TAK 659 
may be found in the Investigator’s Brochure (IB).
Purpose:  To update information on the clinical experience of TAK-659.
The primary change occurs in Section 1.3:
Amended 
text now 
reads:
As of 19 September 2014, TAK 659 has been administered to 11 patients at doses of up to 
120 mg once daily (QD).  The safety and tolerability of TAK-659 are being evaluated.
As of 05 September 2017, 181 patients have been dosed with TAK 659 in 4 ongoing 
studies, including 121 patients in the first-in-human (FIH) Study C34001 (advanced 
solid tumors and lymphoma), 32 patients in Study C34002 (R/R AML), 19 patients in 
Study C34003 (advanced solid tumor)  and 9 patients in Study C34005 (advanced 
NHL). Both the C34001 and C34002 studies are evaluating TAK-659 as a single 
agent while the C34003 and C34005 studies are evaluating TAK-659 in combination 
with nivolumab (C34003) and 5 additional combination partners (C34005). Different 
data cutoff dates were used to provide the most current clinical information, given 
that the ongoing studies are in various stages of execution. The most current safety 
and efficacy data for Study C34001 are from the 02 June 2017 data cutoff date. The 
most current safety and efficacy data for Study C34002 are from the 24 May 2017 
data cutoff date. In Study C34003, the TAK-659 dose has been evaluated across 
3 dose levels of 60mg, 80mg and 100mg and the MTD determination is pending. 
In Study C34005, TAK-659 is currently being evaluated at 60 mg with plans to 
CCI
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
108
escalate to 100 mg.
1.3.1  Ongoing Studies With TAK-659
As of 05 September 2017, 181 patients have been dosed with TAK 659 in 4 ongoing 
studies, including 121 patients in the first-in-human (FIH) Study C34001, 32 patients 
in Study C34002, 19 patients in Study C34003 and 9 patients in Study C34005. 
As of 02 June 2017, in Study C34001, the TAK-659 dose was escalated from 60 mg to 
120 mg (60 mg [10 patients], 80 mg [4 patients], 100 mg [90 patients], and 120 mg 
[7 patients]). The maximum tolerated dose (MTD) for patients with lymphoma and 
solid tumors has been determined to be 100 mg once daily (QD). Expansion cohorts 
for patients with lymphoma were opened in December 2015, and patients in the 
expansion phase of the study are treated at the MTD/recommended phase 2 dose 
(RP2D) of 100 mg. Of the 181 patients treated in this study (92 lymphoma including 
5 chronic lymphocytic leukemia [CLL] and 19 solid tumors), 96 patients had 
discontinued from study by the June data cutoff date. The reasons for 
discontinuation included PD (45 patients), adverse events (AEs) (29 patients), 
withdrawal by subject (1 patient), symptomatic deterioration (13 patients), protocol 
violation (1 patient), initiation of hematopoietic stem cell transplant (2 patients), and 
other (5 patients).
As of 24 May 2017, in Study C34002, 31 patients had enrolled.  TAK-659 has been 
escalated from 60 mg QD to 160 mg QD, and an additional dose level of 80mg BID is 
also being evaluated. The MTD/RP2D has not yet been determined. Of the 31 
patients treated in this study, 28 patients had discontinued from the study as of the 
May data cutoff date. The reasons for discontinuation included PD (5 patients), AEs 
(18 patients), symptomatic deterioration (2 patients), withdrawal by subject 
(1 patient), and other (2 patients).
The reported AEs were generally as expected on the basis of nonclinical toxicology 
findings of TAK 659 and the patient populations being studied. As of 02 June 2017, 
the most common treatment-related AEs reported in Study C34001 (≥20% of 
patients) have been aspartate aminotransferase (AST) increased (49 patients [44%]), 
amylase increased (39 patients [35%]), lipase increased (31 patients [28%]), alanine 
aminotransferase (ALT) increased and diarrhea (28 patients each [25%]), blood 
creatinine phosphokinase (CPK) increased and hypophosphatemia (26 patients each 
[23%]), and fatigue (22 patients [20%]). The most common Grade 3 or greater 
treatment-related AEs (≥5% of patients) have been amylase increased (23 patients 
[21%]), hypophosphatemia (18 patients [16%]), lipase increased (15 patients [14%]), 
neutropenia (14 patients [13%]), CPK increased (13 patients [12%]), anemia and 
AST increased (7 patients each [6%]),and pneumonia (5 patients [5%]). Further 
investigations are required to determine the clinical significance of the laboratory 
abnormalities, many of which have been asymptomatic, such as amylase and lipase 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
109
increased, AST and ALT increased, and blood CPK increased. In Study C34001, as 
of 02 June 2017, there were 35 on-study deaths. Three of the AEs that led to death 
were considered treatment related (multi-organ failure following sepsis, 
disseminated varicella, and respiratory failure in the presence of Pneumocystis 
jiroveci pneumonia [PJP]; cytomegalovirus [CMV] and aspergillus infection; and 
right pneumothorax and renal failure). 
In Study C34001, as of 02 June 2017, 9 of the 48 response-evaluable DLBCL patients 
achieved a complete response (CR) and 4 achieved a partial response (PR). Seven of 
10 response-evaluable patients with indolent lymphomas responded (1 CR and 
6 PRs). Two out of 4 response-evaluable patients with CLL achieved a response 
(both PR). 
In Study C34002, as of 24 May 2017, there were 15 on-study deaths (one drug 
related, multiple organ dysfunction syndrome). To date, the safety profile in Study 
C34002 appears to be similar to that of Study C34001. Early signs of antileukemic 
activity have been observed in a number of patients who have demonstrated 
significant reductions in both peripheral blast and bone marrow blast counts. 
Three patients have achieved objective response per IWG 2003 criteria (1 CR, 
2 CRi) [15] as of the cutoff date.
Purpose:  To update details for the PK and biomarker assessments.
The primary change occurs in Section 1.4:
Amended 
text now 
reads:
Rationale for Pharmacokinetic Assessments
In the AML Dose Escalation cohorts, blood will be collected during Cycle 1 using an 
intensive sampling schedule so as to permit the detailed characterization of the plasma 
pharmacokinetics (PK) of TAK-659. Specifically, serial plasma PK assessments will be 
used to characterize single- and repeat-dose concentration-time profiles of TAK-659, 
calculate PK parameters, evaluate the dose-exposure relationship, assess dose- and time-
dependence of PK parameters, and contribute to the development of a population PK 
model for TAK-659. The PK sampling time points are derived from considerations of 
clinic practicality and patient convenience. Sampling will be conducted on Days 1, 2, 15, 
and 16 of Cycle 1 to allow evaluation of the accumulation of TAK-659 with daily QD or 
twice-daily (BID) dosing. 
In the AML Dose Expansion cohorts, blood will be collected during Cycle 1 (on Days 1 
and 15) using a sparse sampling schedule to support population PK model development 
and to interpret the pharmacodymanic (PD) results in relation to the concurrent plasma 
concentrations of TAK-659.  Sampling will be conducted on Days 1 and 15 of Cycle 1.
CCI
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
110
Purpose:  To update the risks of TAK-659 in nonclinical and clinical studies.
The primary change occurs in Section 1.5:
Amended 
text now 
reads:
Because TAK-659 has been administered to a total of only 11 181 patients as of 19 
September 2014 in Study C34001, the ongoing, first-in-human (FIH), dose escalation 
study of TAK-659 in patients with advanced solid tumors and lymphoma, there are no 
established benefits of this drug, and 05 September 2017, it is not currently possible to 
describe with certainty the potential adverse effects of the compound.
1.5.1  Potential Risks From Nonclinical Studies
Potential risks from nonclinical studies in dogs and rats include the following:
!
Lymphoid/hematopoietic effects that include included lymph node lymphoid 
depletion, atrophy, and myelosuppression that were are associated with 
thrombocytopenia, neutropenia, and reticulocytopenia. These findings may be 
associated with increased susceptibility to infection, bleeding, and anemia.
!
Epithelial effects on the intestinal tract, urinary tract, and lens. Intestinal effects 
included minimal-to-slight mucosal hemorrhaging. Urinary and renal tract 
effects included hyperplasia of transitional epithelium in the kidney and bladder, 
dilatation and hemorrhage in the renal pelvis that led to hematuria and 
proteinuria, and urolithiasis with possible ureter obstruction. Lens effects 
included epithelium hyperplasia leading to anterior axial opacity.
!
Reproductive system effects, including decreased spermatozoa and 
seminiferous tubule degeneration in the testis and corpora luteal necrosis in the 
ovaries.
!
Possible mutation of DNA.
!
Growth plate thickening and disorganization (not relevant to adults).
!
Lymphoid and hematopoietic effects and reproductive system effects are 
CCI
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
111
considered important potential risks.
In addition, mild to moderate elevations in amylase, lipase, and transaminases were 
observed after TAK-659 administration in both rats and dogs.  However, no signs of 
injury to the liver or pancreas were observed upon microscopic evaluation.  Increased 
serum lipase and transaminases were observed in a few patients treated with TAK-659 in 
Study C34001.  However, the patients did not have any related symptoms.  Further 
investigations are required to determine the clinical significance of these asymptomatic 
laboratory abnormalities.
It is also possible that TAK-659 will have toxicities that were not observed in or predicted 
from the studies completed in animals.
1.5.2 Potential Risks From Clinical Studies
Potential risks based on clinical observations include the following:
On the basis of data from Study C34001, asymptomatic elevation in lipase was added 
as an important potential risk of TAK-659. In nonclinical studies, lipase was 
sporadically elevated at high doses of TAK-659; however, there was no evidence of 
microscopic organ damage. In clinical studies to date, asymptomatic lipase or 
amylase elevations are reported commonly (≥10% of patients). Patients in Study 
C34002 have frequent monitoring of lipase and amylase as outlined in the Schedule 
of Events.
Cases of pneumonitis have been reported in clinical studies with B-cell receptor 
pathway kinase inhibitors, including TAK-659, and pneumonitis is considered an 
important potential risk of TAK-659. Pneumonitis and other pulmonary toxicities 
are being closely monitored in TAK-659 clinical studies.
There have been occurrences of opportunistic infections such as PJP in some 
patients who had fever. These patients had other underlying conditions that made 
them prone to infections. With the limited experience we have with TAK-659, we 
have not determined whether TAK-659 is directly associated with the occurrences of 
these infections.
Further details regarding the benefits and risks associated with TAK-659 may be 
found in the current version of the TAK-659 IB.
Purpose:  To update the number of patients and study centers.
The primary change occurs in Section 4.2:
Amended 
text now 
For the phase 1b portion, approximately 12-1540 patients will be enrolled in this study 
from approximately 2 to 46 study centers in the United States.  For the phase 2 portion, up 
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
112
reads:
to 66 patients will be enrolled in this study from approximately 10 to 15 global sites.  
Enrollment is defined as time of initiation of the first dose of study drug.
Purpose:  To update the study duration.
The primary change occurs in Section 4.3:
Amended 
text now 
reads:
It is anticipated that this study will last for approximately 24 to 3266 to 72 months, 
including 9 to 12304 to 36 months in the phase 1b portion and 15 to 2032 to 36 months in 
the phase 2 portion. 
Purpose:  To update contraception methods.
The primary change occurs in Section 5.1:
Amended 
text now 
reads:
5.
Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly2 effective 
methods of contraception and 1 additional effective (barrier) method, at 
the same time, from the time of signing the informed consent through 180 
days after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods], and withdrawal, spermicides only, 
and lactational amenorrhea are not acceptable methods of contraception.
Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study 
treatment period and through 180 days after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods for the female partner], and
withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should 
not be used together.)
Section 6.6 also contains this change.
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
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Purpose:  To update laboratory values regarding lipase and amylase, and to exclude patients with 
moderate renal impairment.
The primary change occurs in Section 5.1:
Amended 
text now 
reads:
9.
Clinical laboratory values as specified in the following:  

Total bilirubin must be ≤1.5 the upper limit of normal (ULN).

Serum ALT and AST must be ≤2.5 the ULN.

Lipase ≤1.5 ULN and amylase ≤1.5 ULN with no clinical symptoms 
suggestive of pancreatitis or cholecystitis.

Serum creatinine must be 1.5 ULN or cCreatinine clearance ≥650 
mL/min either as estimated by the Cockcroft-Gault equation (See Section 
14.3) or based on urine collection (12 or 24 hours).
Purpose:  To clarify exclusion criteria of systemic anticancer treatment.
The primary change occurs in Section 5.2:
Amended 
text now 
reads:
4.
Systemic anticancer treatment (including investigational agents) Prior 
treatment with investigational agents ≤ 21 days or ≤ 5 their half-lives 
(whichever is shorter) before the first dose of study treatment. (For example, if 
the 5 × the half-life is shorter than 21 days, 5 x half-life should be used as the 
washout period. However, aA minimum of 10 days should elapse from prior 
investigational therapy to initiating protocol therapy.
Purpose:  To clarify exclusion criteria regarding use or consumption of substances (medication and 
supplements).
The primary change occurs in Section 5.2:
Amended 
text now 
reads:
14. Use or consumption of any of the following medications, supplements, or 
foods/beverages that are inhibitors or inducers of P-gp or strong inhibitors or 
inducers of CYP3A within the indicated timeframes below. Note that use or 
consumption of these substances: is not permitted during the study.substances:
a)
Medications or supplements that are known to be iInhibitors of P-gp 
and/or strong reversible inhibitors of CYP3A within 5 times the inhibitor 
half-life (if a reasonable half-life estimate is known) or within 7 days (if a 
reasonable half-life estimate is unknown) before the first dose of study drug. 
In general, the use of these agents is not permitted during the study 
except for AE management (see Section 6.7 for details). See Section 14.5
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
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for a nonexhaustive list of prohibited strong CYP3A reversible inhibitors 
and/or P-gp inhibitors based on the US Food and Drug Administration 
(FDA) Draft DDI Guidance.  
b)
Medications or supplements that are known to be sStrong CYP3A 
mechanism-based inhibitors or strong CYP3A inducers and/or P-gp inducers 
within 7 days, or within 5 times the inhibitor or inducer half-life (whichever 
is longer) before the first dose of study drug. In general, the use of these 
agents is not permitted during the study except for AE management (see 
Section 6.7 for details). See Section 14.5 for a nonexhaustive list of 
prohibited strong CYP3A mechanism-based inhibitors or strong CYP3A 
inducers and/or P-gp inducers based on the US FDA Draft DDI Guidance.
c)
Grapefruit-containing food or beverages within 5 days before the first dose 
of study drug. Note that grapefruit-containing food and beverages are 
not permitted during the study.
Purpose:  To update TAK-659 dose adjustments for nonhematologic toxicities.
The primary change occurs in Table 6-2:
Amended 
text now 
reads:
Table 6-2   
TAK-659 Dose Adjustments for Nonhematologic Toxicities
Criteria
Action
Grade 3 nonhematologic toxicities with the 
exception of:

Grade 3 nausea, vomiting, and diarrhea 
resolved to ≤Grade 1 or baseline within 1 
week with optimal antiemetics and 
antidiarrheal following standard of care

Transient Grade 3 fatigue (lasting <1 week)

Asymptomatic lipase elevation (<Grade 4) 
in the absence of significant amylase 
elevation (<Grade 3) considered not dose 
limiting following agreement between 
sponsor and investigators

Asymptomatic amylase elevation (<Grade 
4) in the absence of lipase elevation 
(<Grade 3) considered not dose limiting 
following agreement between sponsor and 
investigators

Asymptomatic Grade 3 elevation of a 
single liver enzyme (AST or ALT) in the 
absence of significant bilirubin elevation 
(<Grade 3) considered not dose limiting 
following agreement between sponsor and 
investigators

Grade 3 hypophosphatemia resolved to 
Hold TAK-659 until resolution to 
≤Grade 1 or baseline or a level 
considered acceptable by the 
investigator (must be ≤Grade 2).

If resolved in ≤7 days, 
then maintain dose level.

If resolved in >7 days, 
then reduce dose by 1 
dose level.

If recurrence occurs, then 
reduce dose by 1 dose 
level.
For the exceptions listed, maintain 
the dose level (no dose hold 
required). 
Permanent discontinuation should 
be considered if the toxicities 
persist as ≥Grade 3 for more than 
21 days despite temporary 
disruption of study drug.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
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Grade ≤1 or baseline within 72 hours with 
phosphate repletion

Other aAsymptomatic Grade 3 laboratory 
abnormalities that are considered to be not 
clinically significant, as determined jointly 
by the investigators and the sponsor 
Grade 4 nonhematologic toxicities with the 
exception of:

Asymptomatic Grade 4 lipase elevation in 
the absence of significant amylase 
elevation
(<Grade 3).

Asymptomatic Grade 4 amylase elevation 
in the absence of significant lipase 
elevation (<Grade 3).

Asymptomatic Grade 4 elevation of a 
single liver enzyme (AST or ALT) in the 
absence of significant bilirubin elevation 
(<Grade 3).

Grade 4 hypophosphatemia resolved to 
≤Grade 1 or baseline value within 72 
hours with phosphate repletion.

Other Grade 4 asymptomatic enzyme 
elevations not considered clinically 
significant following agreement between 
sponsor and investigator.
Consider permanently 
discontinuing TAK-659, except in 
the case where the investigator 
determines the patient is obtaining 
a clinical benefit and has discussed 
this with the project clinician or 
designee. Dose reduction of ≥1 
dose level is required if study 
treatment resumes after 
resolution to ≤Grade
1 or baseline values.
For the exceptions, hold TAK-
659 until resolution to ≤Grade
1 or baseline values or to a level 
that is clinically acceptable as 
determined by Investigator 
(≤Grade 2) , then:

If resolved in ≤7 days, 
maintain dose level.

If resolved in >7 days, 
reduce dose by 1 dose 
level.

If recurs, reduce dose 
by 1 dose level.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
116
Purpose:  To provide updates to concomitant medications and procedures.
The primary change occurs in the Section 6.5:
Amended 
text now 
reads:
6.5 Excluded Concomitant Medications and Procedures
During the study, patients will be instructed not to take any additional medications 
(including over-the-counter products and supplements) without prior consultation 
with the investigator. At each visit, the investigator will ask the patient about any 
new medications he/she is taking or has taken while on study. All concomitant 
medications (defined as any medication given during the study) and significant 
nondrug therapies, including physical therapy and blood transfusions, should be 
recorded from signing of the informed consent form (ICF) through 28 days after the 
last dose of study drug or the start of subsequent antineoplastic therapy, whichever 
occurs first. 
The following restrictions apply during the study:
The following medications and procedures are prohibited during the study:

Any antineoplastic therapy other than TAK-659 (with the exception of 
hydroxyurea for the first 28 days of study drug treatment).  This includes chronic 
use of corticosteroids at daily doses greater than the equivalent of 10 mg of 
prednisone as part of any anticancer treatment regimens.  If alternative therapy is 
required for treatment of the patient’s tumor, the patient should be removed from 
this study and the reason for removal recorded in the electronic case report form 
(eCRF).

Radiation therapy (note that, in general, the requirement for local radiation 
therapy indicates disease progression).  Palliative radiotherapy for pain control in 
a pre-existing lesion may be considered after discussion with the sponsor’s 
clinical representative. 

Prophylactic use of myeloid growth factors (eg, granulocyte colony stimulating 
factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF]) 
in Cycle 1 during dose escalation.  Patients who experience severe and/or febrile 
neutropenia can be managed with growth factor support if needed in accordance 
with American Society of Clinical Oncology (ASCO) guidelines.

Concurrent systemic administration of TAK-659 with inhibitors or inducers 
of P-gp or strong inhibitors or inducers of CYP3A should be avoided in this 
study. In vitro studies indicate that TAK-659 is a substrate for P-gp and 
that, among CYP isozymes, TAK-659 is preferentially metabolized by 
CYP3A4/5. Refer to the list below and Appendix 14.5 for a nonexhaustive 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
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list of medications, supplements, and food products that are inhibitors or 
inducers of P-gp or strong inhibitors or inducers of CYP3A based on the US 
FDA draft guidance for DDI studies.
Systemic treatment with inhibitors or inducers of P-gp or strong inhibitors or inducers of 
CYP3A is not permitted in this study because in vitro studies indicate that TAK-659 is a 
substrate for P-gp and that, among CYP isozymes, TAK-659 is preferentially metabolized 
by CYP3A4/5.  Refer to the list below and Section 14.5 for a list of excluded medications, 
supplements, and food products; Section 14.5 also provides the required washout period 
for these substances prior to the first dose of study drug. Note that medications used to 
treat HIV or hepatitis C infection are not listed below or in Section 14.5 because patients 
with known HIV infection or known or suspected active hepatitis C infection are excluded 
from study participation. In addition, oncology medications are not listed because they are 
prohibited during the study (with the exception of hydroxyurea for the first 28 days of 
study drug treatment). If a medication, supplement, or food/beverage is suspected or 
known to be a or P-gp inhibitor or inducer and/or strong CYP3A inhibitor or inducer, but 
is not on the list below and in Section 14.5, then its use must be approved on a case by 
case basis by the Medical Monitor after consultation with the Clinical Pharmacologist and 
assessment of the relative benefit and risk.

Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole

Antibiotics: azithromycin, clarithromycin, erythromycin, telithromycin

Antimycobacterials: rifabutin, rifampin, rifapentine

Antiepileptics: carbamazepine, phenobarbital, phenytoin, primidone

Antidepressant: nefazadone

Immunosuppressant: cyclosporine

Calcium channel blockers: diltiazem, felodipine, mibefradil, verampamil

Antiarrhythmics: amiodarone, dronedarone, quinidine

Antiplatelet: ticagrelor

Antilipid: avasimibe

Other cardiovascular: captopril, carvedilol,  ranolazine

Vasopressin antagonist: conivaptan

Food/Herbals/Supplements: grapefruit-containing food and beverages, St. John’s 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
118
wort, quercetin
If a patient experiences an AE on study and TAK-659 dosing is temporarily interrupted 
because of that AE, the medications listed above and Appendix 14.5 may be used for AE 
management if there is no appropriate alternative treatment available per the 
investigator’s judgment and the dosing is not concurrent with study drug. This situation 
requires discussion between the investigator and the medical monitor, and the discussion 
will be documented in the study file. Patients should be closely monitored for potential 
toxicities. This situation will be handled on a case by case basis, and requires 
discussion between the investigator and the medical monitor to assess the relative 
benefit and risk for a given patient. The discussion will be documented in the study 
file. Patients should be closely monitored for potential toxicities.
Note that medications used to treat HIV or hepatitis C infection are not listed above or in 
Appendix 14.5 because patients with known HIV infection or known or suspected active 
hepatitis C infection are excluded from study participation. In addition, oncology 
medications are not listed because they are prohibited during the study. If a medication, 
supplement, or food/beverage is suspected or known to be a or P-gp inhibitor or inducer 
and/or strong CYP3A inhibitor or inducer, but is not on the list above or in Appendix 
14.5, then its use must be discussed on a case-by-case basis with the medical monitor or 
designee to assess the relative benefit and risk. The discussion will be documented in 
the study file. Patients should be closely monitored for potential toxicities.
Purpose:  To provide details on managing pneumonitis, edema, hypophosphatemia, enzyme elevations 
(including transaminase, amylase and lipase, and CPK elevations, in addition to lactate dehydrogenase 
elevations).
The primary change occurs in Section 6.7:
Added
text:
Pneumonitis
Patients with serious lung events that do not respond to conventional antimicrobial 
therapy should be assessed for drug-induced pneumonitis after ruling out infectious 
causes and alternative etiologies. If pneumonitis is suspected, TAK-659 treatment 
should be interrupted and the patient treated per standard of care. If pneumonitis is 
moderate/severe, discontinue TAK-659. Patients should be monitored for 
respiratory signs and symptoms throughout treatment and be advised to promptly 
report respiratory symptoms.
...
Edema (Including Periorbital)
Peripheral and periorbital oedema have been observed in patients treated with 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
119
TAK-659. Management of the event, if it occurs, should follow the standard local 
practice and dose modification should proceed following the dose modification 
guideline in Table 6-2.
...
Hypophosphatemia
Hypophosphatemia has been observed in patients treated with TAK-659. Consider 
prophylaxis; otherwise refer to dose modification guideline in Table 6-2.
Enzyme Elevations 
Transaminase, Amylase and Lipase, and CPK Elevations
Elevations of the enzymes above have been observed. Events are generally 
asymptomatic and reversible with dose interruption. See dose modification guideline 
in Table 6-2.
Lactate Dehydrogenase Elevations
Lactate dehydrogenase (LDH) elevations have been observed in the majority of 
patients exposed to TAK-659. These elevations have been asymptomatic and the 
clinical significance is unknown. No doses have been interrupted due to increased 
LDH; however, LDH elevations have been observed to be reversible in patients who 
had TAK-659 interrupted due to other reasons. 
Purpose:  To provide updated details on managing infections.
The primary change occurs in Section 6.7:
Amended 
text now 
reads:
Prophylaxis Against Infections
The severe and prolonged period of neutropenia seen with therapy is frequently associated 
with neutropenic fevers and a high risk of infection with bacteria or fungi and viral 
reactivation.  To minimize the risk of infection, it is recommended that patients be placed 
on “neutropenic precaution”, with or without the addition of prophylactic antibiotics, 
antifungals, or antivirals.  In addition, patients should be screened for possible infectious 
foci (eg, dental status).
The components of “neutropenic precaution” may vary by institution but most commonly 
include:  a high efficiency particulate air-filtered room, a diet free of raw berries or 
vegetables grown in dirt, no sick visitors, and no smoking.  In addition, hand washing by 
all visitors and caregivers should be strictly enforced.
Consideration should be given to antibiotic, antifungal, and antiviral prophylaxis 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
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during therapy, particularly if the patient is more prone to developing neutropenia; 
however, the use of such agents should be at the discretion of investigators based on 
the local standard practice. Patients who develop neutropenic fever should be 
evaluated promptly and treated immediately with parental antibiotics tailored to the 
prominent organisms and resistance patterns of the institution.
Patients with lymphopenia and neutropenia may be more prone to developing 
infections, such as respiratory tract infections or pneumonia. Consider a diagnosis of 
opportunistic infection including PJP in patients presenting with shortness of breath, 
cough, or fever. Prophylaxis for PJP may be initiated (either at baseline or during
treatment) if clinically indicated. For older patients, patients with recent exposure to 
steroids or immunosuppressive agents, or patients who, in the investigator’s opinion, 
are more susceptible to opportunistic infection at baseline, PJP prophylaxis should 
be considered at the start of the study treatment. When steroids and/or any 
immunomodulatory agents need to be used to manage the AEs during the study, PJP 
prophylaxis should be considered when the study treatment resumes or is co-
administered. Trimethoprim-sulfamethoxazole is recommended as the treatment of 
choice for PJP prophylaxis unless contraindicated. However, investigator discretion 
in selecting a more appropriate prophylaxis regimen for their patients is permitted. 
Myelosuppression can also be associated with reactivation of herpes zoster, CMV, 
herpes simplex and other viruses. Antiviral therapy such as acyclovir, gancyclovir, 
valacyclovir, or other antiviral agents may be initiated as clinically indicated. 
Testing of CMV replication by a local polymerase chain reaction (PCR) assay will be 
required at baseline, and further monitoring and prophylactic or preemptive 
therapy to asymptomatic patients, if indicated, should follow the institutional 
standard practice. The following agents should be considered for prophylaxis or 
preemptive treatment against CMV: ganciclovir intravenously (IV), valganciclovir 
(orally), foscarnet (IV), or cidofovir (IV). Duration of antiviral therapy generally is 
for at least 2 weeks until CMV is no longer detected by PCR.
Antiviral prophylaxis, such as acyclovir, is recommended for herpes simplex 
virus-seropositive patients.  The use of prophylactic antibiotics and antifungals should be 
at the discretion of investigators based on the local standard practice.
Patients who develop neutropenic fever should be evaluated promptly and treated 
immediately with parental antibiotics tailored to the prominent organisms and resistance 
patterns of the institution. 
Purpose:  To provide updated details on managing rash with or without pruritus.
The primary change occurs in Section 6.7:
Amended 
text now 
Prophylactic measures should also be considered if a patient develops a rash (eg, using a 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
121
reads:
thick, alcohol-free emollient cream on dry areas of the body).  In the case of rash, the use 
of a topical or oral steroid (eg, prednisone ≤ 10 mg per day or equivalent) is permitted.  
Treatment with TAK-659 must be withheld in the event of Grade 3 or 4 rash. Refer 
to dose modification guideline in Table 6-2.
Purpose:  To update temperature of storage conditions to make consistent with other protocols.
The primary change occurs in Section 6.12:
Now 
reads:
TAK-659 tablets should be stored in the original dispensing bottles at room temperature 
of 1°C to 25°C (33.8°F to 77°F).  Drug supply must be kept in an appropriate, limited 
access, secure place until it is dispensed to the enrolled patients, returned to sponsor, or 
forwarded to the sponsor’s designee for destruction.  Drug supplies received at the clinical 
sites will be counted and reconciled before being returned to the sponsor.
Purpose: To update language for concomitant medications and procedures.
The primary change occurs in Section 7.4.9:
Now 
reads:
Concomitant medications and procedures will be recorded in the eCRF from the time of 
the first dose of study drug through 28 days after the last dose of study drug or to the start 
of subsequent anticancer therapy, whichever occurs first.  See Section 6.5 for a list of 
medications and therapies that are prohibitedshould be avoided during the study unless 
otherwise specified.   
Purpose:  To update clinical laboratory evaluations to reflect addition of CMV testing.
The primary change occurs in Section 7.4.13:
Amended 
text now 
reads:
Clinical Chemistry, Hematology, and Urinalysis, and Virology 
Blood samples for analysis of the following clinical chemistry and hematological 
parameters and urine samples for urinalysis will be obtained as specified in the Schedule 
of Events.
...
When creatinine clearance is estimated, the Cockroft-Gault formula will be 
employed as follows (see Section 14.3):
For female patients, the result of the formula above should be multiplied by 0.85. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 
Clinical Study Protocol C34002 Amendment 02
122
Virology 
!
CMV
Purpose:  To clarify PD population will be derived from the plasma inhibitory assay.
The primary change occurs in Section 8.1.3:
Amended 
text now 
reads:
Pharmacodynamics population:  Patients with sufficient dosing in Cycle 1 and sufficient 
pharmacodynamics data derived from the Plasma Inhibitory Assay will be used for 
pharmacodynamics analyses.
Purpose: To remove the PD assessment from the PK analysis.
The primary change occurs in Section 8.1.7:
Deleted 
text:
Plasma PK data from the AML Dose Escalation cohorts and the AML Dose Expansion 
cohorts may be used to explore the relationship between PD markers of SYK and FLT-3 
inhibition and TAK-659 exposure (as described in Biomarker Analysis) and may be used 
to explore the relationship between exposure and toxicity and exposure and effectiveness 
using graphical and/or pharmacostatistical approaches, as permitted by the data.
Purpose:  To update product complaint telephone number.
The primary change occurs in Section 10.11:
Now reads:
Purpose:  To add CRp, CRh, and CRc to the definition of a response for purposes of disease 
assessment.
The primary change occurs in Section 7.4.15:
Amended text 
now reads:
CR, CRi, CRp, CRh, CRc, and PR are defined using the following criteria:
CR:  A CR designation requires that the patient achieve the 
morphologic leukemia-free state and have an ANC of more than 
1000/μL and platelets of ≥100,000/μL.  A morphologic leukemia-free 
state requires less than 5% blasts in an aspirate sample with marrow 
spicules and with a count of at least 200 nucleated cells.  There should 
be no blasts with Auer rods.  The peripheral blood should have no 
leukemic blasts.  Hemoglobin concentration or hematocrit has no 
Property of Take
Amende
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now
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add C
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imary
da
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nt 
nt
for 
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m
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TAK-659 
Clinical Study Protocol C34002 Amendment 02
123
bearing on remission status, although the patient must be independent 
of transfusions.  There should be no residual evidence of 
extramedullary leukemia. 
Morphologic CRi (complete response with incomplete recovery of 
blood counts):  After chemotherapy, some patients fulfill all of the 
criteria for CR except for residual neutropenia (<1000/µL) or 
thrombocytopenia (<100,000/µL).
CRp (complete response without platelet recovery): CRp satisfies 
all CR criteria except platelets < 100,000/μL, but platelet 
transfusions are not necessary.
CRh (complete response with partial hematologic recovery): CRh
is defined as no evidence of peripheral blasts and partial recovery 
of peripheral blast counts including ANC above 500/μL and 
platelets above 50,000/μL.
CRc: A composite complete remission is defined as the sum of 
patient achieving a CR, CRh, CRi, or CRp.
PR:  This designation requires all of the hematologic values for a CR 
but with a decrease of at least 50% in the percentage of blasts to 5% to 
25% in the bone marrow aspirate.  Thus, if the pretreatment bone 
marrow blast percentage was 50% to 100%, the percentage of blasts 
must decrease to a value between 5% and 25%; if the pretreatment 
blast percentage was 20% to less than 49%, they must decrease by at 
least half to a value of more than 5%.  A repeat bone marrow aspiration 
after several weeks may be required to distinguish between a PR and 
increased blasts caused by bone marrow regeneration.  A value of ≤5% 
blasts may also be considered a PR if Auer rods are present.
Response assessments above generally follow the standard criteria except 
patients who achieve a CR, CRh, CRi, CRp, or PR are not required to be 
transfusion independent.
Sections that also contain this change are:

Section 3.1

Section 4.1
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: n Open-Label, Phase 1b/2 Study Investigating Recommended Phase 2 Dose, Safety, 
Tolerability, and Preliminary Efficacy of TAK-659 in Adult Patients With Relapsed or 
Refractory Acute Myelogenous Leukemia (AML)
NCT Number: NCT02323113
SAP Approve Date: 08 November 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C34002
An Open-Label, Phase 1b/2 Study Investigating Recommended Phase 2 Dose, Safety, 
Tolerability, and Preliminary Efficacy of TAK-659 in Adult Patients with Relapsed or 
Refractory Acute Myelogenous Leukemia (AML)
PHASE 1b/2
Version: 1.0
Date: 08 NOVEMBER 2018
Prepared by:
Based on:
Protocol Version: Amendment 02
Protocol Date: 05JAN2018
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
d Phase
Phase
Patient
Patien
emia (A
emia (A
1b/2
1b/2
Versi
Vers o
e: 08
08 N
Protoc
Proto
Pr
For Non-C
ope


C34002
Page 2 of 25
Statistical Analysis Plan
08 November 2018
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


C34002
Page 3 of 25
Statistical Analysis Plan
08 November 2018
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objectives ....................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Exploratory Objectives ..............................................................................................8
4.4
Study Design .............................................................................................................8
5.0
ANALYSIS ENDPOINTS.............................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Data Presentation ...............................................................................................12
7.1.2
Definition of Study Days....................................................................................13
7.1.3
Conventions for Missing/Partial Dates in Screening Visit...................................13
7.1.4
Conventions for Missing Adverse Event Dates...................................................13
7.1.5
Conventions for Missing Concomitant Medication/Therapy Dates .....................14
7.2
Populations for Analysis ..........................................................................................15
7.3
Disposition of Subjects ............................................................................................15
7.4
Demographic and Other Baseline Characteristics.....................................................15
7.5
Medical History and Concurrent Medical Conditions...............................................16
7.6
Medication History and Concomitant Medications...................................................16
7.7
Study Drug Exposure and Compliance.....................................................................16
7.7.1
Study Treatments ...............................................................................................16
7.7.2
Extent of Exposure.............................................................................................16
7.7.3
Action on Drug ..................................................................................................17
7.8
Efficacy Analysis.....................................................................................................17
7.8.1
Primary Efficacy Endpoint(s).............................................................................17
7.8.2
Secondary Efficacy Endpoint(s).........................................................................17
7.8.3
Additional Efficacy Endpoint(s).........................................................................18
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................19
7.9.1
Pharmacokinetic Analysis ..................................................................................19
7.10
Pharmacodynamic Analysis .....................................................................................20
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7.11
Other Outcomes.......................................................................................................20
7.11.1 Pharmacogenomic Analysis ...............................................................................20
7.11.2 Safety Analysis ..................................................................................................21
7.11.3 Adverse Events ..................................................................................................21
7.11.4 Clinical Laboratory Evaluations .........................................................................22
7.11.5 Vital Signs .........................................................................................................22
7.11.6 12-Lead ECGs ...................................................................................................23
7.11.7 Other Observations Related to Safety.................................................................23
7.12
Interim Analysis ......................................................................................................23
7.13
Changes in the Statistical Analysis Plan...................................................................23
8.0
REFERENCES..............................................................................................................24
9.0
DATA LISTINGS .........................................................................................................25
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3.0
LIST OF ABBREVIATIONS
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ASH
American Society of Hematology
AST
aspartate aminotransferase
AUCtau
BID
Area under the plasma concentration versus time curve over the dosing interval
twice daily
BSA
body surface area
BUN
blood urea nitrogen
CD
compact disc
CI
confidence interval
CLss/F
apparent clearance at steady state
Cmax
maximum plasma concentration
CO2
carbon dioxide
CR
CRh
complete response 
complete response with partial hematologic recovery
Cri
complete response with incomplete hematologic recovery
CRO
contract research organization
CRp
complete response with incomplete platelet recovery
CYP
cytochrome 
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
EC50
Concentration producing half-maximal response
ECG
electrocardiogram
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Statistical Analysis Plan
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Abbreviation
Term
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOS
End of Study (visit)
FDA
United States Food and Drug Administration
FIH
first-in-human
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GI
gastrointestinal
GM-CSF
granulocyte macrophage-colony stimulating factor
GVHD
graft-versus-host disease
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HSCT
hematopoietic stem cell transplant
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
ITAM
immunoreceptor tyrosine-based activating motifs
ITD
internal tandem duplication
IV
intravenous; intravenously
IWG
International Working Group
LC/MS/MS
liquid chromatography tandem mass spectrometry
LDH
lactate dehydrogenase
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
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Abbreviation
Term
NYHA
New York Heart Association
ORR
overall response rate
OS
overall survival
PD
progressive disease
PIA
plasma inhibitory assay
PK
pharmacokinetic(s)
PR
partial response 
PTR
peak-trough ratio
QD
once daily
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QTcB
Bazette’s corrected QT interval
QTcF
Fridericia’s corrected QT interval
Rac
accumulation ratio
RP2D
recommended phase 2 dose
RBC
red blood cell
SAE
serious adverse event
tmax
first time to reach maximum plasma concentration
TTP
time to progression
ULN
upper limit of the normal range
WHO
World Health Organization
WT
wild type
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4.0
OBJECTIVES
4.1
Primary Objectives
!
Phase 1b dose finding phase: to determine the safety, tolerability, and maximum tolerated 
dose (MTD)/recommended phase 2 dose (RP2D) of TAK-659 administered orally on a daily 
or twice daily dosing schedule in patients with relapsed or refractory AML
!
Phase 2 expansion phase: to evaluate preliminary efficacy of TAK-659 in relapsed or
refractory AML as measured by overall response rate (ORR)
4.2
Secondary Objectives
!
To evaluate additional efficacy measures of TAK-659, such as duration of response (DOR), 
time to progression (TTP), mortality rate at 3 and 6 months, and overall survival (OS)
!
To evaluate differential efficacy of TAK-659 in patients with or without FLT-3-ITD 
mutation
!
To characterize the plasma pharmacokinetics (PK) of TAK-659 in patients with relapsed or 
refractory AML
4.3
Exploratory Objectives
4.4
Study Design
This study will include a phase 1b dose finding portion and a single arm phase 2 expansion 
portion in relapsed or refractory AML.
The starting dose for the phase 1b portion of this study (Study C34002) will be directed by the
current Study C34001, the first-in-human (FIH) dose escalation study of TAK-659 in patients 
with advanced solid tumors and lymphoma. The starting dose in Study C34002 will not exceed 
the highest dose determined to be safe in Study C34001 at the time Study C34002 starts. A dose
of 60 mg QD has been determined to be tolerable based on a 3 + 3 dose escalation schema after
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Statistical Analysis Plan
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evaluation of 6 patients. Dose escalation is ongoing in Study C34001. Based on these data, the
starting dose will be 60 mg QD for Study C34002. Since the initiation of Study C34002, dose 
escalation has been completed in Study C34001 with 100 mg QD determined as the MTD. In the 
expansion phase of the ongoing FIH study, lymphoma patients are being evaluated at 100 mg 
and early clinical activity has been observed in this population. In the NHL population, the more 
relevant target for TAK-659 is SYK.  
A 3 + 3 dose escalation design will be used to determine the MTD of TAK-659 in AML. Each
28-day treatment cycle will be composed of 28 consecutive days of QD or BID TAK-659 
treatment. Planned dose escalation will follow 20-mg increments of escalation (eg, from 60 mg 
to 80 mg QD or BID). A more aggressive dose escalation (more than 20-mg increments but not 
exceeding 100% escalation), evaluation of alternative dosing regimens (eg, BID), and expansion 
of an existing dose level up to 12 evaluable patients are all permissible following discussions 
between the sponsor and the investigators based on evolving safety, tolerability, and PK data of 
TAK-659. Dose escalation will continue until either MTD is reached or the RP2D (if different 
from MTD) has been determined based on safety, tolerability, preliminary PK, PIA, and 
preliminary efficacy data, if available. At least 6 patients will be evaluated at RP2D (either the 
MTD or at a lower dose as determined) before making a decision to advance to the phase 2 
expansion phase. In the process of determining or refining RP2D, expansion of more than 1 dose
level to at least 6 patients (up to a maximum of 12 evaluable patients per dose level) is 
permissible so that early signs of clinical activity can be assessed to a greater extent to assist 
dose selection.
The phase 2 expansion study in relapsed or refractory AML will be conducted using a Simon’s 
2-stage design. The primary objective of the phase 2 portion of the study is to detect an efficacy 
signal that warrants further development of TAK-659 in AML. The primary measure of efficacy 
for the phase 2 portion will be the ORR, which will include complete response (CR), CR with 
incomplete platelet recovery (CRp), CR with incomplete hematologic recovery (CRi), CR with 
partial hematologic recovery (CRh), a composite complete remission (CRc defined as the sum of 
patient achieving a CR, CRh, CRi, or CRp), and partial response (PR). Nine and 15 response-
evaluable patients will be enrolled initially in the FLT-3 WT and FLT-3 ITD/tyrosine kinase 
domain (TKD) mutant cohorts, respectively, during the first stage. Best response will be assessed 
by the end of Cycle 4 of TAK-659 treatment for the purpose of an interim analysis between 
Stage 1 and Stage 2. The FLT-3 WT and FLT-3 ITD/TKD mutant cohorts will proceed to the 
second stage if ≥2 and ≥6 patients, respectively, respond to treatment (ORR). Other efficacy 
measures, such as DOR, TTP, and mortality rate will also be considered in the decision to 
expand the study to the second stage. If the FLT-3 WT and/or FLT-3 ITD/TKD mutant cohort(s) 
proceed(s) to the second stage, a further 14 and 17 evaluable patients will be assessed in the 2 
cohorts, respectively. Best responses from both cohorts will be assessed individually and 
combined in an effort to understand the all-comer response rate. 
 
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5.0
ANALYSIS ENDPOINTS
Primary Endpoints:
!
Dose finding phase: adverse events (AEs), serious adverse events (SAEs), dose-limiting 
toxicities (DLTs) (Cycle 1), clinical laboratory values, and vital sign measurements
!
Phase 2 dose expansion phase: ORR (which will include complete response [CR], CR with 
incomplete platelet recovery [CRp], CR with incomplete hematologic recovery [CRi], CR 
with partial hematologic recovery [CRh], a composite complete remission [CRc defined as 
the sum of patient achieving a CR, CRh, CRi, or CRp], and partial response [PR])
Secondary Endpoints:
!
DOR
!
TTP
!
Mortality rate at 3 and 6 months
!
OS
!
ORR, DOR, TTP, mortality rate at 3 and 6 months, and OS in FLT-3-ITD mutant versus WT 
populations
!
Plasma PK parameters, including but not limited to maximum plasma concentration (Cmax), 
first time to reach maximum plasma concentration (tmax), area under the plasma concentration 
versus time curve over the dosing interval (AUCtau), apparent clearance at steady state 
(CLss/F), accumulation ratio (Rac), and peak-through ratio (PTR)
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6.0
DETERMINATION OF SAMPLE SIZE
During the dose escalation phase, dose escalation will be conducted according to a standard 3 + 3 
dose escalation schema, and approximately 40 response-evaluable patients will be enrolled. The 
MTD/RP2D cohort will have at least 6 patients.
The sample sizes for the AML expansion cohort are estimated using a one-sided test at a 
significance level of α = 0.1 with power of 80%. The FLT-3 WT cohort uses a null hypothesis of 
response rate ≤ 15%, versus an alternative hypothesis of response rate ≥ 35%. Based on a Simon 
2-stage design and a 15% dropout rate, approximately 11 patients will be needed if the trial fails 
in the first stage, or 28 patients will be needed if the FLT-3 WT cohort succeeds in going to the 
second stage. The mutant cohort uses a null hypothesis of response rate ≤ 30%, versus an 
alternative hypothesis of response rate ≥ 50%. Based on a Simon 2-stage design and a 15% 
dropout rate, approximately 18 patients will be needed if the trial fails in the first stage, or 40 
patients will be needed if the mutant cohort succeeds in going to the second stage.
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Statistical Analysis Plan
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles
All statistical analyses will be conducted using SAS® Version 9.4.
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, but prior to, the start of study drug administration.  Cycle 1 day 1 values are considered pre-
dose. Screening values are used for baseline values if a Cycle 1 Day 1 value is unavailable.  
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
For the categorical variables, the count and proportions of each possible value will be tabulated. 
The denominator for the proportion will be based on the number of subjects who provided non-
missing responses to the categorical variable. For continuous variables, the number of subjects 
with non-missing values, mean, median, SD, minimum, and maximum values will be tabulated.  
A month is operationally defined to be 30.4375 days. 
For the phase 1 analysis, statistical summaries will be descriptive and graphical in nature. 
For the phase 2 expansion cohorts, ORR in the response-evaluable population will be tabulated 
descriptively with 95% exact binomial confidence intervals (CIs).  Time-to-event data will be 
analyzed using the Kaplan-Meier method and results will be summarized by the 25th, 50th, and 
75th percentiles with associated 2-sided 95% CIs, as well as percentage of censored 
observations, by FLT-3 WT, FLT-3 mutant cohorts, and overall phase 2 expansion population.
No formal statistical hypothesis testing will be performed.  
7.1.1
Data Presentation
In general, data will be presented as follows:
TAK-659
Dose 
escalation
60 mg QD
N=xx
TAK-659
Dose 
escalation
100 mg QD
N=xx
TAK-659
Dose 
escalation
120 mg QD
N=xx
TAK-659
Dose 
escalation
140 mg QD
N=xx
TAK-659
Dose 
escalation
160 mg QD
N=xx
TAK-659 
Dose 
escalation
QD Total
N=xx
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Statistical Analysis Plan
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TAK-659
Dose 
escalation
60 mg BID
N=xx
TAK-659
Dose 
escalation
80 mg BID
N=xx
TAK-659
Dose escalation
BID Total
N=xx
TAK-659
Dose escalation
Total
N=xx
7.1.2
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of study 
drug. Other study days are defined relative to the Study Day 1 with Day 1 being Study Day 1 and 
Day -1 being the day prior to Study Day 1.
7.1.3
Conventions for Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded during the screening visits. 
1. If only the day-component is missing, the first day of the month will be used if the year and 
the month are the same as those for the first dose of study drug. Otherwise, the fifteenth will 
be used. 
2. If only the year is present, and it is the same as the year of the first dose of study drug, the 
fifteenth of January will be used unless it is later than the first dose, in which case the date of 
the first of January will be used. 
3. If only the year is present, and it is not the same as the year of the first dose of study drug, the 
fifteenth of June will be used, unless other data indicates that the date is earlier.
7.1.4
Conventions for Missing Adverse Event Dates
Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:

If the start date has a month and year but the day is missing, the event will be considered 
treatment emergent if the month and year of the start date of the event are: 
–
On or after the month and year of the date of the first dose of study drug
and 
–
on or before the month and year of the date of the last dose of any study drug plus 28 
days, or the start date of subsequent anticancer therapy, whichever occurs first.
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Statistical Analysis Plan
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
If the start date has a year, but the day and month are missing, the event will be considered 
treatment emergent if the year of the start date of the event is:
–
On or after the year of the date of the first dose of study drug
and 
–
on or before year of the date of the last dose of any study drug plus 28 days, or the start 
date of subsequent anticancer therapy, whichever occurs first.

If the start date of an event is completely missing then the event is assumed to be treatment 
emergent.
However, if the end date is complete or partially missing but it is clear that the end date is before 
the first dose of study drug, the event will not be considered treatment emergent.
7.1.5
Conventions for Missing Concomitant Medication/Therapy Dates
Concomitant medications/therapies with start dates that are completely or partially missing will 
be analyzed as follows:
1. If the start date has a month and year but the day is missing, the event will be considered 
concomitant if the month and year of the start date of the event are: 
–
On or after the month and year of the date of the first dose of study drug
and 
–
on or before the month and year of the date of the last dose of any study drug plus 28 
days, or the start date of subsequent anticancer therapy, whichever occurs first.
2. If the start date has a year, but the day and month are missing, the event will be considered 
concomitant if the year of the start date of the event is:
–
On or after the year of the date of the first dose of study drug
and 
–
on or before the year of the date of the last dose of any study drug plus 28 days, or the 
start date of subsequent anticancer therapy, whichever occurs first.
3. If the start date of an event is completely missing then the event is assumed to be 
concomitant.
However, if the end date is complete or partially missing but it is clear that the end date is before 
the first dose of study drug, the event will not be considered concomitant. 
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Statistical Analysis Plan
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When the start date is complete and is before the first dose, and the concomitant medication is 
not ongoing but the end date is missing completely or partially, a similar algorithm should be 
used to assess whether the end date is before the last dose of study drug plus 28 days to be 
included.
7.2
Populations for Analysis
The populations used for analysis will include the following:

Safety population: All enrolled patients who have received at least 1 dose of TAK-659 will 
be used for all safety analyses.

Pharmacokinetic population: All patients in the AML dose escalation cohorts who have 
sufficient dosing and PK data to reliably estimate 1 or more PK parameters will be used for 
PK analyses.

Pharmacodynamics population: All patients with sufficient dosing in Cycle 1 and sufficient 
pharmacodynamics data derived from the Plasma Inhibitory Assay will be used for 
pharmacodynamics analyses.

Response-evaluable population: All patients who receive at least 1 dose of study drug, have 
baseline bone marrow blast counts (use aspirate if available, otherwise use biopsy), and 1 
post-baseline disease assessment will be used for analyses of response. 

DLT-evaluable population: the DLT-evaluable population is defined as all patients in the 
phase 1b portion of the study at each dose cohort who either experience a DLT during Cycle 
1 or complete at least 75% of planned doses of TAK-659 and have sufficient follow-up data 
to allow both Sponsor and the investigators to determine whether a DLT occurred.
7.3
Disposition of Subjects
The date first subject signed ICF, date of last subject’s last visit/contact, date of last subject’s last 
procedure for collection of data for primary endpoint, MedDRA Version, WHO Drug Dictionary 
Version, and SAS Version will be generated in a summary table.
The number of patients in the safety population, in the pharmacokinetics population, in the DLT 
evaluable population, and the reason study drug was discontinued will be summarized. 
All percentages will be based on the number of patients in the safety population. 
7.4
Demographic and Other Baseline Characteristics
Summaries of demographic and baseline characteristics will be presented for subjects in the 
safety population.
The number and percent of patients will be summarized by geographic region, country and site.
Baseline demographic data to be evaluated will include age, sex, race, ethnicity, height, weight. 
Age will be calculated from date of birth to date of informed consent.
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Statistical Analysis Plan
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No inferential statistics will be generated.
Baseline characteristics assessments consist of: disease primary diagnosis, years since initial 
diagnosis, disease type, disease subtype, evidence of extramedullary disease, leukemia cells in 
central nervous system, revised WHO classification of AML, modified Charlson comorbidity 
index, risk status (favorable, intermediate, poor), FLT3 status (FLT3-WT or FLT3 Mutant  FLT3 
Mutant is defined by FLT3-ITD, FLT3-TKD, FLT3-ITD/TKD), other gene mutations (NPM1, 
CBP1alpha, IDH1, IDH2, KIT, DNMT3A and other gene), Eastern Cooperative Oncology 
Group (ECOG) performance status.
A separate table will summarize the numbers and percentages of patients who received prior 
therapy, prior radiation, prior transplant, number of prior anticancer therapies, median number of 
prior anticancer therapy, type of prior anticancer therapy and best response to the first and last 
prior anticancer therapies.
7.5
Medical History and Concurrent Medical Conditions
No summary for medical history and concurrent medical conditions.
7.6
Medication History and Concomitant Medications
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary.  The number and percentage of patients taking concomitant medications will be 
tabulated by WHO standard medication name for the safety population.
7.7
Study Drug Exposure and Compliance
7.7.1
Study Treatments
The study drug will be dosed continuously in 28-day cycles.  The study drug should be taken on 
an empty stomach, at least 1 hour before and no sooner than 2 hours after ingestion of food 
and/or beverages other than water.  Each tablet should be swallowed separately with a sip of 
water.  A total of approximately 8 ounces (240 mL) of water should be taken with the prescribed 
dose.  Patients should swallow the study medication whole. The study medication should not be 
chewed, crushed, or manipulated in any way before swallowing. Administration of the tablets 
will be guided by the dosing tables included in the Pharmacy Manual.  
7.7.2
Extent of Exposure
The exposure to TAK-659 will be characterized by duration of treatment in weeks ((last dose 
date – start dose date + 1)/7), cumulative dose in mg, relative dose intensity (%), number of 
treated cycles, numbers and percentages of patients who had ≥1, ≥2, …, ≥6 treated cycles for 
patients in the safety population. A treated cycle is defined as a cycle in which the patient 
received any amount of study drug. 
Relative dose intensity (RDI) (%) will be presented for cycles 1, 2, …, 6 and overall. Overall 
RDI is defined as 100 x (total dose received in mg) / (initial prescribed dose per day x number of 
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Statistical Analysis Plan
08 November 2018
treated days).  Where the number of treated days is defined as (reference end date for study drug 
– reference start date for study drug) + 1.
For Relative Dose Intensity by cycle the same formula is used as overall relative dose intensity, 
but the number of treated days is derived differently.  Cycle RDI is defined as 100 x (total dose 
received in mg in cycle) / (initial prescribed dose per day x number of treated days in cycle). 
Where the number of treated days in cycle is defined as (last dose date of a cycle – first dose day 
of cycle) + 1, however, if a patient discontinues during the cycle then use (date of drug 
discontinuation – first dose day of cycle) + 1.
Prescribed dose is determined by the dose level to which a patient is enrolled at the onset of the 
study. 
7.7.3
Action on Drug
Action on study drug (e.g. dose reduced due to AE) will be summarized by each cycle 
(Cycles 1-6), sum of the remainder cycles, and total, for each dose level in the safety population.  
7.8
Efficacy Analysis
Analysis of efficacy measures will be descriptive.  Antitumor activity of TAK-659 will be based 
on the best overall response.  Investigators will assess disease response following the criteria 
outlined in the Revised 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 [1] at each time point, and the best overall 
response for each patient will be derived programmatically from among the reported responses.
7.8.1
Primary Efficacy Endpoint(s)
There is no primary efficacy endpoint for the dose escalation portion of the study.
The primary endpoint for the AML expansion cohort is ORR (which will include complete 
response [CR], CR with incomplete platelet recovery [CRp], CR with incomplete hematologic 
recovery [CRi], CR with partial hematologic recovery [CRh], a composite complete remission 
[CRc defined as the sum of patient achieving a CR, CRh, CRi, or CRp], and partial response 
[PR]).
7.8.2
Secondary Efficacy Endpoint(s)
There is no secondary efficacy endpoint for the dose escalation portion of the study. 
The secondary efficacy endpoints for the AML expansion cohort are ORR in FLT-3 mutant and 
FLT-3 WT populations, DOR, TTP, mortality rate at 3 and 6 months, and OS (by FLT-3 mutant 
cohort, FLT-3 WT cohort, and phase 2 overall).  
DOR is defined as the time from the date of first documentation of a response to the date of first 
documented progressive disease, and DOR will be analyzed for all responders using the Kaplan-
Meier method by FLT-3 mutant, FLT-3 WT cohorts and combined phase 2 cohort. For a patient 
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Statistical Analysis Plan
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who has not progressed, duration of response will be censored at the last response assessment 
that is SD or better.
TTP is defined as the time from the date of first study drug administration to the date of first 
documentation of PD by the investigator, and TTP will be analyzed based on the response-
evaluable population using the Kaplan-Meier method, by FLT-3 mutant, FLT-3 WT populations
and phase 2 overall. For a patient that has not progressed, TTP will be censored at the last 
response assessment that is SD or better. 
Comparisons of TTP between the FLT-3 WT and FLT-3-ITD mutant cohorts using log rank test
may be carried out when appropriate.
OS is defined as the time from the date of study entry to the date of death, and OS will be 
analyzed based on the safety population using the Kaplan-Meier method, by FLT-3 mutant, FLT-
3 WT populations and overall. For a patient that did not die during the study or lost to follow-up, 
OS will be censored at the last known surviving date. Comparisons of OS between the FLT-3 
WT and FLT-3-ITD mutant cohorts using log rank test will be carried out when appropriate.
In general, time-to-event data will be analyzed by the Kaplan-Meier method and results will be 
summarized by the 25th, 50th, and 75th percentiles with associated 2-sided 95% CIs, as well as 
percentage of censored observations. The corresponding Kaplan-Meier curves will also be 
plotted.
ORR is defined as the proportion of patients who achieved CRs, CRps, CRis, CRhs, CRcs and 
PRs in the response-evaluable population, and ORR will be tabulated. Point estimates as well as 
95% binomial confidence intervals will be presented.  The number and percentage of patients 
falling into each response category (eg, CR, CRp, CRi, PR, SD, PD) will be tabulated.
Mortality rate at 3 and 6 months will be summarized and tabulated.
Response rate will also be tabulated by baseline prognostic factors, if applicable. The prognostic 
factors will include, but will not be limited to, age, any precursor disease (MDS / MPD or not), 
additional genetic mutation data if available and cytogenetic abnormalities.
7.8.3
Additional Efficacy Endpoint(s)
Additionally, the following will be summarized:

Percent of patients with at least 50% decrease in bone marrow blast count

Percent of patients with at least 50% decrease in peripheral blast count.
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Statistical Analysis Plan
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7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
The PK population will be used for the description of the plasma TAK-659 PK profiles and for 
the estimation of plasma TAK-659 PK parameters in the AML Dose Escalation cohorts. The 
specifics of pharmacokinetic analysis are described in a separate Clinical Pharmacology Analysis 
Plan.
Blood samples for PK analysis will be collected in dose escalation cohorts during Cycle 1 on 
Days 1, 2, 15 and 16 and in dose expansion cohorts during Cycle 1 on Days 1 and 15.
Pharmacokinetic Concentrations
For escalation cohorts, plasma TAK-659 concentrations will be summarized by nominal time 
postdose, grouped by dosing schedule, dose level, and dosing cycle and day.  For expansion 
cohorts, plasma TAK-659 concentrations will be summarized by nominal time postdose and 
grouped by dosing cycle and day. Summary statistics will be reported at nominal sampling times 
with at least 2 patients in the PK evaluable population; means will be reported if the number of 
observations above the lower limit of quantitation (NALQ) is ≥ 50% of the number of patients.
The summary statistics will consist of: N, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of variation, geometric mean, median, minimum, and maximum.  Plasma 
concentrations that are BLQ will be set to zero for calculation of summary statistics, except for 
geometric means, where BLQ values will be considered missing.
Mean and individual plasma TAK-659 concentration data from dose escalation patients will be 
plotted over time, grouped by dosing schedule, dose level, with separate panels for dosing cycle 
and day (Cycle 1 Day 1 and Cycle 1 Day 15 only) on both linear and semi-logarithmic scales. 
Mean concentrations will be plotted by nominal sampling times. Individual concentrations will 
be plotted by actual sampling times. BLQ values will be plotted as zero on a linear scale and 
treated as missing on a semi-logarithmic scale.
Mean and individual plasma TAK-659 concentration data from dose escalation patients will be 
plotted over time, grouped by dosing cycle and day (Cycle 1 Day 1 and Cycle 1 Day 15 only)
and with dosing schedule, dose level in separate panels on both linear and semi-logarithmic 
scales.
Pharmacokinetic Parameters
PK parameters will be estimated for the AML Dose Escalation cohorts (Cycle 1 Day 1 and Cycle 
1 Day 15) using non-compartmental methods with WinNonlin® Professional Version 7.0 or 
higher (Certara USA, Inc., Princeton, NJ).  The plasma PK parameters will be estimated from the 
concentration-time profiles for all PK population patients. In estimating the PK parameters, BQL 
values at the beginning of the profile will be set to zero. BQL values that occur after the first 
quantifiable point will be considered missing. Values that are embedded between BQLs, or 
quantifiable values occurring after two or more BQLs, will be set to missing at the discretion of 
the pharmacokineticist.  Actual sampling times, rather than scheduled sampling times, will be 
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Statistical Analysis Plan
08 November 2018
used in all computations involving sampling times. If an actual time is missing the nominal time 
may be used.
All individual patient PK parameter data will be in a data listing. Descriptive statistics (number 
of patients, arithmetic mean, arithmetic standard deviation, arithmetic coefficient of variation, 
geometric mean, median, minimum value, and maximum value) will be used to summarize the 
calculated PK parameters. For tmax, only median, minimum value, and maximum value will be 
presented.  
Summary statistics of PK parameter data will be reported for doses with at least 2 patients in the 
PK parameter population.  Individual PK parameters will be listed by patient, dosing schedule, 
dose group, and dosing cycle and day.
Boxplots will be generated for selected PK parameters i.e. Cycle 1, Day 1 Cmax versus dose, 
Cycle 1, Day 15 Cmax versus dose, Cycle 1, Day 1 AUCtau versus dose, and Cycle 1, Day 15 
AUCtau versus dose.  
Dose proportionality of TAK-659 plasma exposures will be evaluated by visual inspection of 
plots of individual PK parameter values versus dose.  If data permit, regression analysis using a 
power model will also be used to assess dose proportionality.
TAK-659 plasma concentration-time data collected in this study, together with data collected 
from other studies, may contribute to population PK analysis.  If applicable, the specifics of the 
population PK modeling approaches will be described separately in a population PK analysis 
plan, and the results will be reported separately from the clinical study report.  
7.10
Pharmacodynamic Analysis
7.11
Other Outcomes
7.11.1 Pharmacogenomic Analysis
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Statistical Analysis Plan
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7.11.2 Safety Analysis
These analyses will be performed using the safety population. And summaries will be provided
by dose level in dose escalation and phase 2 part.
7.11.3 Adverse Events
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary for the purpose of summarization.  Treatment-emergent AEs are defined as any 
AE that occurs after administration of the first dose of study treatment and up through 28 days 
after the last dose of study medication, or until the start of subsequent antineoplastic therapy, 
whichever occurs first. Treatment-emergent AEs will be tabulated according to the MedDRA by 
system organ class and preferred terms and will include the following categories:
!
Treatment-emergent AEs
!
Drug-related treatment-emergent AEs
!
Grade 3 or higher treatment-emergent AEs
!
Grade 3 or higher drug-related treatment-emergent AEs.
!
The most commonly reported treatment-emergent AEs (i.e., those events reported by ∀10% 
of all patients in the safety population) by preferred term.
!
The most commonly reported treatment-emergent AEs (i.e., those events reported by ∀10% 
of all patients in the safety population) by cycle.
!
Non-serious treatment-emergent AEs reported by >5% of patients in any dose level in dose 
escalation part or phase 2 cohort (5% cutoff will be applied before any rounding)
!
SAE
!
AE leading to discontinuation of the study drug
Patients with the same AE more than once will have the maximum intensity of that event 
counted within each body system, and once within each preferred term.
An overall summary treatment-emergent AE table will include numbers and percentages of 
patients who had any treatment-emergent AE, drug-related treatment-emergent AE, grade 3 or 
higher treatment-emergent AE, grade 3 or higher drug-related treatment-emergent AE, serious 
AE (SAE), drug-related SAE, treatment-emergent AE resulting in discontinuation, and on-study 
deaths.
All grade 3 or higher AEs will be summarized by creatinine clearance <30, 30-60, 60-90, 
90-120, >120.
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Statistical Analysis Plan
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All deaths occurring on-study and during follow-up will be displayed (regardless of treatment-
emergent AE status). An on-study death is defined as a death that occurs between the first dose 
of study drug and 28 days of the last dose of study drug.
7.11.4 Clinical Laboratory Evaluations
Whenever available, laboratory values will be assigned toxicity grades using the NCI CTCAE
v4.03. The number and proportion of patients with shifts in NCI CTCAE toxicity grades from 
baseline to the worst post baseline toxicity grade will be summarized for each dose level in dose 
escalation part and Phase 2 part for the following tests:

Hematology:  Hemoglobin decreased, Lymphocyte count decreased, Lymphocyte count 
increased, Neutrophil count decreased, Platelet count decreased, White blood cell count 
decreased.

Chemistry: Alanine aminotransferase (ALT) increased, Alkaline phosphatase increased, 
Aspartate aminotransferase (AST) increased, Bilirubin (total) increased, Creatinine 
increased, Gamma glutamyl transferase (GGT) increased, Calcium - decreased, Calcium –
increased, Glucose – decreased, Glucose – increased, Potassium – decreased, Potassium –
increased, Magnesium – decreased, Magnesium – increased, Sodium – decreased, Sodium –
increased, Albumin – decreased, Phosphate – decreased, Amylase – increased, Lipase -
increased.
Mean laboratory values over time will be plotted for key lab parameters, including Hgb, WBC, 
lymphocytes, ANC, platelets, phosphate and liver function tests (ALT/SGPT, AST/SGOT, 
alkaline phosphatase, total bilirubin, LDH, creatinine, lipase and amylase for each regimen 
(overlay line for each dose level and total within each regimen) for all patients up to 6 cycles. A 
matching summary table will be created.
Baseline and post baseline values of creatinine clearance and LDH will be tabulated. Total LDH 
will be presented graphically in a spaghetti plot. Temperature over time during Cycle 1 will be 
presented in boxplot.
7.11.5 Vital Signs
Vital sign results (diastolic and systolic blood pressure, pulse, temperature, and body weight)
will be summarized by dose level in dose escalation and phase 2 part as follows:

Baseline value

Minimum post-baseline value

Maximum post-baseline value
Changes to the minimum and maximum post-baseline values will be calculated relative to the 
baseline value. 
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Statistical Analysis Plan
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7.11.6 12-Lead ECGs
ECG intervals (QT and Bazette’s and Fridericia’s corrected QT intervals [QTcB and QTcF], PR, 
QRS, and heart rate) will be summarized by dose levels in dose escalation part and phase 2 part 
as follows:

Baseline value

Minimum post-baseline value

Maximum post-baseline value
Changes to the minimum and maximum post-baseline values will be calculated relative to the 
baseline value. ECG abnormalities by time point will be tabulated.
In addition, the number and percent of patients with increases >30 ms and >60 ms from pre-dose 
in QTcF will also be summarized.
7.11.7 Other Observations Related to Safety
Ophthalmology
Any ophthalmic findings that are determined to be abnormal, clinically significant by the 
investigators will be listed.
7.12
Interim Analysis
Not applicable
7.13
Changes in the Statistical Analysis Plan 
CR with partial hematologic recovery [CRh] and a composite complete remission [CRc defined 
as the sum of patient achieving a CR, although mentioned in the protocol amendment 2, the 
database has not been updated yet to collect these and there were no patients who were enrolled 
or consented under protocol amendment 2.
Change in definition for response-evaluable population.
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8.0
REFERENCES
1. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH. 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. Journal of Clinical Oncology 2003;21(24):4642-9.
2. Levis M, Brown P, Smith BD, Stine A, Pham R, Stone R, et al. Plasma inhibitory activity 
(PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to 
FLT3 inhibitors. Blood 2006;108(10):3477-83.
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9.0
DATA LISTINGS
The below subject-level listings will be generated:

Disposition (date of first dose, date of last dose, number of cycles, reason for discontinuation 
of study treatment)

Populations (can be included with disposition listing)

Demographics

Baseline characteristics

Prior therapy

Concomitant procedures

Study drug exposure

TEAEs of grade 3 or higher (cycle date information for the AE onset and end dates will be 
included)

TEAEs leading to study drug discontinuation

TEAEs resulting in dose modifications

Serious AEs (all SAEs regardless of treatment emergent AE status)

On-study deaths (defined as death that occurs between the first dose of study drug and 28
days after the last dose of study drug (adverse events with an outcome of death) as well as
during follow-up)

DLTs during Cycle 1 

Pharmacokinetic concentrations

Pharmacokinetic parameters

Ophthalmic findings

Investigator response assessment (including FLT3 mutation status)

Best response (including FLT3 mutation status)

Cytogenetic results, risk classification, mutation status (FLT3 and other), prior therapy, 
duration of response for patients with CR, Cri and PR

Peripheral blood levels

Bone marrow levels

Significant protocol deviations

Chromosomal abnormalities and genetic mutations

FLT3 inhibition
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