Clinical trial NCT04079738
Conditions: AML AML, Adult
Sponsor: H Scott Boswell
Start date: 2019-09-20; Completion date: 2022-02-23
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase I/II study augmenting TAK-659 action in relapsed/refractory AML by addition of the proteasome inhibitor Ixazomib. Phase I of the study will determine the safety, tolerability, and maximum tolerated dose (MTD) of the combination of TAK-659 and Ixazomib. During the phase I, dose escalation will be conducted according to a standard 3+3 dose escalation schema, and up to 18 response-evaluable patients will be enrolled. Phase II of the study will evaluate the efficacy of the combination by measuring the overall response rate (ORR).

Detailed description:

Arms: arm 1: Phase I: TAK-659 (Days 1-15) + Ixazomib dose escalation (Days 1, 8, 15) arm 2: Phase II: TAK-659 at MTD (Days 1-15) + Ixazomib at MTD (Days 1, 8, 15)
Interventions: intervention 1: TAK-659 intervention 2: Ixazomib
Intervention descriptions: intervention 1: TAK-659 intervention 2: Ixazomib

Protocol documents:
Prot_SAP_000.pdf: 
  
Clinical Study Protocol 
 
 
 
 
BTCRC-HEM17-092 
 
Phase I/II study augmenting TAK-659 action in relapsed/refractory AML by addition of 
the proteasome inhibitor Ixazomib 
Big Ten Cancer Research Consortium BTCRC-HEM17-092 
 
Sponsor Investigator 
H Scott Boswell, MD 
Indiana University Melvin and Bren Simon Cancer Center 
 
Co-Investigators
Brian Parkin, MD 
University of Michigan Rogel Cancer Center 
Irum Khan, MD 
University of Illinois Cancer Center 
Uma Aryal, PhD 
Purdue University Center for Cancer Research 
Ruben Kapur, PhD 
IU Simon Cancer Center 
Heiko Konig, MD, PhD 
IU Simon Cancer Center 
Big Ten CRC Myeloid Committee Co-Chair 
Larry Cripe, MD 
IU Simon Cancer Center 
Hamid Sayar, MD, MS 
IU Simon Cancer Center
 
 
Statistician 
Hao Liu, PhD 
Indiana University Melvin and Bren Simon Cancer Center 
 
Trial Management Provided by  
Big Ten CRC Administrative Headquarters at Hoosier Cancer Research Network, Inc. 
500 N. Meridian, Suite 100 
Indianapolis, IN 46204 
 
Trial Supported by  
Takeda Pharmaceutical Company 
IISR-2017-101984; X34004 
 
Investigational New Drug (IND) Number: 
142213 
 
 
 
Initial Protocol Version Date: 16MAY2019 
 
Protocol Amendment Version Date:  
06DEC2019 (current) 
 
 


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PROTOCOL SIGNATURE PAGE 
Phase I/II study augmenting TAK-659 action in relapsed/refractory AML 
by addition of the proteasome inhibitor Ixazomib 
 
 
VERSION DATE:  06DEC2019 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to the 
ethical principles stated in the latest version of the Declaration of Helsinki, the applicable guidelines for 
good clinical practices, whichever provides the greater protection of the individual.  I will accept the 
monitor’s overseeing of the study.  I will promptly submit the protocol to applicable ethical review 
board(s). 
 
 
 
 
____________________________________ 
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 Signature of Site Investigator 
 
 
  
 Date 
 
 
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 Site Investigator Title 
 
 
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 Location of Facility (City and State) 
 
 
 
PLEASE EMAIL COMPLETED FORM TO  
BIG TEN CRC ADMINISTRATIVE HEADQUARTERS 
 
 
 


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SYNOPSIS 
TITLE 
Phase I/II study augmenting TAK-659 action in relapsed/refractory AML 
by addition of the proteasome inhibitor Ixazomib
PHASE 
Phase I/II 
OBJECTIVES 
Primary Objective: 
Phase I:  to determine the safety, tolerability, and maximum tolerated dose 
(MTD), recommended phase 2 dose(s) (RP2D) of the combination of TAK-
659 and Ixazomib administered orally on a daily and weekly dosing 
schedule, respectively, in patients with relapsed or refractory AML 
Phase II:  to evaluate preliminary efficacy of TAK-659 plus Ixazomib in 
relapsed or refractory AML as measured by overall response rate (ORR) 
Secondary Objectives: 
 To evaluate the differential efficacy measures of TAK-659 with 
Ixazomib, involving presence or absence of Flt3 mutation(s), and/or 
mutational profile by NGS, additionally affecting epigenetic modifiers 
 To evaluate additional efficacy measures of TAK-659 with Ixazomib, 
such as duration of response (DOR), time to progression (TTP), mortality 
rate at 3 and 6 months, and overall survival (OS) 
 To evaluate the influence of multiple cycles of the combination on the 
outcome measures when applied in context of subsequent feasibility for 
bridge to transplantation as consolidation therapy 
Exploratory Objectives: 
 To quantitatively examine before, and at early timepoint of therapy, the 
primary mechanistic transcriptional drivers of these AMLs (HOXA and 
MEIS1), which are postulated to be extinguished by the drug 
combination, for their ability, when extinguished, to predict subsequent 
response 
 To implicate Syk, Wnt pathway (ID1, JUN, FOXM1, -catenin) and Wnt 
antagonist RUNX3 in responses affected by combination of TAK-659 
and Ixazomib 
 To use digital PCR technology to examine the participation of 
collaborating mutations on depth of remission for the class 1 and class 2 
drivers 
STUDY DESIGN 
This study will include a phase I dose finding portion, and a single-arm 
phase II portion in relapsed or refractory AML, for use of TAK-659 and 
Ixazomib in combination. 
The starting TAK-659 dose for the phase I portion of the combination trial 
will use a dose below RP2D dose of TAK-659 established in C34002, 100 
mg po once daily.  If 2 DLTs are recorded in the second cohort of this 3+3 
dose-tier of C34002, then a dose of 80mg in single dose administration will 
be recommended.  The TAK-659 treatment duration in the combination trial 
will be days 1-15 of a 21day cycle (as compared to a 28 day course of 
single agent administration in C34002).   


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For the addition of Ixazomib into the combination, we will adopt the 
experience for single agent Ixazomib use, which revealed similar 
pharmacokinetics (AUC 0-168h) and 2 or 3-fold accumulation during a 
cycle for weekly and twice-weekly schedules, respectively (the MTD for 
Ixazomib dosing given alone was 2mg/m2 twice weekly d1, 4, 8, 11 of a 21 
day cycle, whereas once weekly dosing given alone was at 2.97 mg/m2 on 
days 1, 8, 15 of a 28 day cycle). Thus, when initiating a dose-finding 
escalation, in a schedule with TAK-659, significant dose reduction from the 
single agent Ixazomib RP2D weekly 4mg amount may not require more 
than two dose-steps, thus resulting in a plan for Ixazomib 2.3mg po day 1,8, 
15 of the 21 day cycle. From this dose, escalation will be undertaken. 
Given the expected toxicity associated with Ixazomib, where diarrhea or 
neuropathy have previously been implicated, if 2/6 patients were to develop 
such ≥ grade 3 nonhematologic toxicity at the +1 dose of 3mg, then the next 
cohort would receive reduced dosing at 2.3mg po days 1,8,15.  However, if 
increased amylase and/or AST elevations were to occur, implicating TAK-
659 as culprit, then one-step dose reduction of that agent would provide 
direction for further pursuit of the algorithm.  
Dose escalation will continue until either MTD is reached or the RP2D (if 
different than MTD) has been determined based on safety, tolerability, PD, 
and preliminary efficacy data. The culmination of the 3+3 algorithm would 
be an expected MTD involving 15 days administration of derived daily dose 
for TAK-659, along with derived weekly dose for Ixazomib on days 1, 8, 
15. The process for determining or refining the RP2D, will allow expansion 
of more than 1 dose/schedule level to at least 6 patients (up to a maximum 
of 12 evaluable patients per dose/schedule level is permissible) so that 
pharmacodynamic measures and early signs of clinical activity can be 
assessed.  This is important in a disease process as AML, for which some 
immediate level of required drug-induced myelosuppression during blast 
clearance, will defer endpoint recognition. 
The sample sizes for the Phase II study are estimated using a one-sided test 
at a significance level of = 0.1 with power of 80%. To perform the phase 2 
study, we will consider 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 the 
combination in AML, which will likely be annotated by molecular genetic 
mutational subgroups.  It is most likely those will exist within the rubric of 
Flt3 mutation.  The primary measure of efficacy for the phase 2 portion will 
be ORR, which will include CR, CRp, CRi, and PR. Best response will be 
assessed by the end of Cycle 3 of TAK-659/Ixazomib combination for the 
purpose of an interim analysis between Stage 1 and Stage 2.  The Flt3WT 
and Flt3mut cohorts will proceed to the second stage if patients respond by 
CR, CRp, CRi. The Flt3WT cohort uses a null hypothesis response rate of ≤ 
15%, versus an alternative hypothesis of response rate ≥ 40%.  Based on a 
Simon 2-stage Minimax design, approximately 9 patients will be accrued in 


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the first stage.  If there are 1 or fewer responses in the 9 patients, the study 
will be stopped. Otherwise, 7 additional patients will be accrued for a total 
of 16.  The treatment will be recommended for further study if 5 or more 
responses are observed in 16 patients The Flt3 mutant cohort uses as null 
hypothesis of response rate ≤30%, versus an alternative hypothesis of 
response rate ≥ 55%.  Based on a Simon 2-stage Optimal design, 8 patients 
will be accrued in the first stage.  If there are 2 or fewer responses in the 8 
patients, the study will be stopped.  Otherwise, 12 additional patients will be 
accrued for a total of 20.  The treatment will be recommended for further 
study if 8 or more responses are observed in 20 patients. Other efficacy 
measures, such as DOR, TTP, ability of the therapy to provide bridge to 
transplant, and mortality rate will also be considered in the decision to 
expand the study. 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 for response, including the expressions of Syk, and the 
Wnt pathway agonists (ID1, JUN, FOXM1, -catenin) and antagonist 
RUNX3, and the end-targets expected of TAK-659 and Ixazomib, HOXA 
and MEIS1, when measured before and then sampled early into therapy.  
Interpretation of these measures will be made in context of mutational 
profile of cooperating epigenetic mutations, especially involving TET2, 
IDH2/1, WT1, as well as DNMT3A, without or with Flt3 mutation, 
available by next-generation sequencing of patient marrow samples. 
KEY ELIGIBILITY 
CRITERIA  
Patients will be males and females age 18 years or older with 
histopathologically documented primary or secondary AML as defined by 
World Health Organization, other than acute promyelocytic leukemia, or 
complex karyotype or monosomy 7 (or containing monosomy 7), with 
relapsed or refractory disease for whom no standard therapies are 
anticipated to result in durable remission according to the clinical judgment 
of the treating physician, or who refuse standard therapies. (See body of 
protocol for full criteria.) These AML’s will have been further phenotyped 
genetically to include normal karyotype, tMLL, or nonrecurring 
mutation(s). For the phase 2 portion of the study, relapsed/refractory 
patients must be refractory to or relapsed after no more than 2 prior 
chemotherapy regimens and must not have prior exposure to any 
investigational Flt3 inhibitors (midostaurin and gilteritinib are allowed).  
Patients must have adequate organ function and an Eastern Cooperative 
Group (ECOG) performance status of 0 to 2.  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/Ixazomib, or clinically significant graft-versus-host disease requiring 
ongoing immunosuppressive therapy.


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STATISTICAL 
CONSIDERATIONS 
During the dose escalation phase, dose escalation will be conducted 
according to a standard 3+3 dose escalation schema, and up to 18 response-
evaluable patients will be enrolled.  The MTD/RP2D cohort will have at 
least 6 patients. 
The sample sizes for the Phase II study are estimated using a one-sided test 
at a significance level of = 0.1 with power of 80%.  To perform the phase 
2 study, we will consider a Simon’s stage 2 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 the 
combination in AML, which will likely be annotated by molecular genetic 
mutational subgroups.  It is most likely those will exist within the rubric of 
Flt3 mutation.  The primary measure of efficacy for the phase 2 portion will 
be ORR, which will include CR, CRp, CRi, and PR. Best response will be 
assessed by the end of Cycle 3 of TAK-659/Ixazomib combination for the 
purpose of an interim analysis between Stage 1 and Stage 2.  The Flt3WT 
and Flt3mut cohorts will proceed to the second stage if patients respond by 
CR, CRp, CRi. The Flt3WT cohort uses a null hypothesis response rate of ≤ 
15%, versus an alternative hypothesis of response rate ≥ 40%.  Based on a 
Simon 2-stage Minimax design, approximately 9 patients will be accrued in 
the first stage.  If there are 1 or fewer responses in the 9 patients, the study 
will be stopped. Otherwise, 7 additional patients will be accrued for a total 
of 16.  The treatment will be recommended for further study if 5 or more 
responses are observed in 16 patients The Flt3 mutant cohort uses as null 
hypothesis of response rate ≤30%, versus an alternative hypothesis of 
response rate ≥ 55%.  Based on a Simon 2-stage Optimal design, 8 patients 
will be accrued in the first stage.  If there are 2 or fewer responses in the 8 
patients, the study will be stopped.  Otherwise, 12 additional patients will be 
accrued for a total of 20.  The treatment will be recommended for further 
study if 8 or more responses are observed in 20 patients. Other efficacy 
measures, such as DOR, TTP, ability of the therapy to provide bridge to 
transplant, and mortality rate will also be considered in the decision to 
expand the study. Best responses from both cohorts will be assessed 
individually and combined in an effort to understand the all-comer response 
rate. 
TOTAL NUMBER 
OF SUBJECTS 
N = 54 
Phase I= up to 18; Phase II= up to 36 (16+20) 
ESTIMATED 
ENROLLMENT 
PERIOD 
24-32 months, including 9-12 months in the phase I portion and 15-20 
months in the phase 2 portion 
ESTIMATED 
STUDY DURATION  
48 months 
 
 


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TABLE OF CONTENTS 
 
Synopsis ...................................................................................................................................................... 3 
Table of Contents ........................................................................................................................................ 7 
Phase I Schema ........................................................................................................................................... 9 
Phase II Schema ........................................................................................................................................ 10 
Study Overview Diagrams ........................................................................................................................ 11 
List of Abbreviations and Glossary of Terms ........................................................................................... 12 
1. 
Background and Rationale ................................................................................................................ 16 
1.1 
Summary ................................................................................................................................... 16 
1.2 
Acute Myeloid Leukemia: Current Standard of Care ............................................................... 17 
1.3 
Acute Myeloid Leukemia Mutations ........................................................................................ 17 
1.4 
TAK-659 ................................................................................................................................... 23 
1.5 
Ixazomib (MLN9708) ............................................................................................................... 33 
1.6 
Dose Rationale .......................................................................................................................... 39 
2. 
Study Objectives and Endpoints ....................................................................................................... 40 
2.1 
Objectives ................................................................................................................................. 40 
2.2 
Endpoints .................................................................................................................................. 40 
3. 
Eligibility Criteria ............................................................................................................................. 41 
3.1 
Inclusion Criteria ...................................................................................................................... 41 
3.2 
Exclusion Criteria ..................................................................................................................... 43 
4. 
Subject Registration .......................................................................................................................... 45 
5. 
Treatment Plan .................................................................................................................................. 45 
5.1 
Number of Patients ................................................................................................................... 46 
5.2 
Duration of Study ...................................................................................................................... 46 
5.3 
Phase Ib Dose Escalation .......................................................................................................... 47 
5.4 
Dose Escalation Rules and MTD Definition ............................................................................ 49 
5.5 
Definition of Dose Limiting Toxicity ....................................................................................... 52 
5.6 
Phase II Study ........................................................................................................................... 53 
5.7 
TAK-659 and Ixazomib Administration ................................................................................... 53 
5.8 
Concomitant Medications ......................................................................................................... 54 
5.9 
Reproductive Considerations .................................................................................................... 56 
6. 
Toxicities and Dose Delays/Dose Modifications .............................................................................. 57 
6.1 
Dose Delays/Dose Modifications ............................................................................................. 57 
6.2 
Dose Levels for Dose Reduction .............................................................................................. 62 
6.3 
Management of Clinical Events ................................................................................................ 62 
6.4 
Protocol Therapy Discontinuation ............................................................................................ 66 
6.5 
Completion of Study ................................................................................................................. 67 
6.6 
Protocol Discontinuation .......................................................................................................... 67 
7. 
Study Calendar: Dose Escalation Cohorts (Phase 1) ........................................................................ 68 
8. 
Study Calendar: Phase 2 ................................................................................................................... 70 
8.1 
Study Procedures ...................................................................................................................... 73 
8.2 
Disease Assessment .................................................................................................................. 75 
8.3 
Bone Marrow Biopsy and Aspirate Collection Analysis .......................................................... 76 
8.4 
Pharmacokinetic Measurements ............................................................................................... 77 
8.5 
Phase II Interim Analysis .......................................................................................................... 78 


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8.6 
Safety Follow-up Evaluations ................................................................................................... 78 
8.7 
Long Term Follow-up Evaluations ........................................................................................... 78 
9. 
Biospecimen Studies and Procedures ............................................................................................... 79 
9.1 
Source and Timing of Biospecimen Collections ...................................................................... 84 
10. 
Criteria for Disease Evaluation ..................................................................................................... 86 
11. 
Drug Information .......................................................................................................................... 87 
11.1 
TAK-659 ................................................................................................................................... 87 
11.2 
Ixazomib ................................................................................................................................... 88 
12. 
Adverse Events ............................................................................................................................. 89 
12.1 
Definitions................................................................................................................................. 89 
12.2 
Reporting................................................................................................................................... 91 
13. 
Statistical Methods ........................................................................................................................ 94 
13.1 
Study Design ............................................................................................................................. 94 
13.2 
Sample Size and Accrual .......................................................................................................... 94 
13.3 
Randomization and Stratification ............................................................................................. 96 
13.4 
Populations for Analysis ........................................................................................................... 97 
13.5 
Procedures for Handing Missing, Unused, and Spurious Data ................................................. 97 
13.6 
Demographic and Baseline Characteristics .............................................................................. 97 
13.7 
Data Analysis Plan .................................................................................................................... 97 
13.8 
Exploratory Objectives and Pharmacokinetic Analysis ............................................................ 98 
13.9 
Biomarker Analysis .................................................................................................................. 99 
13.10 
Safety Analysis ..................................................................................................................... 99 
13.11 
Interim Analysis .................................................................................................................. 100 
14. 
Trial Management ....................................................................................................................... 100 
14.1 
Data and Safety Monitoring Plan (DSMP) ............................................................................. 100 
14.2 
IUSCC Data Safety Monitoring Committee and Protocol Progress Committee .................... 100 
14.3 
DSMC DLT Review ............................................................................................................... 101 
14.4 
Data Quality Oversight Activities ........................................................................................... 101 
14.5 
Compliance with Trial Registration and Results Posting Requirements ................................ 102 
15. 
Data Handling and Record Keeping ........................................................................................... 102 
15.1 
Data Management ................................................................................................................... 102 
15.2 
Case Report Forms and Submission ....................................................................................... 102 
15.3 
Record Retention .................................................................................................................... 103 
15.4 
Confidentiality ........................................................................................................................ 103 
16. 
Ethics........................................................................................................................................... 103 
16.1 
Institutional Review Board (IRB) Approval ........................................................................... 103 
16.2 
Ethical Conduct of the Study .................................................................................................. 103 
16.3 
Informed Consent Process ...................................................................................................... 103 
17. 
References ................................................................................................................................... 105 


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PHASE I SCHEMA 
 
 
Treatment:  
Cycle = 21 days 
 
TAK-659 (Days 1-15) 
Ixazomib dose escalation (Days 1, 8, 15) 
 
Preliminary efficacy signals addressed after 2 cycles 
and beyond, pending tolerance 
MTD/RP2D 
Registration 
Evaluation of Eligibility Criteria 
Phase II 
Diagnosis of primary or secondary AML including relapsed or 
refractory disease other than acute promyelocytic leukemia, or complex 
karyotype or monosomy 7 (or containing monosomy 7). 


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PHASE II SCHEMA 
 
 
Treatment (extended to efficacy measures): 
Cycle = 21 days 
 
TAK-659 at MTD (Days 1-15) 
Ixazomib at MTD (Days 1, 8, 15) 
< Partial remission 
after 2 cycles 
≥ Partial remission 
after 2 cycles 
Stop treatment 
Continue treatment 
Registration 
Evaluation of Eligibility Criteria 
Diagnosis of primary or secondary AML including relapsed or 
refractory disease other than acute promyelocytic leukemia, or complex 
karyotype or monosomy 7 (or containing monosomy 7). 


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STUDY OVERVIEW DIAGRAMS 
 
Phase II FLT-3- WT vs. -MUT cohorts: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SUBJECT SCHEMA FOR THERAPY 
 
Subsequent cycles 
Stable reduction in bone marrow blasts 
compared with previous marrow
Post‐cycle 4 bone marrow in phase I 
only; done in phase II 3rd cycle in lieu of 
cycle 2,4
Subsequent cycles
At least partial remission, but less 
than complete remission
Post‐cycle 2 bone marrow in phase I,
post ‐cycle 3 in phase II (below)
Second cycle
Response or no progression
Post‐cycle 1 bone marrow 
Days 4 or 8 bone marrow (for correlatives only)
First Cycle
Treatment with TAK‐659, Ixazomib
Pre‐treatment bone marrow
Consent & Registration
Additional cycles
Complete
remission
Disease progression
Less than partial remission
or progression
Progression 
Discontinue
treatment
PD Bone 
marrow
Aspirate 
Phase II
2nd cohort of 
7 patients 
(16 total) 
≥2/9 responders 
Arm 1: 
FLT-3 wild type (WT) 
Initial cohort 
of 9 patients 
2nd cohort of 
12 patients 
(20 total) 
≥3/8 responders 
Arm 2: 
FLT-3 mutation (MUT) 
Initial cohort 
of 8 patients 


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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 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
ASCT 
Allogenic stem-cell transplant 
ASH 
American Society of Hematology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC24 hr 
area under the plasma concentration versus time curve from zero to 24 
hours 
AUCinf 
area under the plasma concentration versus time curve from zero to 
infinity 
AUCτ 
area under the plasma concentration versus time curve during the dosing 
interval 
BCR 
B-cell receptor 
BCRP 
breast cancer resistance protein 
hCG
beta-human chorionic gonadotropin 
BID 
bis in die; twice a day 
BIW 
Twice weekly 
BSA 
body surface area 
BUN 
blood urea nitrogen 
BZD 
Benzodiazepines 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL 
clearance, IV dosing 
CLL 
Chronic lymphocytic leukemia 
CLM 
Correlative Laboratory Manual 
CLR 
Renal clearance 
CLP 
plasma clearance 
CLSS /F 
apparent clearance at steady-state after extravascular administration 


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Abbreviation Term 
CLTotal 
total clearance 
Cmax 
maximum (peak) observed concentration   
CNS 
central nervous system 
CO2 
carbon dioxide 
CPK 
Creatinine phosphokinase 
CR 
complete remission or complete response     
CRM 
continual reassessment method 
CRP 
C-reactive protein 
CSF-1R 
colony-stimulating factor 1 receptor 
CT 
computed tomography 
Ctrough 
end of dosing interval (trough) concentration 
CV 
 cardiovascular  
CYP 
cytochrome P450 
DDI 
Drug-drug interaction 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FLT3 
FMS-like tyrosine kinase-3 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 


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Abbreviation Term 
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go related gene 
HIV 
human immunodeficiency virus 
HNSCC 
Head and neck squamous cell carcinoma 
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 activation-motifs 
IV 
intravenous; intravenously 
IVRS 
interactive voice response system 
Ki 
inhibition constant 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MAPK 
Mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDSC 
myeloid-derived suppressor cells 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition (scan) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NF-kB 
nuclear factor kappa-B 
NGS 
Next Generation Sequencing 
NK 
Normal karyotype 
NHL 
non-Hodgkin lymphoma 
NPO 
nothing by mouth 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
PBMC 
peripheral blood mononuclear cell 


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Abbreviation Term 
PCR 
polymerase chain reaction 
PD 
Pharmacodynamics  
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
pSYK 
phosphorylated SYK 
QD 
quaque die; each day; once daily 
QID 
quater in die; 4 times a day 
QOD 
quaque altera die; every other day 
QOL 
quality of life 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
RBC 
red blood cell 
RECIST 
response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
stable disease 
SmPC 
summary of Product Characteristics 
SYK 
spleen tyrosine kinase 
t1/2 
terminal disposition half-life 
TGI 
tumor growth inhibition 
Tmax 
time of first occurrence of Cmax concentration 
TNBC 
triple-negative breast cancer 
ULN 
upper limit of the normal range 
US 
United States 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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1. 
BACKGROUND AND RATIONALE 
1.1 
Summary 
This trial was conceptually founded on the results of a recently completed clinical trial from our 
institution addressing relapsed/refractory AML. That trial had involved use of a combination of targeting 
agents:  acting at the levels of signal transduction (Flt3/Raf-selective inhibitor Sorafenib), and chromatin 
remodeling (Vorinostat and Bortezomib). Results from that trial demonstrated to us that, at least in 
Flt3ITD-positive disease, chemotherapy-free remissions could be achieved by cyclical administration of 
the combination, and the remissions were associated with a pretreatment gene expression signature of 
resistance effectors, whose expression-related impact was reversed in a very early phase of treatment 
initiation to predict success. In fact, introduction of Bortezomib was pivotal in enhancing the rate and 
depth of responses in our cases. We found early reversal of the resistance signature resulted in an 
inverted signature that characterizes good-risk core-binding factor AML, a form known to be curable 
with conventional chemotherapy when presenting de novo.  The conclusion that the signature reversal 
we observed may be clinically meaningful in this relapsed/refractory stage was validated not only by 
rapidly occurring (within 1-2 weeks) deep morphologic eradication of bone marrow blasts, but by the 
occurrence of a pathway to successful transplant consolidation or to an unmaintained remission. 
 
It appears likely that the concept for targeted AML therapy consisting of a combination of 
epigenetically-active agents that may precede not only transplant consolidation in relapsed/refractory 
AML, but prior to (“sensitivity priming”) induction chemotherapy in de novo cases is germaine, because 
single targeted agents have not addressed the impact of combined mutational interaction involving 
signaling and chromatin-modeling effectors that is intrinsic to AML development. A combination of 
agents acting at the nexus of influence by mutations occurring in signaling and chromatin effectors that 
elicit resistance pathways, is needed so that resistance phenotype may be effectively reprogrammed.  
 
Here, we have proposed a combination strategy using TAK-659 with Ixazomib because of extensive 
experience with agents, like Bortezomib, impacting pivotal targets whose influence is also neutralized 
by TAK-659 plus Ixazomib.  This combination is likely to result in not only morphologic remissions, 
but also sensitivity priming for subsequent consolidation therapies delivered in near sequence. Indeed, 
most experts believe that continuous administration alone of single agent or even targeted therapy 
combinations, except in acute promyelocytic leukemia, is premature, and that the only rational 
application in high-risk AML is to plan cyclical administrations of 2-3 agents with a significant dose 
intensity. Given that TAK-659 and, particularly, Ixazomib have defined RP2D, and that they have only 
partial overlap in main toxicities, it is our strategy to perform a 3+3 escalation phase I trial beginning 
with the RP2D of TAK-659 in a shortened schedule compared to the current phase Ib duration, and to 
initiate Ixazomib with a one-dose step down from RP2D, in order to hasten the early identification of 
meaningful activity of the combination.  This will allow for leukemic cytoreduction, and then a rest 
phase to allow regrowth of normal marrow precursors while avoiding toxicity from chronic exposure.  
Based on extensive experience with this type of approach from our prior trial, it is important to note that 
dose-interruption during the induction phase of therapy should not be tied to the occurrence of 
neutropenia or thrombocytopenia, but, rather, transfusion of platelets at the time of weekly or twice 
weekly outpatient visits should be undertaken, and prophylaxis against neutropenic infections is given, 
with a rule for admission for high-risk febrile episodes. 


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1.2 
Acute Myeloid Leukemia: Current Standard of Care 
Accumulating evidence points to initial clinical efficacy for single targeted agents in AML patients, 
when their primary blasts are annotated for single mutations as target.  However, it has become clear 
that targeting must address at least two cooperative driver mutations in most AML cases, because single 
agents have only short-term benefit. Distinct patient outcomes have also been observed following 
uniform intensive chemotherapy for AML subsets described by pairing of driver mutations (1).  
However, the underlying origins for these chemotherapy outcomes are remote and reflect complex 
pathways, even when supplemented with single targeted agents as adjunct. Limited data exist to suggest 
an effective, and lasting combination targeted therapy in the context of paired driver mutations. Only 
then may targeting neutralize mutational impact on unsatisfactory chemotherapy outcomes. 
Investigation is needed to consider the leukemogenic program resulting from the summed burden of 
mutant drivers in the context of targeted therapy. Flt3-selective tyrosine kinase inhibitors (TKI’s), as 
monotherapy, and along with chemotherapy, have perceived utility in AML, eg. Flt3ITD+ve (a class 1 
mutation). However, co-existing mutant epigenetic landscaping genes (class 2 mutations) within AML 
founder clones affect resistance of leukemic stem cells (LSCs), thus preventing sustained remission. 
1.3 
Acute Myeloid Leukemia Mutations 
Poor outcomes are frequent among certain acute myeloid leukemias (AMLs) characterized by small 
numbers of cooperating mutations (1). In particular, this group represents the largest fraction of AMLs 
in young adults. The cooperating mutations commonly involve epigenetic mechanisms amenable to 
targeted interventions. Such targeted interventions may, collectively in combinations, but only rarely 
when given alone, reverse resistance both to single tyrosine kinase inhibitors (TKIs) (eg. Those for 
Flt3ITD) and to a range of chemotherapies (2). A notable example is the ability of proteasome inhibitor 
(PI), Bortezomib, to silence HoxA expression, which is a major resistance factor for AML (2). 
 
Figure 1-1 (below).  EZH2/PRC2 upregulation by PI 
One of the earliest recognized, and most frequently 
occurring, driver mutations for AML is Flt3ITD. It does 
appear that prolonged maintenance administration of single 
TKIs may not be an optimal option for Flt3ITD AML as 
has proved to suffice for efficacy in chronic myeloid 
leukemia (CML).  
 
Unlike the primacy of BCR-ABL mutation in the origins of 
CML, Flt3 tyrosine kinase oncogene mutations in AML 
arise late in the process of leukemogenesis and are most 
commonly preceded by mutations of epigenetic effectors 
such as DNMT3A, ASXL1, TET2, IDH1/2, WT1 (3). 
Mutations in these latter effectors, functioning at the level of chromatin and DNA, have a common end-
function for promoting leukemic stem cell expansion, which involves master regulators from the Hox-A 
and -B alleles. Thus, a major attribute for Flt3ITD poor-risk AMLs is HoxA/B overexpression, and also 
expression of the TALE-factor collaborator Meis1, whose abundance distinguishes these AML subsets 
from those curable, but less frequent forms of AML with core-binding factor mutations (CBF+ve), 
which are largely devoid of HoxA/B and Meis1(4,5).  
 
It is of crucial importance to emphasize the collaboration that occurs in essentially all cases of AML 
mutDNMT3A           mutFlt3
EZH2 in
PRC2
increase
EZH2
HOXA 9, 10
Bortezomib/Ixazomib
excess
EZH2 in
proteasome


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bearing Flt3 mutations with one of the noted epigenetic modifiers (6). 
 
Figure 1-2 (below).  Virtually all Flt3 mutant AMLs have co-mutation of epigenetic effectors, affecting the 
Wnt pathway and HOXA locus 
We have recently treated relapsed/refractory AML, 
in patients with a disease form bearing Flt3ITD and 
TET2 mutations, by using a combination of the dual 
Flt3/raf inhibitor Sorafenib, the pan-histone 
deacetylase inhibitor Vorinostat, and the proteasome 
inhibitor Bortezomib. This combination, absent 
chemotherapy, proved to be quite effective at 
inducing severe depletion of blasts in the peripheral 
blood and marrow within a week’s time, and this 
was preceded by early reversal of an intrinsic gene 
expression signature consisting of repressed RUNX3, 
and hyperexpressions of Id1, c-jun, and HoxAs (7). 
 
Early gene signature inversion, in blasts from patients so treated, presaged remissions, which led to the 
possibility of curative allogeneic bone marrow transplant for patients achieving those remissions. All of 
these epigenetic effectors present in the signature link to the AML resistance phenotype marked by 
HoxA overexpression: 1) RUNX3 is a Wnt pathway inhibitor of -catenin which is repressed by TET2 
mutation or other mutations in the group IDH1/2, WT1/TET2 (8,9); 2) Id1 is a Wnt pathway agonist of 
-catenin downstream of Flt3 (via repression of Cullin E3 ubiquitin ligase)(10); and 3) c-jun and -
catenin can cooperate for HoxA transcription, and c-jun is known to transactivate Meis1 (11-14) (Figure 
1-3, below).  
 
Therefore, we were led to wonder whether an even more potent combination might be devised to target 
these pathways for reversal of AML resistance, which may involve inhibition of a common pathway to 
allow re-establishment of that core-binding factor AML phenotype of therapeutic sensitivity marked by 
low/non-expression of HoxAs/Meis1. 
Very recently, the non-receptor tyrosine kinase Syk was linked to the development of a resistance 
phenotype by Flt3ITD+ve AML, in part, via upstream and downstream effects at amplifying the Flt3-to-
HoxA pathway (15). First, Syk is in a signaling complex, along with p85 PI-3 kinase, for Flt3ITD in 
AML (16).  
 
AML therapy, continued….
2012‐2016:  “What lies beneath‐ an 
epiphany”
Flt3 mutation (tip of the iceberg)
Cooperating 
mutation:
IDH1/2:  10‐15%
TET2/WT1: 10‐
15%/20%
DNMT3A: 40%
Wnt
antagonists 
(RUNX3)
Beta‐catenin
HOXA’s
RESISTANCE


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Figure 1-3. 
Box1,2) RUNX3 is repressed in 
context of WT1/TET2 pathway 
inactivation, which prevents its 
antagonism of -catenin nuclear 
function. 
Box 3) Id1 is a repressor of Cullin, 
whose loss heightens DVL2, leading 
to -catenin stabilization, which 
along with jun can bind and 
transactivate HOXA9/10. 
Box 4) FOXM1, transactivated by 
jun (ENCODE) binds -catenin and 
chaperones nuclear translocation 
(17) (additionally, jun and -catenin 
heterodimerize for transactivation 
TCF4 motif) (14, see below). 
 
In the receptor-related complex, mutual reciprocal 
cross-phosphorylations by Flt3 and Syk amplify the 
signal downstream to c-myc, among other targets. In 
addition, it was recently found that Meis1 upregulates 
Syk, via repression of miR-146a-a Syk modulator, and 
that Syk drives Meis1 expression, resulting in a 
positive feedback loop (18). (Figure 1-4, left) 
 
These features strongly recommend the addition of a 
dual Flt3/Syk inhibitor into a targeted agent 
combination trial for Flt3ITD AML. In addition, we 
and others have found the ability of dual Flt3/Syk 
inhibitors to bypass the TKD 835 mutation, which 
represents an advantage over Sorafenib used as the 
Flt3-selective TKI in our prior trial.  
 
Flt3/Syk or Syk inhibitors also have demonstrated efficacy in disease subtypes of AML not involving 
Flt3ITD. For example, use of a dual Flt3/Syk inhibitor was able to cause in vitro differentiation of a 
variety of primary AML blast phenotypes (19). In addition, in an ongoing phase I trial utilizing a 
priming approach of administration of the Syk inhibitor entospletinib (GS-9973) as a lead-in prior to 
chemotherapy, it has been observed that one patient with a tMLL AML achieved complete remission 
prior to the onset of chemotherapy. (20) Such a result would seem to reflect a mechanism similar to that 
noted above in relation to downstream effects on HoxA/Meis1, which dominate the mechanism of tMLL 
AML.  
 
Another crucial observation from our first trial was the dramatic impact Bortezomib made, when added 
to the therapeutic combination of Sorafenib with Vorinostat, upon the depth and rapidity of remissions 
HOXA and MEIS1 are co‐dependent
final common pathway variables
• Meis 1 regulation via Syk and vice versa
» mutFlt3
Syk
Meis1
mIR‐
146a
Tak‐659
Interruption by TAK‐659
of positive feedback for 
expressions
RUNX3
TET2
(WT1)
miR29-B
& mutation TET2, or
Mutation WT1, IDH2
β-catenin
LSC
hoxA9, 10
Id1
?
1‐Wang Y, Xiao M, et al. Mol Cell. 2015;57(4):662‐
73. 
2‐Shih AH, et al. Cancer Cell. 2015;27:502-15.
3‐Jin X et al.  Cell Rep. 2016; 16:1829
4-Zhang N et al. Cancer Cell 2011; 20: 427-
42
CULLIN3
DVL
JUN
1
2
3
FOXM1
4


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compared to the combination of Sorafenib and Vorinostat given in only a doublet combination (7). This 
has led us to speculate that the most important components of an epigenetically-active combination 
similar to the one we have previously studied, may in fact be the coupling of Bortezomib, or another 
proteasome inhibitor, with the TKI, which should optimally possess dual Flt3 and Syk selectivity.  
 
Indeed, it is known that proteasome inhibitors degrade FOXM1 in several cancers and that FOXM1 is a 
necessary chaperone for -catenin on Wnt/TCF4 target gene promoters, such as HOXA10 (17).  This 
proteasome inhibitor activity against FOXM1 appears to occur as a result of upregulation of HSP70, 
which binds and sequesters FOXM1 protein, preventing it from positively autoregulating its promoter 
(21).  The resulting inactivation of FOXM1 leads to loss of nuclear transport of -catenin destined for 
Wnt/TCF4 promoters. 
 
Further, we examined other putative measures for AML sensitivity to the combination used for the 
previous trial. In this regard, Sorafenib is not an active inhibitor of Syk kinase, and we found that Syk 
overexpression within blasts was a predictor for failure to achieve remission, where there was a 20-fold 
difference in transcript expression for Syk among responders vs. nonresponders (p=0.002). Several of 
these cases were found to be quite sensitive to a dual Flt3/Syk inhibitor when tested in vitro prior to 
commencing Sorefenib-based therapies in the patient (data not shown).  
 
Our prior study using Bortezomib along with TKI is striking in its support for the central thesis of our 
proposed study. In addition, we have generated preliminary data to support the concept that TAK-659 is 
an attractive and efficacious agent for combination with proteasome inhibitors (Figs. 1-5 to1-9):  
 
 
In Figure 1-5, a patient treated 
on the Sor/Vor/Bor clinical 
trial failed to achieve a 
remission, but the marrow 
tested prior to onset of therapy 
was sensitive to TAK-659 and 
demonstrated enhanced cell 
extinction (visible apoptosis) 
measured by tritiated thymidine 
uptake with the combination of 
TAK-659 with Bortezomib 
over a range of concentrations.   
 
 
 
 
Figure 1-5 (above). JAK2 mutant secondary AML is quite sensitive to TAK-659/Bortezomib. 
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In addition, we noted dramatic synergy of TAK-
659 with Bortezomib in an aggressive de novo 
AML with the same functional phenotype as the 
Flt3ITD/TET2 mutation pair that we studied in our 
accompanying manuscript (WT1 mutation is the 
functional equivalent to TET2 mutation because 
they are binding partners and perform cooperative 
function [see ref (22)] (Figure 1-6, below).  
Figure1- 6 (right). Co-Occurrence of Flt3ITD with 
WT1/TET2 disruption sensitizes cells to TAK- 
659/Bortezomib combination in patient blasts #3220.  
 
The same results were seen in another patient with 
high allele frequency WT1 mutation, again 
accompanying modest burden Flt3ITD mutation.  
This patient was found to be highly refractory to 
cycles of induction and reinduction chemotherapy, 
including Midostaurin (Fig1-7, below). 
 
Fig. 1-7 (left).  Low allele burden Flt3ITD 
plus WT1 mutation confers Midostaurin 
resistance, but sensitivity to TAK-
659/Bortezomib at easily achieved plasma 
levels in patients. 
 
Although Bortezomib alone had a 
propensity to dramatically inhibit 
proliferation and induce visible apoptosis 
of blasts when used alone at concentrations 
at or above 125 nM, at medium doses 
stimulation of cell survival occurred, which was overridden by the combination with TAK-659.  At 
higher doses or very low doses of Bortezomib (the latter below 15nM) the combination of TAK-659 
with Bortezomib was supradditive/synergistic for cell extinction (with visible apoptosis). 
Flt3ITD (5%), mutWT1 (52%), mutASXL1 (18%), 
mutKRAS (16%)
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Synergy TAK‐659 with Bortezomib in NK 
AML with WT1 mutation along with 
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Figure 1-8.  High allele burden Flt3ITD and DMT3A mutations sensitive to combination TAK-659/Bortezomib 
(below) 
Further, based on the mechanism demonstrated for 
proteasome inhibition to silence HoxA9 via EZH2 in 
AML (2), we have also demonstrated strong synergism in 
vitro between TAK-659 and Bortezomib in a patient with 
high allele burdens of Flt3ITD and DNMT3A muations 
(Figure 1-8). In fact, DNMT3A mutation is a specific de-
repressor for HoxA expression (1), occurring in 40% 
normal karyotype AMLs, which thus the combination 
TAK-659 and either Bortezomib or Ixazomib should 
target in those particularly risk-averse patients as 
demonstrated above. In fact, in this patient’s blasts with 
extremely high burden of Flt3ITD (allele frequency 
>50% at diagnosis shown) and TAK-659 IC50 less than 
19nM, the combination of Bortezomib with TAK-659 
was better than TAK-659 save for 3 doses of Bortezomib 
in the combination. 
Similarly, AML blast cells with the pairing of Flt3ITD with TET2 mutations, as previously reported, 
demonstrated the same synergy for antileukemic 
activity by TAK-659 and proteasome inhibitor.   
Fig. 1-9 (right):  Fl3ITD and TET2 mutant 
sensitivity to TAK-659/Bortezomib. 
We have also demonstrated extreme sensitivity to 
TAK-659 in blasts of a patient with low allele 
burden of Flt3TKD mutation (2%) along with 
IDH2/DNMT3A mutations (50% allele burden 
each) with an IC50 TAK-659 of 150nM (data not 
shown). 
All these data validate conclusions we had made 
based on pretreatment in vitro testing of blasts from a patient (#14, Sor/Vor trial [ 7]) who was 
subsequently found to achieve a VGPR with Sor/Vor.  That patient’s blasts were tested in vitro with 
Sorafenib vs. R406 (Tamatinib, an investigational SYK inhibitor) in combination with either Vorinostat 
analogue SBHA or Botezomib.  In that testing, tamatinib was superior in vitro to Sorafenib, and 
Bortezomib combination with tamatinib was vastly superior to the combination with SBHA. 
Thus, the underlying hypothesis derived from our experience is the following: Because of a known 
nuclear-to-cytoplasmic signal feedback loop that ties together Syk, HoxA, and Meis1, the combination 
of TAK-659 and proteasome inhibitors will target AMLs at this pivotal feedback junction where poor-
risk AML is promoted:  
a) upstream at the locus of Flt3/Syk receptor signal initiation, and  
b) downstream at HoxA/Meis1 transcription. These distinct inhibitors acting simultaneously are 
needed in order to achieve optimal responses in relapsed/refractory Flt3ITD+ve and Flt3ITD-ve 
AML.  
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BORT 1uM‐0.5nM _____
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Flt3ITD (>50%), mutDNMT3A (52%),mutNPM1 (60%),
mutASXL1 (5%)
Patient #3229
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In particular, Bortezomib and the similar proteasome inhibitor, Ixazomib, may act synergistically with 
TAK-659 to accomplish reversal of HoxA overexpression, and abolish Meis1 transcription driven by c-
jun and Syk, in the context of Wnt pathway activity that we have observed (7). The planned experiments 
pursue the detailed events relating the participants in this larger pathway to the superior outcome 
expected of the combination as compared to single agent impact on AML blasts with the drivers noted 
above.  Particular attention will be paid to the impact of distinct mutant epigenetic modifiers (TET2, 
IDH1, IDH2, WT1, ASXL1,BCOR/BCORL1) which are known AML drivers of category 2, in their 
interaction with mutant drivers of category 1 acting within a TK pathway (Flt3mutant vs. in Flt3WT: 
KRAS, NRAS, JAK2, CBL).  
1.4 
TAK-659 
TAK-659 is an orally (PO) bioavailable, potent and reversible inhibitor of SYK and FLT3 currently 
under development for the treatment of patients with advanced malignancies. 
SYK is a nonreceptor protein tyrosine kinase with SH2-binding domains that bind to phosphorylated 
immunoreceptor tyrosine activation motifs (ITAMs) located in B and T cells and certain natural killer 
(NK) cells. SYK becomes activated upon ITAM binding and subsequently controls the activity of 
downstream signaling pathways, eg, phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase 
(MAPK), and nuclear factor kappa-B (NF-kB) that mediate diverse cellular responses, including 
proliferation, differentiation, and survival. The SYK pathway is implicated in hematological tumors as 
well as select solid tumors development (eg, Epstein-Barr virus [EBV]-mediated naso-pharyngeal 
tumors). 
FLT3 is a receptor tyrosine kinase that plays a role in hematopoiesis. Activating mutations in tyrosine 
kinase genes, including FLT3, are found in approximately 30% of patients with de novo acute 
myelogenous leukemia (AML). Mutations in the FLT3 gene most often involve internal tandem 
duplication of the juxtamembrane domain coding region or point mutations of the tyrosine kinase 
domain, resulting in ligand-independent proliferation due to constitutive activation of the FLT3 receptor 
conferring poor prognosis for patients (1, 7).  
Figure 1-10. 
Chemical Structure of TAK-659 
 
TAK-659 drug substance is a white to off-white crystalline powder. The pKa values were determined to 
be 0.95 (acidic) and 9.5 (basic). 
1.4.1 Non-clinical Experience 
1.4.1.1 Pharmacology (see Investigator’s Brochure) 
Nonclinical enzymatic and cell-based studies demonstrated that TAK-659 is a potent, reversible SYK 
and FLT3 inhibitor. TAK-659 inhibited SYK and FLT3 purified enzymes with a concentration 
producing 50% inhibition (IC50) of 3.2 and 4.6 nM, respectively. Among a panel of kinases also 


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inhibited by TAK-659, the IC50 ranged from 1.4- to 115-fold higher than those for SYK. In addition, in a 
study of the cellular kinase selectivity of TAK-659, the IC50 for TAK-659 in a cell line expressing SYK 
was 116 nM, which was lower than the IC50 for any other kinase tested in this model (about 2-fold lower 
than the next lowest IC50 for ROS). 
TAK-659 inhibited the B-cell receptor (BCR) signaling pathway, as indicated by inhibition of the 
autophosphorylation of SYK, as well as inhibition of the phosphorylation of several downstream targets. 
TAK-659 potently inhibited SYK and FLT3 activities in hematopoietic malignancy-derived, cultured 
human cell lines, including T-cell lymphoblastoma, megakaryoblastoma, and AML, with a 
concentration producing half-maximal response (EC50) ranging from 11 to 775 nM in sensitive cell 
systems.  
TAK-659 demonstrated significant antitumor activity after oral (PO) administration  to xenografts: MV-
4-11 (AML cell line model; 30 and 60 mg/kg; p0.001), KG-1 (AML cell line model; 60 mg/kg; 
p0.001), Additionally, pharmacodynamic analysis of MV-4-11 tumors from mice treated with TAK-
659 demonstrated an apparent reduction of SYK phosphorylation at tyrosine residues Y525/526 
(phosphorylated SYK [pSYK] Y525/526), as well as an increase in terminal biomarker cleaved caspase-
3, CC3, a critical marker of apoptosis. 
1.4.1.2 Pharmacokinetics 
In nonclinical species, TAK-659 has good oral bioavailability, low plasma protein binding, moderate to 
large volumes of distribution, and moderate to high plasma clearance. TAK-659 was relatively stable 
with low extent of metabolism in human liver microsomes, S9, and hepatocytes; therefore, the 
metabolism is expected to be low in humans. TAK-659 is a major substrate of CYP3A4/5 and P-gp; 
thus, there is potential for an interaction between the corresponding inhibitor and inducer drugs. TAK-
659 is not anticipated to perpetrate CYP- or P-gp/BCRP-mediated interactions in the clinic.  
1.4.1.3 Toxicology 
The nonclinical toxicology assessment of TAK-659 supports clinical trials in patients with advanced 
malignancies. GLP-compliant studies were conducted in accordance with ICH S9 guidance. In 
summary, the TAK-659 nonclinical toxicology profile supports its use in patients with advanced 
malignancies.  However, there was evidence of genotoxicity in the Ames assay. 
On the basis of in vitro and in vivo safety pharmacology studies, TAK-659 has low potential for 
cardiovascular (CV), respiratory, or central nervous system (CNS) effects in patients. 
Detailed information regarding the nonclinical pharmacology and toxicology of TAK-659 can be found 
in the Investigator’s Brochure (IB). 
1.4.2 Clinical Experience 
TAK-659 is being evaluated in a number of indications including NHL, AML, and advanced solid 
tumors (including triple-negative breast cancer[TNBC], non-small cell lung cancer [NSCLC], and head 
and neck squamous cell carcinoma [HNSCC]). An overview of ongoing studies is given in the table 
below.


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Table 1. 
Overview of TAK-659 Clinical Studies 
Protocol No.; 
Status 
Study Objective(s) 
Study Design and Population 
Dose, Regimen,  
Route, Duration 
C34001; 
closed to 
enrollment 
Primary: safety, tolerability, 
MTD/RP2D.  
Secondary: PK, 
pharmacodynamics, 
preliminary efficacy.
Open-label, multicenter, phase 1, 
dose escalation study of 
TAK-659 in adult patients with 
advanced solid tumors and 
lymphoma malignancies.
Increasing oral doses of 60 mg, 80 mg, 100 mg, and 
120 mg QD were assessed during dose escalation; a 
RP2D of 100 mg QD is being further explored in 
patients with lymphoma during dose expansion. 
C34002;  
closed to 
enrollment 
Primary: safety, tolerability, 
and MTD/RP2D in the phase 
1b dose-finding portion and 
preliminary efficacy in the 
phase 2 dose expansion 
portion.  
Secondary: PK, 
pharmacodynamic, and 
differential efficacy 
depending on FLT3 mutation.
Open-label, multicenter, 
phase 1b/2, dose escalation study 
of TAK-659 in adult patients with 
relapsed or refractory AML. 
Starting dose of 60 mg QD; additional doses of 
100 mg, 120 mg, 140 mg, and 160 mg QD; 60 mg 
BID and  80 mg BID evaluated;  
C34003; 
ongoing 
Primary: determine 
MTD/RP2D of TAK-659 in 
combination with nivolumab 
and efficacy of the 
combination. 
Secondary: safety, 
tolerability, and efficacy of 
the combination; PK of TAK-
659. 
Open-label, multicenter, phase 
1b, dose escalation and dose 
expansion study of TAK-659 in 
combination with nivolumab in 
adult patients with advanced solid 
tumors 
Starting TAK-659 dose of 60 mg QD; dose has been 
escalated to 100 mg QD. Once determined, RP2D 
will be used in expansion cohorts. Nivolumab: 3 
mg/kg IV dosing over 60 minutes every 2 weeks 
(Days 1 and 15 of each 28-day cycle). If the 240 mg 
fixed-dose cohort is evaluated and deemed safe and 
tolerable, the dosing regimen may switch to 240 mg 
on the basis of change in clinical practice and 
discussion between the investigator and sponsor. 
For patients participating in the 2-week 
monotherapy run-in with TAK-659, the first dose 
will be on Cycle 1 Day 15.
C34004, 
ongoing 
Primary: efficacy 
Secondary: progression-free 
survival and efficacy 
Open-label, multicenter, phase 2 
study in adult patients with 
relapsed or refractory DLBCL, 
beginning with a lead-in dose 
exploration phase with 2 TAK-
659 dose regimens 
Cohort 1 = TAK-659 100 mg QD in 28-day 
treatment cycles.  
Cohort 2 = TAK-659 increasing dose (every 28 
days) beginning with 60 mg QD, followed by 80 mg 
QD, up to 100 mg QD. 


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Protocol No.; 
Status 
Study Objective(s) 
Study Design and Population 
Dose, Regimen,  
Route, Duration 
C34005; 
ongoing 
Primary: to determine 
MTD/RP2D when 
administered with each of the 
combination partners  
Secondary: PK of TAK-659 
and preliminary efficacy with 
each of the combination 
partners 
Open-label, multicenter, phase 
1b, dose escalation study of 
TAK-659 in combination with 1 
of 5 combination partners 
(bendamustine, bendamustine + 
rituximab, gemcitabine, 
lenalidomide, and ibrutinib) in 
adult patients with NHL after at 
least 1 prior line of therapy 
Starting dose of 60 mg QD; dose will be escalated 
to 100 mg QD until MTD is reached. 
Combination partners include:  
 
Bendamustine: 90 mg/m2 administered IV over 
10 or 60 minutes (depending on which 
formulation is used) on Days 1 and 2 of a 21-
day cycle, up to 8 cycles. 
 
Bendamustine + rituximab: 90 mg/m2 
bendamustine administered IV over 10 or 60 
minutes (depending on which formulation is 
used) on Days 1 and 2 of a 21-day cycle, up to 8 
cycles; and 375 mg/m2 rituximab administered 
IV per local guidelines and labeling on Day 1 of 
a 21-day cycle, up to 8 cycles. 
 
Gemcitabine: 1000 mg/m2 IV infusion over 30 
minutes on Days 1 and 8 of a 21-day cycle. 
 
Lenalidomide: 25 mg PO QD for Days 1 to 21 
of a 28-day cycle. 
 
Ibrutinib: 560 mg PO QD of a 28-day cycle. 
C34007; 
ongoing 
Primary: to determine safety, 
tolerability, and MTD/RP2D 
and to characterize plasma 
and urine PK 
Secondary: to evaluate 
preliminary efficacy 
Open-label, multicenter, 2-part, 
phase 1 study in East Asian adult 
patients, including a dose 
escalation in patients with NHL 
and an expansion in patients with 
DLBCL 
Starting TAK-659 dose of 60 mg QD; dose will be 
escalated to 100 mg QD and will then follow 20 mg 
increments until MTD and/or RP2D is reached.  
Expansion phase will use RP2D. 


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Protocol No.; 
Status 
Study Objective(s) 
Study Design and Population 
Dose, Regimen,  
Route, Duration 
C34008;  
ongoing 
Primary: determine the MTD 
and/or RP2D of TAK-659 
and venetoclax, and to 
evaluate safety and 
tolerability 
Secondary: PK and 
preliminary efficacy of TAK-
659 and venetoclax 
 
Dose Escalation Phase: adult 
patients with advanced NHL of 
any histology. Patients will be 
refractory or relapsed after at 
least 1 prior line of therapy with 
no effective standard therapy 
available. 
Safety Dose Expansion Phase: 
MTD/RP2D + venetoclax will be 
explored in 2 dose safety 
expansion cohorts, advanced 
DLBCL and FL.
TAK-659: planned 60 or 100 mg PO, QD (or 
intermediate dose levels if appropriate), plus one of 
the following venetoclax regimens administered in 
28-day cycles after Cycle 1 (35 days): 
 50 mg QD increasing to 200 mg QD by Day 16. 
 50 mg QD increasing to 400 mg QD by Day 17. 
 50 mg QD increasing to 800 mg by Day 19.  
Expansion phase will use MTD/RP2D of TAK-659 
and venetoclax combination 
MLN1117-1003; 
completed 
Primary safety: to determine 
DLT and MTD/RP2D for 
MLN1117 when administered 
with each of the combination 
partners. 
Primary efficacy: to evaluate 
the ORR as the primary 
efficacy measure of 
MLN1117 in combination 
with each of the combination 
partners in patients with 
gastric or gastroesophageal 
adenocarcinoma 
An umbrella study to evaluate 
MLN1117 in combination with 
taxanes (docetaxel or paclitaxel) 
and other investigational 
anticancer agents (including 
TAK-659) for the treatment of 
patients with previously treated 
advanced and metastatic gastric 
and gastroesophageal 
adenocarcinoma 
Details are included in the MLN1117 Investigator’s 
Brochure. 
AML=acute myeloid leukemia, BID=twice daily, DLBCL=diffuse large B-cell lymphoma, DLT=dose limiting toxicity, MTD=maximum tolerated dose, 
NHL=non-Hodgkin lymphoma, ORR=overall response rate, PK=pharmacokinetics, QD=once daily dosing, RP2D=recommended phase 2 dose. 


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1.4.2.1 Pharmacokinetics 
Preliminary plasma pharmacokinetics (PK) results are available from lymphoma, solid tumor, and AML 
patients enrolled in Studies C34001 and C34002. In addition, preliminary urine PK results are available 
from lymphoma and solid tumor patients enrolled in the dose escalation cohorts of Study C34001. TAK-
659 is characterized by fast absorption (overall median Tmax [time of first occurrence of Cmax (maximum 
observed concentration)] of 2 hours) in patients with hematologic and nonhematologic malignancies. 
Moderate variability is observed among dose-normalized steady-state AUC(area under the plasma 
concentration-time curve during the dosing interval) values in lymphoma, solid tumor, and AML 
patients (coefficient of variation of 20.0%, 43.5%, and 34.8%, respectively). An approximately dose-
proportional increase in steady state AUCwas observed over the 60 to 160 mg range in patients with 
AML. Mean accumulation ratios ranging from 1.90-fold to 2.54-fold and mean peak-to-trough ratios 
ranging from 4.34 to 5.09 were observed across the study populations after repeated QD dosing for 15 
days. Based on data in lymphoma and solid tumor patients, renal clearance accounted for about 30% of 
TAK-659 apparent clearance, and therefore at least about 30% of TAK-659 systemic clearance. Active 
tubular secretion appeared to be the predominant component of renal clearance, based on comparison of 
unbound renal clearance to glomerular filtration rate. Geometric mean terminal disposition half-life of 
34.4 hours was determined in a single dose PK run-in phase of the indolent NHL expansion cohort of 
Study C34001.  Additional details on TAK-659 PK are provided in the TAK-659 IB.  
 
A preliminary population PK model simulated results predicted 44% vs 30% of pts (N=2000) exposed to 
80 mg BID vs 160 mg QD, respectively, would have a steady-state trough concentration of >100 ng/mL, 
a level leading to >90% pFLT-3 inhibition per (plasma inhibitory activity for Flt3mutant cell line in 
vitro) PIA(23, 24); thus forming the basis for evaluating the BID dose schedule.   
1.4.3 
Drug- Drug and Drug-Food Interactions 
1.4.3.1 Drug-Drug Interactions 
To date, no drug-drug interaction (DDI) studies have been conducted in humans. Because the metabolic 
and disposition pathways of TAK-659 remain to be fully characterized in humans in vivo, the risk of PK 
DDIs between TAK-659 and concomitantly administered drugs has been informed by data obtained 
from human in vitro systems. 
In vitro studies indicate that TAK-659 is a substrate of P-gp and is metabolized by CYP3A4/5, 
CYP2D6, and CYP1A2, with relative contributions of 69.1% to 73.0%, 16.6% to 30.9%, and 0% to 
8.40% for these respective CYPs. There is a potential risk for TAK-659 PK to be altered by drugs that 
are strong CYP3A inhibitors or inducers, or P-gp inhibitors or inducers. Consequently, until such 
potential interactions can be assessed in vivo, concomitant treatment with CYP3A strong inhibitors or 
inducers or with P-gp inhibitors or inducers should be avoided in clinical studies of TAK-659. 
Treatment with CYP3A strong inhibitors or inducers or P-gp inhibitors or inducers must be discontinued 
within a designated timeframe before the first dose of TAK-659 as specified in the individual study 
protocols. 
In cell-based assays, TAK-659 was not a substrate of the efflux transporter BCRP or the uptake 
transporters OAT1, OAT3, OCT2, OATP1B1, or OATP1B3. Therefore, there is low predicted risk for 
inhibitors or inducers of these transporters to affect TAK-659 exposure. 


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1.4.3.2 Drug-Food Interactions 
To date, the effect of food on the PK of TAK-659 has not been characterized in humans. Accordingly, 
TAK-659 should be administered on an empty stomach, at least 1 hour before and no sooner than 2 
hours after food and beverages except water. 
Because grapefruit juice is considered a strong CYP3A inhibitor, there is a potential risk for TAK-659 
PK to be altered by grapefruit-containing food and beverages. Accordingly, consumption of grapefruit-
containing food and beverages is prohibited during clinical studies of TAK-659. 
1.4.4 
Clinical Pharmacodynamics 
Pharmacodynamic markers are being assessed across TAK-659 studies. In the C34002 AML study 
specifically, assessments of TAK-659 activity on FLT3 signaling pathway levels have been examined 
through plasma inhibitory activity assays. The results presented reflect data across multiple QD and BID 
dose levels as of October 2017 and the degree of FLT3 inhibition observed at the Cycle 1 Day 15 time 
point, the first time point at which FLT3 inhibition is measured after control. 
 
The level of pFLT3 inhibition achieved at QD dose levels per plasma inhibitory activity assay was not 
consistently reaching 90%, a level of target modulation beyond which is believed to be necessary to 
achieve clinical efficacy in evaluation of single-agent Flt3 inhibitor administration (23). Therefore, an 
alternative BID dosing schedule was evaluated in the C34002 AML study, with a total daily dose not 
exceeding 160 mg.  
 
The BID regimen proved advantageous over the QD regimen with respect to FLT3 inhibition, as 3 of the 
4 patients at 80 mg BID achieved at least 90% inhibition of FLT3 by Cycle 1 Day 15. Whether this 
earlier and improved level of FLT3 inhibition translates to enhanced clinical activity remains to be seen. 
Analysis of additional cohorts (60 mg BID) and patient samples from this study was also pursued and is 
under analysis. 
1.4.5 
Clinical Efficacy 
In Study C34002, 26 patients were evaluable for response, with 6 patients achieving >90% FLT3 
inhibition at Cycle 1 Day 15 (100 mg QD, n = 1; 120 mg QD, n = 1; 160 mg QD, n = 1; 80 mg BID, n = 
3). An additional 7 patients achieved >90% FLT3 inhibition at a subsequent time point. Early signs of 
clinical activity were observed in both FLT3-mutated and FLT3-WT patients. Three patients achieved 
response per International Working Group criteria at higher TAK-659 dose levels: 1 CR (FLT3-WT/160 
mg QD) and 2 CRs with incomplete hematologic recovery (FLT3-WT/140 mg QD; FLT3-ITD/160 mg 
QD). An additional 6 patients achieved >50% bone marrow blast reduction from baseline without bone 
marrow recovery (n = 2, FLT3-ITD/100 mg QD; n = 1, FLT3- tyrosine kinase domain/120 mg QD; n = 
1, FLT3- tyrosine kinase domain/160 mg QD; n = 2, FLT3-ITD/80 mg BID). The FLT3-WT patient 
who achieved CR at Cycle 4 maintained the CR through Cycle 10 despite achieving a maximal FLT3 
inhibition of only 47% (Cycle 1 Day 15), suggesting that SYK inhibition may have contributed to this 
patient’s response (24). 
1.4.6 
Summary of Safety 
In Study C34001, the TAK-659 dose was escalated from 60 to 120 mg QD (60 mg [10 patients], 80 mg 
[4 patients], 100 mg [107 patients], and 120 mg [7 patients]). The MTD for patients with lymphoma and 
solid tumors is 100 mg 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/RP2D of 100 mg. 


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Of the 128 patients treated in Study C34001 (109 lymphoma [including 5 patients with CLL] and 19 
solid tumors), 109 patients had discontinued from the study as of 22 October 2017. Reasons for 
discontinuation included progressive disease (PD) (51 patients), AEs (34 patients), symptomatic 
deterioration (14 patients), withdrawal by patient (2 patients), initiation of stem cell transplant (2 
patients), protocol violation (1 patient), and other (5 patients). Nineteen patients were still receiving 
study drug as of the data cutoff date. 
 
In Study C34002, the TAK-659 dose has been escalated from 60 to 160 mg (60 mg [4 patients], 100 mg 
[7 patients], 120 mg [4 patients], 140 mg [5 patients], 160 mg [9 patients], and 80 mg BID [6 patients]). 
The dosing C34002, starting at 60mg po qd, and expanding up to and including 80mg po bid and a 
subsequent cohort testing 60mg po bid, were an expansion phase I escalation intended to test not only 
tolerance, but also PK and a PD measure (Plasma inhibitory activity tested on a model cell line in vitro) 
as well as preliminary efficacy.  Adverse events largely occurred at doses beginning at 160mg po qday 
and above.  The doses of 60mg po and 100mg po daily were considered safe and the major reason for 
stopping included the occurrence of infections after several 28 day cycles.  This, of course, is an 
inevitable outcome of continued myelosuppressive targeting agent therapy delivered for AML induction, 
which is problematic across the full spectrum of Flt3-selective tyrosine kinase inhibitor therapy without 
a rest period, including the experience of gilteritinib and quizartinib, which have been given in 
continuous dosing schedules.  
  
In clinical trials, the incidence of grade =/ >3 pneumonia and sepsis were 35% with gilteritinib; or 
febrile neutropenia, pneumonia and sepsis of 48% with quizartinib.  During study of both these agents 
the protocols had initially prohibited use of strong CYP inhibitors, which increase the drug levels of the 
TKIs.  However, in the case of gilteritinib, the increased level affected by itraconazole as an example of 
strong CYP3A inhibitor was 120%.  In both cases, avoidance was recommended but interruption of TKI 
therapy and/or significant dose reduction with stringent monitoring for toxicity in situations of necessity 
were allowed. An optimal strategy for mold-related infections has been use of isovuconazole, a 
moderate CY3A inhibitor. 
 
Of the 35 patients treated in C34002 with continuous dosing schedule, 33 patients had discontinued from 
the study as of the data cutoff date. The reasons for discontinuation included AEs (21 patients), PD (5 
patients), withdrawal by patient (2 patients), and other (5 patients). As regards DLTs, at the time of the 
last clinical reporting (K Pratz, et al Blood 2017 130:2622] [ref. 24[) (data cutoff 06Oct17), there were 
only two defined DLTs observed on study (35 patients)- one at 160mg QD (GR 3/4 amylase/lipase) and 
one at 80mg BID (Gr 3 bleeding).  
 
Since that data cutoff, an evaluation of the QD and BID doses was performed at an End of Cohort 
Meeting in May 2018. At this meeting, per the 3+3 design, 160mg QD was considered the MTD and 
140mg QD was considered the RP2D for QD dosing as determined by sponsor and investigators. 80mg 
BID was considered above the MTD having observed 2 DLTs at this dose level (Gr 3 bleeding, Gr 3 
amylase/lipase), therefore 60mg BID was considered the MTD/RP2D for the BID single agent dosing 
regimen. A grade 3 pancreatitis event (with associated grade 3 lipase and amylase increase) occurred in 
one patient dosed at 100mg QD on day 1 of cycle 2 (day 29 overall) but this patient had comorbid 
Crohn’s disease, acute kidney injury and concomitant use of amphotericin.  These factors would be 
considered fully exclusionary for the continuation of study medication currently, as renal failure causes 


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significant accumulation of TAK-659 levels.  Nevertheless, that investigator discontinued TAK-659 and 
the episode resolved, and the event was not considered directly related to study drug. Thus, there were 
no DLTs identified at the 100mg QD dose under acceptable rules for our study. 
 
In Study C34003, the TAK-659 dose has been escalated from 60 to 100 mg (60 mg [6 patients], 80 mg 
[8 patients], and 100 mg [5 patients]). Of the 16 patients treated in this study, 11 patients had 
discontinued from the study as of the data cutoff date (Juric, D, unpublished data, 2017). In Study 
C34005, the TAK-659 dose has been escalated from 60 to 100 mg (TAK-659 + bendamustine [6 
patients], TAK-659 + bendamustine/rituximab [6 patients], TAK-659 + gemcitabine [3 patients], TAK-
659 + lenalidomide [3 patients], and TAK-659 + ibrutinib [1 patient]). Of the 19 patients treated in this 
study, 17 patients had discontinued from the study at the time of this report including 13 patients who 
discontinued due to PD (Assouline, S, unpublished data, 2017). 
 
TEAEs, from a pooled analysis of the larger studies (C34001 and C34002), were generally as expected 
based on the patient population being studied and the nonclinical toxicology findings of TAK-659. In 
these studies, as of 22 October 2017, the most common TEAEs (reported in ≥30% of patients) were 
AST increased (92 patients [56%]), pyrexia (78 patients [48%]), amylase increased (64 patients [39%]), 
diarrhea (61 patients [37%]), anemia (57 patients [35%]), fatigue (55 patients [34%]), lipase increased 
(54 patients [33%]), hypophosphataemia (54 patients [33%]), and ALT increased (52 patients [32%]). 
The most common treatment-related TEAEs (reported in ≥20% of patients) were AST increased (76 
patients [47%]), amylase increased (57 patients [35%]), lipase increased (50 patients [31%]), ALT 
increased (42 patients [26%]), blood CPK increased (38 patients [23%]), 31iarrhea (36 patients [22%]), 
and hypophosphataemia (36 patients [22%]). 
 
The most common Grade 3 or greater TEAEs (≥10% of patients) have been amylase increased (35 
patients [21%]), anemia (35 patients [21%]), hypophosphataemia (31 patients [19%]), neutropenia (29 
patients [18%]), lipase increased (28 patients [17%]), febrile neutropenia (23 patients [14%]), 
thrombocytopenia (17 patients [10%]), AST increased (16 patients [10%]), and blood CPK increased 
(16 patients [10%]). The most common Grade 3 or greater treatmentrelated AEs (≥5% of patients) have 
been amylase increased (31 patients [19%]), lipase increased (25 patients [15%]), hypophosphataemia 
(24 patients [15%]), neutropenia (18 patients [11%]), blood CPK increased (15 patients [9%]), AST 
increased (10 patients [6%]), and anemia (9 patients [6%]). Further investigations are required to 
determine the clinical significance of the laboratory abnormalities, many of which have been 
asymptomatic, such as increased amylase, lipase, AST, ALT, and blood CPK. 
 
As regards C34002 specifically, however, grade 3+ AST increases and ALT increases occurred in only 
9% and 11%, respectively, across all dose levels 140qd-160qd-80bid-60 bid, and no DLTs were 
observed at 60mg and 100mg in this category. 
 
Amylase and lipase grade 3 increases occurred in only 9 and 11%, respectively, and were absent, except 
as noted above, from 60mg and 100mg qd cohorts.  Gastric hemorrhage occurred at 80mg bid in one 
case as noted. In addition, 13/35 (37%) patients received equal to or greater than 3x 28 day cycles of 
TAK-659 at the stated dose.   
 
Two cases of pancreatitis were reported (both in Study C34002). One case, as noted above, was reported 
as a Grade 3 serious adverse event (SAE) occurring 29 days after first dose of TAK-659 and considered 


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by the investigator to be possibly related to study treatment, albeit with several confounding factors (eg, 
AML, Crohn’s disease, acute kidney injury, and concomitant use of amphotericin B). The patient had 
experienced abdominal discomfort but denied severe abdominal pain, nausea, vomiting, diarrhea, or 
other GI problems. An imaging workup also showed peripancreatic edema. The event resolved within 16 
days of diagnosis, and the patient resumed TAK-659 at a reduced dose. The patient was discontinued 
from the study within the following month for Grade 3 treatment-related rash. The second case of 
pancreatitis was a Grade 2 AE with only laboratory enzyme elevation and unrelated Grade 1 abdominal 
distension. This patient subsequently died due to progression of AML. Changes in pancreatic enzymes 
continue to be monitored with high frequency in Cycle 1 and then at least once per month across studies. 
 
LDH increases have been observed in almost all patients across ongoing studies. There has been no 
obvious correlation with dose level, tumor type, baseline LDH levels, or relationship to PD. No dose 
modifications have occurred strictly based on LDH elevations; however, LDH values have generally 
decreased with a TAK-659 dose hold due to other reasons. 
 
According to all available data sources, there have been 59 deaths: 39 patients in Study C34001, 17 
patients in Study C34002, 2 patients in Study C34003 (Juric, D, unpublished data, 2017), and 1 patient 
in Study C34005 (Assouline, S, unpublished data, 2017). Six of the AEs that led to death were 
considered treatment related and are described in Section 5.5.7 of the current IB. 
1.4.7 
Summary of Toxicities and Potential Risks 
1.4.7.1 Potential Risks Based on TAK-659 Clinical Studies 
Lipase Elevations 
Asymptomatic elevation in lipase is a potential risk of TAK-659. In nonclinical studies, lipase was 
sporadically elevated at high doses of TAK-659 in both rats and dogs; however, there was no evidence 
of microscopic organ damage. In Studies C34001 and C34002, 54 patients (33%) overall have reported a 
TEAE of lipase increased, and of those, 50 patients (31%) have reported treatment-related TEAEs of 
lipase increased. These included 1 Grade 4 and 1 Grade 3 lipase increased. The Grade 4 lipase increased 
had a corresponding event of amylase increased (Grade 3 laboratory result) and a concurrent event of 
unrelated Grade 1 cholelithiasis; the Grade 3 lipase increase did not have a corresponding event of 
amylase increased. A careful review of both cases revealed no evidence of pancreatitis or organ damage. 
In addition, lipase values declined with discontinuation of TAK-659. The lipase events were classified 
as DLTs, and per the protocol, the 60 mg cohort was expanded. The current protocols include frequent 
screening of serum lipase, and these values will continue to be closely monitored. As of 22 October 
2017, 3 additional lipase events have been reported (Studies C34001 and C34002): 1 patient in the 
C34001 100 mg cohort (Grade 3 event), and 2 patients in Study C34002 (in the 160 and 80 mg bid 
cohort, respectively). As noted, there were no DLTs identified at the 100mg QD dose under acceptable 
guidance rules for our proposed study. In Study C34005, 16% of patients experienced an elevation 
(related or nonrelated, any grade) in lipase (Assouline, S, unpublished data, 2017). Asymptomatic 
elevation in lipase is included as a potential risk of TAK-659. 
 
Pneumonitis 
There were 5 SAEs of pneumonitis (4 reported in Study C34001 and 1 reported in C34002), which were 
all considered by the investigator to be possibly related to study drug. The first patient developed 
pneumonitis 46 days after starting treatment with TAK-659 at 80 mg QD. The event of pneumonitis was 


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considered possibly related to TAK-659 treatment; it was determined to be an unanticipated problem 
and was reported to health authorities. Pneumonitis was added as a potential risk of TAK-659, safety 
letters were sent to the study sites, and the drug safety information in the informed consent forms was 
updated. The event was the first SAE of pneumonitis in TAK-659 program. Subsequently, 2 SAEs of 
pneumonitis were reported during the previous reporting period: 1 patient with DLBCL who 
experienced pneumonitis 34 days after starting and 10 days after discontinuing treatment with TAK-659 
at a dose of 100 mg QD, and another patient with CLL who experienced pneumonitis 3 months after 
starting TAK-659 at a dose of 100 mg QD. In the current reporting period, 2 new SAE cases of 
pneumonitis were reported (C34001 100 mg QD and C34002 160 mg QD). No cases of pneumonitis 
have been observed at 100mg QD in C34002. Pneumonitis has been reported in clinical experiences of 
other FLT3 and BCR pathway kinase inhibitors. No other safety signals or changes to the known 
benefit-risk profile of TAK-659 in relation to the additional cases of pneumonitis were identified from 
review of these SAEs. Investigators are advised to closely monitor patients for respiratory signs and 
symptoms throughout TAK-659 treatment. 
 
Intestinal, Renal, and Lens Epithelial Effects and Related Epithelial Effects 
In rats, the primary epithelial effects were lens epithelium disorganization/hyperplasia and renal and 
urinary bladder transitional epithelium hyperplasia. Correlating with changes in the urinary tract were 
decreases in urine volume. Throughout the digestive tract (from duodenum to rectum) and usually 
occurring in the crypts or at the base of the mucosa, there was single-cell necrosis with hemorrhages at 
nontolerated doses, Other effects on epithelial tissues included stomach glandular mucosa hemorrhage, 
lacrimal gland atrophy/necrosis, and mammary gland and skin hair bulb single-cell atrophy/necrosis. 
The lens hyperplasia had some single-cell necrosis and correlated with slight axial subcapsular anterior 
cortical lens opacity. All the epithelial effects in rats were reversing or reversed by the end of the 28-day 
recovery period, except for lens opacity.  
 
In dogs, the primary epithelial effect was on the intestine and included hemorrhage of the intestinal 
mucosa (ileum, cecum, and/or colon). A dose-dependent increased incidence of liquid/soft feces was 
observed and was consistent with intestinal changes. All intestinal effects were reversed by the end of 
the 28-day recovery period. 
 
During the clinical studies, patients will receive eye exams to monitor for any changes to the eye lens; 
effects on other epithelial tissues will be monitored via routine laboratory tests, urinalysis, physical 
examinations, and AE monitoring as detailed in the protocols. 
 
Genotoxicity  
TAK-659 was mutagenic in an Ames assay (S typhimurium TA1537) after metabolic activation with rat 
liver enzymes and was aneugenic in micronucleus evaluations. Increased micronucleus formation in 
human peripheral blood lymphocytes was primarily associated with positive kinetochore staining and, 
thus, was positive for aneugenic genotoxicity. SYK has been implicated in mitotic spindle function (25); 
therefore, the aneugenic effect of TAK-659 was consistent with its pharmacologic mechanism of action. 
Based on the genotoxic nature of TAK-659, its toxicity profile would be acceptable for patients with 
advanced malignancies. 
1.5 
Ixazomib (MLN9708) 
1.5.1 Preclinical Experience 


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Please refer to the current ixazomib Investigator’s Brochure (IB). 
1.5.2 Clinical Experience 
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have included patients with 
advanced solid tumors, lymphoma, relapse/refractory MM (RRMM), and relapsed or refractory light-
chain (AL) amyloidosis, as well as AML, and demonstrated early signs of activity. Ongoing studies 
continue to investigate both single-agent ixazomib and ixazomib in combination with standard 
treatments. Based on encouraging preliminary data observed in patients with MM requiring systemic 
treatment, 2 phase 3 trials in newly diagnosed MM (NDMM) (C16014) and RRMM (C16010) patient 
populations have evaluated ixazomib in combination with Revlimid and Dexamethasone (RevDex) 
versus placebo/RevDex. Both trials combine ixazomib at a weekly dose of 4.0 mg on Days 1, 8, and 15 
in a 28-day cycle to a standard dose of lenalidomide with a weekly dexamethasone dose of 40 mg. In 
addition, clinical pharmacology studies have evaluated drug-drug interactions with ketoconazole, 
clarithromycin, and rifampin, as well as the effect of food, renal impairment, and hepatic impairment on 
the PK of ixazomib.  
 
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) studies (47%). 
Other common AEs reported in the pooled intravenous (IV) and PO safety populations include nausea, 
thrombocytopenia, diarrhea, and vomiting. Rash is also a commonly reported treatment-emergent event; 
however, there is some variety in its characterization and causality resulting in different preferred terms 
to describe it. A high-level term outline of rash events includes rashes, eruptions and exanthems NEC; 
pruritus NEC; erythemas; papulosquamous conditions; and exfoliative conditions. The dose escalation 
phases of most trials reported in the IB have now completed enrollment, and gastrointestinal (GI) 
symptoms were the common dose-limiting toxicities (DLTs) when the use of prophylactic anti-emetics 
was not permitted per protocol. In the expansion cohorts or phase 2 cohorts (as per each study), the 
incidence and severity of GI symptoms was mitigated by the use of the lower maximum tolerated dose 
(MTD)/recommended phase 2 dose (RP2D) (as per each study) and standard clinical usage of anti-
emetics and/or antidiarrheal medications as deemed appropriate. Prophylactic use of anti-emetics has not 
been required as with other agents but (as outlined in Section 6.3) has been used according to standard 
practice and are effective. 
 
In addition to the experience gained in myeloma, early data are available regarding attempts to blend 
ixazomib into chemotherapeutic salvage chemotherapy for AML (26, 27).  However, the early phase I 
design of the initial trial lent only suggestive information regarding efficacy or impact on potential 
targets. A recent phase I trial of Ixazomib along with standard cytarabine/anthracycline (daunorubicin 
60mg/m2) “7+3” ([27] PC Amrein et al.  Blood ASH abstract 4059A, 2018) used a 3+3 design of 
cohorts at Ixazomib doses of 1-,2-,3-mg given twice weekly, and reached a dose of 3mg given on days 
2,5,9, 12, with only 1 DLT (hematologic) in the 3mg cohort of 6 patients. Almost all AEs were 
hematologic, but 1 patient each in this treatment cohort had grade 3 elevation of ALT or AST, 
respectively.  These data do not significantly differ from toxicities expected from the chemotherapy 
alone. It should be noted that in both trials above, twice weekly Ixazomib dosing was used, and that such 
twice weekly Ixazomib dosing schedules lead to significant accumulation based on the long half-life. By 
contrast, in single-agent phase I studies the MTD of the weekly dose of Ixazomib given alone on days 
1,8,15 of a 28 day cycle was 2.97mg/m2 (ie. almost 6mg per dose). That is the schedule employed in 
this combination study, where the maximal dose would be the FDA-approved dose, which is roughly 
one-half that MTD, and the starting dose is two-step reduced.  In addition, we have previously published 
the easy tolerability of  Bortezomib at the full FDA-approved dose for myeloma, of 1.3mg/m2 IV day 


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1,4,8,11 (7), which is in accordance with the conclusion that accumulation pharmokinetics of Ixazomib, 
as compared to Bortezomib might explain any problems with twice weekly dosing in a combination 
setting..  No adverse events in the dose escalation phase of twice weekly administered Ixazomib with 
MEC chemotherapy were attributed to ixazomib alone (26).  There is no evidence to suggest, based on 
our combination of Bortezomib using its maximal FDA-approved dosing combined with TKIs, that 
equal or greater than grade 3 toxicity might occur with the combination of Ixazomib added to TAK-659.  
No data are available on the cardiac toxicity of the combination of Ixazomib and TAK-659, but data on 
the QTc effect of Ixazomib single agent is summarized in reference (28). 
 
Additional detailed information regarding the clinical experience of ixazomib may be found in the 
current IB.   
1.5.3 Pharmacokinetics and Drug Metabolism 
Source: Ixazomib Investigator’s Brochure 11.  (see also, ref. 29, 30) 
After oral dosing, absorption of ixazomib is rapid with a median first time to maximum observed plasma 
concentration (Tmax) of approximately 1 hour postdose. The plasma exposure (AUC) of ixazomib 
increases in a dose-proportional manner over a dose range of 0.2 to 10.6 mg based on population PK 
analysis. The absolute oral bioavailability (F) of ixazomib is estimated to be 58% based on population 
PK analysis.  A high-fat meal reduced ixazomib Cmax by 69% and AUC0-216 by 28%.  This indicates that 
a high-fat meal decreases both the rate and extent of absorption of ixazomib. Therefore, ixazomib should 
be dosed at least 2 hours after food or 1 hour before food. 
 
The steady-state volume of distribution of ixazomib is large and is estimated to be 543 L based on a 
population PK model. Based on in vitro plasma protein binding measurements on samples from clinical 
studies (Studies C16015 and C16018), ixazomib is highly bound to plasma proteins (99%). Ixazomib 
concentrations are higher in whole blood than in plasma, indicating extensive partitioning of ixazomib 
into red blood cells, which are known to contain high concentrations of the 20S proteasome. 
 
Metabolism appears to be the major route of elimination for ixazomib. In vitro studies indicate that 
ixazomib is metabolized by multiple cytochrome P450 (CYP) and non-CYP proteins. At concentrations 
exceeding those observed clinically (10 µM), ixazomib was metabolized by multiple CYP isoforms with 
estimated relative contributions of 3A4 (42.3%), 1A2 (26.1%), 2B6 (16.0%), 2C8 (6.0%), 2D6 (4.8%), 
2C19 (4.8%), and 2C9 (≤1%). At 0.1 and 0.5 µM substrate concentrations, which are closer to clinical 
concentrations of ixazomib following oral administration of 4 mg ixazomib, non-CYP mediated 
clearance was observed and seemed to play a major role in ixazomib clearance in vitro.  These data 
indicate that at clinically relevant concentrations of ixazomib, non-CYP proteins contribute to the 
clearance of ixazomib and no specific CYP isozyme predominantly contributes to the clearance of 
ixazomib. Therefore, at clinically relevant concentrations of ixazomib, minimal CYP-mediated DDIs 
with a selective CYP inhibitor would be expected. 
 
Ixazomib is neither a time-dependent inhibitor nor a reversible inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 
2C19, 2D6, or 3A4/5.  Ixazomib did not induce CYPs 1A2, 2B6, and 3A4/5 activity or corresponding 
immunoreactive protein levels. Thus, the potential for ixazomib to produce DDIs via CYP isozyme 
induction or inhibition is low. 
 


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Ixazomib is not a substrate of BCRP, MRP2 and OATPs. Ixazomib is not an inhibitor of P-gp, BCRP, 
MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1 and MATE2-K. Ixazomib is unlikely to 
cause or be susceptible to clinical DDIs with substrates or inhibitors of clinically relevant drug 
transporters. 
 
The geometric mean terminal half-life (t1/2) of ixazomib is 9.5 days based on population PK analysis. 
For both IV and oral dosing, there is an approximately average 3-fold accumulation (based on AUC) 
following the Day 11 dose for the twice-weekly schedule and a 2-fold accumulation (based on AUC) 
following the Day 15 dose for the once-weekly schedule. 
 
Mean plasma clearance (CL) of ixazomib is 1.86 L/hr based on the results of a population PK analysis. 
Taken together with the blood-to-plasma AUC ratio of approximately 10, it can be inferred that 
ixazomib is a low clearance drug. Using the absolute oral bioavailability (F) estimate of 58% (also from 
a population PK model), this translates to an apparent oral plasma clearance (CL/F) of 3.21 L/hr. The 
geometric mean renal clearance for ixazomib is 0.119 L/hr, which is 3.7% of CL/F and 6.4% of CL 
estimated in a population PK analysis. Therefore, renal clearance does not meaningfully contribute to 
ixazomib clearance in humans. Approximately 62% of the administered radioactivity in the ADME 
study (Study C16016) was recovered in the urine and 22% of the total radioactivity was recovered in the 
feces after oral administration. Only 3.2% of the administered ixazomib dose was recovered in the urine 
as unchanged ixazomib up to 168 hours after oral dosing, suggesting that most of the total radioactivity 
in urine was attributable to metabolites.  
 
The PK of ixazomib was similar with and without co-administration of clarithromycin, a strong CYP3A 
inhibitor, and hence no dose adjustment is necessary when ixazomib is administered with strong CYP3A 
inhibitors. Consistently, in a population PK analysis, co-administration of strong CYP1A2 inhibitors did 
not affect ixazomib clearance. Therefore, no dose adjustment is required for patients receiving strong 
inhibitors of CYP1A2.  Based on information from the clinical rifampin drug-drug interaction (DDI) 
study, ixazomib Cmax and AUC0-last were reduced in the presence of rifampin by approximately 54% and 
74%, respectively. Therefore, the co-administration of strong CYP3A inducers with ixazomib is not 
recommended.  
 
Mild or moderate renal impairment (CrCL ≥ 30 mL/min) did not alter the PK of ixazomib based on the 
results from a population PK analysis. As a result, no dose adjustment is required for patients with mild 
or moderate renal impairment.  In a dedicated renal impairment study (C16015), unbound AUC0-last was 
38% higher in patients with severe renal impairment or ESRD patients requiring dialysis as compared to 
patients with normal renal function.  Accordingly, a reduced starting dose of ixazomib is appropriate in 
patients with severe renal impairment or ESRD requiring dialysis.  Pre- and post-dialyzer concentrations 
of ixazomib measured during the hemodialysis session were similar, suggesting that ixazomib is not 
readily dialyzable, consistent with its high plasma protein binding (99%). 
 
The PK of ixazomib is similar in patients with normal hepatic function and in patients with mild hepatic 
impairment, as defined by the National Cancer Institute Organ Dysfunction Working Group (total 
bilirubin <1.5 times the upper limit of normal [ULN]), based on the results from a population PK 
analysis. Consequently, no dose adjustment is required for patients with mild hepatic impairment. In a 
dedicated PK study in patients with moderate (total bilirubin >1.5 to 3 times the ULN) or severe (total 
bilirubin >3 times the ULN) hepatic impairment (Study C16018), unbound dose-normalized AUC0-last 


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was 27% higher in patients with moderate or severe hepatic impairment as compared to patients with 
normal hepatic function. Therefore, a reduced starting dose of ixazomib is appropriate in patients with 
moderate or severe hepatic impairment.  
 
There was no statistically significant effect of age (23-91 years), sex, body surface area (1.2-2.7 m2), or 
race on the clearance of ixazomib based on the results from a population PK analysis. 
 
Based on a pooled analysis of data from 4 phase 1 studies, ixazomib does not prolong the QTc interval 
or have a clinically meaningful effect on heart rate at clinically relevant exposures. (27) At the 4 mg 
dose, the mean model-predicted change from baseline in QTcF was 0.0710 msec (90% CI; -0.221, 
0.363). Also, there was no discernible relationship between concentration and the RR interval, 
supporting the lack of a clinically meaningful effect of ixazomib on heart rate. These results collectively 
support the conclusion of low pro-arrhythmic risk associated with ixazomib. 
 
Further details on these studies are provided in the IB. 
1.5.4 Clinical Trial Experience Using the Oral Formulation of Ixazomib 
As detailed in IB-11, preliminary clinical data are available as of 27 March 2017 for a total of 3623 
patients across 26 studies; in these studies, 24 were studies with oral ixazomib. (The overall safety 
population comprises 941 patients who received at least 1 dose ixazomib [oral or IV formulation] in 
open-label studies, but aggregate data for SAEs and deaths are provided for an additional 2682 patients 
enrolled in the ongoing phase 3 Studies C16010, C16010CCS, C16011, C16014, C16014KES, C16019, 
and C16021. Therefore, for SAE and death data, the total number of patients is 3623.) The emerging 
safety profile indicates that ixazomib administration can lead to AEs that are generally manageable and 
reversible with dose reduction and supportive care. Additionally, the AEs in the combination studies are 
consistent with the safety profile of the individual agents in the combination regimen (eg, 
myelosuppression is common in regimens containing melphalan, and rash is common in regimens 
containing lenalidomide). While some of these potential toxicities may be severe, they can be managed 
by clinical monitoring and standard medical intervention. The AEs presented in this section are pooled 
from all dose regimens and dose levels. Results from clinical pharmacology studies support the 
continued exclusion of strong CYP3A inducers in the ongoing clinical studies [31] and that ixazomib 
should be administered on an empty stomach (at least 1 hour before or at least 2 hours after food). [32]  
Based on clinical experience from the phase 1 studies, the dose selected for the phase 3 studies is 4 mg 
given weekly for 3 weeks in a 28-day cycle. 
 
Late-stage ixazomib development is currently focused on the oral formulation.  
 
Rash, although a common AE in aggregate, was characterized in many ways; therefore, it is less 
common when considering individual preferred terms. Rash may range from limited erythematous areas, 
macular and/or small papular bumps that may or may not be pruritic over a few areas of the body, to a 
more generalized eruption that is predominately on the trunk or extremities. The frequency of rash was 
higher with the twice-weekly schedule and when ixazomib was combined with an agent where rash is an 
overlapping toxicity, such as lenalidomide. Data from Global Study C16010 demonstrate an incidence 
of 36% in the ixazomib+LenDex regimen and 23% in the placebo+LenDex regimen, with the difference 
between groups driven primarily by Grade 1 and 2 events. The difference in frequency of TEAEs in 
Skin and subcutaneous tissue disorders was primarily driven by the HLT Rashes, eruptions, and 
exanthemas not elsewhere classified (NEC) (20% and 13%, respectively). The rash events occurred 


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primarily in the first 3 months after initiation of the study regimen and were frequently self-limiting 
(21% of patients in the ixazomib+LenDex regimen and 12% of patients in the placebo+LenDex regimen 
reported the events resolved without intervention). [33] The first incidence of rash events occurred early 
during treatment, and there was no evidence of increased frequency of rash with prolonged exposure. 
The rare risks of Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with 
eosinophilia and systemic symptoms (DRESS) syndrome, and pemphigus vulgaris have been reported in 
ixazomib-containing oncology studies (or blinded studies containing ixazomib or placebo) when given 
in a multi-therapy regimen in combination with agents associated with skin reactions (eg, Bactrim, 
aspirin, lenalidomide). 
 
In Global Study C16010, antiviral agents for herpes zoster prophylaxis were allowed at the physician’s 
discretion and were prescribed for 60% (431/720) of patients. The incidence of herpes zoster 
reactivation was 8% (11 patients) in the ixazomib+LenDex regimen and 3% (5 patients) in the 
placebo+LenDex regimen for patients who did not receive antiviral prophylaxis compared with <1% (2 
patients) in the ixazomib+LenDex regimen and 1% (3 patients) in the placebo+LenDex regimen for 
patients who received antiviral prophylaxis. In the blinded C16019 study of ixazomib maintenance vs 
placebo in patients who have undergone ASCT (a population at high risk for herpes virus reactivation), 
there was an 8% incidence of herpes zoster, primarily in patients not receiving antiviral prophylaxis. In 
Study C16010CCS, less antiviral prophylaxis was used; herpes zoster was reported in 21% compared 
with 3% of patients treated with the ixazomib regimen and placebo regimen, respectively; all were 
reported as related to study treatment. Investigators should consider the use of antiviral prophylaxis for 
patient being treated with ixazomib. 
1.5.5 Overview of the Oral Formulation of Ixazomib 
The emerging safety profile indicates that ixazomib is generally well tolerated. The adverse events 
(AEs) are consistent with the class-based effects of proteasome inhibition and are similar to what has 
been previously reported with VELCADE though the severity of some, for example peripheral 
neuropathy, is less.  While some of these potential toxicities may be severe, they can be managed by 
clinical monitoring and standard medical intervention, or, as needed, dose modification or 
discontinuation.   
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent oral 
ixazomib in patients with differing malignancies (multiple myeloma, AL amyloidosis, nonhematologic 
cancers, and lymphoma), a total of 201 patients have been treated as of 27 March 2013.  
 
These data for single agent, although of older study are the basis for unfettered interpretation for 
subsequent combination trials such as X34004 herein. These patients have been treated with different 
doses of ixazomib as they are all phase 1 trials.  
 
The most frequent TEAEs (those reported in at least 10% of the total safety population, excluding phase 
3 Studies C16011, C16014, C16014KES, C16019, and C16021), regardless of study drug causality, are 
described in the current ixazomib IB. The emerging safety profile indicates that ixazomib administration 
can lead to AEs that are generally manageable and reversible with dose reduction and supportive care. 
The most common AEs pooled across oral formulation studies (single agent and in combination) include 
nausea, diarrhea, fatigue, vomiting, thrombocytopenia, and constipation. Rash, although a common AE 
in aggregate, is characterized in many ways; therefore, it is less common when considering individual 
preferred terms. The rash may range from limited erythematous areas, macular and/or small papular 


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bumps that may or may not be pruritic over a few areas of the body, to a more generalized eruption that 
is predominately on the trunk or extremities. 
 
Study drug-related TEAEs were reported for 84% of patients in the oral studies; 49% were Grade 3 or 
higher. Most were in the system organ classes of GI disorders (59% overall, 10% ≥Grade 3), general 
disorders (43% overall, 8% ≥Grade 3), blood and lymphatic system disorders (38% overall, 27% ≥Grade 
3), and nervous system disorders (37% overall, 4% ≥Grade 3). The most common preferred terms 
included nausea (35% overall, 3% ≥Grade 3), diarrhea (32% overall, 6% ≥Grade 3), fatigue (28% 
overall, 6% ≥Grade 3), vomiting (25% overall, 3% ≥Grade 3), and thrombocytopenia (24% overall, 16% 
≥Grade 3). 
1.6 
Dose Rationale 
Patients will receive TAK-659 once daily for fifteen days and will receive Ixazomib capsules once 
weekly on days 1, 8, 15.  The length treatment will be 15 days out of 21 days (one week rest). 
 
In contrast with the continuous dosing of TAK-659 in C34002, in this combination study, cyclical 
administration will occur during only 15 days of a 21 day cycle (one week rest period). We anticipate 
this rest period will accommodate myeloid recovery following a period of intensive cytoreduction that 
has been noted when TAK-659 is combined with proteasome inhibitor in vitro (and as observed with a 
combination of proteasome inhibitor Bortezomib with Sorafenib in our recently completed trial).  
 
The starting dose for the respective drugs in the Phase I portion of the current study will be directed by: 
a) a dose below the RP2D of TAK-659 (140mg po daily) from C34002, where TAK-659 at 100mg once 
daily will only be given 15 of the 21 days that have already been explored in its phase Ib trial (thus 
representing a dose and schedule reduction); and b) a two dose-level reduction (2.3mg) from the 
Ixazomib approved dose (4 mg) and given in a schedule of day 1, 8, 15 out of 21 days.  As noted in the 
introductory section (and data not shown) we have extensive in vitro evidence for cytotoxicity of the 
relevant AML molecular genetic phenotypes, across a range of doses of these agents in combination. 
 
Thus, in this trial we would be initially assessing tolerability at two dose levels below the approved 4 mg 
Ixazomib dose, but nevertheless where activity may be seen with the combination in Ixazomib run-in to 
escalation.  Activity of the combination would be expected to appear early, within the 15 day treatment- 
timeframe for Ixazomib (and continued without another dose administration due to the prolonged half-
life), as was previously demonstrated for cyclical administrations in our prior combination trial.  Again, 
our prior study of drug combinations demonstrated that responses occur early, associated with profound 
blast cell cytoreduction in marrow and peripheral blood, and those responses observed were found to 
involve a recovery phase, for regrowth of mature differentiated cells sustaining hematopoiesis, in a 
cyclical fashion.  This would be expected to occur without a possibility for differentiation syndrome that 
is known to describe the experience using a number of single agent TKIs.  Therefore, toxicity of the 
combination will have been avoided by the cyclical administration schedule, while allowing for deep 
response to occur, and also avoiding differentiation syndrome, due to the earlier achievement active drug 
doses in the combination. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
To perform Phase I and Phase II studies of the combination of TAK-659 with Ixazomib in order to 
assess the safety and tolerability of the combination (in phase I) and in the phase II to evaluate the 
preliminary efficacy of the combination. 
2.1.1 Primary Objective 
Phase I:  To determine the maximum tolerated dose (MTD) and recommended phase 2 dose(s) (RP2D) 
of the combination of TAK-659 and Ixazomib in patients with relapsed or refractory AML. 
 
Phase II:  To evaluate preliminary efficacy of TAK-659 plus Ixazomib in relapsed or refractory AML 
as measured by overall response rate (ORR) 
2.1.2 Secondary Objectives 
 To evaluate the differential efficacy measures of TAK-659 with Ixazomib, involving presence or 
absence of Flt3 mutation(s), and/or mutational profile by NGS, additionally affecting epigenetic 
modifiers 
 To evaluate additional efficacy measures of TAK-659 with Ixazomib, such as duration of 
response (DOR), time to progression (TTP), mortality rate at 3 and 6 months, and overall 
survival (OS) 
 To evaluate the influence of multiple cycles of the combination on the outcome measures when 
applied in context of subsequent feasibility for bridge to transplantation as consolidation therapy 
 To evaluate the safety and tolerability using NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5. 
2.1.3 Tertiary/Exploratory Objectives 
 To measure the changes in TAK-659 plasma concentrations when given in combination with 
ixazomib. 
 To quantitatively examine before, and at early timepoint of therapy, the primary mechanistic 
transcriptional drivers of these AMLs (HOXA and MEIS1), which are postulated to be 
extinguished by the drug combination, for their ability, when extinguished, to predict subsequent 
response 
 To implicate Syk, Wnt pathway (ID1, JUN, FOXM1, -catenin) and Wnt antagonists RUNX3 
and Cullin 3 and EZH2 in responses affected by combination of TAK-659 and Ixazomib 
 To use digital PCR technology to examine the participation of collaborating mutations on depth 
of remission for the class 1 and class 2 drivers 
2.2 
Endpoints 
2.2.1 Primary Endpoint 
Phase I: Maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) for the combination 
of TAK-659 plus Ixazomib in relapsed or refractory AML  
 


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Phase II: Overall response rate (ORR) defined as CR, CRp, CRi, and PR per 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. 
2.2.2 Secondary Endpoints 
 DOR defined as the time from the date of first documentation of a response to the date of first 
documented progressive disease 
 TTP defined as the time from first dose of study drug until tumor progression as defined by 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 
 Mortality rate at 3 and 6 months 
 OS defined as the time from the date of study entry to death 
 ORR, DOR, TTP, mortality rate at 3 and 6 months, and OS in Flt3mutant vs. WT populations 
2.2.3 Tertiary/ Exploratory Endpoints 
 Changes in TAK-659 plasma concentrations when given in combination with ixazomib. 
 Identification of the cytogenetic and next-generation sequencing-derived mutational complement 
that predicts response to the combination therapy. 
 Identification of a gene expression signature which identifies patients prior to therapy whom will 
achieve remission based on reversal of a pattern for repression of tumor suppressors, esp. 
RUNX3, and also achieve downregulation of pre-existing overexpressed HOXA and MEIS1, 
with participation in loss of Wnt pathway agonists (ID1, JUN, FOXM1, -catenin). 
3. 
ELIGIBILITY CRITERIA 
3.1 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health information. 
NOTE:  HIPAA authorization may be included in the informed consent or obtained separately. 
2. Male or female patients 18 years or older at the time of consent. 
3. Patients must have a diagnosis of primary or secondary AML with relapsed or refractory disease 
(WHO update 2016, [34]) other than acute promyelocytic leukemia, or complex karyotype or 
monosomy 7 (or containing monosomy 7) for whom no standard therapies are anticipated to 
result in a durable remission according to the clinical judgment of the treating physician, or in a 
patient who refuses standard therapies. However, if the qualifying 3-5 complex karyotypic 
abnormalities entail recurring translocations/deletions normally of intermediate risk (5q- or 7q-, 
11q23, MLL-PTD, t(3;21)(q26; q22), CBF+); and/or the mutational profile by NGS has revealed 
a profile which renders sensitivity to: 1) TAK-659 (DNMT3A; Flt3N676K, Flt3 S451F, in 
addition to the common Flt3ITD/TKD; combination of ASXL1 plus EZH2; or TET2 or IDH1/2) 
or to: 2) Ixazomib (NRAS,KRAS, PTPN11/SHP2, PDCD11, WT1), the patient will be eligible. 
4. Must have submitted  for Next Generation Sequencing (NGS) testing by: 1) (preferred) having 
submitted a tumor sample for commercial myeloid NGS from Foundation One, Mayo, Tempus, 
Quest, ARUP or an institutional CLIA-certified laboratory and/or 2) obtaining a bone marrow 


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aspirate during screening for submission to Foundation One, Mayo, Tempus, Quest, ARUP or an 
institutional CLIA-certified laboratory and ordered as standard of care. If bone marrow 
aspiration has failed, a peripheral blood sample with circulating blasts may be substituted. 
Screening reports on tumor cytogenetics and/or mutation assays (eg, FLT-3, and NGS) 
performed as part of the standard of care will be recorded in the study database or obtained at the 
time of screening if not previously available. 
5. Patient’s disease must be characterized for the presence/absence of Flt3ITD/TKD mutation from 
an FDA-approved vendor (ex. LabPMM).  
6. In addition, patients for the phase 2 portion of the study must meet the following: 
a. Patients, if relapsed/ refractory, must have exposure to no more than 2 prior chemotherapy 
regimens.  Re-induction with the same regimen or stem cell transplant will not be considered 
a separate regimen. 
b. Patients must not have prior exposure to any investigational Flt3 inhibitors (midostaurin or 
gilteritinib are allowed) 
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 
8. Life expectancy of greater than 3 months as determined by the treating physician. 
9. 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 2 effective methods of contraception 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 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.) 
 Agree not to donate eggs (ova) during the course of this study or 180 days after receiving 
their last dose of study drug. 
10. Male patients, even if surgically sterilized (i.e., status post-vasectomy), 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 are not acceptable methods of contraception. 
Female and male condoms should not be used together.) 
 Agree not to donate sperm during the course of this study or within 180 days after receiving 
their last dose of study drug. 
11. 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 
12. In the absence of rapid progressive disease, the interval from prior systemic anticancer treatment 
to time of TAK-659/Ixazomib administration should be at least 2 weeks for cytotoxic agents 


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(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 21 days while participating 
in this study. NOTE: For patients with a white blood cell count >50,000/uL, 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 21 days of the study. 
13. Suitable venous access for the study-required blood sampling, and transfusion support. 
14. Demonstrate adequate organ function as defined in the table below; all screening labs to be 
obtained within 28 days prior to registration. 
System 
Laboratory Value 
Renal 
Calculated creatinine clearance 
≥ 60 mL/min using the Cockcroft-Gault formula 
Pancreas 
Lipase 
≤1.5xULN with no clinical symptoms suggestive of 
pancreatitis or cholecystitis 
Amylase 
Hepatic 
Total Bilirubin 
≤ 1.5 × upper limit of normal (ULN) 
Aspartate aminotransferase (AST) 
≤2.5 × ULN 
Alanine aminotransferase (ALT) 
≤2.5 × ULN 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Clinically active central nervous system leukemia. 
2. Female patients who are lactating and breastfeeding (NOTE: breast milk cannot be stored for 
future use while the mother is being treated on study) 
3. Female patients who 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. 
4. 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. 
5. Prior treatment with investigational agents ≤ 21 days or ≤ 5 half-lives (whichever is shorter) 
before the first dose of study treatment.  A minimum of 10 days should elapse from prior 
investigational therapy to initiating protocol therapy. 
6. Persistent clinically significant toxicity from prior chemotherapy that is Grade 2 or higher by the 
NCI CTCAE (v5). 
7. Receipt of HSCT within 60 days of the first dose of TAK-659/Ixazomib; clinically significant 
graft-versus-host disease (GVHD) requiring ongoing immunosuppressive therapy post HSCT at 
the time of screening (use of topical steroids for ongoing skin GVHD is permitted). 
8. Active, systemic infection requiring intravenous (IV) antibiotic, antifungal, or antiviral therapy 
or other serious infection within 10 days before the first dose of study drug. 


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9. Major surgery within 14 days before the first dose of study drug and have not recovered fully 
from any complications from surgery. 
10. Radiotherapy less than 2 weeks before the first dose of study treatment or have not recovered 
from acute toxic effects from radiotherapy. 
11. Known human immunodeficiency virus (HIV) positive. 
12. Known hepatitis B surface antigen positive, or known or suspected active hepatitis C infection 
(testing not required). 
13. Any of the following cardiovascular conditions: 
 Acute myocardial infarction within 6 months before starting study drug. 
 Current or history of New York Heart Association Class III or IV heart failure. 
 Evidence of current, uncontrolled cardiovascular conditions including cardiac arrhythmias, 
angina, pulmonary hypertension, or electrocardiographic evidence of acute ischemia or active 
conduction system abnormalities. 
 Fridericia corrected QT interval (QTcF) >450 milliseconds (msec) (men) or >475 msec 
(women) on a 12-lead ECG during the Screening period. 
 Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and intervals 
that, in the opinion of the treating physician, are considered to be clinically significant. 
14. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption 
or tolerance to study drugs, including difficulty swallowing tablets, diarrhea > Grade I despite 
supportive therapy. 
15. Use or consumption of any of the following medications, supplements, or foods/beverages that 
are inhibitors or inducers of P-gp or strong reversible inhibitors or inducers of CYP3A within the 
indicated timeframes below.  Note that use or consumption of these substances is not permitted 
during the study. 
a) 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 in cases where an AE must be managed. See 
Section 5.7.2 and the Documents/Info tab of the electronic data capture (EDC) system for a 
nonexhaustive list of strong CYP3A reversible inhibitors and/ or Pgp inhibitors based on the 
FDA Draft DDI Guidance. 
b) 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. However, if a patient has a strong indication for fungal 
prophylaxis, then the moderate CYP3A inhibitors fluconazole or isovuconazole (mold-
active) is recommended for prophylaxis, and the TAK-659 dose should be reduced to 60mg, 
along with increased scrutiny for toxicity. Similarly, if the patient develops a fungal infection 
during a productive intervention with TAK-659/Ixazomib combination, isovuconazole 
(mold-active) should be used, along with increased scrutiny for toxicity. In general, the use 
of these agents is not recommended during the study except in cases where such an AE must 
be managed, and the intermittent schedule of TAK-659/Ixazomib combination will not 
prevent profound neutropenia. See Section 5.7.2 and the Documents/Info tab of the EDC for 


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a non-exhaustive list of strong CYP3A mechanism-based inhibitors or strong CYP3A 
inducers and/or P-gp inducers based on the FDA Draft DDI Guidance. 
c) Grapefruit-containing food or beverages within 5 days before the first dose of study drug. 
16. Lack of suitable venous access for the study-required blood sampling.  
17. Diagnosed or treated for another malignancy within 2 years before study enrollment or 
previously diagnosed with another malignancy and have any evidence of residual disease.  
Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they 
have undergone complete resection. 
18. Patient has  Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during 
the screening period. 
19. Known allergy to any of the study medications, their analogues, or excipients in the various 
formulations of any agent. 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through Big Ten Cancer Research Consortium (Big Ten CRC) 
Administrative Headquarters’(AHQ) electronic data capture (EDC) system.  
 
Subjects must be registered prior to starting protocol therapy. Subjects should begin therapy within 5 
business days of registration. However, beginning therapy outside that timeframe will not be considered 
a deviation. 
5. 
TREATMENT PLAN 
This study is an open-label, multicenter, phase I dose escalation and phase IIa study of TAK-659 in 
combination with Ixazomib, in adult patients with relapsed or refractory AML.  This study will include a 
phase I portion for evaluating the safety of the TAK-659 and Ixazomib, along with monitoring for early 
efficacy signal, and a single-arm phase II portion. It is expected that up to 18 patients will be enrolled in 
the phase I portion and up to 36 patients will be enrolled in the phase II portion of this study.  
 
Once enrolled, patients will be given TAK-659 tablets and Ixazomib capsules, once daily for fifteen 
days (TAK-659) and once weekly (Ixazomib) on days 1, 8, 15, respectively.  The cycle length will be 15 
days of treatment out of 21 days (one week rest). 
 
To determine the MTD of the combination, a 3+ 3 approach to dose escalation design will be used.  
Prior to commencing dose/schedule advance, patients in the immediately preceding cohort will have 
completed two full cycles of the regimen and will have been evaluated for toxicity.  Next, Ixazomib 
dose escalation will be undertaken (in context of the 15-day treatment cycle/21-day complete cycle 
including 1 week rest schedule).   
 
At least 6 patients will be evaluated at RP2D (either at MTD or at lower doses as determined) before 
making a decision to advance to the phase 2 study.  In the process of determining or refining RP2D, 
expansion of more than 1 dose level to at least 6 additional patients is permissible so that 
pharmacodynamic measures and early signs of clinical activity can be assessed to assist dose selection. 
 


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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 the combination.  Toxicity will be evaluated according to NCI Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 5.  Dose-limiting toxicities (DLTs) are 
defined in Section 5.5. 
 
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 safety follow up visit 
30 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. 
 
Pharmacodynamic activity of the combination regimen will be assessed in Phase I and Phase II by 
evaluating bone marrow AML blasts at the time-points specified in the study calendar.  Bone marrow 
biopsies and aspirates for disease response monitoring will be obtained as described in the study 
calendar. Residual and/or designate samples from bone marrow biopsies and aspirates collected for 
disease assessment will also be used for analysis of biomarkers as specified in the study calendar. 
5.1 
Number of Patients 
For the phase I portion, up to 18 patients will be enrolled in this study from approximately 2 to 4 study 
centers in the US.  For the phase II portion, 36 patients will be enrolled from these centers.  
 
Patients who are withdrawn from treatment during Cycle 1 for reasons other than toxicity during the 
phase I portion of the study will be replaced.  Patients in the phase II portion of the study, beyond the 
Simon’s two-stage threshold, who are not evaluable for response will be replaced; however, patients 
who receive at least 1 dose of study drugs, and have measurable disease on bone marrow exam or by 
biopsy-documented extramedullary tumor at baseline, will be used for futility analyses, including the 
Simon’s two-stage response evaluation. 
 
Duration of Study 
Patients, including those who achieve a CR, may receive the combination until they experience disease 
progression.  Patients will discontinue treatment if they have an unacceptable drug-related toxicity. The 
maximum duration of treatment, however, will be 12 months from Cycle 1 Day 1 (C1D1) unless it is 
determined that a patient would derive benefit from continued therapy beyond 12 months. 
 
Patients will be followed for 30 days after the last dose of the combination, 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 up to 12 months 
after discontinuation of the study drug for survival (every month until death), loss to follow-up, or 
withdrawal of consent for further follow-up. 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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The final analyses for the clinical study report may be conducted after all patients enrolled in the study 
have had the opportunity to complete 3-4 cycles of combination therapy (while still not progressing). 
 
It is anticipated that this study will last for approximately 24-32 months, including 9 to 12 months in the 
phase I portion, and 15 to 20 months in the phase II portion. 
5.2 
Phase Ib Dose Escalation 
Dose escalation will involve only Ixazomib, increasing from 2.3 mg and then to 3 mg. Patients in each 
cohort will continue to the completion of the second cycle, and undergo evaluation of 
toxicity/tolerability prior to consideration of dose-escalation to the next cohort.  The maximal dose of 
Ixazomib at 4mg was determined as in aforementioned myeloma studies. 
Dose Cohort 
Number of 
patients 
TAK-659 
(PO) 
Days 1-15 
Ixazomib 
(PO) 
Days 1, 8, 15 
1 
3-6 
100 mg, once daily 
2.3 mg 
2 
3-6 
100 mg, once daily 
3 mg 
3 
3-6 
100 mg, once daily 
4 mg 
 
Patients within each cohort will be followed for toxicity occurring within the first 2 cycles prior to 
initiating a dose/schedule escalation of the individual drugs in the next cohort, in context of the type of 
dose limiting toxicity (DLT) observed and to what study drug(s) the toxicity is related. 
 
In cohort 1, If 1/3 patients develop grade ≥ 3 DLT toxicity, then 3 more patients will be entered at this 
dosing level; if < 2/6 patients develop DLT, then the next cohort will involve escalation of Ixazomib in 
dose. 
 
If, on the other hand, toxicity attributable to the combination is seen in the first cohort at ≥ 2 patients, 
then we will consider modification of the protocol to reduce the initial dose of TAK-659 and/or 
Ixazomib.  Again, our prior experience involving the addition of pharmacodynamically-active dosing as 
starting to a combination of Sorafenib and Vorinostat suggest we will not see this reduction as 
necessary. The dose modification plan will be based on the nature of the DLT:  
 
Dose Cohort 
Number of 
patients 
TAK-659* 
(PO) 
Days 1-15 
Ixazomib* 
(PO) 
Days 1, 8, 15 
1 
3-6 
100 mg, once daily 
2.3 mg 
 
 
 
Dose modification plan  
 
 
80 mg, once daily 
2.3 mg 
Contact sponsor-investigator for 
consideration of schedule below 2.3mg.
*On clinic days for PK determination, TAK-659 will be taken first and then Ixazomib. 


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In cohort 2, if 1/3 patients develop grade ≥ 3 DLT toxicity, then 3 more patients will be entered at this 
dosing level; if < 2/6 patients develop DLT, then the next cohort will involve escalation of Ixazomib in 
dose. 
Dose 
Cohort 
Number of 
patients 
TAK-659* 
(PO) 
Days 1-15
Ixazomib* 
(PO) 
Days 1, 8, 15
2 
3-6 
100 mg, once daily 
3 mg 
 
 
 
Dose modification plan based on the nature of DLT 
If DLT at least possibly related to TAK-659 OR not related to Ixazomib 
 
 
80 mg, once daily 
3 mg 
If DLT at least possibly related to Ixazomib OR not related to TAK-659 
 
 
100 mg, once daily 
2.3 mg 
If DLT at least possibly related to TAK-659 AND Ixazomib 
 
 
80 mg, once daily 
2.3 mg 
*On clinic days for PK determination, TAK-659 will be taken first and then Ixazomib. 
 
In cohort 3, if ≥2/6 patients develop DLT, a consultation will be made between the sponsor and 
investigators: either the previous dose level will be considered the MTD (if 6 or more patients have been 
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 we will modify the the protocol to add a dose level intermediate between 
the current and the previous dose level. 
 
Dose 
Cohort 
Number of 
patients 
TAK-659* 
(PO) 
Days 1-15
Ixazomib* 
(PO) 
Days 1, 8, 15
3 
3-6 
100 mg, once daily 
4 mg 
 
 
 
Dose modification plan based on the nature of DLT 
If DLT at least possibly related to TAK-659 OR not related to Ixazomib 
 
 
80 mg, once daily 
4 mg 
If DLT at least possibly related to Ixazomib OR not related to TAK-659 
 
 
100 mg, once daily 
3 mg 
If DLT at least possibly related to TAK-659 AND Ixazomib 
 
 
80 mg, once daily 
3 mg 
*On clinic days for PK determination, TAK-659 will be taken first and then Ixazomib. 
 


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As in usual protocol for MTD/RP2D determination, dose escalation will continue until these endpoints 
are determined based on safety, tolerability, PD, and preliminary efficacy data, if available.  We also 
realize that if ≥ 2 patients experience DLT in each of the first two cohorts at founding TAK-659 dose 
used in the 3+3 escalation, then one (half) dose reduction step of TAK-659 will be needed. 
5.2.1 TAK-659 Dose Accomodation with required concomitant dosing anti-fungal agent as 
moderate activity CYP3A inhibitor  
Despite the institution of a more favorable intermittent schedule of the combination of TAK-659 with 
Ixazomib presented here, when compared to continuous single agent TKI, AML is an intrinsic cause of 
primary neutropenia leading to fungal infections. Patients considered to have high risk for the 
development of fungal infection, or with a prior history of an aspergillus/mold infection, now recovered, 
may require concomitant administration of a moderate CYP3A inhibitor such as fluconazole, or, in the 
case of the latter ongoing infection more likely to involve aspergillus/mold, isovuconazole. Similarly, 
patients whom are being treated with benefit, on the existing dose level of the combination, may develop 
a fungal infection and require isovuconazole.  
 
Patients requiring prophylaxis with fluconazole or patients whom develop active fungal infection, where 
isovuconazole would be appropriate, continuation of TAK-659 in the combination will require dose 
reduction to 60mg po daily of the TKI, and careful analysis of toxicity parameters, especially including 
QTc and hepatic and pancreatic enzymes. Dosing of Ixazomib will not require modification in the 
absence of relatable toxicity. The above determined TAK-659 dose cannot be escalated. If toxicity 
supervenes, the patient will be taken off study for alternative anti-infective therapy as needed. Should no 
toxicity be observed in a cohort, stepwise dose escalation, first to 80mg, may be considered based on 
review of concurrent PK measurements of specific antifungal impact on TAK-659 levels. 
5.2.2 Dose Reduction or Discontinuation in the setting of Pneumonitis 
Should the patient develop grade 1 or 2 pneumonitis, the combination therapy will be held until the 
episode resolves and the TAK-659 and Ixazomib doses will undergo 1-step reductions, respectively. If 
the episode recurs the patient will be taken off study. Similarly, should the patient develop grade 3+ 
pneumonitis, permanent drug discontinuation will be required. 
5.3 
Dose Escalation Rules and MTD Definition 
Dose escalation will be determined based on the number of toxicities as noted by the algorithm noted in 
the following Figure 5-1. 
 


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To define the Maximum Tolerated Dose (MTD), subjects will be evaluated for DLT following  two 
cycles (56 days) of treatment. Decisions to move to next dose escalation cohort will not be made until all 
subjects complete 2 cycles of therapy at a given dose. 
 
The MTD is defined as the dose level at which fewer than 33% of subjects experience a dose limiting 
toxicity (DLT), and specifically is the dose level at which less than 2 out of 6 subjects experience DLT.  
The minimal safe and effective dosing with pharmacodynamic and pharmacokinetic parameters pointing 
toward the goal of efficacy optimization, will be the recommended dose (RP2D) for the Phase II 
component of the study. To achieve this, the developing results of safety, tolerability, efficacy, PK and 
PD in each dose-escalation cohort will be reviewed in real time after each cohort, to determine whether 
maximal safety and evolving efficacy milestones will have been reached based on examination of two 
consecutive cohorts, when safety and tolerability measures are within criteria for each.   
 The criterion for safety will be DLT <20% within the cohort.   
 The criterion for tolerability will be the administration of >80% of expected dose within the 
cohort.   
 The criterion for efficacy will be the dose with an estimation of greater or equal to 25% ORR in 
the Flt3 mutant cohort, or greater than or equal to 10% ORR in the Flt3 wild-type cohort.   
 The criterion for optimizing PK will be: on day 1, equal or greater than 100ng/ml peak (Cmax) 
TAK-659, or its trough equal or greater than 15ng/ml; on day 15, peak at least 200ng/ml, trough 
at least 40ng/ml.  On the other hand, the day 15 peak should be less than 400ng/ml, and trough 
should be less than or equal to 100ng/ml. 
Enter 3
0 DLTs
1 DLT
2‐3 DLTs
Escalate to next dose
Enter 3 at same dose
1 of 6 DLT
>1 of 6 DLTs
Stop
MTD = Previous Dose
TAK‐659/Ixazomib
Clinical Study Protocol 
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
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 5‐1 Dose/Schedule Escalation Algorithm TAK‐659 and 
Ixazomib


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 The criteria for defining an optimization of PD will be the reduction in more than one of the 
epigenetic drivers by 50%:  JUN, ID1, -catenin, HOXA 9/10, MEIS1 or rise by 50% of the 
epigenetic repressor RUNX3. 
 
Subjects will initially be enrolled onto dose level 1. Three to six evaluable subjects will be enrolled at 
each dose level. All subjects assigned to a dose level must be followed for at least 2 cycles before dose 
escalation to the next cohort level can begin. 
 
Note: Subjects not evaluable for DLT assessment (i.e. do not complete at least 1 cycle of therapy due to 
reasons other than toxicity) on the Phase I portion of the protocol will be replaced for determination of 
dose escalation. 
 
The following rules will be followed: 
 An initial three subjects will be enrolled in cohort 1. If all 3 subjects in cohort 1 complete 2 cycles of 
therapy without dose limiting toxicity (DLT), the study will proceed to enroll 3 subjects at cohort 2. 
If all 3 subjects in cohort 2 complete 2 cycles of therapy without DLT, the study will proceed to 
Phase II with the MTD of each drug established.  
 Alternatively, if 1 of the first 3 subjects in any given dose cohort experiences DLT, an additional 3 
subjects will be enrolled at that dose level. If only 1 of the total 6 subjects in a dose level experience 
DLT, the study will proceed to the next dose level as planned. If 2 of the total 6 subjects in any given 
dose cohort experience DLT, the next lower dose level will be explored and considered the 
maximum tolerated dose (MTD) if no more than 1 of 6 subjects experience a DLT. That dose will be 
recommended for the Phase II study. 
 
Number of subjects 
with DLT at given 
dose level 
Escalation decision 
0 out of 3 
Enter 3 subjects at the next dose level. 
≥2 out of 3 
Dose escalation will be stopped. This dose level will be declared the 
maximum administered dose. Three (3) additional subjects will be 
entered at the next lower dose level if only 3 subjects were treated 
previously at that next lower dose level. 
1 out of 3 
Enter at least 3 more subjects at this dose level: 
 If 0 of these additional 3 subjects experience DLT, proceed to the next 
dose level. 
 If 1 or more of these additional 3 subjects experience DLT, then dose 
escalation is stopped and this dose is declared the maximum 
administered dose. Three (3) additional subjects will be entered at the 
next lower dose level if only 3 subjects were treated previously at that 
dose.  
≤1 out of 6 at 
highest dose level 
below the maximum 
administered dose 
This will be defined as the MTD. This dose level will be the 
recommended Phase II dose.  


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5.3.1 Number of treatment cycles 
Given our experience with this sort of treatment algorithm, we will follow the cues previously 
established in the Sorafenib/Vorinostat/Bortezomib trial to determine the course.  
 
We will follow the peripheral blood blast reduction during the first cycle of therapy. When peripheral 
blasts have been reduced by at least 50% , we will perform a bone marrow, either day 4 or 8, to 
document if similar effects are occurring in the marrow as in the periphery. Also, excess cells obtained 
from the marrow at this early time point will be used to inform the impact of changes in gene signature 
from baseline marrow, which will have been obtained on the registration/pretreatment visit at day -4 to 
0.  
 
Usual supportive care transfusions will occur during the treatment cycle to maintain platelet count >10k 
at weekly assessments, and hematopoietic growth factors are not mandated as long as ANC >200/uL. 
Treatment outcome assessment will involve a bone marrow performed at day 15.  
 
Assuming achievement of 50% or greater reduction in marrow blast score (cellularity x blast percentage) 
after 2 cycles, another cycle will be given. If the patient has had a response (CR, CRp or CRi) after 2 
cycles, every attempt will be made to transition the patient to transplant.  
 
However, if the patient is not a transplant candidate but the response after 2 cycles reaches the threshold 
50% reduction, continuation of therapy cycles can continue with follow up bone marrow after the next 2 
cycles as long as no evidence of peripheral progression occurs. Evidence for progression in the bone 
marrow would be a cue for discontinuation of therapy. 
5.4 
Definition of Dose Limiting Toxicity 
Toxicity will be evaluated according to the NCI CTCAE version 5.  
DLT is defined as any of the following events occurring within the first 2 cycles that are considered by 
the treating physician to be at least possibly related to therapy with study drug(s). AEs in which the 
relationship to study drug cannot be ruled out should be considered possibly related to study drugs TAK-
659 and/or Ixazomib. 
 Prolonged myelosuppression with the persistence of ≥ Grade 4 neutropenia or thrombocytopenia in 
the absence of leukemia (blast count <5% in bone marrow) at least 42 days after the initiation of  
therapy. 
 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 (5-HT3) 
antagonist and a corticosteroid given in standard doses and according to standard schedules.  
Grade 3 nausea, vomiting must not require tube feeding, total parenteral nutrition, or require 
prolonged hospitalization. 
o Grade 3 diarrhea that resolved to ≤ Grade 1 or baseline in a week after receiving the maximal 
supportive therapy based on standard practice. Grade 3 diarrhea must not require tube feeding, 
total parenteral nutrition, or require prolonged hospitalization. 
o Brief (<1 week) Grade 3 fatigue. 
o Electrolyte abnormalities correctable within 72 hours 


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o Grade 3 or 4 tumor lysis syndrome if it is successfully managed clinically and resolves within 7 
days without end-organ damage. 
 Failure to administer ≥ 75% of planned doses of the study drug due to TAK-659- or Ixazomib-
related or possibly related hematologic (considered not related to leukemic infiltration) or 
nonhematologic toxicities. 
 Other TAK-659- or Ixazomib-related Grade 2 or greater nonhematologic toxicities that, in the 
opinion of the investigator, require a dose reduction or discontinuation of therapy. 
 Confirmed Hy’s law/guideline cases of drug-induced liver injury: ALT or AST >3× upper limit of 
normal and total bilirubin >2× ULN, which is not cholestatic (ALT value ÷ ALT ULN] ÷ [Alkaline 
phosphatase value ÷ Alk  phos ULN]= <2), and not caused by disease. This will require permanent 
drug discontinuation. 
 Any confirmed grade 4 elevation of a single liver enzyme, even absent bilirubin elevation, will 
require permanent discontinuation from protocol therapy. 
 
Although DLT-like events may occur at any point during treatment, DLTs defined during Cycles 1-2 of 
treatment will be given more influence for decisions regarding dose escalation for cohorts, expansion of 
a dose level, or evaluation of intermediate dose levels for purposes of MTD determination. Patients will 
be monitored through all cycles of therapy for treatment-related toxicities. 
5.5 
Phase II Study 
Upon enrollment, the mutational profiles from Foundation One, Mayo, Tempus, Quest, ARUP or an 
institutional CLIA-certified laboratory will be recorded in the study database with minimum gene 
coverage as noted in Section 8.3. Subjects will be enrolled into either the FLT-3 mutant cohort or the 
FLT-3 WT cohort according to their mutation assay results. 
5.6 
TAK-659 and Ixazomib Administration 
Drug 
Dose 
Route1 
Schedule2 
Cycle 
Length 
TAK-659 
RP2D 
PO  
Days 1-15 
21days 
Ixazomib 
RP2D 
PO 
Days 1, 8, 15 
1: Please see details below regarding administration of oral study drugs. On clinic days for PK 
determination, TAK-659 will be taken first and then Ixazomib. NOTE: Patients will be asked to 
keep a diary of dosing and bring to each clinic visit. 
2: A window of ± 3 days may be applied to all study visits to accommodate observed holidays, 
inclement weather, scheduling conflicts etc. Date and time of each drug administration should be 
clearly documented in subject’s chart and electronic case report forms (eCRFs). 
5.6.1 TAK-659 Administration 
TAK-659, 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 
doses of TAK-659. Patients must swallow the tablets whole; the tablets must not be chewed, crushed, or 
manipulated in any way before swallowing. 


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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. If a patient fails to take TAK-659 one day, or if a 
patient does not take TAK-659 at their scheduled dosing time (± 6 hours of the scheduled dosing time), 
that dose should be skipped, and the patient must not make dose adjustments to account for the missed 
dose on subsequent days, for example, by taking a double dose of study drug(s) on the following day.   
Patients should record any skipped doses in their dosing diary (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 TAK-659 ingestion, patients should not re-dose following emesis and should record the 
time of the emesis in their dosing diary. Patients should resume dosing at the next scheduled time with 
the prescribed dosage. 
On clinic visit days, patients should be instructed to hold their dose until predose assessments are 
performed. The timing of the visit should be planned so that the pre-dose PK draw occurs near the same 
time as the previous day’s dosing. TAK-659 administration guidelines described above will still be 
followed on clinic days. On clinic days for PK determination, TAK-659 will be taken first and then 
Ixazomib. Patients should be instructed to return their empty blister packs to the clinic, rather than 
discarding them. Reconciliation will occur accordingly when the patient returns for their next cycle of 
take-home medication. 
5.6.2 Ixazomib Administration 
Ixazomib should be taken once a week on the same day and at approximately the same time for the 
escalating cycle. Ixazomib should be taken at least one hour before or at least two hours after food. The 
whole capsule should be swallowed with water. A total of approximately 8 ounces (240 mL) of water 
should be taken with the capsules. Patients should be instructed to store the medication between +2°C 
and +30°C (35.6°F-86°F) for the duration of each cycle. Do not freeze Ixazomib or store above 30°C.  
Any extreme in temperature should be reported as an excursion and should be dealt with on a case-by-
case basis. 
 
The capsule should not be crushed, chewed or opened.  
 
If an Ixazomib dose is delayed or missed, the dose should be taken only if the next scheduled dose is ≥ 
72 hours away. A missed dose should not be taken within 72 hours of the next scheduled dose. A double 
dose should not be taken to make up for the missed dose. If the patient vomits after taking a dose, the 
patient should not repeat the dose but should resume dosing at the time of the next scheduled dose. 
On clinic visit days, patients should be instructed to hold their dose until pre-dose assessments are 
performed. Ixazomib administration guidelines described above will still be followed on clinic days. On 
clinic days for PK determination, TAK-659 will be taken first and then Ixazomib.  
5.7 
Concomitant Medications 
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 30 days after the last dose of study drug or the start of subsequent 
antineoplastic therapy, whichever occurs first. 


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5.7.1 Allowed Concomitant Medications 
All treatments considered necessary for a subject’s welfare may be administered at the discretion of the 
treating physician in keeping with the community standards of medical care. 
5.7.2 Prohibited Concomitant Medications 
The following restrictions apply during the study: 
 Any antineoplastic therapy other than TAK-659 is prohibited during the study (with the exception of 
hydroxyurea for the first 21 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 local pain/symptom control in a preexisting nontarget lesion 
may be considered. 
 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 in Cycle 1 of dose escalation 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 in the Documents/Info tab of the EDC 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. 
o Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole. 
o Antibiotics: azithromycin, clarithromycin, erythromycin, telithromycin. 
o Antimycobacterials: rifabutin, rifampin, rifapentine. 
o Antiepileptics: carbamazepine, phenobarbital, phenytoin, primidone. 
o Antidepressant: nefazodone. 
o Immunosuppressant: cyclosporine. 
o Calcium channel blockers: diltiazem, felodipine, mibefradil, verapamil. 
o Antiarrhythmics: amiodarone, dronedarone, quinidine. 
o Antiplatelet: ticagrelor. 
o Antilipid: avasimibe. 
o Other cardiovascular: captopril, carvedilol, ranolazine. 
o Vasopressin antagonist: conivaptan. 
o 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 in the Documents/Info tab of the EDC may be used for AE 
management if there is no appropriate alternative treatment available per the treating physician’s 
judgment and the dosing is not concurrent with study drug. This situation should be evaluated by the 
sponsor investigator and patients should be closely monitored for potential toxicities.   
 


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Please note that strong CYP3A inducers should not be administered with Ixazomib.  Among those are 
rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, and St. John’s Wort.  
 
Note that medications used to treat HIV or hepatitis C infection are not listed above because patients 
with known HIV infection or known hepatitis C infection are excluded from study participation. 
5.7.3 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. 
 Fluid deficit should be corrected before initiation of treatment and during treatment. 
 Nonsteroidal anti-inflammatory drugs (NSAIDS) should be avoided with impaired renal function 
given reported NSAID-induced renal failure in patients with decreased renal function 
5.8 
Reproductive Considerations 
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 methods of contraception 
and 1 additional effective (barrier) method, at the same time, from the time of signing of the 
informed consent form through 180 days(or longer, as mandated by local labeling [eg, USPI, SmPC, 
etc;]) 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 
patient. (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.) 
 Agree to not donate eggs (ova) during the course of this study or 180 days after receiving their last 
dose of study drug(s). 
 
Male patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to 1 of the following: 
 Agree to practice highly 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 
patient. (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.) 
 Agree not to donate sperm during the course of this study or 180 days after receiving their last dose 
of study drug. 


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Acceptable non-hormonal birth control methods: 
 Total sexual abstinence ie, refrain from any form of sexual intercourse in line with the patients’ 
usual and/or preferred lifestyle. Abstinence must be for the total duration of the study treatment 
and for at least 1 month (for female patients) or 3 months (for male patients) after the last dose of 
study treatment.  
 NOTE: Periodic abstinence (eg, calendar ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
 Vasectomised sexual partner PLUS male condom. With participant assurance that partner 
received post-vasectomy confirmation of azoospermia. 
 Tubal occlusion PLUS male condom 
 Intrauterine Device PLUS male condom. Provided coils are copper-banded. 
 
Acceptable hormonal methods: 
 Etonogestrel implants (eg, Implanon®, Norplant®) PLUS male condom 
 Normal and low dose combined oral pills PLUS male condom 
 Hormonal shot or injection (eg, Depo-Provera) PLUS male condom 
 Intrauterine system device (eg, levonorgestrel-releasing intrauterine system –(Mirena®) PLUS 
male condom 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade adverse 
events.  
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests before and 
at regular intervals during their participation in this study as specified in Study Calendar & Evaluations. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse events 
requiring study drug interruption or discontinuation as specified in Study Calendar & Evaluations.   
6.1 
Dose Delays/Dose Modifications 
All toxicities that occur during the study will be actively managed following the standard of care unless 
otherwise specified in the protocol.  
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 been established as a safe dose during dose escalation 
or is lower by a 20-mg increment. 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 


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to ≤ Grade 1, or baseline, or a level considered acceptable by the physician. The patient will continue to 
be followed for 30 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 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. 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. 
 
Detailed dose modification guidelines are provided in Section 6.2.  In the case of TAK-659, which is 
administered once daily orally, a 1-step reduction of dose (by 20mg) may occur and if toxicity occurs at 
that dose, a second reduction may be considered.  This second reduction will be subject to the judgment 
of the treating physician.  In the case of Ixazomib, further reductions below the -2 dose step reduction 
from the starting dose that already exists below the RP2D in myeloma is not anticipated. 
 
When a dose reduction occurs, no dose-reescalation will be permitted intrapatient.  If study drug dosing 
is delayed for >21 days despite supportive treatment per standard clinical practice or more than 2 dose 
reductions are required in a patient, this patient will have study treatment discontinued. 
 
There exist both unique and overlapping toxicities of TAK-659 and Ixazomib, which will influence dose 
modification of one or both within the combination.  As compared with its predecessor Bortezomib, 
Ixazomib possesses lower incidence of neuropathy, but the incidence of diarrhea may be higher.  
However, that diarrhea is usually below grade 3, except in 15-20 % cases in the phase I weekly 
administration trial. Both Ixazomib and Bortezomib affect thrombocytopenia, but in the context of AML 
induction therapy, thrombocytopenia is an intrinsic feature, which is supported by transfusion.  
 
By contrast, diarrhea occurs as AE with TAK-659, at 32% rate, and the grade is not high, but in 
preclinical animal models, gastrointestinal hemorrhage and/or bowel intimal damage was noted at high 
doses.  In the phase Ib C34002 AML trial, the major DLTs included hemorrhage, possibly related to 
thrombocytopenia, or to functional inactivation of the platelets, at the highest dose of TAK-659: 80 mg 
po bid.  In addition, asymptomatic elevation of lipase, AST and ALT have been observed frequently, but 
pancreatitis or hepatitis are rare.  Pneumonitis felt related to TAK-659 is rare. 
6.1.1 TAK-659/Ixazomib Dose Adjustments 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.5) will be performed.  When severe hematological AE’s 
occur (≥ Grade 4 events, febrile 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 6.3) 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 


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bone marrow aplasia is seen, the study drugs should be continued for completion of the current cycle if 
less than 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 drugs 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 (along with Ixazomib) 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 a DLT.  The patient will continue to be 
followed until resolution or stabilization of the event, initiation of another anti-leukemia therapy, or 
overt AML progression, whichever occurs first. 
When a dose reduction of TAK-659 or ixazomib is required in a patient, no re-escalation of dose will be 
permitted. 
6.1.2 TAK-659 dose modifications for Nonhematologic Toxicities 
Please refer to the Table below for dose held and dose reduction recommendations for non-hematologic 
toxicities.  When the dose of TAK-659 is withheld based on the following criteria, 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 treating 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 after discussion with the sponsor investigator. 
 
 
Criteria 
Action 
All Grade 3 Nonhematologic Toxicities with the exception of: 
 Grade 3 nausea, vomiting and diarrhea resolved to ≤ Grade 1 
or baseline within 48 hours with optimal antiemetics and 
antidiarrheal following SOC 
 Transient Grade 3 fatigue (lasting < 72 hours) 
 Asymptomatic lipase elevation (< Grade 4) in the absence of 
significant amylase elevation (< Grade 3) considered not dose 
limiting  
 Asymptomatic amylase elevation (< Grade 4) in the absence 
of lipase elevation (< Grade 3) considered not dose limiting 
 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  
 Grade 3 hypophosphatemia resolved to Grade ≤ 1 or baseline 
within 72 hours with phosphate repletion 
 Other asymptomatic Grade 3 laboratory abnormalities that the 
investigator considers not clinically significant
 Hold TAK-659 until resolution to Grade ≤ 1 or 
baseline or a level considered acceptable by the 
investigator (must be ≤Grade 2).  
o If resolved in ≤ 7 days, then maintain the dose 
level. 
o If resolved in > 7 days, then dose reduce by 1 
dose level.  
o If recurs, then dose reduce by 1 dose level. 
 For the exceptions listed, maintain 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 
 Permanently discontinue TAK-659 for any grade 
4 nonhematologic toxicities that are at least 
possibly related to TAK-659. 


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In general, the study drug(s) will resume only after the resolution of AEs to ≤Grade 1 or baseline or as 
specified in these dose modification guidelines. However, retreatment with study drug(s) could start 
when the AEs are resolved to a level deemed acceptable by the investigator.  When a dose reduction of 
TAK-659 is required, no re-escalation of dose will be permitted. 
6.1.3 Ixazomib Dose Adjustments for Hematologic Toxicities 
 
Ixazomib Dose Adjustments for Hematologic Toxicities 
Criteria 
Action 
Within-Cycle Dose Modifications In Induction 
(< 2 cycles and marrow blasts present) 
 
 
Within-Cycle Dose Modifications In 
consolidation (after documentation of 
morphologic blast clearance, generally 
beginning after the second cycle) 
 
Dose reduction is not required 
 
 
 
 
See below 
 If platelet count  20  109/L or ANC ≤ 0.20  
109/L on a ixazomib dosing day (other than 
Day 1) 
 
Ixazomib dose should be withheld.   
 
Complete blood count (CBC) with 
differential should be repeated at least twice 
weekly until the ANC and/or platelet counts 
have exceeded the prespecified values.   
 
Upon recovery, ixazomib may be reinitiated 
with 1 dose level reduction.  
Dose Modifications for Subsequent Treatment Cycles
 Delay of 1 week in the start of a subsequent 
cycle due to lack of toxicity recovery as ANC < 
0.5  109/L, platelet count < 30  109/L 
 
Hold ixazomib until resolution as per 
criteria  
 
Upon recovery, reduce ixazomib 1 dose 
level. 
 
The maximum delay before treatment 
should be discontinued will be 2 weeks or 
at the discretion of the PI. 
Dose Modifications for Subsequent Treatment Cycles
 All hematologic toxicities 
 
For hematologic toxicity that occurs during 
a cycle but recovers in time for the start of 
the next cycle,: 
o  If dose was reduced within the cycle, 
start the next cycle at that same dose. 
o If due to toxicity timing, ie, after Day 
15 dosing thus a dose reduction was not 
required at that point in the cycle, 
reduce ixazomib by 1 dose level at the 
start of that cycle. 
o Do not reduce the dose both within a 
cycle and at the start of the cycle for the 
same most severe toxicity. 
 


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Ixazomib Treatment Modification (Delays, Reductions, and Discontinuations) Due to Adverse Events 
(Non-Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Peripheral Neuropathy: 
Grade 1 peripheral neuropathy 
 
 
No action 
 
Grade 1 signs and symptoms:  
asymptomatic; without pain or loss of 
function; clinical or diagnostic 
observations only [27] 
New or worsening Grade 1 
peripheral neuropathy with pain 
or Grade 2 
 
Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
Grade 2 signs and symptoms:  
Moderate symptoms; limiting 
instrumental activities of daily living 
(ADL) [27] 
New or worsening Grade 2 
peripheral neuropathy with pain 
or Grade 3 
 
Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
 
Reduce study drug to next 
lower dose upon recovery
Grade 3 signs and symptoms:  severe 
symptoms; limiting self-care ADL; 
assistive device indicated [27] 
New or worsening Grade 4 
peripheral neuropathy 
 
Discontinue study drug 
 
Grade 2 Rash 
 
Symptomatic 
recommendations as per 
section 6.3 
The investigator and project clinician 
may discuss considerations for dose 
modifications and symptom 
management.
Grade 3 nonhematologic 
toxicity judged to be related to 
study drug 
 
Hold study drug until 
resolution to Grade < 1 or 
baseline 
Symptomatic recommendations noted 
in Section 6.3 
If not recovered to < Grade 1 or 
baseline within 4 weeks 
 
Reduce study drug 1 to 
next lower dose upon 
return to < Grade 1 or 
baseline 
 
Subsequent recurrence Grade 3 
that does not recover to < 
Grade 1 or baseline within 4 
weeks 
 
Hold study drug until 
resolution to Grade < 1 or 
baseline 
 
Reduce study drug to next 
lower dose  
Monitor closely, take appropriate 
medical precautions, and provide 
appropriate symptomatic care 
Grade 4 nonhematologic 
toxicities judged to be related to 
study drug 
 
Consider permanently 
discontinuing study drug 
Exceptions are cases in which the 
investigator determines the patient is 
obtaining a clinical benefit  
Once ixazomib is reduced for any toxicity, the dose may not be re-escalated. 
 


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6.2 
Dose Levels for Dose Reduction 
 
Dose 
level 
Dose of TAK-659 
Days 1-15 
Dose of Ixazomib 
Days 1, 8, 15 
Starting 
Dose 
100mg po once 
daily 
2.3 mg  
3mg  
4mg 
Dose 
level (-1) 
80mg po once 
daily 
Contact sponsor-
investigator for 
consideration of 
schedule below 2.3mg.
2.3mg  
3mg 
Dose 
level (-2) 
60mg po once 
daily 
-- 
Contact sponsor-
investigator for 
consideration of 
schedule below 2.3mg. 
2.3mg. 
If study drug dosing is delayed for >21 days despite supportive treatment per standard 
clinical practice or more than 2 dose reductions are required in a patient, this patient will 
have study treatment discontinued. 
 
6.3 
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 erythropoietin, G-CSF, 
blood products (RBC and platelet transfusions), 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. 
6.3.1 
Prophylaxis Against Infection 
Patients with advanced hematological malignancies may be at an increased risk of infection. Prophylactic 
use of antibiotic, antiviral, or antifungal medication can be considered as clinically indicated and as per 
local standard practice. Ciprofloxacin is considered a standard for patients with ANC <500. Antifungal 
prophylaxis with fluconazole or isovuconazole which are a moderate CYP inhibitory agents is permitted 
with dose reduction of TAK-659 as in 5.3.1. Patients requiring prophylaxis with fluconazole or  patients 
whom develop active fungal infection, continuation of TAK-659 in the combination will require dose 
reduction to 60mg po daily of the TAK-659 with the mold-active agent isovuconazole, and careful 
analysis of toxicity parameters, especially including QTc and hepatic and pancreatic enzymes.  Dosing of 
Ixazomib will not require modification in the absence of relatable toxicity. The above determined TAK-
659 dose cannot be escalated. If toxicity supervenes, the patient will be taken off study for alternative 
anti-infective therapy as needed. Should no toxicity be observed in a cohort, stepwise dose escalation, 
first to 80mg, may be considered. 
 
Antiviral therapy such as acyclovir may be initiated as clinically indicated.  
 
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 


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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” while inpatient 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, either 
as an outpatient or as an inpatient; however, the use of such agents should be at the discretion of the 
treating physician 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 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis carinii pneumonia) 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, cytomegalovirus (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. 
Institutional guidelines may be used in the management of viral reactivation. 
6.3.2 
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 21 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. 


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6.3.3 
Prophylaxis Against Risk of Reactivation of Herpes Infection 
Patients may be at an increased risk of infection including reactivation of herpes zoster and herpes 
simplex viruses.  Antiviral therapy such as acyclovir, valacyclovir, or other antivirals may be initiated as 
clinically indicated.  Other antivirals are also acceptable. 
6.3.4 
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/Ixazomib treatment should be interrupted and the patient treated 
per standard of care. If pneumonitis is moderate/severe, discontinue TAK-659/Ixazomib. Patients 
should be monitored for respiratory signs and symptoms throughout treatment and be advised to 
promptly report respiratory symptoms. 
6.3.5 
Nausea and/or Vomiting 
Prophylactic antiemetics before the first dose of the study drug is not recommended. Antiemetics may be 
used prophylactically as clinically indicated following the occurrence of a first event of TAK-
659/Ixazomib drug-related or possibly related nausea and/or vomiting. 
6.3.6 
Diarrhea 
Prophylactic antidiarrheals is not recommended before the first dose of study drugs. 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. 
6.3.7 
Edema (Including Periorbital) 
Peripheral and periorbital oedema have been observed in patients treated with TAK-659. 
Management of the event should follow the standard local practice and dose modification as 
required. 
6.3.8 
Rash With or Without Prutitus 
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 a topical or oral steroid 
(eg, prednisone ≤ 10 mg per day or equivalent) is permitted. 
 
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any SAE 
involving rash is recommended.  Prophylactic measures should also be considered if a patient has 
previously developed a rash (eg, using a thick, alcohol-free emollient cream on dry areas of the body or 
oral or topical antihistamines).  A rare risk is Stevens-Johnson Syndrome, a severe and potentially life-
threatening rash with skin peeling and mouth sores, which should be managed symptomatically 
according to standard medical practice.  Punch biopsies for histopathological analysis are encouraged 
at the discretion of the investigator. 
6.3.9 
Thrombocytopenia 
Blood counts should be monitored regularly. Platelet transfusion is allowed to manage severe 
thrombocytopenia to prevent and minimize bleeding according to ASH/ASCO guidelines and should be 
proactive to consider functional defects within platelets as a result of Syk/Tec inhibition.  Every attempt 
should be made to adjust the platelet count threshold to a higher level (beginning at 10k without 


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demonstrated bleeding) at any signs of bleeding, such as oral purpura.  Each transfusion episode, 
including the type of transfusion (platelets), should be recorded. 
 
Ixazomib administration should be modified as noted as per dose modification recommendations in the 
protocol when thrombocytopenia occurs, after remission has been established by bone marrow testing. 
In that context, continuation therapy can be reinitiated at a reduced level upon recovery of platelet 
counts. However, prior to attainment of remission or in the period prior to completion of cycle 2, 
Ixazomib administration should not be altered due to thrombocytopenia alone, if it can be ameliorated 
by transfusion to attain minimum platelet count 10,000/uL. 
 
A rare risk is thrombotic thrombocytopenic purpura (TTP), a rare blood disorder where blood clots form 
in small blood vessels throughout the body characterized by thrombocytopenia and hemolysis, 
petechiae, fever, or possibly more serious signs and symptoms. TTP should be managed 
symptomatically according to standard medical practice. 
6.3.10 Neutropenia 
Blood counts should be monitored regularly. 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. 
6.3.11 Anemia 
Hemoglobin should be monitored regularly. 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. 
6.3.12 Hypophosphatemia 
Hypophosphatemia has been observed in patients treated with TAK-659. Consider prophylaxis; 
otherwise refer to dose modification guideline. 
6.3.13 Enzyme Elevations (Transaminase, Amylase and Lipase, CPK and LDH Elevations) 
Elevations of the enzymes above have been observed. Events are generally asymptomatic and 
reversible with dose interruption.  
 
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. 
6.3.14 Fluid Deficit 
Fluid deficit should be corrected before initiation of study drug and during treatment. 


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6.3.15 Hypotension 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been reported with 
ixazomib.  Blood pressure should be closely monitored while the patient is on study treatment and fluid 
deficit should be corrected as needed, especially in the setting of concomitant symptoms such as nausea, 
vomiting, diarrhea, or anorexia.  Patients taking medications and/or diuretics to manage their blood 
pressure (for either hypo- or hypertension) should be managed according to standard clinical practice, 
including considerations for dose adjustments of their concomitant medications during the course of the 
trial.  Fluid deficit should be corrected before initiation of study drug and as needed during treatment to 
avoid dehydration. 
6.3.16 Posterior Reversible Encephalopathy Syndrome 
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has been reported 
with ixazomib.  This condition is characterized by headache, seizures and visual loss, as well as abrupt 
increase in blood pressure.  Diagnosis may be confirmed by magnetic resonance imaging (MRI).  If the 
syndrome is diagnosed or suspected, symptom-directed treatment should be maintained until the 
condition is reversed by control of hypertension or other instigating factors. 
6.3.17 Transverse Myelitis 
Transverse myelitis has also been reported with ixazomib. It is not known if ixazomib causes transverse 
myelitis; however, because it happened to a patient receiving ixazomib, the possibility that ixazomib 
may have contributed to transverse myelitis cannot be excluded. 
6.4 
Protocol Therapy Discontinuation 
Patients will be informed that they have the right to withdraw from the study at any time for any reason, 
without prejudice to their medical care. In addition to discontinuation from therapy related to toxicities 
as outlined in section 6.1, a subject will also be discontinued from protocol therapy and followed up per 
protocol under the circumstances outlined below. The reason for discontinuation of protocol therapy 
will be documented on the electronic case report form (eCRF). 
 
Documented disease progression  
 
The treating physician determines a change of therapy would be in the best interest of the subject 
 
The subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or for 
other reasons 
o If a subject decides to prematurely discontinue protocol therapy (“refuses treatment”), the 
subject should be asked if he or she may still be contacted for further scheduled study 
assessments. The outcome of that discussion should be documented in both the medical 
records and in the eCRF. 
 
A female subject becomes pregnant  
 
If protocol therapy is interrupted for ≥ 21 days.  
 
Protocol violation or non-compliance of the patient 
 
Study terminated 
 
If the responsible physician thinks a change of therapy would be best for the patient 
 
Noncompliance of the patient 
 
Pregnancy 
 
Death 


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6.5 
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 investigator or funder (Millennium Takeda) terminates the study 
6.6 
Protocol Discontinuation 
If a subject decides to withdraw from the study (and not just from protocol therapy) all efforts should be 
made to complete the final study assessments. The site study team should contact the subject by 
telephone or through a clinic visit to determine the reason for the study withdrawal. If the reason for 
withdrawal is an adverse event, it will be recorded on the eCRF. 


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7. 
STUDY CALENDAR: DOSE ESCALATION COHORTS (PHASE 1)  
Cycle = 21days
Screen 
Cycle 1 
Cycles 2-4 
Cycles 5+ 
Safety 
follow up
Long-term 
follow up
-28 
days1
D 
1
D
4
D
8
D 
15
D 
1 
D 
8
D 
15
D 
1
D 
8
D 
15
30 days 
post Tx2
Q month 
(±14)3
REQUIRED ASSESSMENTS 
 
Informed consent4, Eligibility criteria 
X
 
Medical history, Disease characteristics
X
X
 
Physical exam5 
X
X5
Sx
Sx
X 
Sx
X
X
Ophthalmic Exam6 
X
C2 
C7D1; q6
X
Height (screen only); Weight 
X
X
X 
X
X
Vital signs (BP, pulse, temperature) 
X
X
X
X
X 
X
X
X
ECOG Performance status 
X
X
X 
X
X
12-lead ECG7 
X
×2
×2
 
X
X
X
AEs & concomitant medications8 
X
X
X
X 
X
X
X
Drug Diary Review 
X
X
X
X 
X
X
LABORATORY ASSESSMENTS9 
 
CBC with diff, platelets, ANC. Chemistry10
X
X10
X
X10
X
X 
C2
X
X
X
Uric acid, Mag, Amylase, Lipase, GGT10
X
X10
X
X10
X
X 
X
X
X
Urinalysis 
X
X
X 
X
X
X
Pregnancy test for WOCBP11 
X
X
X 
X
DISEASE ASSESSMENT 
 
NGS results or submit for NGS testing 
X
 
 
 
 
Bone marrow biopsy and aspirate12 
X
X
 
C2,4
as indicated 
TREATMENT EXPOSURE 
 
TAK-659 (Daily ×15 days) 
D1-15
D1-15
D1-15
Ixazomib (Days 1, 8, 15) 
X
X
X
X 
X
X
X
X
X
CORRELATIVE STUDIES (SPECIMEN COLLECTION)
 
Buccal swab for germline DNA analysis
X
 
Bone marrow aspirate for biomarker analyses and PD 
X
X13
X
 
C2,4
Serum for proteomic analysis 
X
X
 
Plasma for PK14 
×2
×2
 
×2
BANKING SAMPLES (SPECIMEN COLLECTION)
 
Whole Blood15 
X
 
Serum and Plasma15 
X
 
X
FOLLOW-UP 
 
Survival status, subsequent therapy 
 
X


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Phase I calendar footnotes: 
Evaluations/laboratory assessments performed on visit days will occur before dosing unless otherwise indicated. On these days, patients will 
be instructed to hold dosing until relevant assessments have been completed. 
1. Screening assessments performed within 3 days before Cycle 1 Day 1 do not need to be repeated, unless otherwise specified. 
2. Safety follow up visit will occur 30 days (+10 days) after the last dose of study drug or before the start of subsequent anticancer therapy (other 
than hydroxyurea) whichever occurs first.   
3. All patients, including those no longer on treatment, will be followed for survival. Patients who discontinue the study will be followed for survival 
every month for up to 12 months after discontinuation of the study drug until death, loss to follow-up, or withdrawal of consent. Information on 
subsequent anticancer therapies will also be collected. For patients who achieve CR but discontinue study treatment while still in remission, 
disease progression based upon available local data will also be collected. 
4. Informed consent may be obtained before the Screening period (28 days before Cycle 1 Day 1 dosing). 
5. Complete physical examination (PE) will be done at screening, including a neurological exam. Complete PEs will also be done on Day 1 of each 
cycle and at the 30-day Safety follow up visit. Symptom- or finding-directed PEs will be done on C1D8 and 15 and C2-4 D15. 
6. An ophthalmic exam will be done at screening, C2D1, C7D1, q 6 cycles thereafter (±2 wks), and at 30-day Safety follow up visit.  See Section 8.1. 
7. Single 12-lead ECGs will be performed within 1 hour predose and 3 hours postdose (±15 min) on C1D1 and C1D15. All other ECGs will be done 
only at predose. When the timing of a blood sample coincides with the timing of an ECG, the ECG will be completed first. 
8. AEs & con meds will be recorded from first dose of study drugs through 30 days after the last dose of study drugs or the start of subsequent 
anticancer therapy, whichever occurs first. SAEs will be reported from signing of informed consent through 30 days after the last dose of study 
drug, even if the patient starts nonprotocol therapy. 
9. Laboratory assessments may be conducted within -3 days of the scheduled visit, except PK/PD assessments, or unless otherwise noted. Day 1 
visits of Cycle 2 and beyond may be modified by up to 3 days due to inclement weather, holidays, vacations, etc. 
10. The hematology and chemistry blood samples for C1D1 may be collected within 3 days before dosing to ensure patient eligibility on Day 1. The 
percentage of leukemic blast cells should be noted in the hematology panel. Monitor CBCs and CMPs at least twice weekly for the first 2 weeks 
(including tumor lysis labs) and then check CBCs and CMPs at least weekly to complete the first 2 cycles. 
11. Women of childbearing potential: A serum pregnancy test will be done at screening. A urine pregnancy test will be done predose D1 of all cycles, 
with negative results available prior to dosing. If a negative serum test is done within 3 days of C1D1, the C1D1 urine test will be waived. 
12. Bone marrow biopsy and aspirate for disease burden (blast counts), cytogenetics, and cellular composition by flow cytometry will be done at 
screening. In addition, BM biopsies and/or aspirates will be done to assess disease response at Cycles 1, 2, and 4 between Days 15-21, provided 
the results are available before Day 1 of the next cycle. After Cycle 4, BM 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: a BM biopsy is 
required only at screening. Residual and/or additional bone marrow samples will be requested for biomarker analysis. In cases when insufficient 
bone marrow aspirate is collected, peripheral blood will be collected and submitted per the instructions in the CLM.  
13. Bone marrow will be done at C1D4 for the 1st 5 patients. Thereafter, BM timing (D4 vs 8) will determined from the results in the first 5 patients.  
14. Blood for PK plasma samples will be collected at: C1D1 (pre-dose, 2-4 hr post-dose), C1D15 (pre-dose, 2-4 hr post-dose), Cycle 2, 3, 4 Day 15 
(pre-dose, post-dose anytime during clinic visit). Instruct patient to withhold study drug(s) for that day. The timing of the visit should be planned 
so that the pre-dose PK draw occurs near the same time as the previous day’s dosing. When a blood sample coincides with the timing of an ECG, 
the ECG will be completed first. Refer to the CLM for detailed instructions on collection, processing, storing, and shipping of PK samples. 
15. Whole blood for banking is to be collected at pre-dose C1D1. Serum and plasma for banking are to be collected at pre-dose C1D1 and at the 30-
Day Safety Follow up visit. See CLM for collection, processing, labeling and shipping instructions. 
 


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8. 
STUDY CALENDAR: PHASE 2 
Cycle = 21days
Screen
Cycle 1 
Cycles 2-4 
C 3 
Cycles 5+ 
Safety 
follow up
Long-term 
follow up
-28 
days1
D 
1
D
4
D
8
D 
15
D 
1 
D 
8 
D 
15
D 
22
D 
1
D 
8
D 
15
30 days 
post Tx2
Q month 
(±14)3
REQUIRED ASSESSMENTS 
 
Informed consent4, Eligibility criteria 
X
 
Medical history, Disease characteristics 
X
X
 
Physical exam5 
X
X5
Sx
Sx
X 
 
Sx 
X
X
Ophthalmic Exam6 
X
C2 
 
C7D1; q6
X
Height (screen only); Weight 
X
X
X 
 
X
X
Vital signs (BP, pulse, temperature) 
X
X
X
X
X 
 
X
X
X
ECOG Performance status 
X
X
X 
 
X
X
12-lead ECG7 
X
X
 
X
X
X
AEs & concomitant medications8 
X
X
X 
 
X
X
X
Drug Diary Review 
X
X
X 
 
X
X
LABORATORY ASSESSMENTS9 
 
CBC with diff, platelets, ANC. Chemistry10
X
X10
X
X10
X
X 
C2 
X
X
X
Uric acid, Mag, Amylase, Lipase, GGT10
X
X10
X
X10
X
X 
 
X
X
X
Urinalysis 
X
X
X 
 
X
X
X
Pregnancy test for WOCBP11 
X
X
X 
 
X
DISEASE ASSESSMENT 
 
NGS results or submit for NGS testing 
X
 
 
 
 
 
Bone marrow biopsy and aspirate12 
X
X
 
C3D2212
as indicated
TREATMENT EXPOSURE 
 
TAK-659 (Daily ×15 days) 
D1-15
D1-15
D1-15
Ixazomib (Days 1, 8, 15) 
X
X
X
X 
X 
X
X
X
X
CORRELATIVE STUDIES (SPECIMEN COLLECTION)
 
Buccal swab for germline DNA analysis
X
 
Bone marrow aspirate for biomarker analyses and PD 
X
X13
X
 
C3D2212
@ PD13
Serum for proteomic analysis 
X
X
 
Plasma for PK14 
×2
×2
 
×2
BANKING SAMPLES (SPECIMEN COLLECTION)
 
Whole Blood15 
X
 
Serum and Plasma15 
X
 
X
FOLLOW-UP 
 
Survival status, subsequent therapy 
 
X


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Phase II calendar footnotes: 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. 
1. Screening assessments performed within 3 days before Cycle 1 Day 1 do not need to be repeated, unless otherwise specified. 
2. Safety follow up visit will occur 30 days (+10 days) after the last dose of study drug or before the start of subsequent anticancer therapy (other 
than hydroxyurea) whichever occurs first. 
3. All patients, including those no longer on treatment, will be followed for survival. Patients who discontinue the study will be followed for 
survival every month for up to 12 months after discontinuation of the study drug until death, loss to follow-up, or withdrawal of consent. 
Information on subsequent anticancer therapies will also be collected. For patients who achieve CR but discontinue study treatment while still in 
remission, disease progression based upon available local data will also be collected. 
4. Informed consent may be obtained before the Screening period (28 days before Cycle 1 Day 1 dosing). 
5. Complete physical examination (PE) will be done at screening, including a neurological exam.  Complete PEs will also be done on Day 1 of 
each cycle, and at the 30-day Safety follow up visit.  Symptom- or finding- directed PEs will be done on C1D8 and 15 and C2-4 D15. 
6. An ophthalmic exam will be done at screening, C2D1, C7D1, q 6 cycles thereafter (±2 wks), and at 30-day Safety follow up visit. See Sect. 8.1. 
7. Single 12-lead ECGs will be done at screening, predose during each cycle and at the 30-day Safety follow up visit. When the timing of a blood 
sample coincides with the timing of an ECG, the ECG will be completed first.  
8. AEs & con meds will be recorded from first dose of study drugs through 30 days after the last dose of study drugs or to the start of subsequent 
anticancer therapy, whichever occurs first. SAEs will be reported from signing of the informed consent form through 30 days after the last dose 
of study drug even if the patient starts nonprotocol therapy.  
9. Laboratory assessments may be conducted within - 3 days of the scheduled visit, except PK/PD assessments, or unless otherwise noted.  Day 1 
visits of Cycle 2 and beyond may be modified by up to 3 days due to inclement weather, holidays, vacations, etc. 
10. The hematology and chemistry blood samples for C1D1 may be collected within 3 days before dosing to ensure patient eligibility on Day 1. The 
percentage of leukemic blast cells should also be noted in the hematology panel. Monitor CBCs and CMPs at least twice weekly for the first 2 
weeks (including tumor lysis labs) and then check CBCs and CMPs at least weekly to complete the first 2 cycles.  
11. Women of childbearing potential: A serum pregnancy test will be performed for at screening.  A urine pregnancy test will be done predose D1 of 
all cycles, with negative results available prior to dosing. If a negative serum test is done within 3 days of C1D1, the C1D1 urine test is waived. 
12. Bone marrow biopsy and aspirate for disease burden (blast counts), cytogenetics, and cellular composition by flow cytometry will be done at 
screening. In addition, BM aspirates and/or biopsies will be done to assess disease response at Cycle 1 Day 15 and Cycle 3 Day 22, so that the 
results are available before Day 1 of the next cycle. In the post-Cycle 3 assessment, aspirate and biopsy are suggested on day 22 (or within 3 
days prior to C4D1), simultaneous with the plan to continue onto C4 D1, to serve as record establishing the optimal response/composite CR. 
Such planning should be guided by the trend of blast reduction observed during Cycles 1, 2. After Cycle 3 assessment, BM 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: a BM biopsy is required at screening and post-Cycle 3 D22. Residual and/or additional bone marrow samples 
will be requested for biomarker analysis. In cases when insufficient BM aspirate is collected, peripheral blood will be submitted per the 
instructions in the CLM. 
13. BM timing (D4 vs D8) will be determined from results in the Phase I patients. At the time of relapse (PD) of any patient who had initially 
responded to TAK-659, bone marrow aspirate and/or biopsy materials will be collected for biomarker study.   
14. Blood for PK plasma samples will be collected at : C1D1 (pre-dose, 2-4 hr post-dose), C1D15 (pre-dose, 2-4 hr post-dose), Cycle 2, 3, 4 Day 15 
(pre-dose, post-dose anytime during clinic visit). Instruct patient withhold study drug(s) for that day. The timing of the visit should be planned so 
that the pre-dose PK draw occurs near the same time as the previous day’s dosing. When a blood sample coincides with the timing of an ECG, 


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the ECG will be completed first. Refer to the CLM for detailed instructions on collection, processing, storing, and shipping of PK samples. 
15. Whole blood for banking is to be collected at predose C1D1. Serum and plasma for banking are to be collected at pre-dose C1D1 and at the 30-
Day Safety Follow up visit. See CLM for collection, processing, labeling and shipping instructions. 


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8.1 
Study Procedures 
Patients will be evaluated at scheduled visits over the following study periods:  Screening, 
Treatment, and Safety Follow up.  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. 
 
The timing of PK, PD, and proteomic 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). 
 
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 received. Sites will be required to record any screening reports on tumor cytogenetics 
and/or mutation assays (eg, FLT-3, and NGS) performed as part of the standard of care. 
 
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 safety follow up.  Symptom- or finding-directed PEs will be performed on 
Day 8 and 15 of Cycle 1 and Day 15 of Cycles 2, 3, and 4.  
 
Note:  Physical examinations at screening will include a neurological examination. 
 
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. 
 
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. 
 
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. 
 
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 30 days after the last dose of study drug or to the start of subsequent anticancer 


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therapy, whichever occurs first.  See Section 5.8 for a list of medications and therapies that are allowed/ 
prohibited during the study. 
 
Electrocardiogram 
12-lead ECGs will be performed and interpreted locally. 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. 
 
All scheduled ECGs should be performed pre-dose, unless otherwise specified, and after the patient has 
rested quietly for at least 5 minutes in a supine position. When the timing of a PK, PD, 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. 
 
Estimates of QTc for study eligibility should use QT correction formula (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 QTc finding can be corrected based on change in medication and/or 
corrections of electrolyte abnormalities, and a repeat ECG meets eligibility requirements, the patient 
may enroll to the study upon review and agreement by the sponsor investigator. 
 
Following initiation of treatment, if a QTc value is confirmed as>500 msec for any ECG, the following 
will occur: 
 The sponsor investigator 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). 
 Additional ECGs may be performed at more frequent intervals 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 benefitted 
from TAK-659 treatment with either disease control or response will be agreed to by the local 
investigator and the sponsor investigator on a case-by-case basis. 
 
The ECGs performed should be reviewed by the local investigator or his/her delegate before the patient 
leaves the clinic on visit days. 
 
Hematology 
Will include: Hemoglobin; Leukocytes with differential; Hematocrit; Neutrophils (absolute neutrophil 
count [ANC]); Platelet (count); Percentage of leukemic blast cells 
 
Serum Chemistry 
Will include: Blood urea nitrogen (BUN); Albumin; Calcium; Alkaline phosphatase; Chloride; 
Creatinine; Carbon dioxide (CO₂); Bilirubin (total) Aspartate aminotransferase (AST); Alanine 
aminotransferase (ALT); Uric acid; Magnesium; Lactate dehydrogenase (LDH); Amylase; Lipase; Total 
protein; Gamma glutamyl transferase (GGT); Glucose; Phosphate; Sodium; Potassium 


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Urinalysis 
Turbidity and Color; Ketones; Urobilinogen; pH; Bilirubin; Glucose; Specific gravity; Occult Blood; 
Leukocytes; Protein; Nitrite 
 
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 the Safety follow up. On the basis of 
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 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. 
8.2 
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. (35)  
Investigators are encouraged to consult the reference for more detailed explanation of response criteria. 
 
CR, CRi/CRp, and PR are defined using the following criteria: 
 
Morphologic CR:   
 A CR designation requires that the patient achieve the morphologic leukemia-free state and have an 
ANC of more than 1,000/uL and platelets of > 100,000/uL.  
 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.   
 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. 
 
Morphologic CRi, CRp:  
After chemotherapy, some patients fulfill all of the criteria for CR except for residual neutropenia 
(<1,000/uL) or thrombocytopenia (<100,000/uL). 
 
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% to 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. 
 


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Progressive Disease: 
Because the IWG criteria for AML do not provide a standardized definition for progressive disease, 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. 
 
8.3 
Bone Marrow Biopsy and Aspirate Collection Analysis 
If prior results are not available, bone marrow biopsy and aspirate collection at screening will be 
required to assess disease burden, and exclusively from aspirate: cytogenetics, karyotype, mutations by 
NGS and Flt3 mutations by quantitative PCR and cellular composition by flow cytometry.  Both of these 
tests should be done by CLIA- and/or FDA-approved vendors as standard of care.  In the case of NGS 
testing, preference would be to have results obtained from Foundation One,  Mayo, Tempus, Quest, 
ARUP or an institutional CLIA-certified laboratory, rendering results for a least 27 AML/MDS driver 
genes. If bone marrow aspiration has failed, a peripheral blood sample with circulating blasts may be 
substituted. 
 
A minimum 27 gene mutational profile standard in practice for tracking mechanism and prognosis 
(1,3):  
AML Mutations by NGS (ASXL1, CEBPA, DNMT3A, ETV6/TEL, FLT3, HRAS, IDH1, IDH2, KIT, 
KRAS, MLL, NPM1, NRAS, PHF6, RUNX1, TET2, TP53, WT1)  
MDS Mutations by NGS (ASXL1, ATRX, BCOR, BCORL1, ETV6/TEL, DNMT3A, EZH2, GNAS, 
IDH1, IDH2, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF1, ZRSR2).  
MPN Mutations by NGS (ASXL1, BRAF, CALR, CSF3R, EZH2, IKZF1, JAK2, JAK3, KDM6A, 
KIT, MPL, PDFGRA, SETBP1, TET2)  
(the latter two panels have certain targets that apply more commonly to secondary AMLs)  
 
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 and during the study for biomarker analysis.   
 
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 (BMA) or blood (if BMA not available) 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, as well as to determine the mutational burden by NGS for cooperating mutant 
epigenetic effectors.  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 Sponsor Investigator or 
delegate.  In this circumstance, the site is required to investigate whether adequate residual material 
from the last bone marrow aspirate procedure remains available for collection and whether the tissue 
processing procedures for these remaining samples conform to the requirements of this trial for the 


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purpose of biomarker evaluation.  If so, these samples should be collected and sent to the study-
designated laboratory(ies). 
 
 Note that a bone marrow biopsy is required only at screening.  After 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, Phase I bone marrow aspirate and/or biopsy specimens (if needed) will be collected to 
assess pharmacodynamics (PD) at day 4 or day 8 (based on tempo of peripheral blood blast reduction), 
and to assess disease response between Days 15 and 21 and 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 during dose-
escalation.  The Cycle 2 marrow during dose-escalation/phase I is needed to gauge impact of marrow 
findings on dose-modifications if patients are not routinely in remission at this stage.  
 
In the Phase II, best response will be graded on marrow on day 22 of Cycle 3, when indicated by the 
trend of prior assessments, in order to document the status of composite CR, or otherwise between days 
15-21 if that milestone does not appear imminent. At Cycle 2 or 4 bone marrow is not required unless 
cytopenias demand clarification of persistence of marrow blasts. 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 study-designated 
laboratory(ies) for exploratory biomarker studies. 
 
Bone marrow aspirates and/or biopsies will be collected during Phase II for biomarker studies at the 
time of relapse in patients who have had initial response to TAK-659/Ixazomib. 
 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 study-
designated laboratory(ies) after discussion with the sponsor investigator 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 study-designated laboratory(ies). 
 
Details regarding the preparation, handling, and shipping of these samples are provided in the 
Correlative Laboratory Manual. 
8.4 
Pharmacokinetic Measurements 
The primary aim of PK sampling in this study is to measure the plasma concentrations of  TAK-659 
when given in tandem with Ixazomib.  It is not intended that these measurements be intensive, but all 
patients (Phase I and Phase II) should have the following samples drawn: 
After the morning dose: 


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Cycle 1 Day 1 (predose, 2-4 hour postdose) 
Cycle 1 Day 15 (predose, 2-4 hour post dose) 
Cycle 2 Day 15 (predose, a postdose sample any time during the clinical visit) 
Cycle 3 Day 15 (predose, a postdose sample any time during the clinical visit) 
Cycle 4 Day 15 (predose, a postdose sample any time during the clinical visit) 
However, plasma collected for TAK-659 PK measurements may additionally be used for exploratory 
measurement of metabolites of TAK-659, if technically feasible and considered necessary for further 
understanding the metabolism and clearance of TAK-659.  Details on the collection, storage, processing, 
handling, and shipping of the PK samples are provided in the Laboratory Manual. The evaluable 
pharmacokinetic population would be those patients whom have at least one measurable post TAK-659 
dose concentration. 
8.5 
Phase II Interim Analysis 
An interim analysis for futility stopping will be conducted to determine whether continuation of the 
Phase II study 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 8 response-evaluable 
patients have completed 3 cycles of therapy or have discontinued therapy before 3 cycles.  If  more than 
2 responders are observed out of these initial 8 evaluable patients, patient enrollment will continue.  The 
number of evaluable patients needed in the second stage is 12.   
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 3 cycles of therapy or have discontinued therapy 
before 3 cycles.  If more than 1 responder is observed out of these initial 9 evaluable patients, patient 
enrollment will continue.  The number of evaluable patients needed in the second stage is 7.  These 
parameters were developed in context of the Statistical Methods described in Section 13. 
8.6 
Safety Follow-up Evaluations 
A safety follow-up visit should occur when subjects permanently stop study treatment for whatever 
reason (toxicity, progression, or at discretion of site investigator) and should be performed 30 days (±7 
days) after the last dose of treatment. Subjects who have an ongoing ≥ grade 2 or serious AE (SAE) at 
this visit will continue to be followed until the AE resolves to ≤ Grade 1 or baseline, is deemed clinically 
insignificant, and/or until a new anti-cancer treatment starts, whichever is earlier. 
8.7 
Long Term Follow-up Evaluations 
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 for up to 12 months after discontinuation of the study drug or until death, loss to follow-up, or 
withdrawal of consent for further follow-up, whichever comes first.  In addition, information on any 
subsequent anticancer therapies will be collected during the survival follow-period. For patents who 
achieve CR but discontinue study treatment while still in remission, disease progression data will also be 
collected during the survival follow-up period. 
 


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Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. 
9. 
BIOSPECIMEN STUDIES AND PROCEDURES 
This trial informs an overriding impasse to prevent progress in therapy of AML. That impasse results 
from the fact that a majority of AMLs are of high risk for failure of induction chemotherapy, or subject 
to early relapse, due to intrinsic genetic and epigenetic features. 
 
Unfortunately, these general features are quite diverse and yet an inroad against each scenario is almost 
always specific to the existence of a combination of 2 or 3 of such mutations within each case. This 
applies to the majority of AMLs of normal karyotype or those with nonrecurring cytogenetic changes, as 
opposed to AMLs with complex karyotype. Complex karyotype AMLs have the more profound defect 
for TP53 mutation that belies easy remedy. 
 
On the other hand, those normal karyotype AMLs are characterized by vulnerability to targeting agent 
combinations that unravel epigenetic silencing or enhancement of those participants in a final common 
pathway to therapeutic resistance embodied by HoxA overexpression, which is imparted by the 
combination of 2 or 3 individual mutations, as noted in the Rationale. 
 
Indeed, we and others have pursued and identified the existence of ameliorative interventions against 
this hurdle to sensitivity for both tyrosine kinase inhibitors and chemotherapy, and, in fact, both 
inhibition of Syk and application of proteasome inhibitors are a pathway to such sensitization 
2,7,15,17, 18). Bortezomib, either alone, or in our prior combination with Sorafenib, Vorinostat, was 
found to sharply curtail HoxA expression, leading to sensitivity. Mechanisms identified within these 
remedies included 1) prevention of proteasomal degradation of EZH2, thus leading to reengagement of 
PRC2-mediated repression of HoxA9 (2); 2) AMLs with Meis1 overexpression are 3x more sensitive to 
Syk inhibition in vitro, leading in vivo to prolonged survival in animals with xenografts (17). In our 
study, Bortezomib in combination with Vorinostat/Sorafenib, led to strong downmodulation of HoxAs, 
following upon de-repression of RUNX3, an antagonist of the HoxA pathway, and sharp 
downregulation of Id1, a HoxA pathway agonist. In our study, the efficacy of the combination was 
significantly linked to co-occurrence of mutations of Flt3(ITD) and TET2 (7).  
It is our hypothesis that the novel Flt3/Syk inhibitor TAK-659 is key to further sensitization in AMLs 
described by a combination of mutations that drive high HoxA and Meis1 expression, such as category 
1 mutations: Flt3ITD/TKD,KRAS, and mNPM1, as well as mutant JAK2, when they combine with 
category 2 mutations: either IDH1/2, TET2, ASXL1, or WT1 (mutually exclusive with TET2 mutation 
conferring the same phenotype as mutation of its binding partner, TET2 )(Ref 22). Mutations within all 
of these components feed into the final common pathway for WNT, affecting repression of WNT 
antagonists, such as RUNX3. Efficacious intervention involving TAK-659 and Ixazomib would be 
expected to interrupt the pathway to HoxA/Meis1 via RUNX3 upregulation and dampened -
catenin (see ref 2, ref 7 and ref 17, as well as Figures 1-2, -3 (in vitro confirmation of the hypothesis 
regarding sensitivity)). In addition, we have in vitro data to support the synergistic activity of TAK-
659 with Bortezomib against very high risk AML with high allele burden Flt3ITD and DNMT3A 
mutations, which likely add an additional pathway independent of WNT to HOXA (see above).  
This sensitization by TAK-659/Ixazomib is also expected to be reflected in a broader transcriptional 
upregulation/derepression of the tumor suppressor gene repression cohort characterizing the sensitive 
AML subtypes, in addition to RUNX3 (see ref 6): CDKN2A, DAPK1(see ref 7).  


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We will apply statistical methods to validate these mechanistic associations which predict 
responsiveness and drug efficacy in patients as in our prior work (7), and that of other recent 
targeted therapy trials (36, 37). 
Thus, the stage is set for our correlative studies to define what are the mutational combinations within 
normal karyotype/nonrecurring karyotype AML lending sensitivity to TAK-659 and Ixazomib. To 
pursue this infrastructure in detail: 
1. All patients on this protocol with relapsed/refractory AML will have undergone cytogenetic studies 
to annotate them as AML without complex karyotype or core-binding factor mutations as 
exclusionary categories.  
 
2. Patients’ AML blasts will have undergone analysis by next-generation sequencing, at a minimum, 
for a 27-gene panel of those genes important for prognostic and functional phenotypic classification. 
This is a routine clinical practice served by a CLIA certified laboratory such as Foundation One, 
Mayo, Tempus, Quest, ARUP or an institutional CLIA-certified laboratory:  
A minimum 27 gene mutational profile standard in practice for tracking mechanism and prognosis 
(1): 
 AML Mutations by NGS (ASXL1, CEBPA, DNMT3A, ETV6/TEL, FLT3, HRAS, IDH1, 
IDH2, KIT, KRAS, MLL, NPM1, NRAS, PHF6, RUNX1, TET2, TP53, WT1)  
 MDS Mutations by NGS (ASXL1, ATRX, BCOR, BCORL1, ETV6/TEL, DNMT3A, EZH2, 
GNAS, IDH1, IDH2, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF1, ZRSR2).  
 MPN Mutations by NGS (ASXL1, BRAF, CALR, CSF3R, EZH2, IKZF1, JAK2, JAK3, 
KDM6A, KIT, MPL, PDFGRA, SETBP1, TET2)  
 (the latter two panels have certain targets that apply more commonly to secondary AMLs)  
 
3. Mutational species leading to combinatorial mutational categories include: mutations of Flt3: ITD 
and TKD (35-40% overall), TET2 (15-20% overall), DNMT3A (40% overall), ASXL1 (10% 
overall), WT1 (<5% overall, 20% Flt3mutants), IDH1/2 (10-12% each among all AMLs as well as 
among Flt3mutants).  
 
Translational laboratory pharmacodynamic analysis will be undertaken in the laboratory of Reuben 
Kapur, PhD, Associate Director of Indiana University Cancer Center (Co-Director of Hematopoiesis, 
Hematologic Malignancy, Immunology) and Director of Leukemia Translational Research for the IU 
Cancer Center. In addition, select assays will be performed in other Big Ten institution labs:  Dr. Brian 
Parkin-digital PCR for determination of clonal minimal residual disease.  Certain proteomic assays, 
including mass spectroscopic determination of peptide identity, including -catenin and FOXM1 will be 
done by Drs. Irum Khan and Uma Aryal at University of Illinois, Chicago and Purdue University, 
respectively.   
 
Cells for in vitro analyses: Bone marrow blast cells are obtained from patients within 7 days prior to 
treatment and at the end of 3-4 days of therapy, and processed as previously described (7).  
 
DNA Measurements 
At screening, duplicate buccal swab specimens will be obtained from patients enrolled in Phase I and 
Phase II. These will be used to establish the multiclonal origins of the individual AML from non-
germline mutation(s) and to accurately assign allele frequency decrement(s) or not with therapy for 


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proper MRD assessment. Detailed instructions for the collection, processing, and shipment of samples 
are provided in the Correlative Laboratory Manual. 
 
Real-time RT PCR analysis in a focused gene-set array panel  
This is as described (38). qRT-PCR for 30 AML related genes and one housekeeping gene will be 
performed at low-density array (LDA) format according to the manufacturer’s protocol (TaqMan Gene 
Expression Micro Fluidic card, 4346799, Applied Biosystems/Life Technologies). 18S rRNA will be 
chosen from TaqMan Human Endogenous Control Plate (Applied Biosystems) as internal control. 
Relative expression will be calculated using RQ manager Ver 1.2 (Applied Biosystems) using one-
patient volunteer as a calibrator sample (fusion core-binding factor-positive (CBF+ve[inv(16)]), negative 
for Flt3ITD, and very low c-jun and Meis-1 expression). Copy number or fold-change in expression will 
be calculated using the 2-ΔΔCt method.(38)  
 
Immunoblot analysis Cytosolic or nuclear proteins will be subjected to Western blotting with indicated 
antibodies as described. (7)  
 
Responders will be annotated with this information as to the AML genetic and epigenetic phenotype, as 
well as into categories of pathways involved as in our prior study, using those statistical association 
platforms.  
 
Hypothesis: Experimentation will be performed to further elucidate the validity of an hypothesis 
generated within the prior combination targeted therapy with Bortezomib, Sorafenib, Vorinostat.  That 
hypothesis holds that Flt3 mutant AML requires collaboration from among mutant epigenetic modifiers: 
1) that selectively act within the Wnt pathway in order to disrupt antagonists to -catenin-the end-
effector of this pathway en route to HOXA, including RUNX3; or 2) they may have more direct action 
on DNA/chromatin methylation density of specific gene effectors, particularly HOXA’s, that leads to an 
upregulation of this crucial gene’s expression.  Examples of the former mutationally affected 
epigenetically-active enzymes required for cooperation with Flt3mutants are:  WT1, IDH1/2, TET2.  
Example of the latter is mutant DNMT3A. 
 
A corollary hypothesis is that Syk is a necessary collaborator in leukemic transformation in that its 
activity is required for expression of MEIS1, which is necessary for direct collaboration with HOXA to 
promote leukemic transformation.  Thus, utilization of the dual Flt3/Syk inhibitor TAK-659 is crucial to 
abrogation of both HOXA and MEIS1, and, as a result, the leukemic endgame of progression and 
therapeutic resistance.   
 


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The fact that proteasome inhibitors such as Bortezomib and Ixazomib can also lead to prevention of 
proteasomal degradation of the tumor suppressor EZH2, in order to engage HOXA repression by PRC2, 
while, at the same time, lead to Flt3 protein degradation through autophagy, is a necessary reinforcement 
of the prior set of events toward clonal extinction of the leukemic phenotype.  Additionally, FOXM1 is a 
required chaperone for nuclear entry of -catenin, and has recently been demonstrated a proteasome 
inhibitor target via HSP70 
upregulation and capture for 
inactivation 
 
Testing of RNA and protein 
(cytosolic and nuclear) of 
the recovered blast cells 
from the patient at inception 
of the study, and at 4 days 
into the therapy, will 
provide direct answers about 
mechanisms required to 
transpire in the interval of 
time 0 to early response (day 
4+) required for remission to 
evolve.  As suggested in the 
diagram, are the following 
specific questions to be 
asked. 
 
Mechanistic Studies of Required Pathways for drug activity (Indeed, understanding the mechanism 
will allow further modulation by additional epigenetically-active agents toward optimal responsiveness 
for chemotherapy sensitization) 
 
#1.  Is extinguished ID1 expression an early required event en route to remission, and does this feed into 
the pathway of  -catenin downregulation because ID1 is no longer able to repress CULLIN3, thus 
blunting Wnt pathway activation and further resulting in downregulation of the DVL/JUN complex to -
catenin activity? 
 
Approach: CULLIN levels in protein lysates will be tested, along with DVL/JUN/-catenin complexes 
by immunoprecipitation and immunoblotting in conjunction with determination of ID1mRNA levels in 
marrow blasts, before and at day 4 or 8 into therapy. 
 
#2.  Is RUNX3 mRNA de-repression also required for early steps in remission by way of its role in 
RUNX3 protein’s availability for binding and antagonizing -catenin, thus preventing TCF4 target 
transcriptional activation (c-myc, cyclin D1, HOXA)? 
 
Approach: Corresponding with determination of RUNX3 mRNA upregulation during early initiation of 
therapy, RUNX3 protein levels will be determined in cytosolic and nuclear lysates, and compared with 
simultaneous existence of -catenin in those distinct compartments by immunoprecipitation and 
immunoblotting.  We will expect that heightened RUNX3 expression will sequester -catenin in the 
RUNX3
TET2
(WT1)
miR29-B
& mutation TET2, or
Mutation WT1, IDH2
β-catenin
LSC
hoxA9, 10
Id1
?
1‐Wang Y, Xiao M, et al. Mol Cell. 2015;57(4):662‐
73. 
2‐Shih AH, et al. Cancer Cell. 2015;27:502-15.
3‐Jin X et al.  Cell Rep. 2016; 16:1829
4-Zhang N et al. Cancer Cell 2011; 20: 427-
42
CULLIN3
DVL
JUN
1
2
3
FOXM1
4


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cytoplasm.  We will also determine in subsequent cases described by the same events related to RUNX3 
upregulation, whether promoters of TCF4/-catenin target genes are, as a result, now devoid of these 
transactivating proteins JUN/-catenin by ChIP. 
 
#3.  Are there circumstances where treatment-induced RUNX3 mRNA upregulation does not occur, 
however, early during therapy it is observed that Wnt target genes are abrogated?  This might occur by 
virtue of TAK-659 activity to prevent PAK1-mediated phosphorylation of resident RUNX3 ( a binding 
partner of PAK1), thus preventing its sequestration/inactivation of -catenin. 
 
Approach: RUNX3 and -catenin compartment localization will be studied, and the autonomous 
phosphorylation of threonine 209 of RUNX3 in untreated cells will be correlated with the demonstrated 
apartheid of RUNX3 from -catenin in distinct cellular compartments, which, under control conditions, 
would ensure -catenin availability in the nucleus to bind to TCF4-dependent target promoters.  It is 
expected that treatment will reverse this state, dependent upon loss of TK-to-PAK1 activation and its 
RUNX3 phosphorylation. 
 
#4.  Is there a required mechanistic interaction between FOXM1 and -catenin that explains dramatic 
synergy of TAK-659 with proteasome inhibitor Ixazomib?  Indeed, it is known that proteasome 
inhibitors degrade FOXM1 in several cancers and that FOXM1 is a necessary chaperone for -catenin 
on Wnt/TCF4 target gene promoters, such as HOXA9/10.  This proteasome inhibitor activity against 
FOXM1 appears to occur as a result of upregulation of HSP70, which binds and sequesters FOXM1 
protein from positively autoregulating its promoter.  The inactivation of FOXM1 leads to loss of nuclear 
transport of -catenin destined for Wnt/TCF4 promoters. 
 
Approach:  We will perform reciprocal immunoprecipitations of cytosolic and nuclear proteins from 
lysates of patient blasts prior to and at 4 days into therapy by FoxM1 and -catenin antibodies.  
Subsequent experiments will look at TCF4 elements of the -catenin or HoxA10 promoter for co-
localization at these timepoints (DNA binding activity of FOXM1itself has been demonstrated not to be 
required in the former) by ChIP. 
 
#5.  Alternatively, does the activity of proteasome inhibitor Ixazomib in our cases derive from its 
prevention of active proteasomal degradation of EZH2, which is not mutated, and is overexpressed by 
TK signals like mutantFlt3.  This overexpressed and unmutated EZH2, when posttranslationally 
modified is sensitized to proteasomal degradation, which has been demonstrated to be prevented by 
Bortezomib in AML cells as described in the Rationale. 
 
Approach:  We will isolate nuclear and cytosolic protein from patient blasts prior to and following 
initiation of therapy and perform immunoprecipitation of EZH2 using both direct antibodies as well as 
anti-ubiquitin antibodies to determine EZH2 upregulation.  This will be correlated with remission 
success.  Subsequent experiments in the human Flt3 mutant cell line, Molm14, which has demonstrated 
cooperative sensitivity to TAK-659 and Bortezomib in our lab, will be used to pilot ChIP experiments 
for the HOX locus to identify re-engagement of PRC2 in the process of HOX repression following 
therapy.  This will be translated to select patient samples in the process of treatment. 
 
#6.  To what degree is sensitivity to TAK-659/Ixazomib demonstrable in Flt3 wild-type AML 
phenotypes, and is that sensitivity displayed in context of documented epigenetic mutations (category 2 


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genes) enabling the Wnt pathway in the setting of a paired mutation of category I mutations in the TK 
pathway downstream, such as KRAS, JAK2, NPM1 gene(s), etc. 
 
Approach: Statistical association of remission status imparted by TAK-659/Ixazomib among these 
paired categories (specific category 1 with category 2 drivers) will be sought. 
 
#7.  What is the depth of clonal reduction that describes TAK-659/Ixaxomib-induced remissions within 
Flt3mutant and Flt3 WT cases, and what is the best biomarker for measurement of clonal reduction?  In 
the two scenarios (WT or mutant), is a category 1 mutant marker or category 2 mutant marker/driver 
gene better representative of the clonal reduction? 
 
Approach:  In patient marrows followed in sequential cycles of remission induction with TAK-
659/Ixazomib, we will assess the clonal depth of remission by digital PCR (5-log sensitivity) of variant 
allele frequency for mutant driver genes from category1 and category 2 gene participants, using primers 
created from their mutant sequence at inception of therapy, as described by our Big Ten colleague Dr. 
Brian Parkin at University of Michigan.  This will be a direct demonstration of the possible routes to 
remission: coordinate elimination of TK and epigenetic driver mutants, vs. one class driver vs. the other, 
existing among different clonal populations in the diseased patient.  In particular, given the different 
mechanistic impact of Wnt pathway epigenetic genes (TET2 vs. IDH1/2 vs. WT1) vs. DNMT3A, this 
analysis may also help identify what category of disease may benefit from addition of another drug class 
to the combination in future investigations. 
 
Overall, these supplemental exploratory studies are crucial to better understanding of the 
upstream events prior to HOXA/MEIS1 downregulation that the agent combination targets.  
Later experiments will look at the HOXA/MEIS1 target genes that exert drug resistance, 
including those that mediate DNA damage-repair, whose downregulation may not only sensitize to 
chemotherapy, but also PARP inhibitors. 
9.1 
Source and Timing of Biospecimen Collections 
Details on the collection, storage, processing, handling, and shipping are provided in the Laboratory 
Manual. 
 
Plasma for Pharmacokinetic Measurements 
Phase 1 and Phase 2 
 Cycle 1 Day 1 (predose, 2-4 hour postdose) 
 Cycle 1 Day 15 (predose, 2-4 hour post dose) 
 Cycle 2 Day 15 (predose, a postdose sample any time during the clinical visit) 
 Cycle 3 Day 15 (predose, a postdose sample any time during the clinical visit) 
 Cycle 4 Day 15 (predose, a postdose sample any time during the clinical visit) 
 
Plasma collected for TAK-659 PK measurements may additionally be used for exploratory measurement 
of metabolites of TAK-659, if technically feasible and considered necessary for further understanding 
the metabolism and clearance of TAK-659.   
 
Bone Marrow Aspirate for Biomarker Analyses  


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Bone marrow aspirate will be collected for translational laboratory pharmacodynamic analysis, qPCR, in 
vitro analyses, proteomic assays via Western blotting, and MRD via digital PCR.  Bone marrow aspirate 
samples will be collected at the following timepoints: 
 
Phase 1 
 Screening,  
 Cycle 1 Day 4 or Day 8: Day 4 collection for the 1st 5 patients. Depending on timing of index 
peripheral blood reduction, collection may be moved to day 8 for subsequent patients. 
 Cycle 1 Day 15 
 Cycle 2 Day 15 
 Cycle 4 Day 15 
 
Phase 2 
 Screening 
 Cycle 1 Day 4 or Day 8: depending on findings from Phase I patients. 
 Cycle 1 Day 15 
 Cycle 3 Day 22 (or within 3 days prior to C4D1)* 
 Progression  
Note: In cases when insufficient bone marrow aspirate is collected, peripheral blood will be collected 
and submitted per the instructions in the CLM.  
*In the case of post-Cycle 3 assessment, aspirate and biopsy are suggested on day 22 (or within 3 days 
prior to C4D1), simultaneous with the plan to continue onto Cycle 4 day 1 that same day following the 
procedure, so to serve as record establishing the optimal response/composite CR. Such planning 
should be guided by the trend of blast reduction observed during Cycles 1, 2. 
 
Buccal Swabs for Germline DNA 
Phase 1 and Phase 2 
 Pre-treatment Cycle 1 Day 1 
 
Serum for Proteomic Analysis 
Phase 1 and Phase 2 
 Pre-treatment Cycle 1 Day 1 
 Cycle 1 Day 4 or Day 8: collection day will correspond to BM aspirate 
 
9.1.1 Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples collected for study-specific correlative 
research. Hoosier Cancer Research Network (HCRN), as Administrative Headquarters for the Big Ten 
CRC, will manage the banked samples. Samples will be banked indefinitely in the Hoosier Cancer 
Research Network Biorepository and used for future unspecified cancer-related research.  
9.1.2 Banking Samples for Future Unspecified Research 
Subject consent will be obtained to collect additional samples for future unspecified Big Ten Cancer 
Research Consortium studies. HCRN will manage the banked samples. Samples will be banked 
indefinitely in the HCRN Biorepository.  
 


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This includes: 
 Whole blood: Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
 Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to treatment on Cycle 
1 Day 1 and at the 30-day Safety Follow-up visit.  
 Pre- and Post-treatment serum: Whole blood for serum will be collected prior to treatment on Cycle 1 
Day 1 and at the 30-day Safety Follow-up visit. 
 
Please refer to the Correlative Laboratory Manual (CLM) for all sample collection, processing, labeling, 
and shipping instructions. 
 
9.1.3 Confidentiality of Biospecimens 
Samples will be identified by a subject’s study number assigned at the time of registration to the trial. 
Any material issued to collaborating researchers will be anonymized and only identified by the subject’s 
study number. 
10. 
CRITERIA FOR DISEASE EVALUATION 
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. (34) 
Investigators are encouraged to consult the reference for more detailed explanation of response criteria. 
CR, CRi/CRp, and PR are defined using the following criteria: 
Morphologic CR:  A CR designation requires that the patient achieve the morphologic leukemia-free 
state and have an ANC of more than 1,000/uL and platelets of > 100,000/uL.  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.  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. 
Morphologic CRi, CRp:  After chemotherapy, some patients fulfill all of the criteria for CR except for 
residual neutropenia (<1,000/uL) or thrombocytopenia (<100,000/uL). 
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% to 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. 
Progressive Disease 
Because the IWG criteria for AML do not provide a standardized definition for progressive disease, ⁽¹²⁾ 
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. 


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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. 
 
11. 
DRUG INFORMATION 
11.1 
TAK-659 
11.1.1 Supplier/How Supplied 
TAK-659 has been formulated into immediate-release film-coated tablets for use in phase 1 clinical 
studies via a common granulation process. Three different tablet dosage strengths, 20 mg, 60 mg, 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. 
 
TAK-659 20 mg, 60 mg, and additional dose strength tablets will be packaged into round, white, high-
density polyethylene (HDPE) bottles with induction seal, desiccant pack, and polypropylene child 
resistant caps. Each bottle containing 30 tablets of TAK-659 will be labeled with either a single-panel or 
multi-language label containing pertinent study information, country-specific requirements, and a 
caution statement. 
 
Takeda will supply TAK-659 at no charge to subjects participating in this clinical trial.  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
11.1.2 Storage and Stability 
TAK-659 tablets should be stored in the original dispensing bottles at 1°C to 25°C (33.8°F-77°F) with 
excursions permitted to 30°C (86°F) as long as they do not exceed 7 days. All temperature excursions of 
the tablets must be reported back to the manufacturer for assessment and determination for continued 
use. The TAK-659 tablets must be used before the retest date indicated on the label and/or 
accompanying documentation. Throughout the duration of the clinical trial, the stability of the drug 
product will be monitored. TAK-659 tablets should remain in the original bottle provided to the 
investigational TAK-659 site and patients. Drug supply must be kept in an appropriate, limited access, 
secure place until it is dispensed to the enrolled patients. 
Since TAK-659 is an investigational agent, it should be handled with due care. In the case of broken 
tablets, raising dust should be avoided during the clean-up operation. Damaged tablets may be harmful 
by inhalation, ingestion, or skin and/or eye contact. In the case of contact of damaged tablets with the 
eyes or skin, there should be immediate and thorough flushing and washing for at least 15 minutes with 
water (and soap for skin). Medical personnel should be notified. 
Patients are to be instructed on proper storage, accountability, and administration of TAK-659, including 
that TAK-659 is to be taken as intact tablets.  
A study drug accountability log must be completed for all study drug dispensed and administered to 
study patients. 


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11.1.3 Handling and Disposal 
Patients should be instructed to return their empty blister packs to the investigative site, rather than 
discarding them. Reconciliation will occur accordingly when the patient returns for their next cycle of 
take-home medication. 
11.1.4 Dispensing 
TAK-659 must be dispensed only from official study sites and to eligible subjects under the supervision 
of the site investigator.TAK-659 must be stored in a secure area according to local regulations. The 
investigative site is responsible for dispensing TAK-659 in the correct daily dose configurations. 
Comprehensive instructions should be provided to the patient in order to ensure compliance with dosing 
procedures. Patients who are receiving take-home medication must be given only 1 cycle of medication 
at a time.  
11.1.5 Packaging and Labeling 
TAK-659 20 mg, 60 mg, 100 mg, and additional dose strength tablets will be packaged into round, 
white, high-density polyethylene (HDPE) bottles with induction seal, desiccant pack, and polypropylene 
child resistant caps. Each bottle containing 30 tablets 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. 
11.1.6 Adverse Events 
See summary of adverse events in section 1.4.6. Please also reference the current TAK-659 IB for a 
comprehensive list of adverse events. 
 
11.2 
Ixazomib 
Ixazomib is a reversible proteasome inhibitor. Ixazomib preferentially binds and inhibits the 
chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.  
 
Ixazomib induced apoptosis of multiple myeloma cell lines in vitro. Ixazomib demonstrated in vitro 
cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, 
including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and 
lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, 
ixazomib demonstrated antitumor activity in a mouse multiple myeloma tumor xenograft model.  
11.2.1 Supplier/How Supplied 
Ixazomib will be supplied by Takeda Oncology at no charge to patients participating in this clinical 
trial. The ixazomib drug product will be from investigational supply.  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
11.2.2 Description of Investigational Agent 
The ixazomib drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg capsules as the active 
boronic acid. The dose strengths are differentiated by both capsule size and color as described below: 


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Dose Strength 
Capsule Size
Capsule Color 
4.0 mg 
Size 4
Ivory
3.0 mg 
Size 3
Light gray 
2.3 mg 
Size 2
Light pink 
 
For additional details, please see the ixazomib IB. 
11.2.3 Storage and Stability 
Upon receipt at the investigative site, ixazomib should remain in the blister and carton provided until 
use or until drug is dispensed. Ixazomib should be stored at the investigative site between +2°C and 
+30°C (35.6°F-86°F). Do not freeze ixazomib or store above 30°C. Any extreme in temperature should 
be reported as an excursion and should be dealt with on a case-by-case basis. 
11.2.4 Handling and Disposal 
Ixazomib is a cytotoxic drug. Follow applicable special handling and disposal procedures. Do not open 
or crush capsules. Avoid direct contact with the capsule contents. In case of capsule breakage, avoid 
direct contact of capsule contents with the skin or eyes. If contact occurs with the skin, wash 
thoroughly with soap and water. If contact occurs with the eyes, flush thoroughly with water.  
 
Any unused medicinal product or waste material should be disposed in accordance with local 
requirements. 
11.2.5 Dispensing 
Ixazomib must be dispensed only from official study sites and to eligible subjects under the supervision 
of the site investigator. Ixazomib should be stored in a secure area according to local regulations. It is 
the responsibility of the site investigator to ensure that study drug is only dispensed to subjects. 
11.2.6 Adverse Events 
The most common adverse events associated with ixazomib are thrombocytopenia, gastrointestinal 
toxicity (diarrhea, constipation, nausea, and emesis), peripheral neuropathy, peripheral edema, and 
cutaneous reactions. Please see the current IB for the comprehensive list of adverse events. 
12. 
ADVERSE EVENTS 
12.1 
Definitions 
12.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug that 
appears to change in intensity during the course of the study. The following are examples of AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical signs or 
symptoms or require treatment or further diagnostic tests   


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Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE (e.g., 
surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study regimen by the 
site investigator. 
12.1.2 Serious Adverse Event (SAE) 
An SAE is an adverse event that: 
 Results in death. NOTE: Death due to disease progression should not be reported as a SAE, 
unless it is attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject 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 for >24 hours or prolongation of existing hospitalization. 
NOTE: Hospitalization for anticipated or protocol specified procedures such as administration 
of chemotherapy, central line insertion, metastasis interventional therapy, resection of primary 
tumor, or elective surgery, will not be considered serious adverse events. 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; 
or the development of drug dependency or drug abuse. 
 New primary malignancy 
 Pregnancy 
12.1.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency from 
information provided in the current IB, package insert, or when it is not included in the informed 
consent document as a potential risk. Unexpected also refers to AEs that are mentioned in the IB as 
occurring with a class of drugs or are anticipated from the pharmacological properties of the drug but are 
not specifically mentioned as occurring with the particular drug under investigation.   
12.1.4 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
Unrelated 
The Adverse Event is not related to the drug(s)  
Unlikely 
The Adverse Event is doubtfully related to the drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  


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Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
12.2 
Reporting 
12.2.1 Adverse Events 
 AEs will be recorded from time of signed informed consent until 30 days after discontinuation of 
study drug(s). 
 AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
 All AEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within the EDC system. 
 All AEs considered related to study drug(s) will be followed until resolution to ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 
12.2.2 Serious Adverse Events (SAEs) 
12.2.2.1 Site Requirements for Reporting SAEs to Big Ten CRC Administrative Headquarters 
 SAEs will be reported from time of signed informed consent until 30 days after discontinuation 
of study drug(s).  
 SAEs will be reported on the SAE Submission Form and entered in the SAE tab in the EDC 
system within 1 business day of discovery of the event.   
 SAEs include events related and unrelated to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within the EDC system.   
 All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 1 or 
baseline and/or deemed clinically insignificant and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 
The site will submit the completed SAE Submission Form (see the Documents/Info tab of the EDC) to 
Big Ten CRC AHQ within 1 business day of discovery of the event.  The form will be sent 
electronically to Big Ten CRC AHQ at safety@hoosiercancer.org. The site investigator is responsible 
for informing the IRB and/or other local regulatory bodies of the SAE as per local requirements. 
 
The original copy of the SAE Submission Form and the email correspondence must be kept within the 
study file at the study site. 
 
Once the SAE has resolved, sites must electronically submit a follow up SAE Submission Form within a 
reasonable timeframe to Big Ten CRC AHQ at safety@hoosiercancer.org. 
12.2.2.2 Site Requirements for Reporting Pregnancy and Birth Events to BTCRC Administrative 
Headquarters 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study or within 
90 days after the last dose, she must inform the site investigator immediately and permanently 


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discontinue study drug. The site must immediately submit a completed Pregnancy Form to BTCRC 
AHQ at safety@hoosiercancer.org. 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 (i.e. from the initiation of study drug(s) through 90 days after the last dose of study drug), the site 
investigator must also immediately submit a completed Pregnancy Form to BTCRC AHQ at 
safety@hoosiercancer.org. Every effort should be made to follow the pregnancy for the final pregnancy 
outcome. 
12.2.2.3 Big Ten CRC AHQ Requirements for Reporting SAEs to Takeda Oncology 
Big Ten CRC AHQ will report SAEs to Takeda Oncology within 1 business day of receipt of the SAE 
Reporting Form from a site.  Follow-up information will be provided to Takeda Oncology as reasonably 
requested.   
 
SAE and Pregnancy Reporting Contact Information: 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
12.2.2.4 BTCRC AHQ Requirements for Reporting Pregnancy and Birth Events to Takeda 
Oncology 
BTCRC AHQ will report all pregnancy and birth events to Takeda Oncology within 1 business day of 
receipt of the Pregnancy Form.  Follow-up information will be provided to Takeda Oncology as 
reasonably requested.   
 
SAE and Pregnancy Reporting Contact Information: 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
 
12.2.2.5 Product Complaints or Medication Errors (Including Overdose) 
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 Millennium (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. 
 
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. While overdoses and underdoses 
constitute medication errors, doses missed inadvertently by a patient do not. Investigators must record 
all medication errors (including overdose) on the appropriate CRF form. Individuals who identify a 
potential medication error situation should immediately contact Takeda (see below) and report the event. 
 
For Ixazomib: 
Phone: 1-844-N1-POINT (1-844-617-6468) 
E-mail: GlobalOncologyMedinfo@takeda.com 
FAX: 1-800-881-6092;  Hours: Mon-Fri, 9 a.m. – 7 p.m. ET 
 
For TAK-659: 


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Phone: 1-844-ONC-TKDA (1-844-662-8532) 
E-mail: GlobalOncologyMedIfno@takeda.com 
FAX: 1-800-881-6092;  Hours: Mon-Fri, 9 a.m. – 7 p.m. 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 Millennium Pharmacovigilance. 
12.2.2.6 Sponsor-Investigator Responsibilities 
Big Ten CRC AHQ will send a SAE summary to the sponsor-investigator within 1 business day of 
receipt of SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness. 
12.2.2.7 Big Ten CRC AHQ Responsibilities for Reporting SAEs to FDA 
 
For Protocols Conducted Under an IND 
Big Ten CRC AHQ has been designated to manage the Investigational New Drug Application (IND) 
associated with this protocol on behalf of the sponsor-investigator.  Big Ten CRC AHQ will cross-
reference this submission to Takeda Oncology’s parent IND at the time of submission.  Additionally, 
Big Ten CRC AHQ will submit a copy of these documents to Takeda Oncology at the time of 
submission to FDA. 
 
Big Ten CRC AHQ will be responsible for all communication with the FDA in accordance with 
21CFR312 which includes but is not limited to the 7 and 15 Day Reports, as well as an Annual Progress 
Report. Additionally, Big Ten CRC AHQ will submit a copy of these reports to Takeda Oncology and 
IU DSMC at the time of submission to FDA. 
 
IND Exempted Protocols 
For protocols exempt from the requirements of an IND, the above stated requirements are not 
applicable. Big Ten CRC AHQ will continue to facilitate compliance of applicable requirements for the 
sponsor-investigator in relation to this study. This includes but is not limited to 21 CFR 50.20 informed 
consent, 21 CFR Part 56 IRB, and pertinent sections of the Public Health Service Act and FDAAA. 
12.2.2.8 IND Safety Reports Unrelated to this Trial 
Takeda Oncology will provide Big Ten CRC AHQ with IND safety reports from external studies that 
involve the study drug(s) per their guidelines. Big Ten CRC AHQ will forward the safety reports to the 
sponsor-investigator who will review these reports and determine if revisions are needed to the protocol 
or consent.  Big Ten CRC AHQ will forward these reports to participating sites within 1 business day 
of receiving the sponsor-investigator’s review. Based on the sponsor-investigator’s review, applicable 
changes will be made to the protocol and informed consent document (if required). All IND safety 
reports will also be made available to sites via the EDC system. 
 
Upon receipt from Big Ten CRC AHQ, site investigators (or designees) are responsible for submitting 
these safety reports to their respective IRBs, as per their IRB policies. 
 


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13. 
STATISTICAL METHODS 
13.1 
Study Design 
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.  
For the phase I dose escalation study, data analyses will be primarily descriptive and graphical in nature.  
No formal statistical hypothesis testing will be performed. 
For the Phase IIa study, ORR in the response-evaluable population will be estimated with 95% exact 
binomial confidence intervals (CIs), while considering the adaptive nature of Simon’s two-stage design. 
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, by Flt3WT and mutant populations. 
13.2 
Sample Size and Accrual 
During the dose escalation phase, dose escalation will be conducted according to a standard 3+3 dose 
escalation schema, and approximately 18 response-evaluable patients will be enrolled.  The MTD/RP2D 
cohort will have at least 6 patients. 
 
The sample sizes for the Phase II study are estimated using a one-sided test at a significance level of = 
0.1 with power of 80%.  To perform the phase 2 study, we will consider a Simon’s stage 2 design (See 
Study Overview Diagram) (39, 40).  The primary objective of the phase 2 portion of the study is to 
detect an efficacy signal that warrants further development of the combination in AML, which will 
likely be annotated by molecular genetic mutational subgroups.  It is most likely those will exist within 
the rubric of Flt3 mutation.  The primary measure of efficacy for the phase 2 portion will be ORR, 
which will include CR, CRp, CRi, and PR. Best response will be assessed by the end of Cycle 3 of 
TAK-659/Ixazomib combination for the purpose of an interim analysis between Stage 1 and Stage 2.  
The Flt3WT and Flt3mut cohorts will proceed to the second stage if patients respond by CR, CRp, CRi.  
 
It has been established in other trials involving single-agent Flt3-selective inhibitor(s), such as FDA-
approved Gilteritinib, that a composite complete response rate of approximately 40% occurs in AML 
patients with Flt3 mutations (41).  However, in cases of subclonal mutant Flt3 allele burden, this 
may not occur, especially because the epigenetic co-mutation driver is not addressed by the TKI.  
In such cases, we will stratify response rates of Flt3 mutant cohorts by mutFlt3 Variant Allele 
Frequency (VAF) in order to address the possibility that the proteasome inhibitor Ixazomib may 
contribute to clonal reductions of the clones bearing epigenetic comutational driver allele as well 
as a subclonal mutFlt3 population, or those that lack the mutant Flt3 allele altogether.  However, 
despite this advantage, we would not accept markedly inferior response rates overall should they 
indicate a response rate less than expected for active single agent Flt3 inhibitor, and therefore set the 
futility threshold below 30%. 
 
Therefore, within the Simon’s two-stage design, the Flt3 mutant cohort uses as null hypothesis of 
response rate ≤ 30%, versus an alternative hypothesis of response rate ≥ 55%. Based on a Simon 2-stage 
Optimal design, 8 patients will be accrued in the first stage.  If there are 2 or fewer responses in the 8 


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patients, the study will be stopped.  Otherwise, 12 additional patients will be accrued for a total of 20.  
The treatment will be recommended for further study if 8 or more responses are observed in 20 patients. 
 
On the other hand, we will follow the above rationale that proteasome inhibitor Ixazomib may contribute 
specific targeting of the epigenetic co-mutation driver allele in order to enhance what has been a limited 
contribution to antileukemic efficacy of Flt3-selective TKI’s, such as Gilteritinib, as observed within 
subclonal Flt3 mutant as well as Flt3wild-type disease cohorts (42; see de Boer B, et al. Cancer 
Cell.2018;34:674-689). Indeed, the phase I/II trial for Gilteritinib reported an 8% (average of 120mg and 
200 mg dose cohorts)  composite Complete Response rate (CRc), and an average 16% ORR for 
Flt3wild-type disease which was vastly inferior to Flt3 mutant (AE Perl, et al.  Lancet Oncology 18:  
1061, 2017 [ref 41][see Table S8]).  
 
Thus, there is a great need to establish platforms to target the epigenetic co-mutation drivers of the 
Wnt/-catenin pathway to HoxA, such as TET2 and WT1, as well as DNMT3A, EZH2 and 
ASXL1, where our in vitro evidence obtained on mutationally annotated Flt3 wild-type disease 
demonstrates promising activity of the combination of TAK-659 and Ixazomib.  Indeed, Syk 
inhibition, not simply Flt3 inhibition by the dual Flt3/Syk inhibitor appears to play an important role in 
such settings.  Further, we have evidence that not only does TAK-659’s Syk inhibitory activity target 
resistance mechanisms in Flt3 mutant AML, but that in combination with Ixazomib, there exists unique 
efficacy within the Flt3 wild-type AML’s arising from the above effectors. 
 
 
We will employ an initial comparator for targeted therapy futility of the combination in Flt3-WT 
patients, using a threshold response level similar to that derived from recent phase III trials among all-
comers of  Intermediate-dose cytarabine (IDAC) in different combinations, where the composite 
complete response (CRc) [CR, CRi, CRp ] was approximately 21% among all-comers ([43,44]Roboz 
etal. JCO 2014, Faderl et al. JCO 2012) However, other studies find a much lower aggregate response 
rate equal or less than 12% by supplementation of the IDAC backbone with either gemtuzumab, 
liposomal daunorubicin, or by cytoxan/topotecan ([45]Litzow, etal. BrJ Haem. 2010). Thus, the initial 
futility screen for the Flt3WT cohort uses a null hypothesis response rate of ≤ 15% versus an alternative 
hypothesis of response rate ≥ 40%. Based on a Simon 2-stage Minimax design, approximately 9 patients 
will be accrued in the first stage.  If there are 1 or fewer responses in the 9 patients, the study will be 
stopped. Otherwise, 7 additional patients will be accrued for a total of 16.  The treatment will be 
recommended for further study if 5 or more responses are observed in 16 patients. 
 
In addition, our broader goal is to later compare in exploratory fashion, the response rate among the 
subjects whose epigenetic mutational profile fits that profile of driver mutations acting in the Wnt--
catenin pathway, which our combination is designed to target, to the “investigator choice” standard for 
all-comers noted above.  We propose to assign a response rate among our sensitive population with the 
epigenetically-active mutant drivers noted above,  in an attempt to validate the sensitivity paradigm we 
have enunciated from our in vitro testing of NGS-annotated primary blasts.  Indeed,  we are testing the 
combination whose activity links with a mutational complement of epigenetic effectors for which no 
targeted therapy currently exists (epigenetic co-mutation drivers of the Wnt/-catenin pathway to 
HOXA, such as TET2 and WT1, as well as DNMT3A, EZH2 and ASXL1), where our in vitro evidence 


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obtained on mutationally annotated Flt3 wild-type disease demonstrates promising activity of the 
combination of TAK-659 and Ixazomib. 
 
Other efficacy measures, such as DOR, TTP, ability of the therapy to provide bridge to transplant, and 
mortality rate will also be considered in the decision to expand the study. Best responses from both 
cohorts will be assessed individually and combined in an effort to understand the all-comer response 
rate. Upon enrollment, the mutational profiles from Foundation One, Mayo, Tempus, Quest, ARUP, or 
an institutional CLIA-certified laboratory will be recorded in the database with minimum gene coverage 
as noted in Section 8.3. 
 
Retrospective analysis will be performed to identify additional patient selection markers beyond 
mutational profile, by scrutiny of the expression levels of mRNAs for target drivers in context of 
epigenetic repression of tumor suppressor genes noted in our prior published study.  Particular emphasis 
will be paid to the reversal of a signature for hyperexpression of HOXA9/10 and MEIS1 in a final 
common pathway for treatment resistance that will have been reversed by upmodulation of the repressed 
tumor suppressors RUNX3 and/or DAPK1, while strongly dampening the agonists for -catenin ID1, 
JUN, and FOXM1. 
13.2.1 Toxicity monitoring for phase II study 
Sequential boundaries will be used to monitor dose-limiting toxicity rate, based on the method described 
in Ivanova, Qaqish and Schell (Continuous Toxicity Monitoring in Phase II Trials in Oncology, 
Biometrics 61, 540-545, 2015[46]). This is a Pocock-type boundary where the same significance level is 
used for all looks. For practical implementation, we will look at the toxicity data in real time for every 3 
patients, separately among the two phase II cohorts. 
 
A DLT rate of 20% would be considered as acceptable while a DLT rate of 35% would be considered as 
too high and unacceptable. The type I error is chosen to be 10% and the power is chosen to be 80%. The 
accrual will be halted if excessive numbers of dose-limiting toxicities are seen, that is, if the number of 
dose-limiting toxicities is > the following boundary b out of n patients currently studied:  
 for the Flt3mut cohort, the boundary will be b/n=2/3,   3/6,   4/9,   5/12,   6/15,   7/18,   7/20; 
 for the Flt3WT cohort, the boundary will be b/n=2/3,   3/6,   4/9,   5/12,   5/15,   6/16. 
For example, if among the first 6 patients, there are more than 3 DLTs, then the accrual for the 
corresponding cohort would be paused. This will be looked at separately for the Flt3 WT and mutant 
cohorts. 
 
Based on this rule, for the Flt3mut cohort, if the “true” DLT rate is 20%, then the probability of early 
stopping is about 4.8% with expected sample size of 19.5. If the “true” DLT rate is 35%, then the 
probability of early stopping is about 37% with expected sample size of 16.3. For the Flt3WT cohort, if 
the “true” DLT rate is 20%, then the probability of early stopping is about 7.3% with expected sample 
size of 15.6. If the “true” DLT rate is 35%, then the probability of early stopping is about 45.7% with 
expected sample size of 13.6. 
13.3 
Randomization and Stratification 
For the Phase I study, patients will be enrolled in successive dose cohorts.  In the phase II portion of the 
study, patients will be enrolled in 2 different cohorts based upon their Flt3 mutation status.  No 
randomization is planned for this study. 


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13.4 
Populations for Analysis 
The populations used for analysis will include the following: 
 Safety population:  Patients who receive at least 1 dose of TAK-659 and Ixazomib will be used 
for all safety and analyses. 
 Pharmacokinetic population: Patients who have at least one measurable post TAK-659 dose 
concentration. 
 Pharmacodynamics population:  Patients with sufficient dosing in Cycle 1 and sufficient 
pharmacodynamics data will be used for PD analyses. 
 Response-evaluable population:  Patients who receive at least 1 dose of study drugs, 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 I 
portion of the study who either experience DLT during Cycle 1 or complete at least 75% of the 
planned doses of TAK-659 and Ixazomib within 2 cycles and have sufficient follow-up data to 
allow the investigators and sponsor to determine whether DLT occurred. 
13.5 
Procedures for Handing 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. 
13.6 
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. 
13.7 
Data Analysis Plan 
13.7.1 Primary Objective 
 
Phase I portion:  There is no primary efficacy endpoint for the dose escalation portion of the study. 
Toxicity data will be summarized and tabulated for all and for each dose level.  
 
Phase II portion: The phase II is not intended to demonstrate differences in treatment outcomes among 
disease groups, although potentially informative data will be subjected to exploratory analysis.  The 
primary endpoint is ORR.  ORR is defined as the rate of CRs and PRs in the response-evaluable 
population. It will be estimated with 95% exact binomial confidence intervals (CIs), while considering 
the adaptive nature of Simon’s two-stage design. 
13.7.2 Secondary Objectives: 
There is no secondary efficacy endpoint for the Phase I portion of the study.   


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Phase II study: the secondary efficacy endpoints for are ORR in FLT-3 mutant and 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 (TTP).  OS is defined as the time from the 
date of study entry to death. ORR will be estimated with 95% exact binomial confidence intervals (Cis). 
Time-to-event data will be analyzed by the Kaplan-Meier method. OS at 3 and 6 months and by FLT-3 
mutant cohort, FLT-3 WT cohort, and combined cohort) will be estimated using the Kaplan-Meier along 
with 95% CIs. 
13.8 
Exploratory Objectives and Pharmacokinetic Analysis 
The data analyses for these exploratory objectives are mainly descriptive. We will begin such analyses 
by tabulating the pairwise combinations of class1/class2 mutations that occur within the Flt3- mutant vs. 
-wild type cohorts and summarize the frequency of these mutations (most frequent class 1 are 
Flt3mutation (both ITD and TKD) ~40%; vs. N/KRAS 20%); within class 2 (NPM1 40%, IDH2/IDH1 
~20%, TET2 ~15%, WT1 ~10%, ASXL1 15%).  CR/CRp vs PR/nonresponse rates will be tabulated 
among groups based on presence of combinational number (combinational burden) and type, and will be 
compared by Fisher’s exact test. ORR will summarized with 95%CI and PFS will be analyzed by 
Kaplan-Meier methods in the whole study population and in the subgroups defined by the mutation 
subtypes. Additionally, we will explore the noted response groups based on identified markers from our 
prior trial that were predictive of ability to achieve or not remission, including ID1, JUN, HOXA, as 
well as the currently added markers-β-catenin and FOXM1, examining their individual association with 
remission status using logistic regression model. 
 
The plasma concentrations of TAK-659 will be determined by validated liquid chromatography tandem 
mass spectrometry (LC/MS/MS) assay methods. The pharmacokinetic population will be those patients 
whom have at least one measurable post TAK-659 dose concentration. 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. 
 
Sparse Plasma PK data from Phase I and Phase II will be used for the estimation of PK parameters in the 
PK-Evaluable Population, as noted in the prior section. Dose proportionality of TAK-659 plasma 
exposures will be evaluated by visual inspection of plots of individual PK parameter values versus dose.  
If data permits, regression analysis using a power model will also be used to assess dose proportionality. 
 
Plasma PK data from Phase I and Phase II may be used to explore the relationship between PD markers 
of SYK and FLT-3 inhibition (and their downstream targets) 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. 
 
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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13.9 
Biomarker Analysis 
As noted above, the relationship between observed clinical response and candidate biomarkers will be 
explored to identify a biomarker(s) predictive of sensitivity and/or resistance to TAK-659/Ixazomib. 
Developing the potential predictive biomarker(s) of TAK-659/Ixazomib mediated antitumor activity 
may require analysis of data from multiple patients. 
 
PD changes from baseline will be tabulated and summarized by patient, dose, and patient genotype, 
including Flt3 status and accompanying epigenetic mutations. Additionally, the relationship between 
changes in the PD marker and TAK-659 plasma exposure may be explored graphically and the PK/PD 
relationships may be explored using mathematical models as appropriate and permitted by the data. The 
relationship between changes in the PD marker and clinical response will also be explored. 
13.10 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 30 
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. 
 
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 study period will be classified by 
preferred term according to the WHO drug dictionary. 


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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. 
13.10.1 Electrocardiogram 
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. 
13.11 Interim Analysis 
Due to the two stage designs of the phase II study, there will be a predefined decision rule at the end of 
the first stage to descide on whether the study regimen is are active enough  to move on the second 
stage. This is not a formal interim analysis; there will be no formal interim analysis for this study.  Of 
note, in the phase II study, the FLT-3 mutant and FLT-3 WT cohorts will be evaluated independently 
and could be subject to enrollment hold without affecting the other cohort.    
14. 
TRIAL MANAGEMENT 
14.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted in accordance with the Indiana University Melvin and Bren Simon Cancer 
Center’s (IUSCC) DSMP for High Risk Phase I/II Trials. 
 
BTCRC AHQ facilitated oversight activities for Phase I/II High Risk Trials includes: 
 Review and processing of all AEs requiring expedited reporting as defined in the protocol 
 Provide trial accrual progress, safety information, and data summary reports to the sponsor-
investigator. For any increase in frequency of grade 3 or above adverse events (above the rate 
reported in the Investigator Brochure or package insert), the sponsor investigator will notify BTCRC 
AHQ who will notify the DSMC Chair immediately. The notification will include the incidence of 
study adverse events, grades, and attributions, as well as investigator statements regarding 
comparison with risks per the IB/ package insert. 
 Notify participating sites of adverse events potentially requiring expedited reporting and subsequent 
DSMC recommendations for study modifications. 
 Investigators will conduct continuous review of data and patient safety.  
 BTCRC AHQ will coordinate weekly (Phase I) meetings (Safety Calls) or monthly (Phase II) 
meetings which will include representation from each accruing site. 
o These meetings should include review of data, the number of subjects and significant toxicities 
as described in the protocol. BTCR AHQ should maintain meeting minutes and attendance for 
submission to the DSMC upon request. 
 Conduct the trial across all participating sites in accordance with the requirements set forth in the 
IUSCC DSMP. 
14.2 
Indiana University Data Safety Monitoring Committee Oversight 
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of subject 
safety, regulatory compliance, and data integrity for this trial. The DSMC will review this study to 
assess overall trial progress, toxicity, compliance, data integrity, and accrual per the Institutional DSMP.   


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Trials managed by Big Ten CRC AHQ are not routinely audited or monitored by IUSCC; however, the 
IUSCC DSMC retains the right to audit Big Ten CRC AHQ trials on a for-cause basis.  
 
The IUSCC DSMC will review study data semi-annually during the active treatment and safety follow-
up portion of the trial per the IUSCC DSMP. 
 
In preparation for the IUSCC DSMC review, Big Ten CRC AHQ will provide the following: 
 Monthly Summary Reports 
 Reports of the following, if not already included in the Monthly Summary Report: 
o Adverse event summary report (including serious adverse events) 
o Study accrual patterns 
o Protocol deviations 
 Audit and/or monitoring results, if applicable 
 Data related to stopping/ dose decision rules described in study design 
 Big Ten CRC AHQ Safety Call meeting minutes/ attendance 
Documentation of DSMC reviews will be provided to sponsor-investigator and BTCRC AHQ. The 
IUSCC DSMC will notify the sponsor-investigator and other regulatory bodies, as appropriate, for 
issues of immediate concern. The sponsor-investigator will work with BTCRC AHQ to address the 
DSMC’s concerns as appropriate. 
 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or 
benefits) to the patient warrant early closure of the study, this recommendation should be made in 
writing to the DSMC Chair and Compliance Officer. Alternatively, the DSMC may initiate suspension 
or early closure of the study based on its review of the investigator reports. 
14.3 
DSMC DLT Review 
Prior to making dose escalation/expansion/de-escalation decisions, the sponsor investigator and the Big 
Ten CRC AHQ study team will officially review all toxicity events for each subject for confirming 
treatment-related DLT. The study statistician will assist the determination of DLT and the interpretation 
of the statistical rule for dose escalation. Once a decision has been reached by the investigator, the 
official decision and toxicity data will be submitted to the DSMC  via email (IUSCC-DLT-Review-
L@list.iupui.edu). Treating additional subjects may not proceed until official DSMC correspondence 
confirms approval of dosing decisions for the next stage.  
14.4 
IND Annual Reports 
For trials with an IND held locally by the IU principal investigator or university, the IND Annual Report 
will be prepared and submitted to the IUSCC Compliance Team. This report will be reviewed by the 
DSMC at the time of FDA submission.  
14.5 
Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the life 
cycle of the study.  A summary report (QC Report) of these checks together with any queries resulting 
from manual review of the eCRFs will be generated for each site and transmitted to the site and the site 
monitor. Corrections will be made by the study site personnel. 
 


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Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects of the 
protocol are followed. Additional for-cause visits may occur as necessary. Source documents will be 
reviewed for verification of agreement with data entered into the EDC system.  It is important for the 
site investigator and their relevant personnel to be available for a sufficient amount of time during the 
monitoring visits or audit, if applicable. The site investigator and institution guarantee access to source 
documents by Big Ten CRC AHQ or its designee. 
 
The trial site may also be subject to quality assurance audit by Takeda Oncology or its designee as well 
as inspection by appropriate regulatory agencies. 
14.6 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All results of primary and 
secondary objectives must be posted to CT.gov within a year of completion. The sponsor-investigator 
has delegated responsibility to Big Ten CRC AHQ for registering the trial and posting the results on 
clinicaltrials.gov. Information posted will allow subjects to identify potentially appropriate trials for 
their disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and study site contact information. 
 
15. 
DATA HANDLING AND RECORD KEEPING 
15.1 
Data Management 
Big Ten CRC AHQ will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web-based clinical research platform compliant with Good Clinical Practices and Federal 
Rules and Regulations. Big Ten CRC AHQ personnel will coordinate and manage data for quality 
control assurance and integrity. All data will be collected and entered into the EDC system by study site 
personnel from participating institutions.   
15.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results will be 
captured in the EDC system or other secure database(s). If procedures on the study calendar are 
performed for standard of care, at minimum, that data will be captured in the source document. Select 
standard of care data will also be captured in the EDC system, according to study-specific objectives. 
Please see the Data and Safety Oversight Process (DSOP) guidelines for further details.  
 
The completed dataset is housed at Big Ten CRC AHQ and is the sole property of the sponsor-
investigator’s institution. It should not be made available in any form to third parties, except for 
authorized representatives of appropriate Health/Regulatory Authorities, without written permission 
from the sponsor-investigator and Big Ten CRC AHQ. After the initial publication, the complete data 
set will be available to all Big Ten CRC institutions. 


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15.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/Big Ten CRC AHQ, the site investigator 
agrees to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition.  All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with local and federal regulations. No records will be 
destroyed until Big Ten CRC AHQ confirms destruction is permitted. 
15.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information.  All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, 
will not be made publicly available. Information collected will be maintained on secure, password 
protected electronic systems. Paper files that contain personal information will be kept in locked and 
secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator and 
his/her research associates, Big Ten CRC AHQ, Takeda Oncology, IRB, or government agencies, like 
the FDA, may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in accordance with 
local data protection laws. 
 
If the results of the study are published, the subjects’s identity will remain confidential. 
16. 
ETHICS 
16.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in writing 
by an IRB.  The site investigator must submit written approval by the IRB to Big Ten CRC AHQ before 
he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements.  In addition, the IRB must approve all advertising used to recruit 
subjects for the study.  The protocol must be re-approved by the IRB as local regulations require.  
 
Progress reports and notifications of adverse events will be provided to the IRB according to local 
regulations and guidelines. 
16.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the Declaration of 
Helsinki. Conduct of the study will be in compliance with ICH Good Clinical Practice, and with all 
applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
16.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written information about 
the nature, purpose, possible risks and benefits of the study.  Subjects must also be notified they are free 


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to discontinue from the study at any time.  The subject should be given the opportunity to ask questions 
and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any procedure 
specifically for the study.  The site investigator must store the original, signed informed consent form.  
A copy of the signed informed consent form must be given to the subject. 
 


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