Conditions: Diffuse Large B-Cell Lymphoma Diffuse Large B-Cell Lymphoma Activated B-Cell Type Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type Diffuse Large B-Cell Lymphoma, Not Otherwise Specified High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements High Grade B-Cell Lymphoma, Not Otherwise Specified T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
The purpose of this research study is to evaluate a new investigational drug, TAK-659, given in combination with standard chemotherapy, for the treatment of Diffuse Large B-cell Lymphoma (DLBCL). ?Investigational? means that TAK-659 has not been approved by the United States Food and Drug Administration (FDA) for use as a prescription or over-the-counter medication to treat a certain condition. The primary purpose of this study is to find the appropriate and safe dose of the study drug to be used in combination with standard chemotherapy for the treatment of your disease and to determine how well the drug works in treating the disease. Other objectives include measuring the amount of the study drug in the body at different times after taking the study drug.

Participation in the study is expected to last for up to 3 years after receiving the last dose of the study drug. Patients will receive the study treatment for up to 18 weeks, as long as they are benefitting.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety, tolerability, and maximum tolerated dose of TAK-659 when combined with R-CHOP in the front-line treatment of high-risk diffuse large B cell lymphoma (DLBCL).

SECONDARY OBJECTIVES:

I. To assess preliminary efficacy of TAK-659 combined with R-CHOP in the front-line treatment of high-risk DLBCL.

EXPLORATORY OBJECTIVES:

I. To characterize the pharmacokinetics (PK) of TAK-659 in combination with R-CHOP.

OUTLINE: This is a dose-escalation study of spleen tyrosine kinase inhibitor TAK-659.

Patients receive rituximab intravenously (IV), cyclophosphamide IV, doxorubicin hydrochloride IV over 3-5 minutes, and vincristine sulfate IV on day 1, and prednisone orally (PO) on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning in course 2, patients also receive spleen tyrosine kinase inhibitor TAK-659 PO once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 3 years.

Arms:
arm 1: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV over 3-5 minutes, and vincristine sulfate IV on day 1, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2, patients also receive spleen tyrosine kinase inhibitor TAK-659 Dose Level 1 PO QD on days 1-21. Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV over 3-5 minutes, and vincristine sulfate IV on day 1, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2, patients also receive spleen tyrosine kinase inhibitor TAK-659 Dose Level 2 PO QD on days 1-21. Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV over 3-5 minutes, and vincristine sulfate IV on day 1, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2, patients also receive spleen tyrosine kinase inhibitor TAK-659 Dose Level 3 PO QD on days 1-21. Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cyclophosphamide intervention 2: Doxorubicin Hydrochloride intervention 3: Prednisone intervention 4: Rituximab intervention 5: Spleen Tyrosine Kinase Inhibitor TAK-659 intervention 6: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO intervention 4: Given IV intervention 5: Given PO intervention 6: Given IV

Protocol document:
Prot_SAP_000.pdf: 
NU Study Number: NU 18H02
Other Study Number: IISR-2017-101972
CONFIDENTIAL
This material is the property of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. 
Do not disclose or use except as authorized in writing by the study sponsor.
A phase 1 study of R-CHOP plus SYK inhibitor TAK-659 for the front-
line treatment of high-risk diffuse large B cell lymphoma (DLBCL)
Principal Investigator:
Reem Karmali, MD
Northwestern University 
645 N Michigan Ave, Suite 1020
Chicago, IL 60611 
Phone: (312) 695-0711 
Fax: (312) 695-7814 
reem.karmali@northwestern.edu 
 
Biostatistician:
Masha Kocherginsky, PhD
                                       mkocherg@northwestern.edu
 Study Intervention(s):
TAK-659, R-CHOP 
IND Number:
140223
IND Holder:
Reem Karmali, MD
Funding Source: 
Takeda/Millennium Pharmaceuticals, Inc. 
Version Date:
 4.3.2020  (Amendment 4 ) 
Coordinating Center:
Clinical Trials Office
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL  60611
http://cancer.northwestern.edu/CRO/index.cfm
IRB #: STU00207880-CR0003 Approved by NU IRB for use on or after 4/11/2022 through 4/10/2023.


NU Study Number: NU 18H02
Other Study Number: IISR-2017-101972
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS ............................................................................................................4
STUDY SCHEMA ............................................................................................................................6
STUDY SUMMARY .........................................................................................................................6
1.0
Introduction – BACKGROUND & RATIONALE ................................................................8
1.1
Disease Background .......................................................................................................8
1.2
R-CHOP Background & Overview...................................................................................9
1.3
TAK-659 Background & Overview...................................................................................9
1.4
Rationale for the Current Study.....................................................................................19
1.5
Exploratory Studies .......................................................................................................20
2.0
OBJECTIVES & ENDPOINTS...........................................................................................21
2.1
Primary Objective & Endpoint........................................................................................21
2.2
Secondary Objectives & Endpoints ...............................................................................21
3.0
PATIENT ELIGIBILITY......................................................................................................22
3.1
Inclusion Criteria............................................................................................................22
3.2
Exclusion Criteria...........................................................................................................24
4.0
TREATMENT PLAN ..........................................................................................................27
4.1
Overview........................................................................................................................27
4.2
Treatment Administration ..............................................................................................28
4.3
Phase I Dose Escalation Scheme .................................................................................30
4.4
Toxicity Management & Dose Delays/Modifications......................................................32
4.4.4
Management of Clinical Events.....................................................................................36
4.5
Concomitant Medications/Procedures...........................................................................37
4.6
Precautions and Restrictions.........................................................................................38
4.7
Duration of Therapy.......................................................................................................39
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4.8
Duration of Follow Up....................................................................................................40
4.9
Removal of Subjects from Study Treatment and/or Study as a Whole .........................40
4.10
Patient Replacement .....................................................................................................40
5.0
STUDY PROCEDURES.....................................................................................................41
6.0
ENDPOINT ASSESSMENT...............................................................................................47
6.1
Definitions......................................................................................................................47
6.2
Primary Endpoint ...........................................................................................................48
6.3
Secondary Endpoints ....................................................................................................48
7.0
ADVERSE EVENTS ..........................................................................................................48
7.1
Adverse Event Monitoring .............................................................................................48
7.2
Definitions & Descriptions..............................................................................................49
7.3
Adverse Event Reporting...............................................................................................50
8.0
DRUG INFORMATION ......................................................................................................54
8.1
TAK-659 ........................................................................................................................54
8.2
Rituximab.......................................................................................................................56
8.2.1
Other names..................................................................................................................57
8.3
Cyclophosphamide........................................................................................................58
8.4
Doxorubicin HCl.............................................................................................................59
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LIST OF ABBREVIATIONS
ABC
Activated B Cell
AE
Adverse Event
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
AML
Acute Myeloid Leukemia
ASCO
American Society of Clinical Oncology
ASH
American Society of Hematology
AST
Aspartate Aminotransferase
BCR
B-cell Receptor
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CNS
Central Nervous System
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DDI
Drug-Drug Interaction
DLBCL
Diffuse Large B-Cell Lymphoma
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board
EC#
Effective Concentration
ECOG
Eastern Cooperative Oncology Group
EPOCH-R
Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, Rituximab
FISH
Fluorescent In Situ Hybridization
FOCBP
Female of Childbearing Potential 
GCB
Germinal Center B-cell
G-CSF
Granulocyte Colony Stimulating Factor
H&PE
History & Physical Exam
IHC
Immunohistochemistry
IPI
International Prognostic Index
ITAM
Immunoreceptor Tyrosine Activation Motifs
IV (or iv)
Intravenously
MTD
Maximum Tolerated Dose
NCCN-IPI
National Comprehensive Cancer Network - International Prognostic Index
NCI
National Cancer Institute
NOS
Not Otherwise Specified
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
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PET
Positron Emission Tomography
PFS
Progression Free Survival
PI3K
Phosphoinositide 3-kinase
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response
R-CHOP
Rituximab; Cyclophosphamide; Doxorubicin; Vincristine; Prednisone
RP2D 
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
TEAE
Treatment-emergent Adverse Event
TNBC
Triple Negative Breast Cancer
WBC
White Blood Cells
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STUDY SCHEMA
Cycle 1* (1 cycle = 21 days):
R-CHOP 
Cycles 2-6:
R-CHOP + oral TAK-659 once daily starting at 60 mg**
*The first cycle of R-CHOP may take place on- or off-study. Those patients receiving R-CHOP prior to 
study registration must begin TAK-659 treatment within 21 days. Combination treatment will begin 
“Cycle 2” in both cases 
**A 3+3 dose escalation method will be utilized to find the MTD. Dose levels are 60 mg, 80 mg, and 100 
mg. All patients will have PK’s drawn during Cycle 2 (Day 1, 2, 15, and 16) as outlined in section 5.0.  
Response Assessments
PET/CT after completion of Cycle 3 + PET/CT after Cycle 6
Follow up visits at least every 6 months for up to 3 years from 
discontinuation of treatment
High-risk diffuse large B-cell lymphoma (DLBCL) 
by one of the following:
ABC/non-GCB subtype
High-intermediate or high-risk group by NCCN-IPI (score 
≥4) 
MYC gene rearrangement by FISH
MYC overexpression by IHC (≥40%) and BCL2 
overexpression by IHC (≥ 50%)
Treatment naïve transformed low-grade lymphoma OR 
previously treated transformed low-grade lymphoma with 
prior treatment not including an anthracycline
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NU Study Number: NU 18H02
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STUDY SUMMARY
Title
A phase 1 study of R-CHOP plus SYK inhibitor TAK-659 for the front-line 
treatment of high-risk diffuse large B cell lymphoma (DLBCL)
Version
 4.3.2020(Amendment 4)
Study Design
Phase 1, open-label study
Study Center(s)
Northwestern University
Objectives
Primary Objective
To determine the safety, tolerability, and maximum tolerated dose of 
TAK-659 when combined with R-CHOP in the front-line treatment of 
high-risk DLBCL
Secondary Objective
To assess preliminary efficacy of TAK-659 combined with R-CHOP in the 
front-line treatment of high-risk DLBCL
Exploratory Objective
To assess the pharmacokinetics of TAK-659 in combination with R-
CHOP.
Sample Size
12-18 evaluable patients 
Diagnosis & Key 
Eligibility Criteria
The study population will be patients with high-risk DLBCL by one of the 
following: ABC/non-GCB subtype, high-intermediate or high-risk group 
by NCCN-IPI (score ≥4), MYC gene rearrangement by FISH, MYC 
overexpression by IHC (≥40% and BCL2 overexpression by ICH ≥50%), 
or previously treated transformed low-grade lymphoma to large B cell 
lymphoma with prior treatment not including an anthracycline.
Treatment Plan
This is a single-arm, dose escalation phase I study. All patients will be 
treated with R-CHOP (without the addition of TAK-659) for cycle 1 and 
treatment for cycles 2-6 will include R-CHOP plus TAK-659. TAK-659 will 
be given orally continuously (days 1-21), once daily during these 21 day 
cycles (cycles 2-6) and be discontinued at the completion of cycle 6. 
Dosing of TAK-659 will be via a standard 3+3 dose escalation scheme, 
starting at 60 mg and increase to 80 mg followed by 100 mg, the target 
MTD. R-CHOP will be administered as per clinical standard, with 
rituximab, cyclophosphamide, doxorubicin, and vincristine given 
intravenously on day 1 and prednisone given orally on days 1-5 (or Day 
2-6). 
PK blood samples will be obtained during the first cycle of combination 
therapy (Cycle 2) as outlined in section 5.0. 
Statistical Methodology
A total of 12-18 evaluable patients will be enrolled and complete the 
study according to the 3 + 3 dose escalation scheme. Preliminary 
efficacy will be assessed by calculating the objective response rate 
(ORR) with 95% confidence interval at 3 months, and by estimating 
progression-free survival and overall survival at 12 and 18 months using 
Kaplan-Meier curves.  
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1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Disease Background
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin 
lymphoma, representing about 30% of all NHL. It is estimated that approximately 20,000 
new cases of DLBCL are diagnosed annually in the US.1 DLBCL is a form of aggressive 
B cell non-Hodgkin lymphoma and is invariably fatal without treatment. The standard 
treatment for patients with newly diagnosed DLBCL is R-CHOP (rituximab + 
cyclophosphamide + doxorubicin [hydroxydaunomycin] + vincristine [Oncovin®] + 
prednisone). Treatment with R-CHOP results in a 2-year progression-free survival (PFS) 
of approximately 75%, 5-year PFS of approximately 65%, 2-year overall survival (OS) of 
approximately 80%, and 5-year OS of approximately 75%.2 DLBCL is highly 
heterogeneous in histology, clinical behavior, and underlying biology, and therefore 
exhibits significant variation with regards to outcome after therapy.  There are several 
high-risk disease markers and poor prognostic factors that are associated with a high 
likelihood to be refractory to or relapse after treatment with R-CHOP, illustrating a need 
for improved therapies.  
Cell of origin subtypes of DLBCL can be defined by gene expression profiling and 
correlated with immunohistochemistry via the Hans Algorithm into activated B cell 
(ABC)/non-germinal center B cell (non-GCB) subtype and germinal center B cell (GCB) 
subtype. ABC/non-GCB subtype DLBCL has an inferior outcome when treated with R-
CHOP compared to the GCB subtype.3-5 Efficacy outcomes (response rates and survival 
measures) associated with ABC/non-GCB DLBCL patients treated with R-CHOP vary 
depending on the study. In general, the 2-year progression free survival (PFS) of 
ABC/non-GCB DBLCL and GCB DLBCL are ~60% and ~80%, respectively.3,6 The 5-year 
overall survival of ABC/non-GCB DBLCL has been reported at 56%.3
The human MYC oncogene is responsible for malignant transformation of several types 
of lymphoma, and is a sine qua non mutation associated with Burkitt lymphoma7,8.  MYC 
has been found to be rearranged in up to 10% of cases of DLBCL.9 MYC rearrangement 
and over expression are independent poor prognostic factors.9,10 Other recurrent genetic 
translocations found in lymphoma, including BCL-2 and BCL-6, can co-occur with MYC 
rearrangement, which is referred to as “double-hit lymphoma”, and subsequently confers 
a particularly poor prognosis with a 3-year overall survival of 49%.11-13
Indolent/low-grade lymphomas transform to a more aggressive large B cell lymphoma at 
a frequency of approximately 2-3% per year over the first 5 years.14 Transformed low-
grade lymphoma to large B cell lymphoma in patients who received no prior treatment of 
their low-grade lymphoma (treatment-naïve transformed low-grade lymphoma) have 
outcomes similar to that of de novo DLBCL.15,16 However, cases of previously treated 
transformed low-grade lymphoma have worse prognosis when compared to treatment-
naïve transformed low-grade lymphoma.15,16 Consolidative stem cell transplantation is 
considered in cases of previously treated transformed low-grade lymphoma because of 
this inferior prognosis.16
In addition to these disease-specific factors contributing to a worse prognosis, prognostic 
models that also account for patient-specific factors, such as the IPI and NCCN-IPI, are 
able to separate the higher risk groups from the lower risk groups.  Using the NCCN-IPI, 
patients treated in the rituximab era with a high-intermediate risk score of 4-5 and a high-
risk score of ≥6 had a 5-year overall survival of 64% and 33%, respectively.17
Relapsed/refractory DLBCL is associated with a poor prognosis with treatment options 
including salvage chemotherapy regimens and autologous stem cell transplant. Salvage 
regimens followed by stem cell transplant can result in a remission in approximately 40% 
of cases, but these remissions tend to be less durable.18 Given the poor prognosis in the 
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relapsed/refractory setting, it would be ideal to have more high-risk patients achieve 
favorable outcomes using front-line therapy.  R-CHOP has been compared to the more 
aggressive regimen dose-adjusted EPOCH-R in a randomized clinical trial of front-line 
therapy in patients with DLBCL. The results were presented at the American Society of 
Hematology annual meeting in December 2016, which demonstrated no difference in 
overall survival or event-free survival.19 Therefore, the lymphoma community is 
continuing to investigate regimens that improve upon R-CHOP in the front-line treatment 
of DLBCL, especially in the high-risk setting. 
1.2
R-CHOP Background & Overview
Combination chemotherapy with cyclophosphamide + doxorubicin [hydroxydaunomycin] 
+ vincristine [Oncovin®] + prednisone (CHOP) was established as a standard treatment 
of DLBCL decades ago20. Rituximab, an anti-CD20 monoclonal antibody, was later 
combined with CHOP (R-CHOP) and improved clinical outcomes compared with CHOP 
alone, thus becoming the standard treatment of DLBCL.21,22 R-CHOP has been 
compared to the more aggressive regimen dose-adjusted EPOCH-R in the front-line 
treatment of DLBCL, which demonstrated no difference in overall survival or event-free 
survival.19 Therefore, R-CHOP has remained the standard of care for the front-line 
treatment of DLBCL. R-CHOP in the front-line treatment of DLBCL results in a 2-year 
PFS of approximately 75%, 5-year PFS of approximately 65%, 2-year OS of 
approximately 80%, and 5-year OS of approximately 75%.2 Prognosis is significantly 
worse for certain subsets of DLBCL, as described above (section 1.1). 
The individual drugs of R-CHOP are FDA approved for the treatment of non-Hodgkin 
lymphoma, which includes DLBCL. R-CHOP is typically given on 21-day cycles for a total 
of 6 cycles.2,22 Intravenous rituximab (375 mg/m²), cyclophosphamide (750 mg/m²), 
doxorubicin (50 mg/m²), and vincristine (1.4 mg/m² with maximum dose 2 mg) are all 
given on day 1. Prednisone (100 mg) is given orally on days 1-5. The adverse events of 
R-CHOP are well known given the number of years it has been used in clinical practice. 
Possible grade 3-4 adverse events include neutropenia, infection, febrile neutropenia, 
neurological toxicity, thrombocytopenia, nausea/vomiting, mucositis, and cardiac toxicity.2
1.3
TAK-659 Background & Overview
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.23,24
Figure 1.a
Chemical Structure of TAK-659
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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).
1.3.1
Non-clinical Experience
1.3.1.1 Pharmacology
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 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. In an additional study in cultured human tumor cells treated 
with TAK-659, the EC50 ranged from 134 to 25,000 nM, with the 
greatest inhibitory effects observed in 2 diffuse large B-cell lymphoma 
(DLBCL) cell lines (OCI-Ly10 and HBL-1).
TAK-659 demonstrated significant antitumor activity after oral (PO) 
administration in HBL-1 (DLBCL cell line model; 120 mg/kg; p0.005), 
PHTX-95L (primary DLBCL tumor; 30, 60, and 120 mg/kg; p0.001), 
OCI-Ly10 (activated B-celllike DLBCL [ABC-DLBCL] cell line model; 30, 
60, and 90 mg/kg; p0.001), TMD8 (DLBCL cell line model; 60 and 90 
mg/kg; p0.001 and 0.01, respectively), 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), and PHTXM-32Ga (gastric cancer model; 60 mg/kg; p<0.001) 
mouse xenograft models. Tumor growth inhibition (TGI) correlated with 
markers of SYK pathway modulation in the models where it was 
analyzed (eg, HBL-1, PHTX-95L, and OCI-Ly10) and showed antitumor 
activity after TAK-659 treatment. 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.
In combination antitumor activity studies, treatment with TAK-
659+idelalisib, TAK-659+azacytadine and TAK-659+MLN1117 was 
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additive and treatment with TAK-659+ibrutinib, TAK-659+bendamustine, 
TAK-659-venetoclax, TAK-659 + daunorubicin, and TAK-
659+gemcitabine was synergistic. In a combination study of 
TAK-659+WX-mPD-1 (anti-programmed cell death protein 1 [PD-1]) 
(TAK-659 QD and WX-mPD-1 twice weekly [BIW] dosed for 3 weeks), 
durable TGI was observed until the last reported timepoint at Day 94. 
TAK-659+WX-mPD-1 demonstrated significant benefit (p<0.001) over 
TAK-659 and WX-mPD-1 single agent treatment in maintaining tumor 
regression. Preclinical studies show that SYK inhibition results in loss of 
myeloid-derived suppressor cells (MDSCs) and activation of T-cell 
response both in vitro and in vivo. TAK-659 in combination with anti-PD-
1 therapy has shown regulation of B cells, NK cells, and macrophages in 
syngeneic preclinical mouse models. The combination effects in immune 
cells are model and context dependent, and combination activity would 
be greatest in tumors where SYK-mediated MDSC or B-cell 
immunosuppression is active. The preclinical combination treatment of 
TAK-659 and anti-PD-1 therapy provides therapeutic advantage over 
single agent treatment with durable tumor growth inhibition, maintained 
complete responses, and a vaccinal memory effect. This effect could be 
indirectly attributed to the decrease in CD11b+ MDSC or B220+ B cells 
in the tumor-inflitrating lymphocytes of TAK-659-treated tumors. 
Therefore, the addition of TAK-659 to an anti-PD-1 agent could improve 
tumor regression via modulation of the tumor-infiltrating immune cells 
and other immune cells in the tumor microenvironment25.   
   
1.3.1.2 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. 
1.3.1.3 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 on the basis of the following:

Target organ toxicities were similar between rats and dogs, were 
generally monitorable and reversible, and included hematopoietic and 
lymphoid systems, GI mucosa, bone physis, and testicular and 
ovarian gametes.

Target organs specific to the rat included reversible and monitorable 
effects on the lens of the eye and urothelium of bladder and kidney.

Dose-limiting toxicity in dogs was pharmacologically mediated 
hematopoietic and lymphoid depletion/atrophy in dogs, and these 
same effects were prominent in rats; however, urolithiasis was dose 
limiting in a single rat.

Based on results from in vitro Ames assays and in vitro and in vivo 
micronucleus evaluations, TAK-659 is considered genotoxic 
(mutagenic and aneugenic) with a benefit:risk ratio that is acceptable 
in patients with advanced cancers.
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
TAK-659 was not phototoxic in hairless mice.

TAK-659 was locally tolerated after oral gavage administration.

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).
1.3.2
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]). Currently there are 4 ongoing studies (C34001, C34002, C34003 and 
C34005). A summary of the studies is given in the table below.
Table 1.
Overview of TAK-659 Clinical Studies
Protocol 
No.; Status
Study Objective(s)
Study Design and 
Population
Dose, Regimen,
Route, Duration
C34001;
ongoing
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; 
ongoing
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; dose has been 
escalated to 100 mg, 
120 mg, 140 mg, and 
160 mg QD and will be 
evaluated at 80 mg BID. 
Dose escalation is 
ongoing until MTD or 
RP2D is reached.
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 dose of 60 mg 
QD; dose has been 
escalated to 100 mg 
QD. Once determined, 
RP2D will be used in 
expansion cohorts.
C34004, 
ongoing
Primary: efficacy. 
Secondary: progression-free 
survival and efficacy.
Open-label, single-arm, 
multicenter, phase 2 study 
of TAK-659 in adult 
patients with relapsed or 
refractory DLBCL.
100 mg QD in 28-day 
treatment cycles.
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Protocol 
No.; Status
Study Objective(s)
Study Design and 
Population
Dose, Regimen,
Route, Duration
C34005; on-
going
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.
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 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.
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, refractory or 
relapsed after at least 1
prior line of therapy with 
no effective standard 
therapy available.
Safety Dose Expansion 
Phase: MTD/RP2D in 2 
safety expansion cohorts, 
advanced DLBCL and FL.
TAK-659: dose 
escalation from 60 mg 
in 20 mg increments 
and/or decrements in 
continuous dosing and 
intermittent dosing 
regimens.
Venetoclax: initially with 
a ramp-up to a target 
dose of 400 mg with 
escalation to 800 mg or 
1200 mg and/or de-
escalation to a 200 mg 
target.
Expansion phase will 
use MTD/RP2D of the 
combination
MLN1117-
1003; 
completed
Primary safety: to determine 
DLT 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, 
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ORR=overall response rate, PK=pharmacokinetics, QD=once daily dosing, 
RP2D=recommended phase 2 dose.
   
1.3.2.1 Pharmacokinetics
Preliminary plasma PK results were available from lymphoma, solid 
tumor, and AML patients enrolled in the dose escalation phases of 
Studies C34001 and C34002. In addition, preliminary urine PK results 
were available from lymphoma and solid tumor patients enrolled in the 
dose escalation cohorts of Study C34001. TAK-659 was characterized 
by fast absorption (overall median Tmax of 2 hours) in patients with 
hematologic and non-hematologic malignancies. Moderate variability 
was observed among dose-normalized steady-state AUC values in 
lymphoma, solid tumor, and AML patients (coefficient of variation of 
49.6%, 40.6%, and 38.8%, 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 1.9-fold to 2.6-fold and mean peak-to-trough ratios ranging from 3.2 
to 5.7 were observed across the study populations after repeated QD 
dosing for 15 days. On the basis of data in lymphoma and solid tumor 
patients, renal clearance accounted for 30-34% of TAK-659 apparent 
clearance, and therefore at least 30-34% 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. Terminal disposition half-life will be 
determined in a single dose PK run-in phase of the indolent NHL 
expansion cohort of C34001.
Additional details on TAK-659 PK are provided in the TAK-659 IB. 
1.3.2.2 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.
TAK-659 was not a potent reversible inhibitor of CYP1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, or 3A4/5 in human liver microsomes at concentrations 
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up to 100 M (IC50 values >100 M), nor a time-dependent inhibitor of 
these same CYPs at concentrations up to 50 M. In addition, TAK-659 
was not an inducer of CYP1A2, 2B6, or 3A activity or mRNA expression 
levels in human hepatocytes at concentrations up to 50 M. 
Furthermore, TAK-659 was not an inhibitor of the efflux transporters P-gp 
or BCRP in Caco-2 cells at concentrations up to 100 µM. When these in 
vitro findings are viewed in context of the Cmax observed at doses up to 
120 mg QD in patients with lymphoma or solid tumors or at doses up to 
160 mg QD in patients with AML, there is low predicted risk for TAK-659 
to cause DDIs via induction or inhibition of CYP enzymes, P-gp, or 
BCRP.
1.3.2.3 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.
1.3.2.4 Clinical Pharmacodynamics
Plasma inhibitory activity assays have been performed on plasma 
samples from a number of patients in the Study C34002 to examine 
TAK-659 activity on FLT3 signaling pathways levels. Up to 70% inhibition 
of FLT-3 phosphorylation was observed in samples from patients in the 
60 and 100 mg cohorts and ≥90% inhibition in patients in the 120 mg 
cohort as of the date of data cutoff.
 1.3.2.5 Clinical Efficacy
As of the 22 October 2016 datacut, there were 58 response-evaluable 
patients in Study C34001. Response data were available for 57 patients 
at the time of the data cut. 
Among response-evaluable patients with DLBCL with available data, 
best responses of CR and PR were reported for 8 patients and 4 
patients, respectively. Of the 12 patients with DLBCL who responded, 2 
had transitioned to stem cell transplant prior to the data cutoff and 6 were 
still receiving study drug as of the data cutoff; 1 patient has been on 
study for 19 cycles and another patient for 29 cycles. Seven patients had 
a best response of stable disease (SD), and 22 patients experienced 
progressive disease (PD). No response-evaluable patients with solid 
tumors had a best response of CR or partial response (PR). One patient 
had a best response of SD, and the remaining 9 patients experienced 
PD. Among the 2 response-evaluable patients with CLL, 1 had PR and 
was on study in Cycle 4 as of the data cutoff and 1 had SD. Four patients 
with indolent lymphomas responded to treatment with TAK-659. One 
patient with mucosa-associated lymphoid tissue lymphoma achieved a 
CR and is still on study in Cycle 10 as of the data cutoff, 3 patients with 
FL achieved PR, and 1 patient had SD. One of the FL responders 
remains on study in Cycle 22 as of data cutoff.   
1.3.3
Summary of Safety
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As of 22 October 2018, 338 patients have been dosed with TAK-659, including 
143 patients in the Study C34001, 43 patients in Study C34002, 41 patients in 
Study C34003, 49 patients in Study C34004, 41 patients in C34005, 10 patients 
in Study C34007, and 11 patients in C34008. TEAEs, from the 22 October 2018 
analysis of TAK-659 single agent studies (C34001, C34002, C34004, and 
C34007) and TAK-659 combination studies (C34003, C34005, and C34008), 
were generally as expected on the basis of nonclinical toxicology findings of 
TAK-659 and the patient population being studied. Overall, 244 (99.6%) of 245 
patients in the TAK-659 single agent studies and all 93 patients in the TAK-659 
combination studies experienced ≥1 TEAE. The most common TEAEs reported 
(30% of patients) in these single agent studies and combination studies (N=93) 
have been AST increased (49% and 40%), pyrexia (46% and 49%), amylase
increased (36% and 28%), fatigue (34% and 39%), anemia (34% each), diarrhea 
(33% and 34%), blood creatine phosphokinase increased (26% and 33%), lipase 
increased (30% and 26%), and hypophosphatemia (30% and 32%).
Overall, Grade ≥3 TEAEs occurred in 91% (222 of 245) of patients in the single 
agent studies and 84% (78 of 93) of patients in the combination studies. The 
most common Grade 3 or greater TEAEs (≥10% of patients) in the single agent 
studies and the combination studies have been amylase increased (20% and 
10%), anemia (20% and 25%), hypophosphatemia (18% and 26%), lipase 
increased (16% and 11%), neutropenia (16% and 23%), febrile neutropenia (15% 
and 6%), blood creatine phosphokinase increased (11% and 15%), 
thrombocytopenia (11% and 13%), fatigue (5% and 11%), AST increased (10% 
and 8%), and pneumonia (10% and 4%). Overall, SAEs occurred in 76% (186 of 
245) patients in the single agent studies and 50% (60 of 93) patients in the 
combination agent studies. The most treatment common treatment-emergent
SAEs in the single agent and combination studies were pyrexia (14% each), 
febrile neutropenia (12% and 8%), pneumonia (11% and 4%), and febrile 
neutropenia (12% and 8%). As of 22 October 2018, there have been 85 deaths: 
45 patients in Study C34001, 25 patients in Study C34002, 7 patients in Study 
C34003, 4 patients in C34004, and 8 patients in Study C34005. No deaths have 
been reported in Studies C34007 and C34008. Most causes of death were 
considered related to the disease under study or complications thereof and were 
not considered related to study treatment.
1.3.3.1 Potential Risks Based on TAK-659 Clinical Studies
Identified Risks
Infection
Infections, including pneumonia, P jirovecii pneumonia, CMV, and sepsis 
are an important identified risk for subjects receiving TAK-659 treatment. 
In single agent TAK-659 studies (C34001, C34002, C34004, and 
C34007), most patients (63%) experienced at least 1 TEAE of any grade 
classified under the infections and infestations SOC as defined by the 
MedDRA. Pneumonia was the most frequently reported TEAE (16%), 
followed by CMV infection (11%). Pneumonia (10%), and sepsis (6%) 
were the most frequently reported Grade ≥3 TEAEs. In TAK-659 
combination studies (C34003, C34005, and C34008), 54% (50 of 93 
patients) experienced at least 1 TEAE of any grade classified under the 
infections and infestations SOC as defined by the MedDRA. Pneumonia 
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and oral candidiasis were the most frequently reported TEAEs (9% 
each), followed by urinary tract infection (8%). Pneumonia (4%)was the 
only reported Grade ≥3 TEAE. The majority of the CMV infections were 
reactivations.
Investigators are advised to closely monitor patients for infections 
throughout TAK-659 treatment. Patients should be advised to report 
fever and should be assessed for further management as per standard 
medical practice. Recommendations regarding monitoring and use of 
anti-infective prophylaxis are included in each study-specific protocol.
Pneumonitis
Pneumonitis has been added as a potential risk of TAK-659. There were 
3 SAEs of pneumonitis, all reported in Study C34001 and considered by 
the investigator to be related to study treatment. The first patient 
developed pneumonitis 46 days after starting treatment with TAK-659 at 
80 mg QD. The event of pneumonitis was considered 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 ICFs was updated. The event was the first SAE of 
pneumonitis in the TAK-659 program. Subsequently, 2 new SAE cases 
of pneumonitis have been reported during the current reporting period; 1 
patient with DLBCL who experienced pneumonitis 34 days after starting 
and 10 days after discontinuation of 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. Pneumonitis 
has been reported in clinical experiences of other 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. Pneumonitis and other pulmonary 
toxicities are being closely monitored in TAK-659 clinical studies
Lipase Elevations
Asymptomatic elevation in lipase is an important 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. A TEAE of lipase increased was 
reported in 16% (any Grade) and 14% (Grade ≥3) of subjects treated 
with TAK-659. Theselipase elevations were generally asymptomatic. 
There was 1 SAE of pancreatitis reported in the safety database in 
subjects treated with TAK-659. Monitoring of serum lipase should be 
performed according to the study protocol.
Lymphoid and Hematopoietic Effects
Lymphoid and hematopoietic effects are an important potential risk for 
subjects receiving TAK-659 treatment. Neutropenia (any Grade) was 
reported in 20% of subjects treated with TAK-659 as a single agent and 
in combination; Grade ≥3 neutropenia in 18%, and febrile neutropenia 
(any Grade) in 13% of subjects treated. Neutropenia is commonly 
observed in hematologic malignancies and this may provide alternative 
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causality. Neutropenia management guidelines are provided in study 
protocols. Granulocyte colony stimulating factors can be used
for supportive measures; guidance for their use is per routine local 
oncology practice, as well as protocol-specific.
1.3.3.2 Potential Risks and Benefits based on non-clinical studies
Potential risks identified from nonclinical studies in dogs and rats include:
Lymphoid and hematopoietic effects that include lymphoid depletion 
and myelosuppression that are associated with thrombocytopenia, 
neutropenia, and reticulocytopenia. These findings may be associated 
with increased susceptibility to infection, bleeding, and/or anemia.
Epithelial effects on the intestinal tract, urinary tract, and lens. 
Intestinal effects included minimal-to-slight mucosal hemorrhaging.
Urinary and renal tract effects included hyperplasia of transitional 
epithelium in the kidney and bladder, dilatation and hemorrhage in the 
renal pelvis that led to hematuria and proteinuria, and urolithiasis with 
possible ureter obstruction. Lens effects included epithelium 
hyperplasia leading to anterior axial opacity.
Reproductive system effects, including decreased spermatozoa and 
seminiferous tubule degeneration in the testis and corpora luteal 
necrosis in the ovaries.
Possible mutation of the deoxyribonucleic acid (DNA).
≥1.07-μM TAK-659 can inhibit ADP- and collagen-mediated human 
platelet aggregation in the context of this in vitro study.
Growth plate thickening and disorganization (not relevant to adults).
Risks listed above are based on toxicology findings in the nonclinical 
studies with TAK-659; they may or may not present with similar 
severity in humans. All of the identified nonclinical target organ 
toxicities were generally reversible and are anticipated to be 
manageable with clinical monitoring and intervention. Clinical study 
protocols for TAK-659 will include regular monitoring for the potential 
AEs specified for this compound using routine laboratory evaluations, 
urinalysis, physical examinations, disease assessment, and eye 
exams. The timing of these tests and evaluations will be detailed in the 
protocol Schedules of Events. Additional tests and evaluations will be 
symptom- and finding-guided based on the standard of care. It is 
possible that administration of TAK-659 will result in toxicities that were 
not observed or predicted from the studies completed in rats and dogs.
Lymphoid and Hematopoietic Effects
Lymphoid and hematopoietic effects were observed in animals. 
Lymphoid and hematopoietic depletion consisted of depletion of bone 
marrow hematopoietic precursors and decreased lymphocytes in 
lymphoid tissues. There were correlative decreases in circulating 
lymphocytes, eosinophils, neutrophils, and reticulocytes, along with 
decreases in thymic and splenic weights. These effects were dose 
dependent, pharmacologically mediated, and generally reversible. 
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. Other effects on epithelial tissues included 
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stomach glandular mucosa hemorrhage, cecum crypt necrosis, 
lacrimal gland atrophy/necrosis, and mammary gland and skin hair 
bulb single-cell atrophy/necrosis. Increases in serum amylase, lipase, 
magnesium, urea, and creatinine, along with sporadic hematuria and 
proteinuria, were considered a result of the renal lesions and, to a 
lesser extent, reflective of subclinical dehydration. 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 reversed by the end of the 28-day recovery period, with 
the possible exception of lens opacity (which, mechanistically, is 
expected to be reversible). 
In dogs, the primary epithelial effect was on the intestine and included 
minimal to slight hemorrhage of the intestinal mucosa (ileum, cecum, 
and/or colon). There were also coccidia (parasite) in the ileum and/or 
cecum, and their presence was considered secondary to the observed 
intestinal lymphoid depletion and associated decreased immunity. 
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 adverse event (AE) monitoring as detailed in the 
protocol.
Reproductive Effects
Effects on the reproductive systems included testicular seminiferous 
epithelium degeneration and decreased spermatozoa in the 
epididymides with correlative decreased mean testicular weights in 
male rats and dogs and minimally increased corpora luteal necrosis in 
female rats. The reproductive effects are expected to be reversible.
Skeletal Effects 
Effects on the growth plate and related structures were observed in 
animals. The effects were dose dependent, pharmacologically 
mediated, and reversible and included thickening/disorganization of the 
physis (femur and sternum) and articular-epiphyseal junction, and 
retention/disorganization of the primary spongiosa. Additionally, the 
effects on the growth plate would not be relevant to adult patients 
whose bone growth plate is closed. 
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. 
Spleen tyrosine kinase has been implicated in mitotic spindle function 
(20); 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. 
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1.4
Rationale for the Current Study
The prognosis and outcomes of high-risk subsets of DLBCL treated with standard R-
CHOP are not acceptable and require significant improvement with novel therapies (see 
section 1.1). There is increased expression of B cell receptor (BCR) signaling 
components among the molecularly characterized BCR/proliferation subtype of DLBCL, 
including but not limited to spleen tyrosine kinase (SYK), a non-receptor cytoplasmic 
tyrosine kinase.28 SYK plays a critical role in BCR signaling-driven tumorigenesis. TAK-
659 (Takeda Pharmaceutical Company Limited) is a selective, reversible, and potent 
inhibitor of SYK. With the hypothesis that TAK-659 may generate pronounced antitumor 
effects in lymphomas including DLBCL, it is being clinically investigated in early phase 
clinical trials. Updated results of a phase 1, dose-escalation with expansion cohorts study 
of single agent TAK-659 in mostly relapsed/refractory lymphoma patients was recently 
presented at the International Conference on Malignant Lymphoma in Lugano, 
Switzerland in June 2017.10 The maximum tolerated dose (MTD) has been determined to 
be 100 mg by mouth once daily. 65 patients with relapsed/refractory DLBCL have been 
treated on study with single agent TAK-659. Encouraging clinical responses have been 
seen in these heavily pretreated DLBCL patients with 12 of 45 (27%) achieving an 
objective response. 8 of 45 patients (18%) have obtained a complete response, and most 
of these have been durable at time of last follow-up. These responses have been seen in 
both the ABC/non-GCB and GCB DLBCL subtypes. Of the drug-related serious adverse 
events seen with TAK-659, there does not appear to be a significant overlapping toxicity 
profile with that of standard chemotherapy regimens such as R-CHOP.
Pre-clinical mouse models have demonstrated an anti-tumor vaccinal memory effect in 
mice previously treated with TAK-659 with concurrent anti-PD-1 therapy.29 When these 
mice with syngeneic tumors are treated with TAK-659 with or without concurrent anti-PD-
1 therapy, some mice achieve objective responses including complete responses. The 
mice that remain alive in complete remission after 90 days in the combination group are 
re-inoculated with the same tumor cells. The majority of these mice maintained an 
inhibitory tumor growth response with no tumor formation, suggesting an anti-tumor 
vaccinal memory effect of TAK-659 with concurrent anti-PD-1 therapy. 
Based on these results, including TAK-659 in front-line therapy may potentially lead to 
higher response rates and more durable remissions. Therefore, it is worthwhile 
investigating TAK-659 in combination with R-CHOP in this area of need in the front-line 
treatment of high-risk DLBCL. We hypothesize that the administration of TAK-659 in 
combination with R-CHOP to patients with high-risk DLBCL in the front-line setting will 
have an acceptable toxicity profile and lead to improved durable responses and 
outcomes. TAK-659’s MTD as a single agent has been determined to be 100 mg daily, 
however, the MTD may be different when combined concurrently with R-CHOP.  
Therefore, a dose escalation of TAK-659 is necessary in combining with the standard 
dosing of R-CHOP.
1.5
Exploratory Studies
Pharmacokinetics of the novel combination of TAK-659 and R-CHOP will be explored. 
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NU Study Number: NU 18H02
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Prot Amnd 4/Version Date:04. 3.2020
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2.0
OBJECTIVES 
2.1
Primary Objective & Endpoint
To determine the safety, tolerability, and maximum tolerated dose of TAK-659 when 
combined with R-CHOP in the front-line treatment of high-risk DLBCL
 
 Toxicity and tolerability will be assessed by history and physical, including vital signs and 
ECOG performance status, and laboratory values to determine incidence and grade of 
adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities, as 
defined by the NCI CTCAE v5.0. Maximum tolerated dose will be evaluated using a 3+3 
dose escalation method. Patients will be evaluated for dose-limiting toxicities (DLT’s) 
during the second cycle (21 days) of combination treatment. Dose escalations will be 
followed as described in section 4.3.
2.2
Secondary Objectives & Endpoints
To assess preliminary efficacy of TAK-659 combined with R-CHOP in the front-line 
treatment of high-risk DLBCL
: 
2.2.1 Overall response rate (ORR), using Lugano criteria (2014), will be defined as the 
percentage of subjects with a confirmed complete response (CR) or partial response 
(PR) as assessed by the investigators.This will be assessed at 3 months.
2.2.2 Progression free survival (PFS) will defined as the time from study enrollment until 
progression/recurrence of lymphoma or death from any cause. This will be assessed at 
12 and 18 months.
2.2.3 Overall survival (OS) will be defined as the time from study enrollment until death 
from any cause.  This will be assessed at 12 and 18 months.
2.3
Exploratory Objectives 
To characterize the PK of TAK-659 in combination with R-CHOP.
Endpoint: Summary statistics of maximum (peak) plasma concentration (Cmax), first time 
to reach maximum (peak) plasma concentration (Tmax), area under the plasma 
concentration versus time curve (AUC), and terminal disposition half-life (t1/2) by cohort 
and day.
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NU Study Number: NU 18H02
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Prot Amnd 4/Version Date:04. 3.2020
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3.0
PATIENT ELIGIBILITY
The target population for this study is patients with previously untreated high-risk diffuse large B-
cell lymphoma (DLBCL). This trial will be conducted at Northwestern University. 
A total of 12-18 evaluable subjects will be needed for this trial. Approximately 3 potentially eligible 
patients are seen per month, and it is anticipated that at least 1 per month will be accrued. 
Potential patients may be referred to the Principal Investigator (PI) at Northwestern University, Dr. 
Reem Karmali, at (312) 695-0990.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. Please refer 
to Section 11 for complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have a pathologically confirmed diagnosis of DLBCL (including 
DLBCL NOS, DLBCL GCB type, DLBCL ABC/non-GCB type, T-cell/histiocyte-
rich large B cell lymphoma, high-grade B cell lymphoma with MYC and BCL2 
and/or BCL6 rearrangements, and high-grade B cell lymphoma NOS). 
NOTE: DLBCL transformed from low-grade lymphoma among treatment-naïve 
patients or patients previously treated with a non-anthracycline containing 
regimen are permitted.
3.1.2
Patients may have completed the first cycle of R-CHOP (off study not combined 
with TAK-659) ≤ 30 days prior to the first dose of TAK-659 or plan to receive the 
first cycle of R-CHOP after registration. 
3.1.3
Patients must have at least one high-risk feature, including: 

ABC/non-GCB subtype determined by gene expression profiling or Hans 
algorithm by immunohistochemistry per treating institution standards, 

high-intermediate or high-risk group by NCCN-IPI with score ≥4, at time of 
diagnosis, 

MYC gene rearrangement (by FISH), 

MYC overexpression by IHC (≥40%) and BLC2 overexpression by IHC 
(≥50%),

DLBCL transformed from low-grade lymphoma among treatment-naïve 
patients or previously treated transformed low-grade lymphoma with prior 
treatment not including an anthracycline. 
NOTE: BCL2 and/or BCL6 aberrancy are not required for enrollment, but 
assessment for rearrangement by FISH and overexpression by IHC are required 
if there is presence of MYC rearranged by FISH.
3.1.4
Patients must have measurable disease (defined as ≥1.5 cm in diameter) with 
correlated FDG-avidity on PET scan 
3.1.5
Patients must have recovered (i.e., ≤ Grade 1 toxicity) from the reversible effects 
of prior anticancer therapy, if applicable.
3.1.6
Patients must be age ≥ 18 years with a life expectancy of greater than 3 months.
3.1.7
Patients must exhibit an ECOG performance status of 0-2.
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Prot Amnd 4/Version Date:04. 3.2020
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3.1.8
Patients must have adequate organ and bone marrow function within 14 days 
prior to registration, as defined below:
Bone Marrow Reserve**:
absolute 
neutrophil count
≥ 1,000/mcL
platelets
≥ 75,000/mcl (NOTE: Patients with bone marrow involvement 
may be eligible with platelets ≥50,000)
hemoglobin
≥ 8 g/dL
NOTE: RBC and platelet transfusion allowed ≥14 days prior to registration. 
Note: Cytopenias felt to be disease related will not be excluded from the trial. 
Hepatic
total bilirubin
≤ 1.5x institutional upper limit of normal (ULN)
AST(SGOT)/ALT
(SGPT)
≤ 2.5 X institutional ULN
Renal
Creatinine 
clearance
≥ 60 mL/min either as estimated by the Cockcroft-Gault equation 
(See Appendix B) 
Lipase ≤1.5 x ULN and amylase ≤1.5xULN with no clinical symptoms suggestive of 
pancreatitis or cholecystitis
3.1.9
Patients must have blood pressure ≤Grade 1.
NOTE: Hypertensive patients are permitted if their blood pressure is controlled to 
≤Grade 1 by hypertensive medications. The actual blood pressure value ONLY 
will be assessed/graded using the CTCAE v5 hypertension criteria.
3.1.10
Patients must meet criteria for appropriate contraception, listed as follows.
Female patients must meet at least one of the following criteria:

Are postmenopausal  with last menstrual period at least 1 year before 
registration OR

Are surgically sterile, OR

If they are of childbearing potential, 

Agree to practice 1 highly  effective method of contraception and one 
additional effective (barrier) method at the same time, from the time 
of signing the informed consent  through 180 days after the last dose 
of study drug, or 

Agree to practice true abstinence, when 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.
Male patients, even if surgically sterilized (i.e., status post-
vasectomy), must:

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 [e.g., calendar, ovulation, 
symptothermal, postovulation methods for the female partner] and withdrawal 
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NU Study Number: NU 18H02
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Prot Amnd 4/Version Date:04. 3.2020
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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.
3.1.10
FOCBP must have a negative pregnancy test ≤7 days prior to registration on 
study.
3.1.11
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.
3.1.12
Patients must have the ability to swallow oral medication. 
3.1.13
Patients must be willing and able to complete study-required procedures. 
3.2
Exclusion Criteria
3.2.1
Patients with exposure to chemotherapy or immunotherapy ≤ 30 days prior to 
starting study treatment are not eligible.
NOTE EXCEPTION: Patients may receive a bridge of rituximab or steroids prior 
to C1 of R-CHOP.  Additionally, patients can receive their first cycle of R-CHOP 
prior to enrolment on trial (off study).  
NOTE: If patient is registered prior to completion of washout, start date of 
treatment will need to be confirmed prior to registration. Please see assigned 
QAM with questions.
3.2.2
Patients with prior exposure to a SYK inhibitor are not eligible.
NOTE: Examples of SYK inhibitors include fostamatinib (R788), entospletinib 
(GS-9973), cerdulatinib (PRT062070), and TAK-65930.  
3.2.3
Patients with untreated brain metastases or leptomeningeal metastases are not 
eligible. 
3.2.4
Patients with known hypersensitivity (e.g. anaphylactic and anaphylactoid 
reactions) to TAK-659 or components of R-CHOP are not eligible.
3.2.5
Patients with history of drug-induced pneumonitis requiring treatment with 
steroids; history of idiopathic pulmonary fibrosis, organizing pneumonia, or 
evidence of active pneumonitis on screening imaging are not eligible
NOTE: A history of radiation pneumonitis in the radiation field (fibrosis) is 
permitted
3.2.6
Patients with known hepatitis B surface antigen positive, or known or suspected 
active hepatitis C infection are not eligible.
3.2.7
Patients who are known to be human immunodeficiency virus (HIV) positive are 
not eligible.
3.2.8
Patients must not have had autologous stem cell transplant within 6 months prior 
to registration.
3.2.9
Patients must have not had allogeneic stem cell transplant at any time. 
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Prot Amnd 4/Version Date:04. 3.2020
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3.2.10
Patients who have received systemic anticancer treatment (including 
investigational agents) or radiotherapy less than 3 weeks before the first dose of 
study treatment (≤ 5 times half-life for large molecule agents or ≤4 weeks with 
evidence of disease progression if 5 times half-life is > 4 weeks) are not eligible.
NOTE EXCEPTION: This does not apply to C1 dosing of R-CHOP: it is expected 
that all patients will receive R-CHOP for C1 either on or off study.  Patients will 
also be allowed to receive rituximab and/or steroids as a bridge prior to C1 of R-
CHOP as an exception as outlined in Section 3.2.1.
NOTE: If patient is registered prior to completion of washout, start date of 
treatment will need to be confirmed prior to registration. Please see assigned 
QAM with questions.
3.2.11
Use or consumption of the following substances is not permitted:

Medications or supplements that are known to be inhibitors of P-gp and/or 
strong reversible inhibitors of CYP3A within 5 times the inhibitor half-life (if a 
reasonable half-life estimate is known), or within 7 days (if a reasonable half-
life estimate is unknown), before the first dose of study drug. The use of 
these agents is not permitted during the study. 

Medications or supplements that are known to be strong CYP3A mechanism-
based inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 
days, or within 5 times the inhibitor or inducer half-life (whichever is longer), 
before the first dose of study drug. The use of these agents is not permitted 
during the study. 

Grapefruit-containing food or beverages within 5 days before the first dose of 
study drug. Note that grapefruit-containing food and beverages are prohibited 
during the study.
3.2.12
Patients who have major surgery, per PI discretion, ≤ 14 days before the first 
dose of study drug and those who have not recovered fully from any 
complications from surgery are not eligible.
3.2.13
Patients who have systemic infection requiring parenteral antibiotic therapy or 
other serious infection (bacterial, fungal or viral) ≤ 21 days before the first dose of 
study drug are not eligible. 
NOTE: Patients who are at substantial risk of developing an infection may 
receive prophylaxis at the start of study treatment per investigator’s discretion.
3.2.14
Patients with an active secondary malignancy that requires treatment are not 
eligible. 
NOTE EXCEPTION: Patients with low grade active malignancies such as 
prostate cancer, non-melanoma skin cancer or carcinoma in situ of any type, 
which do not need treatment, are not excluded, Similarly, patients with a history 
of inactive breast cancer on hormone therapy are not excluded. 
3.2.15   Patients with known GI disease or GI procedure that could interfere with the oral 
absorption or tolerance of TAK-659 [per PI discretion] are not eligible (this may 
include difficulty swallowing tablets or diarrhea >Grade 1 despite supportive 
therapy).
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NU Study Number: NU 18H02
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Prot Amnd 4/Version Date:04. 3.2020
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3.2.15
Patients who have known CNS lymphomatous involvement are not eligible. 
3.2.16
Patients who have an uncontrolled intercurrent illness, in the opinion of the 
investigator, including, but not limited to any of the following, are not eligible: 

Uncontrolled pulmonary disease

Active CNS disease that would interfere with study participation

Active infection requiring parenteral systemic treatment

Psychiatric illness/social situations that would limit compliance with study 
requirements

Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s safety or 
study endpoints
3.2.17
Patients with any of the following cardiovascular conditions are excluded:

Acute myocardial infarction within 6 months before starting study drug.

Current or history of New York Heart Association Class III or IV heart failure 
(see Appendix C).

Evidence of current, uncontrolled cardiovascular conditions including cardiac 
arrhythmias, hypertension, angina, pulmonary hypertension, or 
electrocardiographic evidence of acute ischemia or active conduction system 
abnormalities.

Friderichia 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 investigator, are considered to 
be clinically significant.

Abnormal left ventricular function (EF < 50%, as indicated by baseline 
ECHO).
3.2.18
Female patients who are both lactating and breastfeeding or have a positive 
serum pregnancy test during the screening period or a positive urine pregnancy 
test on Day 1 before first dose of TAK-659.
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Prot Amnd 4/Version Date:04. 3.2020
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4.0
TREATMENT PLAN
4.1
Overview
Patients will receive the R-CHOP regimen for a total of six 21-day cycles. Starting with 
Cycle 2, patients will initiate combination treatment with oral TAK-659 once daily for a 
total of five 21-day cycles. All patients will receive one cycle of R-CHOP before initiating 
TAK-659. The first R-CHOP cycle may be received on-study (after completing screening 
procedures and registering to the study), OR prior to study registration. If a patient has 
already completed one cycle of R-CHOP, they must register and begin treatment with 
TAK-659 within 30 days after initiating the R-CHOP regimen. The off-study R-CHOP 
regimen will be referred to as “Cycle 1”, and study treatment will then begin on “Cycle 2 
Day 1” with TAK-659 given in combination with R-CHOP. 
1 Patients will undergo a 3+3 dose escalation of TAK-659 as detailed in section 4.3. The 
starting dose will be 60 mg with subsequent dose levels at 80 mg and 100 mg.  In the 
event that the starting dose is determined to be too toxic, a dose level -1 has been 
included at 40 mg. On days with combination treatment, TAK-659 should be given 
before starting R-CHOP administration with consideration for pre-medications and 
TAK-659 PK’s. 
2 Investigator may choose to administer G-CSF (filgrastim/tbo-filgrastim or pegfilgrastim) 
with Cycle 1 per standard ASCO guidelines. It is also highly recommended for Cycle 2-
6 (combination therapy).
3 Acetaminophen 650 mg PO and diphenhydramine 50-100 mg IV or PO 30-60 minutes 
prior to rituximab. Permitted to give corticosteroids prior to rituximab (up to 10 mg 
prednisone equivalent), in addition to the scheduled prednisone as part of R-CHOP, as 
per the discretion of the investigator.
4 If R-CHOP is administered off-study prior to registration, TAK-659 treatment must begin 
≤30 days after initiating R-CHOP.
5 On any clinic day (for study treatment), patients should NOT take prednisone before 
coming to clinic, but should hold and bring the prednisone tablets to clinic.
Table 4.1: Treatment Administration Summary
Agent
Dose
Route
Schedule
Cycle Length
TAK-659
60 mg - 100 
mg1
PO
once daily continuously 
for 5 cycles (Cycle 2-6)
3 weeks 
(21 days)
R-CHOP2
Rituximab3
375 mg/m2 
IV 
Day 1 
Cyclophosphamide
750 mg/m2
IV
Day 1
Doxorubicin
50 mg/m2
IV 
Day 1
Vincristine
1.4 mg/m2 
(Maximum 
dose:2 mg )
in NS 50 mL 
administered IV 
over 10 mins
IV 
Day 1
Prednisone5
100 mg
[Two 50mg 
tablets 
once daily]
PO 
Days 1-5
(or Days 
2-6)
For 6 cycles 
(Cycle 1-6; 
C1 may take 
place before4 
or after 
registration)
3 weeks 
(21 days)
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Prot Amnd 4/Version Date:04. 3.2020
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4.2
Treatment Administration
No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the patient’s lymphoma.
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified sub-investigator(s).
4.2.1
TAK-659  
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.
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.
Unless otherwise specified, on clinic visit days, patients should be instructed to 
hold their dose until pre-dose assessments are performed in the clinic. PK blood 
samples will also be obtained during Cycle 2 as specified in section 5.0. Every 
effort will be made to obtain PK sampling as outlined. However, if samples 
cannot be obtained due to patient factors such as poor venous access, deferring 
PK sampling would be acceptable. On days with combination treatment, TAK-
659 will be given before starting R-CHOP administration.
4.2.2
R-CHOP  
R-CHOP will be administered per standard of care guidelines over 21-day cycles 
as detailed below. If the first cycle of R-CHOP is given off-study, dosing details 
may vary from those detailed below per institutional practice. Starting with Cycle 
2, ANC must be ≥ 1,000 cells/mm3 to begin the cycle. Delay cycle up to 2 weeks 
if these values are not met on Day 1 of the cycle. Contact the Principal 
Investigator and QAM if delay is greater than 2 weeks. Other dosing 
modifications and delays may be necessary according to section 4.4.2.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone are 
all commercially available, FDA approved medications and will be given as 
standard of care.

Rituximab 375 mg/m2 IV infusion on Day 1 prior to CHOP chemotherapy. 
Dose rate titration per standard of care, defer to investigator.

Cyclophosphamide 750 mg/m2 IV Day 1

Doxorubicin 50 mg/m2 IV Day 1
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
Vincristine 1.4 mg/m2 (Maximum dose: 2 mg ) in NS 50 mL administered IV 
over 10 mins on  Day 1

Prednisone 100 mg PO daily on Days 1-5 (or Days 2-6)
o
Patients will record oral prednisone dosing in their dosing diary to 
monitor compliance
o
On any clinic day (for study treatment), patients should NOT take 
prednisone before coming to clinic, but should hold and bring the 
prednisone tablets to clinic.

G-CSF (filgrastim, tbo-filgrastim or pegfilgrastim) may also be administered 
prophylactically starting with Cycle 1 of R-CHOP at the investigator’s 
discretion per standard ASCO guidelines. It is also highly recommended 
for Cycle 2-6 (combination therapy).
4.2.2.1 Pre-medications

Oral pre-medication 650 mg of acetaminophen and 50-100 mg 
diphenhydramine hydrochloride IV or PO will be administered 30 to 
60 minutes prior to starting each infusion of rituximab.

All patients should receive hydration with 1 liter normal saline at 300-
500 cc/hr with half administered before and half administered after 
cyclophosphamide.

Patients who experience infusion reactions to rituximab should 
receive pre-medications per institutional guidelines
4.2.2.2 Rituximab
Rituximab will be administered intravenously at 375 mg/m2 on day 1 of 
each cycle of R-CHOP, immediately prior to the start of chemotherapy 
(NOTE: Patients may receive subcutaneous rituximab as clinically 
indicated per institutional guidelines). The first rituximab infusion will be 
given with cycle 1 of R-CHOP without TAK-659 and should be infused a 
rates per standard of care, as per investigator discretion. For example, 
the first rituximab infusion could be started at 50 mg/hr, and increased in 
50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr. 
If this rate of escalation is well tolerated the second and subsequent 
infusions can begin at a rate of 100 mg/hr and increase in 100 mg/hr 
increments every 30 minutes to a maximum of 400 mg/hr. CAUTION: DO 
NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
4.2.2.3 Cyclophosphamide
Cyclophosphamide will be administered intravenously at 750 mg/m2 on 
Day 1 of R-CHOP, per standard of care. The total dose of 
cyclophosphamide will be administered by IV. All patients should receive 
hydration with 1 liter normal saline at 300-500 cc/hr with half 
administered before and half administered after cyclophosphamide.
4.2.2.4 Doxorubicin HCl
Doxorubicin will be administered intravenously at 50 mg/m2 on Day 1 of 
R-CHOP, per standard of care. Doxorubicin is administered 
intravenously over 3-5 minutes. Avoid extravasation, as severe local 
tissue necrosis may result. If patient has been treated with prior 
doxorubicin, manage risk for cardiomyopathy per standard practice.
4.2.2.5 Vincristine Sulfate
Vincristine will be administered intravenously at 1.4 mg/m2 (Maximum 
dose: 2 mg ) in NS 50 mL administered IV over 10 mins on Day 1 of R-
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CHOP, per standard of care. Administer without further dilution by slow 
IV push. Precaution: Maximum single dose is 2 mg.
4.2.2.6 Prednisone
100 mg PO daily [2 tablets once daily] on Days 1-5. Prednisone may also 
be given from days 2-6 instead of Days 1-5.  Patients will take oral 
prednisone as indicated by standard of care guidance. They will maintain 
a drug diary (along with oral TAK-659 doses) to monitor compliance of 
prednisone dosing.
Please note: On any clinic day (for study treatment), patients should 
NOT take prednisone before coming to clinic, but should hold and bring 
the prednisone tablets to clinic.
4.2.3
CNS Prophylaxis and Treatment
CNS prophylaxis with intrathecal methotrexate, intrathecal steroids and/or 
intrathecal cytarabine is permitted, timing and dosing at the discretion of the 
investigator. CNS prophylaxis with high-dose intravenous methotrexate and/or 
intravenous cytarabine is not permitted during the six cycles of treatment. CNS 
prophylaxis with high-dose intravenous methotrexate is permitted, however, if 
given after the completion of cycle 6. Specifically, IV HD-MTX for up to 6 doses is 
allowable 3 weeks after the completion of 6 cycles of TAK-659-R-CHOP.  Dosing 
and schedule of HD-MTX is up to the discretion of the treating physician and 
should be carried out per institutional guidelines.
If during the trial, the CSF becomes cytologically positive indicative of CNS 
lymphomatous involvement, he or she must be removed from study treatment. 
4.3
Phase I Dose Escalation Scheme
Patients will be enrolled to dose level 1 initially (TAK-659 60 mg). Dose escalation will 
proceed up to 80mg for dose level 2, and 100 mg for level 3. The table below 
summarizes the dose levels. A dose level -1 is included in the event that level 1 is 
determined to be too toxic.
Table 4.2: Dose Escalation Scheme
Dose Level
TAK-659
# of Patients^
Level -1
40 mg
3-6
Level 1*
60 mg
3-6
Level 2
80 mg
3-6
Level 3
100 mg
3-6
*Starting dose level
^A minimum of 3 patients will be treated per cohort; a total of 
6 patients should be treated at whichever dose level 
is determined to be the MTD.
A standard “3+3” dose escalation design will be utilized. Initially, 3 patients will be 
enrolled at the starting dose (level 1), after which enrollment will be temporarily 
suspended until all 3 patients complete the DLT evaluation period (defined as cycle 2 of 
the study [the first 21-day cycle of TAK-659]).). Once all 3 patients complete the DLT 
period and toxicity data has been submitted, the Data and Safety Monitoring Committee 
(DSMC) will review the data and confirm the presence or absence of any DLTs (defined 
below). The following rules will be used at each dose level to determine whether or not to 
proceed to the next dose level:

If 0 of 3 patients at a given dose level experience a DLT (defined below), then 
escalation will proceed to the next dose level.
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
If 2 or 3 of 3 patients at a given dose level experience a DLT, then one of the 
following must occur:
o
If this happens at level 1, de-escalation to level -1 will occur.
o
If this happens at level 2 or beyond, the previous level will be declared the 
maximum tolerated dose (MTD).
o
If this happens at level -1, the study will be closed to further accrual and the 
regimen of TAK-659 + R-CHOP will be considered too toxic at any dose.

If 1 of 3 patients at a given dose level experiences a DLT, then an additional 3 slots 
will be added (for a total of 6 patients at that level):
o
If 1 of 6 total experiences a DLT, then escalation will proceed to the next level.
o
If ≥ 2 of 6 total experience a DLT, the previous level will be declared the MTD. 
NOTE: Whichever dose level is declared the MTD must have 6 total patients treated at 
that level. For example, if 3 patients are treated at level 2 and 0 patients experience DLT, 
escalation would then proceed to level 3. However, if ≥ 2 patients at level 3 experience 
DLT, enrollment to level 2 would need to be re-opened to enroll an additional 3 patients 
at that level (with 0 or 1 DLT observed in 6 total patients) in order to declare level 2 the 
MTD.
4.3.1
Definitions of Dose Limiting Toxicity
Although DLT-like events may occur at any point during treatment, only DLTs 
defined during Cycle 1 of TAK-659 (Cycle 2 of the study) will influence decisions 
regarding dose escalation, 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. Any DLT-
like events occurring during Cycle 1 of R-CHOP treatment will have to be 
managed to resolution before starting Cycle 2 with TAK-659.
Toxicity will be evaluated according to the NCI CTCAE version 5.0. DLT is 
defined as any of the events listed below. All adverse events meeting this criteria 
will be considered DLT’s unless the event is clearly unrelated to study therapy. 

Grade 4 neutropenia (ANC <500 cells/mm3) unresolved to ≤Grade 1 (ANC 
>1500 cells/mm3) or baseline for more than 7 consecutive days.

≥Grade 3 neutropenia (ANC <1000 cells/mm3) with fever and/or infection, 
where fever is defined as an oral temperature ≥38.3°C. 

Grade 4 thrombocytopenia (<25,000/mm3) unresolved to ≤Grade 1 
(>75,000/mm3) or baseline for more than 7 consecutive days or a platelet 
count <10,000/mm3 at any time. 

≥Grade 3 thrombocytopenia (<50,000/mm3) with clinically significant 
bleeding. 

Grade 4 anemia.

Any Grade 3 or greater non-hematologic toxicity with the following 
exceptions:
o
Grade 3 arthralgia/myalgia.
o
Grade 3 rash lasting ≤7 days with optimal treatment that includes topical 
steroid treatment, PO antihistamines, and pulse PO steroids, if 
necessary.
o
≥Grade 3 nausea and/or vomiting and ≥ Grade 3 diarrhea that has 
resolved to < Grade 3 within 72 hours of optimal antiemetic and/ or 
antidiarrheal treatment. (All patients should receive optimal antiemetic 
and/ or antidiarrheal treatment according to standard of care. An optimal 
antiemetic regimen is defined as one that employs a 5-hydroxytyptamine 
3 serotonin receptor [5-HT3] antagonist and a corticosteroid given in 
standard doses and according to standard schedules).
o
Transient Grade 3 fatigue (≤ 72 hours)
o
Asymptomatic lipase elevation (< Grade 4) in the absence of significant 
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amylase elevation (< Grade 3) considered not dose limiting by the 
treating physician.
o
Asymptomatic amylase elevation (< Grade 4) in the absence of 
significant lipase elevation (< Grade 3) considered not dose limiting by 
the treating physician.
o
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 by the treating physician.

Inability to administer at least 75% of planned doses of study drug within 
Cycle 1 of TAK-659 (Cycle 2 of the study) due to treatment-related toxicity.

Other TAK-659-related non-hematologic toxicities Grade 2 or greater that, in 
the opinion of the investigator, require discontinuation of therapy with TAK-
659.
4.4
Toxicity Management & Dose Delays/Modifications
4.4.1
Recommended TAK-659 Dose Modifications
TAK-659 is administered in continuous cycles; therefore, study drug should be 
administered continuously unless AEs occur that meet the dose modification 
criteria as outlined below.
Per the dose modification guidelines, patients who have the study drug held 
because of treatment-related or possibly related AEs may resume study drug 
treatment after resolution of the AE, but may either maintain the same dose level 
or have doses of study drug reduced (dose reduction) by at least 1 dose level. 
Dose reduction levels for TAK-659 are presented in the table below. When a 
dose reduction of TAK-659 occurs, the TAK-659 dose will be reduced to the next 
lower dose that has been established as a safe dose. The dose reduction of 
TAK-659 will, in general, follow a decrement of 20 mg. If initial dose adjustment 
does not provide sufficient relief, the dose of TAK-659 may 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. Up to 2 dose-level 
reductions of TAK-659 due to AEs are generally recommended. If more than 2 
dose-level reductions of TAK-659 are needed to manage TAK-659-related AEs, 
discontinuation of treatment should be considered unless the treating physician 
feels the patient may benefit from continued study treatment after resolution of 
AEs to <Grade 1 or baseline, or a level (must be ≤Grade 2) that is determined to 
be acceptable by the investigator(s) based on benefit-risk assessment. Dose 
adjustments for R-CHOP are allowed based on standard of care guidelines as 
listed in Table 4.4 and Table 4.6.
Table 4.3: Dose Reduction Schedule for TAK-659
Dose Reduction Levels
Dose (Unit)**
Planned Dose
(-) 1 dose level
Planned dose minus 20 mg
(-) 2 dose level
Planned dose minus 40 mg
Please refer to Table 4.4 and 4.5 for management of hematologic and non-
hematologic toxicities.
4.4.2
Recommended Dose Delays/Modifications for R-CHOP and TAK-659
Dose delays and modifications for the R-CHOP regimen will follow standard of 
care guidelines as listed in Table 4.4 and Table 4.6 below. 
     
Table 4.4: Dose Adjustments for Hematologic Toxicities
The following criteria only apply to Day 1 of each cycle, prior to dosing, to allow for sufficient recovery of 
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cytopenias from the previous cycle of R-CHOP. If dosing is held for toxicity, patients should be reevaluated 
within 7 days to assess recovery for resuming treatment 
Criteria
TAK-659 adjustments
R-CHOP adjustments
Neutropenia
Grade 1 (ANC < LLN - 1500 
cells/mm3)
Maintain dose level
Maintain all agents at dose level.
Grade 2 (ANC 1000-1,499 
cells/mm3)
Maintain dose level
Maintain all agents at dose level.
Investigator may consider pegfilgrastim for all 
subsequent cycles.
Grade 3 (ANC 500-999 
cells/mm3)
Withhold dose until 
resolved to ≤ Grade 2 
(ANC ≥ 1,000 cells/mm3) 
or baseline. 
Maintain dose level if 
patient did not yet receive 
G-CSF when event 
occurred; If occurred after 
G-CSF, reduce TAK-659 
one dose level (see 
Table 4.3)
Withhold all doses until resolved to ≤ Grade 2 
(ANC ≥ 1,000 cells/mm3).  Filgrastim/tbo-
filgrastim or pegfilgrastim should be 
administered for all subsequent cycles. 
Administration of colony stimulating factors at 
time of neutropenia is at the discretion of the 
investigator.
Grade 4 (ANC < 500 
cells/mm3)
Withhold dose until 
resolved to ≤ Grade 2 
(ANC ≥ 1,000
cells/mm3) or baseline. 
Maintain dose level if 
patient did not yet receive 
G-CSF when event 
occurred; If occurred after 
G-CSF, reduce TAK-659 
one dose level (see 
Table 4.3)
Withhold all doses until resolved to ≤ Grade 2 
(ANC ≥ 1,000 cells/mm3). Filgrastim/tbo-
filgrastim or pegfilgrastim should be 
administered for all subsequent cycles. 
Administration of colony stimulating factors at 
time of neutropenia is at the discretion of the 
investigator.
Febrile neutropenia (ANC 
< 500 cells/mm3, fever ≥ 
38.3°C)
Dose withheld until 
resolved to ≤ Grade 2 
(ANC ≥ 1,000 cells/mm3) 
or baseline and 
fever/infection recovered. 
Maintain dose level if 
patient did not yet receive 
G-CSF when event 
occurred; If occurred after 
G-CSF, reduce TAK-659 
one dose level (see 
Table 4.3)
Withhold all doses until resolved to ≤ Grade 2 
(ANC ≥ 1,000 cells/mm3). Filgrastim/tbo-
filgrastim or pegfilgrastim should be 
administered for all subsequent cycles. 
Administration of colony stimulating factors at 
time of neutropenia is at the discretion of the 
investigator.
If febrile neutropenia occurs despite 
filgrastim/tbo-filgrastim or pegfilgrastim 
support, reduce doses of cyclophosphamide 
and doxorubicin by 25% for subsequent 
cycles. If toxicity recurs, cyclophosphamide 
and doxorubicin doses should be reduced by 
an additional 25% for subsequent cycles. If 
grade 4 neutropenia or febrile neutropenia 
persists/recurs despite two dose reductions, 
remove patient from protocol therapy.
Thrombocytopenia (PLT)
Grade 1 (PLT LLN-75,000 
cells/mm3)
Maintain dose level
Maintain all agents at dose levels
Grade 2 (PLT 50,000-74,999 
cells/mm3)
Withhold all doses until 
resolved to ≤ Grade 1 
(PLT ≥ 75,000 cells/mm3) 
or baseline, then:
If resolved in ≤ 7 days, 
Withhold all doses until resolved to ≤ Grade 1 
(PLT ≥ 75,000 cells/mm3) or baseline. 
Maintain all agents at dose levels.
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then maintain dose level
If resolved in > 7 days, 
then dose reduce by 1 
dose level 
Grade 3 (PLT 25,000-49,999 
cells/mm3)
Withhold dose until 
resolved to ≤ Grade 1 
(PLT
≥ 75,000 cells/mm3) or 
baseline, then:
If resolved in ≤ 7 days, 
then maintain dose level
If resolved in > 7 days, 
then dose reduce by 1 
dose level 
Withhold all doses until resolved to ≤ Grade 1 
(PLT ≥ 75,000 cells/mm3) or baseline. 
Maintain all agents at dose levels with next 
treatment.  .
Grade 4 (PLT < 25,000 
cells/mm3)
Withhold dose until 
resolved to ≤ Grade 1 or 
baseline, then reduce by 
1 dose level.
Withhold all doses until resolved to ≤ Grade 1 
(PLT ≥ 75,000 cells/mm3) or baseline. 
Maintain all agents at dose levels with next 
treatment.  
Anemia
Grade 3 anemia (Hgb <8.0 
g/dL or transfusion indicated)
Withhold dose until 
resolved to ≤ Grade 1 
(Hgb ≥ 10.0 g/dL) or 
baseline, then:
If resolved in ≤ 7 days, 
then maintain dose level
If resolved in > 7 days, 
then dose reduce by 1 
dose level.
Maintain all agents at dose levels. RBC 
transfusions at the discretion of the 
investigator.
Grade 4 anemia (life-
threatening consequences or 
urgent intervention indicated 
related to anemia)
Withhold dose until 
resolved to ≤ Grade 1 
(Hgb ≥ stati g/dL) or 
baseline, then:
If resolved in ≤ 7 days, 
then maintain dose level
If resolved in > 7 days, 
then dose reduce by 1 
dose level.
Maintain all agents at dose levels. RBC 
transfusions at the discretion of the 
investigator.
Abbreviations: ANC = absolute neutrophil count; PLT = platelets.
Table 4.5: TAK-659 Dose Adjustments for Non-hematologic Toxicities
Criteria
TAK-659 adjustments
All Grade 3 Non-hematologic Toxicities If attribution to 
TAK-659 is felt to be possible, probable or definite: with the 
exception of:

nausea, vomiting and diarrhea 

fatigue

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 
Hold TAK-659 until resolution to Grade ≤ 1 
or baseline. If resolved in ≤ 7 days, then 
maintain the dose level.
If resolved in > 7 days, then dose reduce by 
1 dose level.
For the exceptions, maintain dose level.
If there is question of relation to TAK-659, 
discuss with PI to determine appropriate 
course of action.
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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 or 
clinical findings (including changes in blood pressure) that 
the investigator considers not clinically significant 
Grade 4 Non-hematologic Toxicities with the 
exception of:

Asymptomatic Grade 4 lipase elevation in the absence of 
significant amylase elevation (<Grade 3)

Asymptomatic Grade 4 amylase elevation in the 
absence of significant lipase elevation (<Grade 3)

Asymptomatic Grade 4 elevation of a single liver enzyme 
(AST or ALT) in the absence of significant bilirubin 
elevation (<Grade 3)

Grade 4 hypophosphatemia resolved to ≤Grade 1 or 
baseline within 72 hours with phosphate repletion

Other Grade 4 asymptomatic, enzyme elevations not 
considered clinically significant 
Consider permanently discontinuing 
TAK-659, except in the case where 
the investigator determines the 
patient is obtaining a clinical benefit. 
Dose reduction of ≥1 dose level is 
required if study treatment resumes 
after resolution to ≤Grade 1 or 
baseline. For
the exceptions, hold TAK-659 until 
resolution to Grade ≤ 1 or baseline.
If resolved in ≤ 7 days, then maintain the 
dose level;
If resolved in > 7 days, then 
dose reduce by 1 dose level; 
Grade 2, 3, or 4 abnormalities in ejection fraction (EF)
Hold TAK-659 until cardiology 
assessment is completed to rule out 
other etiologies. If felt to be drug 
related, patient will discontinue study 
treatment.
Table 4.6: R-CHOP Dose Adjustments for Non-hematologic Toxicities
Criteria
R-CHOP adjustments
Ileus or constipation requiring 
hospitalization
The next dose of vincristine should be reduced by 25%. If 
symptoms do not recur at the reduced dose, then the vincristine 
dose may be re-escalated on subsequent cycles.
Sensory Neuropathy

Grade 2 sensory 
neuropathy 
Can maintain or reduce vincristine by 25-50%, per 
investigator discretion. 

Grade 3 sensory 
neuropathy
Reduce vincristine by 25-50%, per investigator 
discretion. If symptoms improve, doses may be 
increased to previous levels.

Grade 4 sensory 
neuropathy
Discontinue vincristine.
Motor Neuropathy

Grade 2 motor neuropathy
Reduce vincristine by 25%. If symptoms improve, 
doses may be increased to previous level.

Grade 3 motor neuropathy
Reduce vincristine by 50%. If symptoms improve, 
doses may be increased to previous levels.

Grade 4 motor neuropathy
Discontinue vincristine.
Hyperbilirubinemia

Bilirubin ≥ 3 mg/dL
Reduce vincristine by 50%. Dose can be re-
escalated as hyperbilirubinemia improves.

Bilirubin > 7 mg/dL
Hold doxorubicin until bilirubin returns to ≤ 7 mg/dL. 
No doxorubicin dose modifications will be made for 
increased bilirubin ≤ 7 mg/dL.
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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.
Any patient who receives at least one dose of study therapy will be evaluable for 
toxicity endpoints. Each patient will be assessed for the development of toxicity 
according to the timeframe referenced in the Schedule of Events table). Toxicity 
will be assessed according to CTCAE v5.0. 
4.4.3
Criteria for Discontinuation of Study Drug(s)
TAK-659 dosing should be discontinued if patients experience a Grade 4 non-
hematologic toxicity (except those listed in Table 4.5) and/or Grade 4 anemia. If 
TAK-659 dosing is delayed because of TAK-659 related toxicities for >21 
consecutive days despite supportive care treatment for standard of care, stop 
TAK-659. Patients exceeding delays of >21 days for TAK-659 related toxicities 
may be considered on a case-by-case for continuing dosing with TAK-659. PI 
and DSMC approval should be obtained prior to continuing dosing with TAK-659
If a patient must discontinue study treatment with TAK-659, he or she will be 
removed from the study but may continue the R-CHOP regimen off-study.
4.4.4
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.
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. In 
particular, lymphopenia can develop in association with either treatment or with 
the underlying disease (DLBCL).
Lymphopenia can be associated with reactivation of herpes zoster, CMV, 
herpes simplex and other viruses. Antiviral therapy such as acyclovir, 
gancyclovir, valacyclovir, or other antiviral agents may be initiated as clinically 
indicated although it is strongly recommended. 
PJP prophylaxis should be initiated with C2 (first dose of combination 
treatment). 
Given their degree of immunosuppression, patients with posttransplant 
lymphoproliferative disease are often at an increased risk of developing 
infections. Consideration should be given to antibiotic, antifungal, and antiviral 
prophylaxis during therapy, particularly if the patient is more prone to 
developing neutropenia.
Pneumonitis
Patients with serious lung events that do not respond to conventional 
antimicrobial therapy should be assessed for drug-induced pneumonitis after 
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ruling out infectious causes and alternative etiologies. If pneumonitis is 
suspected, TAK-659 treatment should be interrupted and the patient treated 
per standard of care. If pneumonitis is moderate/severe, discontinue TAK-659. 
Patients should be monitored for respiratory signs and symptoms throughout 
treatment and be advised to promptly report respiratory symptoms.
Edema (Including Periorbital)
Peripheral and periorbital edema have been observed in patients treated with 
TAK-659. Management of the event should follow the standard local practice 
and dose modification as required.
Rash With or Without Pruritus
Prophylactic measures should also be considered if a patient develops a rash 
(eg, using a thick, alcohol-free emollient cream on dry areas of the body). In the 
case of rash, the use of a topical or oral steroid (eg, prednisone ≤ 10 mg per 
day or equivalent) is permitted.
Hypophosphatemia
Hypophosphatemia has been observed in patients treated with TAK-659. 
Consider prophylaxis; otherwise refer to dose modification guideline.
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.
4.5
Concomitant Medications/Procedures
During the study, patients will be instructed not to take any additional medications 
(including over-the-counter products and supplements) without prior consultation with the 
investigator. At each visit, the investigator will ask the patient about any new medications 
he/she is taking or has taken while on study. All concomitant medications (defined as any 
medication given during the study) and significant nondrug therapies, including physical 
therapy and blood transfusions, should be recorded from signing of the informed consent 
form (ICF) through 30 days after the last dose of study drug or the start of subsequent 
antineoplastic therapy, whichever occurs first.
4.5.1
Required/Permitted Concomitant Medications 
Required ancillary medications administered during all cycles: 
• Acetaminophen 650 mg PO and diphenhydramine 50-100 mg IV or PO 30-60 
minutes prior to rituximab. 
• PJP prophylaxis should be initiated with C2 (first cycle of combination therapy)
• Those patients who test positive for hepatitis B should be closely monitored for 
evidence of active HBV infection and hepatitis during and for several months 
after rituximab treatment, and should be managed at the discretion of the 
investigator, including possible antiviral medications.

Steroids for anti-cancer treatment are permitted prior to cycle 1

Topical, ocular, intra-articular, intranasal, and inhaled corticosteroids 
(with minimal systemic absorption) are permitted.
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4.5.2
Prohibited Concomitant Medications 
The following restrictions apply during the study:

Any antineoplastic therapy other than TAK-659 and R-CHOP is prohibited 
during the study. 

Radiation therapy is prohibited during the study (note that, in general, the 
requirement for local radiation therapy indicates disease progression). 
Palliative radiotherapy for local pain/symptom control in a preexisting non-
target lesion may be considered.

Intravenous high-dose methotrexate and/or intravenous cytarabine is not 
permitted during study treatment.

Concurrent systemic administration of TAK-659 with inhibitors or inducers of 
P-gp or strong inhibitors or inducers of CYP3A are not permitted in this 
study. In vitro studies indicate that TAK-659 is a substrate for P-gp and that, 
among CYP isozymes, TAK-659 is preferentially metabolized by CYP3A4/5. 
Refer to the list below and Appendix A for a nonexhaustive list of 
medications, supplements, and food products that are inhibitors or inducers 
of P-gp or strong inhibitors or inducers of CYP3A based on the US FDA 
draft guidance for DDI studies.
•
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole.
•
Antibiotics: azithromycin, clarithromycin, erythromycin, telithromycin.
•
Antimycobacterials: rifabutin, rifampin, rifapentine.
•
Antiepileptics: carbamazepine, phenobarbital, phenytoin, primidone.
•
Antidepressant: nefazodone.
•
Immunosuppressant: cyclosporine.
•
Calcium channel blockers: diltiazem, felodipine, mibefradil, verapamil.
•
Antiarrhythmics: amiodarone, dronedarone, quinidine.
•
Antiplatelet: ticagrelor.
•
Antilipid: avasimibe.
•
Other cardiovascular: captopril, carvedilol, ranolazine.
•
Vasopressin antagonist: conivaptan.
•
Food/herbals/supplements: grapefruit-containing food and beverages, St.
John’s wort, quercetin.
If a patient experiences an AE on study and TAK-659 dosing is temporarily 
interrupted because of that AE, the medications listed above and Appendix A 
may be used for AE management if there is no appropriate alternative 
treatment available per the investigator’s judgment and the dosing is not 
concurrent with study drug. This situation should be evaluated by the principal 
investigator. Patients should be closely monitored for potential toxicities.
4.6
Precautions and Restrictions 
Patients should not drive, operate dangerous tools or machinery, or engage in any other 
potentially hazardous activity that requires full alertness and coordination if they 
experience sedation while enrolled in this study.
Patients are to be instructed to limit the use of alcohol while enrolled in this study.
Pregnancy
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.
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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.
4.7
Other Modalities or Procedures
4.7.1
ECG 
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 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.
4.7.2
Ophthalmic Exam
A slit lamp eye examination will be performed by an ophthalmologist at 
Screening; on Cycle 3 Day 1 (±2 weeks); and at EOT. On the basis of nonclinical 
toxicology findings with TAK-659 in rats, slit lamp examinations should focus on 
detecting any posttreatment changes in ocular lenses. 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.
4.8
Duration of Therapy
Patients will continue treatment with TAK-659 and R-CHOP for up to 6 total cycles of 21 
days (5 cycles of TAK-659 as combination therapy). The first cycle of R-CHOP may take 
place prior to study registration. Patients may discontinue before 6 cycles if any of the 
following occur:

Disease progression
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
Development of an inter-current illness that prevents further administration of 
treatment

Unacceptable adverse event(s)

Patient decides to withdraw from either study treatment or the as a whole study

The treating investigator determines that the patient should be taken off treatment for 
any reason (i.e. changes in condition, inability to comply with study treatment or 
procedures)
4.9
Duration of Follow Up
All patients will have an End of Treatment visit within 30 days after treatment 
discontinuation. In addition, patients will be followed for adverse events, including Serious 
Adverse Events, for 30 days after last dose of TAK-659. Patients who discontinue 
treatment for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event. Patients will be followed for survival status every 6 
months by routine clinic visit or phone call for up to 3 years from treatment 
discontinuation. 
4.10
Removal of Subjects from Study Treatment and/or Study as a Whole
Patients can be taken off the study treatment and/or study as a whole at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation must be clearly 
documented on the appropriate eCRF and may include:

Patient voluntarily withdraws from treatment (follow-up permitted)

Patient withdraws consent (no follow-up permitted)

Patient is unable to comply with protocol requirements

Patient demonstrates disease progression (clinical or radiological progression)

Patient experiences unacceptable toxicity 

Treating physician determines that continuation on the study would not be in the 
patient’s best interest

Patient becomes pregnant 

Patient develops a second malignancy that requires treatment which would interfere 
with this study

Patient becomes lost to follow-up (LTF) 

The study is terminated 

Protocol violation 
4.11
Patient Replacement
Patients who sign consent and/or receive R-CHOP but come off study before receiving 
TAK-659 may be replaced. Three patients within a dose level must be observed for one 
cycle (21 days) on TAK-659 before accrual to the next higher dose level may begin. If a 
patient is withdrawn from the study prior to completing 14 days of TAK-659 therapy 
without experiencing a DLT prior to withdrawal, an additional patient may be added to 
that dose level. Patients missing 7 or more doses due to toxicity will not be replaced 
since these patients will be considered to have experienced a dose limiting toxicity.
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5.0
STUDY PROCEDURES
Table 5.1: On-Study R-CHOP
Screening
Study treatment period
(1 cycle = 21 days, each visit ±3 days unless otherwise stated in footnotes)
Off 
treatment
C11
C2
C3
C4
C5
C6
EOT15
F/U8
Day -30 
to Day 1
D1
D2-5
D1
D2
D8
D15
D16
D1
D15
D1
D15
D1
D15
D1
D15
R-CHOP
X
X
X
X
X
X
X
TAK-659 administration 
(21-day supply dispensed 
every cycle)
X
X
X
X
X
Informed consent
X
Physical exam, Vital Signs2, 
ECOG PS, AE assessment, 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG3
X
X
X
X
X
X
X
X
ECHO16
X16
X16
X16
Concomitant meds
X
X
X
X
X
X
X
X
Patient diary review
X
X
X
X
X
X
Viral hepatitis serologies 
(HBV and HCV)4
X
CBC with differential11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry Panel12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Mg, Phos, LDH, Amylase, 
Lipase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
T-cell panel17
X
X
Study Labs13
X13
X13
X13
X13
X13
X13
X13
X13
Urinalysis
X
X
X
X
X
X
X
Ophthalmic Exam14
X
X
X
PET/CT
X5
X6
X7
Pregnancy test (FOCBP)
X
X
X
X
X
X
Survival/disease status 
assessment
X9
1 Patients will receive one cycle of R-CHOP monotherapy (Cycle 1) prior to starting combination therapy with TAK-659 (Cycles 2-6). Cycle 
1 of R-CHOP can take place either prior to study registration (“off-study”, ≤30 days prior to the first dose of TAK-659) or after study 
registration (“on-study”). Screening procedures must take place ≤30 days prior to “registration” unless otherwise specified. 
2 Vital signs include blood pressure 
3 Performed pre-dose and as instructed in section 4.7.1.


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4 Patients must have hepatitis serologies (HBV and HCV) ≤ 90 days prior to study registration.
5 PET/CT should be obtained ≤ 60 days prior to first cycle of R-CHOP (on- or off-study as specified in footnote 1 and section 4.1) 
whenever possible with an optional diagnostic CT component. It is acceptable if a patient had a CT scan alone within the timeframe.
6 PET/CT should be obtained day 15-21 of C3 or day 1 of C4 
7 PET/CT should be completed 4-6 weeks after Cycle 6 R-CHOP treatment
8 Every 6 months (starting 6mo from C6) by routine clinic visit or phone call for up to 3 years, until recurrent lymphoma or death.
  Follow-up  will include collection of survival data, progression/relapse and any new anti-cancer treatment.
9 disease status assessment will simply include documenting whether patient is still in CR or with recurrent disease, as assessed by the 
investigator (and date of recurrence will be documented)
10 A serum pregnancy test will be performed for women of childbearing potential at Screening. 
11 CBC will include hemoglobin, hematocrit, leukocytes (white blood cell [WBC] count), differential WBC count (lymphocytes [ALC], 
neutrophils [ANC]), and platelets.
12 Chemistry panel (CMP) will include sodium, potassium, CO2, chloride, BUN, creatinine, bilirubin, ALP, AST, ALT, GGT, total protein, 
albumin, glucose, urate, and calcium.
13 Patients will have blood samples drawn for PK’s and banking as outlined below. See separate lab manual for more details.
Correlative Blood Draws
Time Points**
Sample Type
C1D1
Pre-dose
Banking 
C2D1
Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose
PK and Banking* (*pre-dose only)
C2D2
Pre-dose
PK
C2D15
Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose
PK
C2D16
Pre-dose
PK
C4D1
Pre-dose
Banking
EOT and 
time of relapse 
(if patient 
willing and 
feasible)
All patients will have an EOT sample drawn. 
If patient has not relapsed at EOT, an 
additional sample should be obtained at the 
time of confirmed progression, within 30 
days if feasible.
Banking
**Timing of all samples (pre-dose and post-dose) is related to the time of TAK-659 dosing; The 
following windows are allowable for PK sample collection:
Pre-dose (within 60 min before TAK-659 dose); 30 mins (±10 mins); 1 hour (±10 mins); 2 hours (±20 
mins); 4 hours (±30mins); 8 hours (±30 mins), 24 hours (±60 mins).
14 Please see section 4.7.2 for further instructions on timing and conduct of ophthalmic exams. 
15 An End of Treatment (EOT) visit will take place within 30 days after completing last dose of study treatment OR before starting new anti-
cancer therapy. 
 
16 For baseline ECHO, a window of 60 days prior to registration is acceptable.Grade 2, 3, or 4 toxicity of EF should require assessment by 
cardiology to rule out other etiologies. If felt to be drug related, patient should be discontinued from protocol treatment. For echocardiogram 
on C4D1, window for procedure can be -7 days and up to C4D1 but prior to dosing; timeline for EOT echo: within 30 days after completing 


NU Study Number: NU 18H02
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last dose of study treatment OR before starting new anti-cancer therapy. 
17 T-Cell panel includes  Total Tcell (CD3)(%); Total T cell(CD3)(/uL); Total Bcell (CD19)(%);  Total B cell (CD19)(/uL); Total Natural Killer 
NK  (CD16/CD56)(%); Total Natural Killer NK (CD16/CD56) (uL); Total Helper (CD3/CD4)(%); Total Helper (C3/C4) (/ul) ; Total 
Suppressor (CD3/CD8) ; Total Suppressor (CD3/CD8) (/uL);  Helper/suppressor ratio


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Table 5.2: Off-Study R-CHOP
Screen
ing
Study treatment period
(1 cycle = 21 days, each visit ±3 days unless otherwise stated in footnotes)
Off 
treatment
C2
C3
C4
C5
C6
EOT
15
F/U
8
Cycle 1
R-
CHOP
(Off-
study)
Day -
30 to 
Day 1
D1
D2
D8
D15
D16
D1
D15
D1
D15
D1
D15
D1
D15
R-CHOP
X1
X
X
X
X
X
TAK-659 administration 
(21-day supply dispensed 
every cycle)
X
X
X
X
X
Informed consent
X
Vital Signs2, ECOG PS, AE 
assessment, Physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG3
X
X
X
X
X
X
X
X
ECHO16
X
X16
X16
Concomitant meds
X
X
X
X
X
X
X
Patient diary review
X
X
X
X
X
X
Viral hepatitis serologies 
(HBV and HCV)4
X
CBC with differential11
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry Panel12
X
X
X
X
X
X
X
X
X
X
X
X
X
Mg, Phos, LDH, Amylase, 
Lipase
X
X
X
X
X
X
X
X
X
X
X
X
X
T-cell panel
X
X
Study Labs13
X13
X13
X13
X13
X13
X13
X13
Urinalysis
X
X
X
X
X
X
X
Ophthalmic Exam14
X
X
X
PET/CT
X5
X6
X7
Pregnancy test (FOCBP)
X
X
X
X
X
X
Survival/disease status 
assessment
X9
1 Patients will receive one cycle of R-CHOP monotherapy (Cycle 1) prior to starting combination therapy with TAK-659 (Cycles 2-6). Cycle 
1 of R-CHOP can take place either prior to study registration (“off-study”, ≤30 days prior to the first dose of TAK-659) or after study 
registration (“on-study”). Screening procedures must take place ≤30 days prior to “registration” unless otherwise specified. 
2 Vital signs include blood pressure 
3 Performed pre-dose and as instructed in section 4.7.1.


NU Study Number: NU 18H02
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4 Patients must have hepatitis serologies (HBV and HCV) ≤ 90 days prior to study registration.
5 PET/CT should be obtained ≤ 60 days prior to first cycle of R-CHOP (on- or off-study as specified in footnote 1 and section 4.1) 
whenever possible with an optional diagnostic CT component. It is acceptable if a patient had a CT scan alone within the timeframe.
6 PET/CT should be obtained day 15-21 of C3 or day 1 of C4
7 PET/CT should be completed 4-6 weeks after Cycle 6 R-CHOP treatment
8 Every 6 months (starting 6mo from C6) by routine clinic visit or phone call for up to 3 years, until recurrent lymphoma or death. Follow-up   
will include collection of survival data, progression/relapse and any new anti-cancer treatment.
9 disease status assessment will simply include documenting whether patient is still in CR or with recurrent disease, as assessed by the 
investigator (and date of recurrence will be documented)
10 A serum pregnancy test will be performed for women of childbearing potential at Screening. 
11 CBC will include hemoglobin, hematocrit, leukocytes (white blood cell [WBC] count), differential WBC count (lymphocytes [ALC] and 
neutrophils [ANC]), and platelets.
12 Chemistry panel (CMP) will include sodium, potassium, CO2, chloride, BUN, creatinine, bilirubin, ALP, AST, ALT, GGT, total protein, 
albumin, glucose, urate, and calcium.
13 Patients will have blood samples drawn for PK’s and banking at the time points listed below. See separate lab manual for more details.
(Please note: If bio banking samples are not collected or patient refuses, it will not be a deviation).
Correlative Blood Draws
Time Points**
Sample Type
C2D1
Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose
PK and Banking* (*pre-dose only)
C2D2
Pre-dose
PK
C2D15
Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose
PK
C2D16
Pre-dose
PK
C4D1
Pre-dose
Banking
EOT and 
time of relapse
(if patient 
willing and 
feasible) 
All patients will have an EOT sample drawn. 
If patient has not relapsed at EOT, an 
additional sample should be obtained at the 
time of confirmed progression, within 30 
days if feasible.
Banking
** Timing of all samples (pre-dose and post-dose) is related to the time of TAK-659 dosing; The 
following windows are allowable for PK sample collection:
Pre-dose (within 60 min before TAK-659 dose); 30 mins (±10 mins); 1 hour (±10 mins); 2 hours (±20 
mins); 4 hours (±30mins); 8 hours (±30 mins), 24 hours (±60 mins).
14 Please see section 4.7.2 for further instructions on timing and conduct of ophthalmic exams.
15 An End of Treatment (EOT) visit will take place within 30 days after completing last dose of study treatment OR before starting new anti-
cancer therapy. 
16 For baseline ECHO, a window of 60 days prior to registration is acceptable. 
Grade 2, 3, or 4 toxicity of ejection fraction (EF) requires assessment by cardiology to rule out other etiologies. If felt to be drug related, 
patient should be discontinued from protocol treatment. For echocardiogram on C4D1, window for procedure can be -7 days and up to 
C4D1 but prior to dosing; timeline for EOT echo: within 30 days after completing last dose of study treatment OR before starting new anti-
cancer therapy.


NU Study Number: NU 18H02
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Prot Amnd 4/Version Date:04. 3.2020
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17 T-Cell panel includes  Total Tcell (CD3)(%); Total T cell(CD3)(/uL); Total Bcell (CD19)(%);  Total B cell (CD19)(/uL); Total Natural Killer 
NK  (CD16/CD56)(%); Total Natural Killer NK (CD16/CD56) (uL); Total Helper (CD3/CD4)(%); Total Helper (C3/C4) (/ul) ; Total 
Suppressor (CD3/CD8) ; Total Suppressor (CD3/CD8) (/uL);  Helper/suppressor ratio.


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6.0
ENDPOINT ASSESSMENT
6.1
Definitions
6.1.1
Response will be evaluated, using the Lugano classification for assessment of 
Lymphoma.31 See Appendix D for specific response assessment criteria.
6.1.2
Clinical evaluation and tumor assessments will be performed periodically, as 
shown in Table 6, based on evaluation of spleen and liver, physical examination 
for superficial disease and B symptoms, radiologic evaluation, and appropriate 
laboratory studies.
6.1.3
A lesion is categorized based on the location as either a nodal lesion or an 
extranodal lesion if it is located in organs other than lymph nodes or nodal mass, 
but including spleen and liver.
6.1.4
All tumor lesions/lymph nodes will be categorized as measurable or non-
measurable as follows:
6.1.4.1
Measurable nodal and extranodal lesions:
A lesion will be called measurable if it can be measured accurately in 2 
perpendicular dimensions and:

For nodal lesion, if the long axis is >15 mm, regardless of the length 
of the short axis

For extranodal lesion, if the long and short axes are ≥10 mm.
Patients should have at least one measurable nodal lesion greater 
than 20 mm in the long axis.
In cases where the patient has no measurable nodal lesions greater 
than 20 mm in the long axis at screening, then the patient must have at 
least one measurable extranodal lesion. 
6.1.5
Classification of lymph nodes
6.1.5.1
Lymph nodes are classified according to their size and/or relationship to 
the disease:

A lymph node meeting the measurability requirement, but with 
long axis > 15 mm (e.g. short axis cannot be measured 
accurately) will constitute a non-measurable nodal lesion.

A lymph node not meeting the measurability criteria, but with a 
size of 11 mm to 15 mm in the long axis and >10 mm in the short 
axis will be checked for relationship to disease:
o
If it is thought to be disease related, it will constitute a 
non-measurable nodal lesion
o
If it is not thought to be disease related, it will constitute 
an abnormal lymph node, but not a lesion.
All other lymph nodes will be considered normal and will not constitute nodal 
lesions.
6.1.6
Criteria for normalization of lesions
6.1.6.1 The normalization of lesions is defined as follow:
o
A measurable nodal lesion must become ≤ 15 mm in long axis to be 
considered normalized.
o
A non-measurable nodal lesion must decrease to ≤10 mm in the 
short axis and be ≤ 15 mm in long axis to be considered normalized.
o
An extranodal lesion must disappear completely (assigned a size of 
0 mm x 0 mm) to be considered normalized.
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6.2
Primary Endpoint
Endpoint: Toxicity and tolerability will be assessed by history and physical, including vital 
signs and ECOG performance status, and laboratory values to determine incidence and 
grade of adverse events (AEs), serious adverse events (SAEs), and dose-limiting 
toxicities, as defined in section 4.3.1 and by the NCI CTCAE v5.0. Patients will be 
evaluated for dose-limiting toxicities during the first cycle (21 days) of TAK-659 combined 
with R-CHOP (study Cycle 2) to determine the maximum tolerated dose. 
6.2.1
Evaluable Patients
All patients who receive at least one dose of TAK-659 will be evaluable for 
general toxicity endpoints. 
DLT-evaluable patients at each dose cohort will consist of patients who have met 
the minimal treatment and safety evaluation requirements of the study and/or 
who experience a DLT during Cycle 2. The minimum treatment and safety 
evaluation requirements are met, if, in Cycle 2, the patient has been treated with 
TAK-659 for ≥ 14 days (receiving at least 75% of planned doses of TAK-659 in 
Cycle 2) and observed for ≥ 21 days following the dose on Cycle 2, Day 1 
(C2D1), and is considered to have sufficient safety data by both the investigators 
and Data Monitoring Committee (DMC) to conclude a DLT did not occur. Patients 
who do not meet these minimum requirements will be regarded as ineligible for 
inclusion as DLT-evaluable patients for the given dose cohort and may be 
replaced within the same cohort. 
6.3
Secondary Endpoints
Endpoints: 
6.3.1 Overall response rate (ORR), using Lugano criteria (2014), will be defined as the 
percentage of subjects with a confirmed complete response (CR) or partial response 
(PR) as assessed by the investigators. Response will be assessed by PET/CT at 
screening, PET/CT after C3, and by PET/CT at the End of Treatment visit. All patients 
who receive at least one dose of TAK-659, have sites of measurable disease at baseline, 
and 1 post-baseline disease assessment are evaluable for this endpoint. This will be 
assessed at 3 months.
6.3.2  Progression free survival (PFS) will defined as the time from study enrollment until 
progression/recurrence of lymphoma or death from any cause. This will be assessed at 
12 and 18 months.
6.3.3 Overall survival (OS) will be defined as the time from study enrollment until death 
from any cause. This will be assessed at 12 and 18 months.
7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer to 
Appendices for additional information). The level of risk attributed to this study requires high-risk 
monitoring, as outlined in the DSMP. In addition, the study will abide by all safety reporting 
regulations, as set forth in the Code of Federal Regulations.  
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial (see Section 5 for time points). In 
addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care. 
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All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until: 

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 

any abnormal laboratory values have returned to baseline; 

there is a satisfactory explanation other than the study drug for the changes 
observed; or

death.
7.2
Definitions & Descriptions
7.2.1
Adverse Event
Adverse Events may be spontaneously identified by the patient and/or in 
response to an open question from study personnel or revealed by observation, 
physical examination, or other diagnostic procedures.  Any clinically relevant 
deterioration in laboratory assessments or other clinical finding is considered an 
AE.  When possible, signs and symptoms indicating a common underlying 
pathology should be noted as one comprehensive event.  
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention. 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation).
7.2.2
Severity of AEs
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
CTCAE v5.0 is available at 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCA
E_v5_Quick_Reference_8.5x11.pdf 
If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.

Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.
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50

Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.

Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.

Fatal (grade 5): the event caused death.
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 30 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:

Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.

Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe.

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of “Serious 
Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
7.2.4
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:

Is unanticipated in terms of nature, severity, or frequency

Places the research subject or others at a different or greater risk of harm

Is deemed to be at least possibly related to participation in the study.   
7.3
Adverse Event Reporting
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF . Routine AEs will be reviewed by the Data Monitoring Committee (DMC) 
according to the study’s phase and risk level, as outlined in the DSMP. 
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly.
1)
Identify the type of adverse event using the NCI CTCAE v 5.0.
2)
Grade the adverse event using the NCI CTCAE v 5.0.
3)
Determine whether the adverse event is related to the protocol therapy.  
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Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unlikely: AE not likely to be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:

the current protocol

the drug package insert

the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
7.3.3.1 Reporting to the Northwestern University QAM/DMC
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE Form, 
provided as a separate document, is required.
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if 
known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.
7.3.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow 
their local IRB guidelines for reporting to their local IRBs.

Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification. 

Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment)

Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 5 working days of notification.

All other deaths of NU subjects not previously reported, other non-
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review.
7.3.3.3 Reporting to the FDA 
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life-
threatening.
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The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DMC).
All other SAEs will be reported on an annual basis as part of the annual 
FDA report.
7.3.3.4 Reporting to Takeda
Adverse Events which are serious must be reported to Takeda 
Pharmacovigilance from the first dose of TAK-659 up to and including 30 
days after administration of the last dose of TAK-659, or until the start of 
subsequent anticancer therapy, whichever occurs first.  Any SAE that 
occurs at any time after completion of TAK-659 treatment or after the 
designated follow-up period that the sponsor-investigator and/or sub-
investigator considers to be related to any study drug must be reported 
to Takeda Pharmacovigilance.  In addition, new primary malignancies 
that occur during the follow-up periods must be reported, regardless of 
causality to study regimen, for a minimum of three years after the last 
dose of the investigational product, starting from the first dose of study 
drug. All new cases of primary malignancy must be reported to Takeda 
Pharmacovigilance.
Planned hospital admissions or surgical procedures for an illness or 
disease that existed before the patient was enrolled in the trial are not to 
be considered AEs unless the condition deteriorated in an unexpected 
manner during the trial (e.g., surgery was performed earlier or later than 
planned).  All SAEs should be monitored until they are resolved or are 
clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness (es).
Since this is an investigator-initiated study, the principal investigator 
Reem Karmali also referred to as the sponsor-investigator, is responsible 
for reporting serious adverse events (SAEs) to any regulatory agency 
and to the sponsor- investigator’s IEC or IRB.   
Regardless of expectedness or causality, all SAEs must also be reported 
in English to Takeda Pharmacovigilance:
Fatal and Life Threatening SAEs within 24 hours of the sponsor-
investigator’s observation or awareness of the event (using the NU CRO 
SAE Form and referencing the Takeda study number, IISR-2017-
101972).
All other serious (non-fatal/non life threatening) events within 4 
calendar days of the sponsor-investigator’s observation or awareness of 
the event
See below for contact information for the reporting of SAEs to Takeda 
Pharmacovigilance. The sponsor investigator must fax or email the SAE 
Form per the timelines above.  
The SAE report must include at minimum:

Event term(s)

Serious criteria
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
Intensity of the event(s): Sponsor-investigator’s or sub-
investigator’s determination.  Intensity for each SAE, including 
any lab abnormalities, will be determined by using the NCI 
CTCAE version specified in the protocol, as a guideline, 
whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html.

Causality of the event(s): Sponsor-investigator’s or sub-
investigator’s determination of the relationship of the event(s) to 
study drug administration. 
Follow-up information on the SAE may be requested by Takeda 
Pharmacovigilance. In the event that this is a multisite study, the 
sponsor-investigator is responsible to ensure that the SAE reports are 
sent to Takeda Pharmacovigilance from all sites participating in the 
study.  Sub-investigators must report all SAEs to the sponsor-
investigator so that the sponsor-investigator can meet his/her foregoing 
reporting obligations to the required regulatory agencies and to Takeda 
Pharmacovigilance, unless otherwise agreed between the sponsor-
investigator and sub-investigator(s).  
Relationship to all study drugs for each SAE will be determined by the 
investigator or sub-investigator by responding yes or no to the question: 
Is there a reasonable possibility that the AE is associated with the study 
drug(s)?
US and Canada
Toll-Free Fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
All other countries (Rest of World)
Fax #: 1 202 315 3560
E-mail: takedaoncocases@cognizant.com
  
7.3.3.4.1 Procedures for Reporting Drug Exposure During 
Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant 
while participating in this study, she must inform the investigator 
immediately and permanently discontinue study drug.  The 
sponsor-investigator must fax a completed Pregnancy Form to 
the Takeda Pharmacovigilance immediately.  The pregnancy 
must be followed for the final pregnancy outcome (i.e., delivery, 
still birth, miscarriage) and Takeda Pharmacovigilance will 
request this information from the sponsor-investigator.
If a female partner of a male patient becomes pregnant during 
the male patient’s participation in this study, the sponsor-
investigator must also immediately fax a completed Pregnancy 
Form to the Takeda Pharmacovigilance.  Every effort should be 
made to follow the pregnancy for the final pregnancy outcome.
Suggested Pregnancy Reporting Form:
Pregnancy Report Form (provided as a separate document)  
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8.0
DRUG INFORMATION
8.1
TAK-659
8.1.1
Other names 
N/A
8.1.2
Classification - type of agent
SYK Inhibitor
8.1.3
Mode of action
TAK-659 inhibits SYK purified enzyme with a concentration producing 50% 
inhibition (IC50) of 2.0 and 3.2 nM.
8.1.4
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.
8.1.5
Protocol dose specifics
The MTD for TAK-659 will be determined using a 3+3 dose escalation method. 
The starting dose will be 60 mg with possible escalation to 80 mg and 100 mg. 
Patients may be de-escalated to 40 mg if DLT’s are met at dose level 1.  
8.1.6
Preparation
TAK-659 is an anticancer drug, and as with other potentially toxic compounds, 
caution should be exercised when handling TAK-659.
8.1.7
Route of administration for this study
Oral
8.1.8
Incompatibilities
The following restrictions apply during the study:
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
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.

Concurrent systemic administration of TAK-659 with inhibitors or inducers of 
P-gp or strong inhibitors or inducers of CYP3A should be avoided in this 
study. In vitro studies indicate that TAK-659 is a substrate for P-gp and that, 
among CYP isozymes, TAK-659 is preferentially metabolized by CYP3A4/5. 
Refer to the list below and Appendix A for a nonexhaustive list of 
medications, supplements, and food products that are inhibitors or inducers 
of P-gp or strong inhibitors or inducers of CYP3A based on the US FDA 
draft guidance for DDI studies.
•
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole.
•
Antibiotics: azithromycin, clarithromycin, erythromycin, telithromycin.
•
Antimycobacterials: rifabutin, rifampin, rifapentine.
•
Antiepileptics: carbamazepine, phenobarbital, phenytoin, primidone.
•
Antidepressant: nefazodone.
•
Immunosuppressant: cyclosporine.
•
Calcium channel blockers: diltiazem, felodipine, mibefradil, verapamil.
•
Antiarrhythmics: amiodarone, dronedarone, quinidine.
•
Antiplatelet: ticagrelor.
•
Antilipid: avasimibe.
•
Other cardiovascular: captopril, carvedilol, ranolazine.
•
Vasopressin antagonist: conivaptan.
•
Food/herbals/supplements: grapefruit-containing food and beverages, St.
John’s wort, quercetin.
8.1.9
Availability & Supply 
TAK-659 will be supplied by Takeda. 
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.
8.1.10
Side effects
Potential risks from nonclinical studies in dogs and rats include: 

Lymphoid/hematopoietic effects that include lymphoid depletion and 
myelosuppression that are associated with thrombocytopenia, neutropenia, 
and reticulocytopenia. These findings may be associated with increased 
susceptibility to infection, bleeding, and/or anemia. 

Epithelial effects on the intestinal tract, urinary tract, and lens. Intestinal 
effects included minimal-to-slight mucosal hemorrhaging. Urinary and renal 
tract effects included hyperplasia of transitional epithelium in the kidney and 
bladder, dilatation and hemorrhage in the renal pelvis leading to hematuria 
and proteinuria, and urolithiasis with possible ureter obstruction. Lens effects 
included epithelium hyperplasia leading to anterior axial opacity. 

Reproductive system effects, including decreased spermatozoa and 
seminiferous tubule degeneration in the testis and corpora luteal necrosis in 
the ovaries. Possible mutation of DNA. Growth plate thickening and 
disorganization (not relevant to adults). 

Lymphoid and hematopoietic effects and reproductive system effects are 
considered important potential risks. 
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
Potential risks based on clinical observations: 

On the basis of data from Study C34001, asymptomatic elevation in lipase 
was added as an important potential risk of TAK-659. In nonclinical studies, 
asymptomatic lipase was sporadically elevated at high doses of TAK-659; 
however, there was no evidence of microscopic organ damage. In clinical 
studies to date, lipase elevations are reported commonly (≥ 10%). Patients in 
the current study will have frequent monitoring of amylase as outlined in the 

Cases of pneumonitis have been reported in clinical studies with BCR 
pathway kinase inhibitors including TAK-659, and pneumonitis is considered 
an important potential risk of TAK-659. Pneumonitis and other pulmonary 
toxicities are being closely monitored in TAK-659 clinical studies. 
The benefits of TAK-659 have not been established; however, early signs of 
clinical antitumor activity were seen. 
Further details regarding the risks and benefits associated with TAK-659 may be 
found in the current version of the TAK-659 IB.  
8.1.11
Nursing implications
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.
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. 
8.1.12
Return and Retention of Study Drug
Patients will return unused tablets to the clinic. The clinical study team will be 
responsible for keeping accurate records of the clinical supplies received from 
Takeda, the amount dispensed to and returned not used by the subjects and the 
amount remaining at the conclusion of the trial. Upon completion or termination 
of the study, all unused and/or partially used investigational product will be 
destroyed at the site per institutional policy. It is the Investigator’s responsibility to 
arrange for disposal of all empty containers, provided that procedures for proper 
disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept.
8.2
Rituximab
Please refer to the FDA-approved package insert for rituximab for product information, 
extensive preparation instructions, and a comprehensive list of adverse events.
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8.2.1
Other names
Rituxan, IDEC-C2B8, chimeric anti-CD20 monoclonal antibody 8.7.2 
Classification – type of agent Antibody.
8.2.2
Classification - type of agent
Chimeric murine-derived monoclonal antibody
8.2.3
Mode of action
Rituximab is a chimeric murine/human gamma 1 kappa monoclonal antibody 
(Chinese hamster ovary [CHO] transfectoma). It recognizes the CD20 antigen 
expressed on normal B cells and most malignant B-cell lymphomas. It binds with 
high affinity to CD20-positive cells, performs human effector functions in vitro, 
and depletes B cells in vivo. The Fab domain of rituximab binds to the CD20 
antigen on B-lymphocytes and the Fc domain recruits immune effector functions 
to mediate B cell lysis in vitro. The biological effect is manifested by B-cell 
depletion in peripheral blood, lymph nodes, and bone marrow.
8.2.4
Storage and stability
Intact vials should be stored under refrigeration. Dilute solutions for infusion (1-4 
mg/mL) are stable for 24 hours under refrigeration, and for an additional 24 hours 
at room temperature.
8.2.5
Protocol dose specifics
Rituximab will be administered as an IV infusion at 375 mg/m2 on day 1 of each 
cycle of R-CHOP, as detailed in section 4.0. Oral premedication 650 mg of 
acetaminophen and 50-100 mg diphenhydramine hydrochloride IV or PO will be 
administered 30 to 60 minutes prior to starting each infusion of rituximab. The 
first rituximab infusion will be given with cycle 1 of R-CHOP without TAK-659 and 
should be infused a rates per standard of care, as per investigator discretion. For 
example, the first rituximab infusion could be started at 50 mg/hr, and increased 
in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr. If this 
rate of escalation is well tolerated the second and subsequent infusions can 
begin at a rate of 100 mg/hr and increase in 100 mg/hr increments every 30 
minutes to a maximum of 400 mg/hr. CAUTION: DO NOT ADMINISTER AS AN 
INTRAVENOUS PUSH OR BOLUS.
8.2.6
Preparation
The desired dose of rituximab should be diluted in 0.9% NaCl or D5W to a final 
concentration of 1-4 mg/mL. The solution should be mixed by gently inverting the 
bag.
8.2.7
Route of administration for this study
IV
8.2.8
Incompatibilities
Do not mix or dilute rituximab with other drugs. No incompatibilities between 
rituximab and polyvinylchloride or polyethylene bags have been observed.
8.2.9
Availability & Supply 
Rituximab is commercially available in 10 mL and 50 mL single-use vials 
containing 100 mg or 500 mg rituximab solution, respectively, at a concentration 
of 10 mg/mL.
8.2.10
Side effects
The most severe serious adverse events associated with rituximab include 
severe infusion reactions, tumor lysis syndrome, and severe mucocutaneous 
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reactions. Severe infusion reactions consisting of hypoxia, pulmonary infiltrates, 
acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation 
or cardiogenic shock may be fatal. Most reported fatal reactions occurred within 
24 hours of the first dose of rituximab. 
Tumor lysis syndrome resulting in renal failure has been described, and 
occasional fatalities noted. Tumor lysis syndrome is more likely in patients with 
high numbers of circulating malignant cells (≥ 25,000/μL). Severe 
mucocutaneous reactions associated with rituximab include Stevens-Johnson 
syndrome and toxic epidermal necrolysis. The onset of these reactions has been 
from 1-3 weeks.
Less severe infusion reactions are common with rituximab. These include fever, 
chills, and dyspnea. The mechanism of rituximab infusion reactions is thought to 
be secondary to release of cytokines. If a reaction occurs, then the infusion 
should be stopped until the symptoms resolve, and then restarted at a 50% 
slower rate. 
Recent reports describe hepatitis B reactivation with fulminant hepatitis, hepatic 
failure and death in some patients with hematologic malignancies treated with 
rituximab. The majority of these patients received rituximab in combination with 
chemotherapy. The median time to diagnosis of hepatitis was approximately 4 
months after starting rituximab and approximately 1 month after the last dose. 
Exacerbation or reactivation of other viral infections has also been reported with 
rituximab. Recent reports describe JC virus reactivation leading to progressive 
multifocal leukoencephalopathy (PML) in patients who were receiving rituximab. 
Patients presenting with new neurologic findings (e.g., major changes in vision, 
unusual eye movements, loss of balance or coordination, confusion) should be 
evaluated for PML.
8.2.11
Nursing implications
Oral pre-medication 650 mg of acetaminophen and 50-100 mg diphenhydramine 
hydrochloride IV or PO will be administered 30 to 60 minutes prior to starting 
each infusion of rituximab. Rituximab will be administered as an intravenous 
infusion at 375 mg/m2 on day 1 of each cycle of R-CHOP, immediately prior to 
the start of chemotherapy. The first rituximab infusion will be given with cycle 1 of 
R-CHOP without TAK-659 and should be infused a rates per standard of care, as 
per investigator discretion. For example, the first rituximab infusion could be 
started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a 
maximum rate of 400 mg/hr. If this rate of escalation is well tolerated the second 
and subsequent infusions can begin at a rate of 100 mg/hr and increase in 100 
mg/hr increments every 30 minutes to a maximum of 400 mg/hr. CAUTION: DO 
NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
8.3
Cyclophosphamide
Please refer to the FDA-approved package insert for cyclophosphamide for product 
information, extensive preparation instructions, and a comprehensive list of adverse 
events.
8.3.1
Other names
Cytoxan®; Neosar®, CTX, CPM
8.3.2
Classification - type of agent
Cyclophosphamide is a prodrug biotransformed to active alkylating metabolites 
by a mixed function microsomal oxidase system.
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8.3.3
Mode of action
Cyclophosphamide metabolites are thought to disrupt cell division primarily by 
crosslinking DNA strands. Cyclophosphamide is considered cell cycle phase 
non-specific.
8.3.4
Storage and stability
Intact vials should be stored at room temperature. Reconstituted and diluted 
solutions are stable for 24 hours at room temperature and 6 days if refrigerated.
8.3.5
Protocol dose specifics
The total dose of cyclophosphamide will be administered by IV. All patients 
should receive hydration with normal saline at the following volumes (based on 
cyclophosphamide dose levels) and rates with half administered before and half 
administered after cyclophosphamide.
8.3.6
Preparation
Refer to Package Insert for preparation instructions
8.3.7
Route of administration for this study
IV
8.3.8
Incompatibilities
Cyclophosphamide undergoes metabolic activation via cytochrome P450 3A4 in 
the liver and may potentially interact with any drug affecting the same isoenzyme. 
Inhibitors of 3A4 (e.g., itraconazole) could theoretically inhibit activation and 
inducers of 3A4 (e.g., phenytoin) could theoretically enhance activation of 
cyclophosphamide to active alkylating species. For the most part, such 
interactions have not yet been documented clinically. 
8.3.9
Availability & Supply 
Cyclophosphamide is commercially available, and will not be provided by the 
study.
8.3.10
Side effects
Myelosuppression, hemorrhagic cystitis (patients must be well-hydrated before, 
during, and after treatment and have adequate renal function). Syndrome of 
inappropriate antidiuretic hormone (SIADH), fatigue, alopecia, anorexia, nausea, 
vomiting, hyperuricemia, azospermia, amenorrhea, cardiotoxicity (myocardial 
necrosis) usually at doses higher than those used in this study
8.3.11
Nursing implications
The total dose of cyclophosphamide will be administered by IV.
All patients should receive hydration with 1 liter normal saline at 300-500 cc/hr 
with half administered before and half administered after cyclophosphamide.
8.4
Doxorubicin HCl
Please refer to the FDA-approved package insert for doxorubicin for product information, 
extensive preparation instructions, and a comprehensive list of adverse events.
8.4.1
Other names
Adriamycin PFSTM, Adriamycin RFSTM, Rubex®, hydroxydaunorubicin, 
hydroxydaunomycin, ADR
8.4.2
Classification – type of agent
Anthracycline antibiotic.
IRB #: STU00207880-CR0003 Approved by NU IRB for use on or after 4/11/2022 through 4/10/2023.


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8.4.3
Mode of action
Intercalation between adjoining nucleotide pairs in the DNA helix causes 
inhibition of DNA and DNA-dependent RNA synthesis. Free radical generation is 
responsible for cardiac toxicity. Doxorubicin also inhibits topoisomerase II
8.4.4
Storage and stability
Intact vials of doxorubicin solution should be stored in the refrigerator. Intact vials 
of powder for reconstitution should be stored at room temperature. Reconstituted 
solutions are stable for 7 days at room temperature and 15 days under 
refrigeration when protected from light. Commercially available solutions labeled 
as such are intended to be multidose vials. Compatibility and stability studies 
were conducted by the Pharmaceutical Development Service [60], Pharmacy 
Department, NIH Clinical Center, simulating concentrations of each drug that 
would be applicable to this trial. Admixtures of vincristine, doxorubicin, and 
etoposide in 0.9% Sodium Chloride Injection, in polyolefin-lined IV bags were 
stable for up to 72 hours at room temperature, provided that the concentration of 
etoposide was < 250 mcg/ml.
8.4.5
Protocol dose specifics
Doxorubicin will be administered  at a 50 mg/m2 on day 1 of each cycle. 
8.4.6
Preparation
Refer to package insert for preparation instructions
8.4.7
Route of administration for this study
IV
8.4.8
Incompatibilities
Physically incompatible with heparin, fluorouracil, aminophylline, cephalothin, 
dexamethasone, diazepam, hydrocortisone, and furosemide.
8.4.9
Availability & Supply 
Doxorubicin is commercially available 
8.4.10
Side effects
Hematologic: Leukopenia (dose-limiting), thrombocytopenia, anemia. Nadir in 10- 
14 days with recovery usually in 21 days. 
Dermatologic: alopecia (usually complete; reversible) radiation recall reactions; 
increased sensitivity to sunlight. 
Gastrointestinal: nausea and vomiting (doxorubicin is generally considered 
moderately to highly emetogenic), anorexia, diarrhea, mucositis (stomatitis, 
esophagitis). 
Cardiovascular: cardiomyopathy may occur and is related to total cumulative 
lifetime dose. The risk for cardiomyopathy increases with total doses > 450 
mg/m2. ECG changes and less often, arrhythmias, are seen. Rarely, sudden 
death has occurred. 
Other: Red discoloration of urine for 24-48 hours after drug administration. 
Doxorubicin is a vesicant and can cause tissue necrosis if extravasated, 
especially at the concentration usually employed for bolus injections (i.e., 2 
mg/mL).
8.4.11
Nursing implications
Doxorubicin is administered intravenously over 3-5 minutes. Avoid extravasation, 
as severe local tissue necrosis may result.
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8.5
Vincristine Sulfate 
Please refer to the FDA-approved package insert for vincristine sulfate for product 
information, extensive preparation instructions, and a comprehensive list of adverse 
events.
8.5.1
Other names
VCR, Leurocristine sulfate, Oncovin®, Vincasar PFS, LCR
8.5.2
Classification - type of agent
Vinca alkaloid (tubulin inhibitor).
8.5.3
Mode of action
Vincristine binds to tubulin, a protein that forms microtubules, thus interfering with 
spindle formation during metaphase and causing cessation of cellular mitosis.
8.5.4
Storage and stability
Unopened vials should be stored under refrigeration and protected from light. 
Commercially available solutions labeled as such are intended to be multidose 
vials. 
8.5.5
Protocol dose specifics
Vincristine will be given at a dose 1.4 mg/m² (with maximum dose 2 mg) in NS 50 
mL administered IV over 10 mins on day 1 of each cycle.
.
8.5.6
Preparation
Refer to package insert for preparation instructions
8.5.7
Route of administration for this study
IV
8.5.8
Incompatibilities
Furosemide; some in-line filters; polysiloxan containers used in portable delivery 
services.
8.5.9
Availability & Supply 
Vincristine is commercially available in 1 mL, 2 mL, and 5 mL vials in a 
concentration of 1 mg/mL.
8.5.10
Side effects
The most common toxicity associated with vincristine is neurotoxicity. Peripheral 
manifestations of neurotoxicity include: numbness of extremities, paresthesias, 
loss of deep tendon reflexes, neuropathic pain and muscle weakness. GI 
manifestations of neurotoxicity include constipation, and adynamic ileus. Cranial 
nerve manifestations include: diplopia, hoarseness, tinnitus, jaw pain (the latter 
usually occurring with the first dose of vincristine). Orthostatic hypotension & 
SIADH may also be seen. Vincristine is a vesicant and may cause tissue 
necrosis upon extravasation. This is more likely with bolus injections as opposed 
to dilute infusions
8.5.11
Nursing implications
Vincristine should befurther diluted in 50 mL 0.9% sodium chloride to final 
concentration 0.0015 – 0.08 mg/ml and infused over 10 minutes 
Precaution: Maximum single dose is 2 mg.
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8.6
Prednisone
Please refer to the FDA-approved package insert for prednisone for product information 
and a comprehensive list of adverse events.
8.6.1
Other names
Deltasone, Orasone, Medicorten, Panasol-S, Liquid-Pred
8.6.2
Classification – type of agent
Adrenal corticosteroid
8.6.3
Mode of action
Prednisone is a potent synthetic glucocorticoid that affects almost every body 
system. It has anti-inflammatory, immunosuppressant, and minimal 
mineralocorticoid activity, and antineoplastic properties. As an antineoplastic 
agent, prednisone may bind to specific proteins (receptors) within the cell forming 
a steroid-receptor complex. Binding of the receptor-steroid complex with nuclear 
chromatin alters mRNA and protein synthesis within the cell.
8.6.4
Storage and stability
Store tablets, solutions and syrup in tightly closed containers at room 
temperature.
8.6.5
Protocol dose specifics
100 mg PO daily [ 2 tablets once daily]  on Days 1-5 (or Days 2-6).
Please note: On any clinic day (for study treatment), patients should NOT take 
prednisone before coming to clinic, but should hold and bring the prednisone 
tablets to clinic. 
8.6.6
Preparation
Not applicable.
8.6.7
Route of administration for this study
Oral
8.6.8
Incompatibilities
None known.
8.6.9
Availability & Supply 
Commercially available 50 mg tablets will be used  
8.6.10
Side effects
Side effects likely to be encountered with intermittent high doses include: GI 
(dyspepsia, ulceration), insomnia, and hyperglycemia. Occasionally a “withdrawal 
syndrome” after short-term high doses, such as in this study, manifest muscle 
aches and pains. Immunosuppression with risk of infection is also seen.
9.0
CORRELATIVES/SPECIAL STUDIES
Patients will have blood samples collected for pharmacokinetic (PK) analysis and future 
unspecified research. 
PK samples will be collected during Cycle 2, when TAK-659 and R-CHOP are first given in 
combination, at the time points listed below:
PK Sample Timing (in relation to TAK-659 dosing)**
C2D1
Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose
C2D2
Pre-dose
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C2D15
Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose
C2D16
Pre-dose
**The following windows are allowable for PK sample collection:
Pre-dose (within 60 min before TAK-659 dose); 30 mins (±10 mins); 1 hour (±10 mins); 
2 hours (±20 mins); 4 hours (±30mins); 8 hours (±30 mins), 24 hours (±60 mins).
The PK samples will be collected and stored at the Robert H Lurie Cancer Center of 
Northwestern University Pathology Core Facility (PCF) and shipped to Q2 solutions for 
analysis. Please refer to laboratory manual for contact information and details about 
collection, processing, storage and shipment of samples.
Blood samples for banking and future unspecified research will be collected at the time points 
listed below: 
Samples for Banking
C1D1
Pre-dose**
C2D1
Pre-dose**
C4D1
Pre-dose**
EOT & time 
of relapse
(if patient 
willing and 
feasible)
All patients will have an EOT sample drawn. If patient has not 
relapsed at EOT, an additional sample should be obtained at the 
time of confirmed progression, within 30 days.
**All pre-dose samples should be collected within 60 minutes before 60 minutes 
within 60 minutes before R-CHOP with C1 or within 60 minutes prior to TAK-659 
dose for C2D1 and C4D1  
(Please note: If bio banking samples are not collected or patient refuses, it will not be a 
deviation).
See separate lab manual for further details on collection and shipping.  
9.1
Specimen Banking
Blood samples are mandatory (if patient willing) and will be collected for our Biobank at 
C1D1 (pre-dose), C2D1 (pre-dose), C4D1 (pre-dose), at completion of therapy and at 
relapse/progression. (Please note: If bio banking samples are not collected or patient 
refuses, it will not be a deviation).
 
Patient samples for banking will be collected for this study. They will be  received by the 
Robert H Lurie Cancer Center of Northwestern University Pathology Core Facility (PCF) 
and  will be sent to,be processed and stored at Dr. Gordon’s laboratory. Specimens will 
be stored indefinitely or until they are used up, and such samples may be shared with 
researchers at other institutions. If future use is denied or withdrawn by the patient, best 
efforts will be made to stop any additional studies and to destroy the specimens. 
Please refer to laboratory manual for contact information and details about collection, 
processing and storage of samples.
 
Dr. Reem Karmali will be responsible for reviewing and approving requests for clinical 
specimen from potential research collaborators outside of Northwestern University. 
Collaborators will be required to complete an agreement (a Material Transfer Agreement 
or recharge agreement) that states specimens will only be released for use in disclosed 
research. Any data obtained from the use of clinical specimen will be the property of 
Northwestern University for publication and any licensing agreement will be strictly 
adhered to.
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The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available:
•
Diagnosis
•
Collection time in relation to study treatment
•
Clinical outcome – if available
•
Demographic data
 
10.0
STATISTICAL CONSIDERATIONS
10.1
Study Design/Study Endpoints
This is a Phase I dose escalation study that will accrue between 12 and 18 patients.  
10.2
Sample Size and Accrual
The design of the study is described in detail in Section 4.3. If there are insufficient 
patients evaluable for toxicity at the end of 18 patients, the protocol will be amended to 
add the required number of additional patients.  
10.3
Data Analyses Plans
Sections 6.2 and 6.3 define evaluability for toxicity, DLT determination and response 
(ORR).
Using only patients evaluable for toxicity (Section 6.2.1), safety and tolerability of TAK-
659 will be determined by summarizing all adverse events as to type, timing, frequency, 
severity and attribution.  
Dose limiting toxicities are defined in Section 4.3.1.  The determination of maximum 
tolerated dose is defined in Section 4.3. The MTD will be determined using only patients 
who are evaluable for DLT determination (Section 6.2.1). 
Preliminary efficacy of TAK-659 will be assessed by calculating the ORR with 95% exact 
binomial confidence intervals, using all response-evaluable patients (Section 6.3) as the 
denominator.  ORR is defined as the percentage of subjects with a confirmed complete 
response (CR) or partial response (PR) as assessed by the investigators. This will be 
assessed at 3 months
Using all patients at all doses, progression-free survival and overall survival at 12 and 18 
months will be assessed using Kaplan-Meier curves.  
11.0
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
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implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
11.2
Amendments
Amendments to the protocol will be initiated and maintained by the assigned Medical 
Writer. Requests for revisions may come from multiple sources, including but not limited 
to the Principal Investigator, study team, drug company, or FDA. All amendments will be 
subject to the review and approval of the appropriate local, institutional, and 
governmental regulatory bodies, as well as by Novocure. Amendments will be distributed 
by the lead institution (Northwestern) to all participating sites upon approval by the 
Northwestern University IRB.
. 
11.3
Registration Procedures
For potential patients, study teams are asked to inform the QAM of the date and time that 
the patient will need to be registered (croqualityassurance@northwestern.edu).  
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number:

Patient’s signed and dated informed consent form (upload to NOTIS and keep 
original hard copy in a secure location/study chart)

Copy of the pathology report (upload to NOTIS)

Signed and dated Eligibility Checklist (upload to NOTIS and keep original hard copy 
in a secure location/study chart)
The QAM will review all source documentation required to confirm eligibility that is readily 
available in the patient’s electronic medical record (EMR).  Any information that is not 
available in the EMR must be de-identified and emailed to the QAM. Once the QAM 
confirms the patient is eligible, he or she will register the patient, assign a subject 
identification number, provide a cohort assignment (as applicable), and send a 
confirmation of registration to involved personnel. Registration will then be complete and 
the patient may begin study treatment. 
11.4
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 Takeda Pharmacovigilance (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 Takeda 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. 
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For Product Complaints or Medication Errors (Including Overdose), contact Takeda 
Pharmacovigilance 
For PIPELINE Products:
Phone: 1-844-ONC-TKDA (1-844-662-8532)
Email: GlobalOncologyMedInfo@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 Takeda Pharmacovigilance.
11.5
Data Submission
Data collection for this study will be done through NOTIS. Access to the trial in NOTIS is 
granted to appropriate roles identified at the time of participating site activation, or upon 
request. Site users will not be able to access the study in NOTIS until all required and 
study specific trainings are completed. 
Once a patient is confirmed and registered to the study, eCRFs should be submitted 
according to the study procedures table.  Generally, all data for phase I patients, or any 
safety run-ins during the time period patients are evaluated for Dose Limiting Toxicities 
(DLTs) must be submitted on a weekly basis.  A set amount of data may also be 
requested for any screen failures, as is defined by the study. In most instances, this will 
include collection of adverse events and baseline data from the time of registration to the 
date of screen failure. 
11.6
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to CTO website  for additional information). The level of risk attributed to this study 
requires high risk monitoring, as outlined in the DSMP. The assigned QAM, with 
oversight from the Data Monitoring Committee, will monitor this study in accordance with 
the study phase and risk level.. In addition, the study will abide by all safety reporting 
regulations, as set forth in the Code of Federal Regulations.
11.7
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
11.6.1
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change. Such modifications also need to 
be reported to the FDA, as applicable, within the appropriate timelines
11.6.2
Other Protocol Deviations
A protocol deviation is any change, divergence, or departure from the study 
design or procedures of a research protocol that is under the investigator's 
control and that has not been approved by the Institutional Review Board (IRB). 
Protocol deviations must be reported according to the policies and procedures of 
the IRB of record.
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A protocol deviation may be considered an instance of Reportable New 
Information (RNI) if it:

Has harmed or increased the risk of harm to one or more research 
participants

Has compromised the rights and welfare of the research subject

Has damaged the scientific integrity of the data collected for the study

Results from willful or knowing misconduct on the part of the 
investigator(s)

Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies
All protocol deviations will be documented by the study team on a paper or 
electronic deviation tracking log (see NOTIS for copy of log) as they occur. The 
deviation tracking log must be made available upon request for review by the 
assigned QAM. The deviation tracking log must be reviewed, signed, and dated 
by the investigator prior to each monitoring visit, or otherwise in a timely manner, 
whichever occurs first. The PI signed and dated deviation tracking log will be 
uploaded to eCRFs prior to each scheduled monitoring visit or upon request. 
Deviations will be reviewed per the DSMP.
11.8
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP. 
11.9
Publication Policy
 
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
DSMC Data Release Policies and Processes. The assigned QAM will prepare a 
preliminary data set for DSMC approval no later than 3 months after the study reaches its 
primary completion date, as defined by ClinicalTrials.gov. This is the date that the final 
subject was examined or received an intervention for the purposes of final collection of 
data for the primary outcome, whether the clinical trial concluded according to the pre-
specified protocol or was terminated. If the investigator would like data release to be 
approved by the DSMC prior to when study design specifies, and/or prior to three months 
after a study’s primary completion date, the PI must send a written request for data 
approval to the QAM which includes justification. Requests must be made a minimum of 
six to eight weeks in advance of the expected deadline. The request will be presented to 
the DSMC at their next available meeting. Any DSMC decisions regarding data release 
will be provided to the PI. If the request is approved, the QAM will present the data set to 
the DSMC for approval. A final, DSMC-approved dataset, as applicable, will then be 
released 6-8 weeks after the request was made. The investigators are expected to use 
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only DSMC-approved data and statistical analyses any time they are disseminating trial 
data. The investigators must send a copy of the draft abstract/poster/manuscript to the 
study’s biostatistician and assigned QAM to confirm that the DSMC-approved data and 
statistical analyses are used appropriately. Once the biostatistician and QAM gives final 
approval, the publication may be submitted to external publisher.
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untreated diffuse large B-cell lymphoma: CALGB/Alliance 50303 [abstract]. . American Society of 
Hematology annual meeting; San Diego, CA. . 2016.
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20.
Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three 
intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 
1993;328(14):1002-1006.
21.
Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-
98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP 
chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. 
Blood. 2010;116(12):2040-2045.
22.
Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus 
CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell 
lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. 
Lancet Oncol. 2006;7(5):379-391.
23.
Moore AS, Faisal A, Gonzalez de Castro D, et al. Selective FLT3 inhibition of FLT3-ITD+ acute 
myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical 
resistance patterns. Leukemia. 2012;26(7):1462-1470.
24.
Tomasson MH, Xiang Z, Walgren R, et al. Somatic mutations and germline sequence variants in 
the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood. 
2008;111(9):4797-4808.
25.
Kannan Kea. TAK-659 a dual SYK/FLT3 inhibitor, leads to complete and sustained tumor 
regression and immune memory against tumor cells upon combination with anti-PD-1 agent. 
European Journal of Cancer.Volume 69(S92).
26.
Kaplan Jea. A Phase 1b/2 Study of TAK-659, an Investigational Dual SYK and FLT-3 Inhibitor, in 
Patients (Pts) with Relapsed or Refractory Acute Myelogenous Leukemia (R/R AML). Poster 
session presented at ASH, San Diego, CA. 2016.
27.
Kaplan Jea. Updated Results from a Phase 1 Study of TAK-659, an Investigational and 
Reversible SYK Inhibitor, in Patients (Pts) with Advanced Solid Tumor or Lymphoma 
Malignancies. . Poster session presented at ASH, San Diego, CA. . 2016.
28.
Mocsai A, Zhou M, Meng F, Tybulewicz VL, Lowell CA. Syk is required for integrin signaling in 
neutrophils. Immunity. 2002;16(4):547-558.
29.
Kannan K ea. TAK-659, a dual SYK/FLT3 inhibitor leads to complete and sustained tumor 
regression and immune memory against tumor cells upon combination with anti-PD-1 agent 
[poster presentation]. . 28th EORTC - NCI - AACR Symposium on Molecular Targets; Nov 2016; 
Munich, Germany. Poster 279. . 2016.
30.
Liu D, Mamorska-Dyga A. Syk inhibitors in clinical development for hematological malignancies. 
Journal of Hematology & Oncology. 2017;10(1):145.
31.
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 
2007;25(5):579-586.
32.
The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, Brown & Co; 1994.
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APPENDICES
Appendix A: Medications, Supplements, & Food Products to be avoided & to be Used Cautiously
Table 1: Medications, Supplements, and Food Products that are Strong CYP3A and/or P-gp Inhibitors or 
Inducers
Medication, Supplement, or Food Product (a, b)
Required Washout Period Before First Dose
Strong CYP3A Reversible Inhibitors and/or P-gp Inhibitors
amiodarone
azithromycin
captopril
carvedilol
cyclosporine
diltiazem
dronedarone
erythromycin
felodipine
ketoconazole
itraconazole
nefazodone
posaconazole
quercetin
quinidine
ranolazine
ticagrelor
verapamil
voriconazole
5 times the inhibitor half-life (if a reasonable 
half-life estimate is known), or 7 days (if a 
reasonable half-life estimate is unknown)
Strong CYP3A Mechanism-based Inhibitors
clarithromycin (c)
conivaptan (c)
mibefradilc (c) (d)
telithromycin
grapefruit-containing foods and beverages 5 days
7 days, or 5 times the inhibitor half-life, 
whichever is longer
5 days
Strong CYP3A Inducers and/or P-gp Inducers
avasimibe (e)
carbamazepine
phenobarbital
phenytoin
primidone
rifabutin
rifapentine
rifampin
St. John’s wort
7 days, or 5 times the inducer half-life, 
whichever is longer
(a) Note that the list of strong CYP3A inhibitors or inducers and/or P-gp inhibitors or inducers is not 
exhaustive and is based on the FDA Draft DDI Guidance (Sources: 
fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf 
and fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm080499.htm). If a medication, supplement, or food/beverage is 
suspected or known to be a P-gp inhibitor or inducer and/or strong CYP3A inhibitor or inducer but is 
not on the list, then its use must be discussed on a case-by-case basis by the PI to assess the 
relative benefit and risk.
(b) Note that medications used to treat HIV or hepatitis C infection that are strong CYP3A inhibitors or 
inducers and/or P-gp inhibitors or inducers are not included in this list, as patients with known HIV 
infection or known or suspected active hepatitis C infection are excluded from study participation. The 
list also does not include oncology medications because they are prohibited during the study.
(c) Also inhibitor of P-gp.
(d) Withdrawn from the US market due to safety reasons.
(e) Not marketed in the US.
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Appendix B: Cockcroft-Gault Equation
For male subjects:
Creatinine clearance = 
(140 − age[years]) × weight [kg] 
____________________________
72 × (serum creatinine[mg/dL])
OR
(140 − age[years]) × weight [kg]
______________________________
0.81 × (serum creatinine[µmol/L])
For female subjects:
Creatinine clearance = 
0.85 (140 − age[years]) × weight [kg] 
______________________________
72 × (serum creatinine[mg/dL])
OR
 0.85 (140 − age[years]) × weight [kg]
________________________________
0.81 × (serum creatinine[µmol/L])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.
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Appendix C: New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of moderately 
severe cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.

Source: The Criteria Committee of New York Heart Association. Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. Ninth Ed. Boston, 
MA: Little, Brown & Co; 1994:253-256.32
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APPENDIX D – LUGANO 2014 RESPONSE CRITERIA
Response and Site
PET-CT–Based Response
CT-Based Response
Complete
Lymph nodes and 
extralymphatic sites
Nonmeasured lesion 
Organ enlargement 
New lesions
Bone marrow
Complete metabolic response
Score 1, 2, or 3* with or without 
a residual mass on 5PS†
It is recognized that in 
Waldeyer’s ring or extranodal 
sites with high physiologic 
uptake or with activation within 
spleen or marrow (eg, with 
chemotherapy or myeloid 
colony-stimulating factors), 
uptake may be greater than 
normal mediastinum and/or liver. 
In this circumstance, complete 
metabolic response may be 
inferred if uptake at sites of initial 
involvement is no greater than 
surrounding normal tissue even 
if the tissue has high physiologic 
uptake
Not applicable 
Not applicable 
None
No evidence of FDG-avid 
disease in marrow
Complete radiologic response 
(all of the following)
Target nodes/nodal masses 
must regress to < 1.5 cm in LDi 
No extralymphatic sites of 
disease
Absent
Regress to normal 
None
Normal by morphology; if 
indeterminate, IHC negative
Partial
Lymph nodes and 
extralymphatic sites
Nonmeasured  lesions 
Organ enlargement
New lesions 
Bone marrow
Partial metabolic response
Score 4 or 5† with reduced 
uptake compared with baseline 
and residual mass(es) of any 
size
At interim, these findings 
suggest responding disease
At end of treatment, these 
findings indicate residual 
disease
Not applicable 
Not applicable
None
Residual uptake higher than 
uptake in normal marrow but 
Partial remission (all of the 
following)
≥50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites
When a lesion is too small to 
measure on CT, assign 5 mm x 
5 mm as the default value
When no longer visible, 0 x 0 
mm
For a node > 5 mm x 5 mm, but 
smaller than normal, use actual 
measurement for calculation
Absent/normal, regressed, but 
no increase
Spleen must have regressed by 
> 50% in length beyond normal
None
Not applicable
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reduced compared with baseline 
(diffuse uptake compatible with 
reactive changes from 
chemotherapy allowed). If there 
are persistent focal changes in 
the marrow in the context of a 
nodal response, consideration 
should be given to further 
evaluation with MRI or biopsy or 
an interval scan
No response or stable disease
Target nodes/nodal masses, 
extranodal lesions
Nonmeasured  lesions 
Organ enlargement 
New lesions
Bone marrow
No metabolic response
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment
Not applicable 
Not applicable 
None
No change from baseline
Stable disease
< 50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met
No increase consistent with 
progression 
No increase consistent with 
progression 
None
Not applicable
Progressive disease
Individual target nodes/nodal 
masses
Extranodal lesions
Nonmeasured lesions
New lesions 
Progressive metabolic disease
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or
New FDG-avid foci consistent 
with lymphoma at interim or end-
of-treatment   assessment
None
New FDG-avid foci consistent 
with lymphoma rather than
Progressive disease requires 
at least 1 of the following 
PPD progression:
An individual node/lesion must 
be abnormal with: LDi > 1.5 cm 
and
Increase by ≥ 50% from PPD 
nadir and 
An increase in LDi or SDi from 
nadir
0.5 cm for lesions < 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, 
the splenic length must increase 
by > 50% of the extent of its prior 
increase beyond baseline (eg, a 
15-cm spleen must increase to
> 16 cm). If no prior 
splenomegaly, must increase by 
at least 2 cm from baseline
New or recurrent splenomegaly
New or clear progression of 
preexisting nonmeasured lesions
Regrowth of previously resolved 
lesions
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Bone marrow 
another etiology (eg, infection, 
inflammation). If
uncertain regarding etiology of 
new lesions, biopsy or
interval scan may be considered
New or recurrent FDG-avid foci
A new node _ 1.5 cm in any axis
A new extranodal site _ 1.0 cm 
in any axis; if _ 1.0 cm in
any axis, its presence must be 
unequivocal and must be
attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to
Lymphoma
New or recurrent involvement
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Amendment 1 (FDA Response) – August 6th, 2018
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
Cover Page
Listed IND Number as 
“TBD”
Includes IND Number: 
140223
Administrative; newly 
available information post-
FDA submission
3.2.19 (Exclusion 
Criteria)
n/a
Adds abnormalities of left 
ventricular function as an 
exclusionary cardiovascular 
condition
FDA request; the current 
TAK-659 IB lists 2 cases of 
LV dysfunction when 
administered with other 
anticancer agents. 
4.3.1 (Definitions of 
Dose Limiting Toxicity)
DLT definition includes 
AE’s meeting the listed 
criteria that are considered 
at least possibly related to 
therapy with study drug. 
Updates language to be 
more stringent; all AE’s 
meeting the listed criteria will 
be considered DLT’s unless 
the event is clearly unrelated 
to study therapy
FDA request; encourages 
more stringent monitoring 
of DLT’s 
4.4.2 (Recommended 
Dose Delays / 
Modifications for R-
CHOP or TAK-659)
n/a
Adds stipulation for holding 
drug in the case of Grade 3 
or 4 EF toxicity. Cardiology 
assessment should take 
place to determine etiology, 
and patient should be 
discontinued if related to 
study drug.
In response to FDA request 
to add cardiology 
monitoring for known cases 
of LV dysfunction.
5.0 (Study Procedures; 
Table 5.1 & 5.2)
n/a
Adds Echo at baseline, post-
Cycle 3, and End of 
Treatment
FDA request to monitor left 
ventricular dysfunction; 
there have been 2 cases 
when TAK-659 was 
administered with other 
anticancer agents.
References
n/a
Moves “Reference” section 
to before the Appendices
Administrative change for 
consistency with internal 
protocols.
Amendment 1b (FDA Response Part 2) – August 8th, 2018
Section(s) Affected
Prior Version
Amendment 1b Changes
Rationale
3.2.19 (Exclusion 
Criteria)
Defines LV function 
abnormality as EF < 45%
Changes definition to EF < 
50%
FDA request
4.4.2 (Recommended 
Dose Delays / 
Modifications for R-
CHOP or TAK-659; 
table 4.5); 
5.0 (Study Procedures 
Table 5.1 & 5.2 #16)
TAK-659 was to be held 
for Grade 3 or 4 EF toxicity
TAK-659 will also be held for 
Grade 2 EF toxicity, pending 
evaluation by cardiology
FDA request; adds more 
stringent LV function 
monitoring in light of recent 
toxicities
Amendment 2 – January 2nd, 2019
Section(s) Affected
Prior Version
Amendment 1b Changes
Rationale
Cover Page
Reference Northwestern 
University’s Clinical 
Research Office
Updates to reference the 
Clinical Trials Office at 
Northwestern University
Administrative update
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Section 1.3 
Background information 
Previous language
Updated with information 
based on latest 
Investigator’s brochure 
received  from Takeda/
Millennium Pharmaceuticals, 
Inc.
Update made based on 
latest Tak-659 IB edition 6 
dated 1.15.19 
Study summary 
Section 2.2 and 6.3
Secondary endpoints 
and objectives
and Section 10
(statistics)
All objectives were stated 
together
Divided the objectives into 
subsections. Also specified 
that
For ORR assessment will be 
done at 3 months
and for PFS assessment will 
be done at 12 and 18 
months. OS has also been 
added as a secondary 
objective and will be 
assessed at 12 and 18 
months. 
For increased clarity and 
specificity. To be able to 
report results as early as 
possible. 
Section 3.1.8
Inclusion  criteria 
Creatinine clearance was 
stated to be calculated by 
C-G equation or based on 
urine collection (12 or 24 
hours)
The 12-24 hour urine 
collection option has been 
removed 
Based on information 
received from Takeda
Section 3.1.9 
Inclusion criteria
Stated that, patients must 
have blood pressure 
≤Grade 1.
NOTE: Hypertensive 
patients are permitted if 
their blood pressure is 
controlled to ≤Grade 1 by 
hypertensive medications
Added language to the note 
stating” The actual blood 
pressure value ONLY will be 
assessed/graded using the 
CTCAE v5 hypertension 
criteria”.
For added clarity
Section 3.2.19
List of cardiovascular 
conditions in the exclusion 
criteria 
Added hypertension to the 
list
For clarity and to be in 
alignment with inclusion 
criteria 3.1.9
Section 4.1 (table)
Treatment 
administration 
summary
Footnote 2. 
and Section 4.2.2
(R-CHOP 
administration)
Stated that, investigator 
may choose to administer 
G-CSF (filgrastim/tbo-
filgrastim or pegfilgrastim) 
with Cycle 1 per standard 
ASCO guidelines
Added language to state that 
it is highly recommended for 
Cycle 2-6 (combination 
therapy)
For safety 
4.1 (Overview); 4.2.1 
(TAK-659)
n/a
Adds that TAK-659 should 
be given before starting R-
CHOP administrative, with 
For clarity.
Was previously unclear 
which treatment should 
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consideration for pre-
medications and TAK-659 
PK’s 
be given first 
Study summary;
Table 4.1, footnote 5
Section 4.2.2
Section 4.2.2.2
Section 8.6.5
(Prednisone dose 
specifics)
Prednisone as part of R-
CHOP regimen was stated 
to be taken from day1-5. 
No language regarding 
prednisone dosing on 
clinic visit days. 
Added language to state that 
Prednisone can be taken on 
Days 2-6 instead of Days 
1-5 as part of
 R-CHOP regimen. 
Also, clearly states that 
on any clinic day (for study 
treatment), patients should 
NOT take prednisone before 
coming to clinic, but should 
hold and bring the 
prednisone tablets to clinic
For clarity and flexibility
Section 4.10
Removal of subjects
One of the criteria stated 
that subject would be 
removed if patient 
demonstrates disease 
progression. 
Added language to specify 
that progression can be 
clinical or radiological
For clarity
5.0 (Study Procedures, 
#11 – Table 5.1 & 5.2)
n/a
Breaks down differential 
WBC count by specifying 
that lymphocytes and 
neutrophils are required
Clarification
5.0 (Study Procedures, 
#13 – Table 5.1 & 5.2); 
9.0 (Correlative / 
Special Studies)
Pre- and post-dose timing 
of correlative samples did 
not specify which drug 
they were in relation to
Clarifies that pre- and post-
dose timing of samples 
should be in relation to TAK-
659 dosing
Clarification
Section 5.1 and 5.2 
Study procedure tables
T-cell panel was included 
in both tables but the 
specific parameters were 
not stated.
Introduced Footnote 17 in 
both tables to state the 
complete T-cell panel that is 
required to be done. 
To ensure consistency 
across all patients and 
study sites
Table 5.2 (Off-Study R-
CHOP, #1)
There was a discrepancy 
between the screening 
window in the table (-21 
days) and footnote 1 (≤30 
days)
Changes footnote 1 to say 
that screening procedures 
should take place ≤30 days 
prior to registration. 
Correction of 
discrepancy; patients 
who received off-study R-
CHOP require a shorter 
screening window to 
keep treatment timing 
consistent 
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Section 5.1, 5.2 
Study procedure tables
Footnote 13  
and Section 9.0
(Correlatives) 
Previous details did not 
clearly state what might 
count as a deviation 
regarding collection of bio 
banking samples. 
Added language to state  that 
Sample collection at EOT & 
time of relapse
(if patient willing and 
feasible)
and 
If bio banking samples are 
not collected or patient 
refuses, it will not be a 
deviation).
For clarity and flexibility
Section 5.1.and 5.2
study procedure tables
 
Footnote 8:Follow-up 
details
Footnote15
End of Treatment visit will 
occur within 30 days after 
completing study 
treatment
Footnote 8: Added language 
to specify that follow-up will 
include collection of survival 
data, progression/relapse 
and any new anti-cancer 
treatment.
Footnote 15 : Added 
language to state that EOT 
visit may occur either as 
stated before OR 
before starting new anti-
cancer therapy. 
For clarity and 
completeness 
8.2.5 (Protocol Dose 
Specifics – Rituximab)
Rituximab was to be 
administered “immediately 
prior to the start of 
chemotherapy”
Rituximab should be 
administered “as detailed in 
section 4.0”
Clarification; previous 
language was confusing 
since rituximab may be 
considered part of the 
chemotherapy regimen; 
details in 4.0 are 
sufficient and should be 
referenced to avoid 
confusion
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Section 4(table 4.1); 
Section 4.2.2;
Section 8.5.5 and
Section 8.5.11
Vincristine sulphate 
administration as part 
of R-CHOP
Language indicated that 
Vincristine would be 
administered as IV push 
throughout protocol except 
in Section 8.5.11 which 
indicated that it should be 
diluted in 25 or  50 mL 
0.9% sodium chloride to 
final concentration 0.0015 
– 0.08 mg/ml and infused 
over 10 minutes
Language modified to 
indicate that Vincristine will 
be given as IVPB. It now 
reads as “
Vincristine will be given at a 
dose 1.4 mg/m² (with 
maximum dose 2 mg) in NS 
50 mL administered IV over 
10 mins on day 1 of each 
cycle.”
Correction of discrepancy 
and in order to align with 
institutional policy
Section 8.6.5
and 8.6.9
and 
Section 4
(table 4.1) and 4.2.2.6
Prednisone tablets were 
stated in several different 
strengths and syrup was 
also included.  
Updated language to clearly 
state that commercial supply 
of 50mg prednisone tablets 
will be prescribed as 
2 tablets once daily PO to 
achieve a dose of 100mg 
daily. 
For clarity and 
convenience and to 
minimize deviations
Section 9.0 
Correlatives/Special 
studies
The PK sample analysis 
laboratory had not been 
specified.
The banking samples were 
to be stored at NU PCF.
Inserted language to state 
that PK samples will be 
received by NU PCF and 
shipped to Q2 solutions for 
analysis.
The banking samples will 
now be received by NUPCF 
and processed and stored at 
Dr.Gordon’s laboratory.
Logistical update 
Section 11.9 
Publication policy
Previous template 
language
Updated with most current 
template language for 
publication policy
Administrative update
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Amendment 3 dated 10.24.19
Section(s) Affected
Prior Version
Amendment 3 Changes
Rationale
Title page 
Listed Craig Boddy as 
Sub-I
Alfred Rademaker as 
Biostatistician
Removed Craig Boddy
Removed Alfred Rademaker 
and added Denise 
Scholtens, PhD as 
Biostatistician
Both have left 
Northwestern University
Added new biostatistician 
who has taken over the 
study.
Throughout
Study was stated to be 
single center
Term single center removed
For flexibility, since 
affiliate sites may join us 
in the near future
Section 3.1.3 
Inclusion criteria
and schema
Eligibility criteria included 
patients with several high 
risk features which 
included “previously 
treated transformed low-
grade lymphoma to large 
B cell lymphoma with prior 
treatment not including an 
anthracycline.” 
This criteria has been 
updated to” DLBCL 
transformed from low-grade 
lymphoma among treatment-
naïve patients or previously 
treated transformed low-
grade lymphoma with prior 
treatment not including an 
anthracycline. “
To increase flexibility of 
eligibility criteria
Section 3.1.4 
Inclusion criteria
Patients with measurable 
disease on PET scan 
required  a definite 
Deauville score for 
eligibility
Removed the requirement of 
a specific Deauville score
To increase flexibility of 
eligibility criteria and to 
minimize protocol
 deviations
Section 3.2.1
Exclusion criteria
Exclusion criteria stating 
prior treatment 
specifications
Added language to clarify 
that the note is an exception 
to the rule, which states that 
“Patients may receive at 
most 1 cycle of R-CHOP, 
rituximab, or systemic 
corticosteroids within this 
timeframe.”
For increased clarity
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Section 3.2.10
Exclusion criteria for 
patients receiving prior 
systemic anticancer or 
radiotherapy. The 
accompanying note 
mentions prior R-CHOP 
cycle. 
The accompanying note has 
been modified to state that 
patients may receive   
systemic steroids or 
rituximab in addition to R-
CHOP and references to 
appropriate sections have 
been made.
For clarity and to be in 
alignment with updates 
made to the rest of the 
protocol
Section 3.2.14
Exclusion criteria
Exclusion criteria 
regarding secondary 
malignancies. The 
accompanying note stated 
that patients with certain 
cancers are not excluded if 
they have undergone 
complete resection and 
are considered disease 
free at the time of 
registration.
The accompanying note has 
been modified to state that 
“Patients with low grade 
active malignancies such as 
prostate cancer, non-
melanoma skin cancer or 
carcinoma in situ of any 
type, which do not need 
treatment, are not excluded. 
Similarly, patients with a 
history of inactive breast 
cancer on hormone therapy 
are not excluded”
To increase flexibility of 
eligibility criteria and to 
comply with DSMC 
recommendation
Section 3.2.15
Exclusion criteria stated 
that patients with known 
GI disease or GI 
procedure that could 
interfere with absorption or 
tolerance of TAK-659 are 
not eligible. 
Language added to clarify 
that this will be per PI 
discretion.
In order to keep wriggle 
room to include patients 
that the PI may think are 
clinically appropriate to 
go on trial. 
Section 3.2.16 
Exclusion criteria for 
steroids
This criteria has been 
removed since language 
regarding steroids has been 
updated in the protocol (as 
described above) [steroids 
for anti-cancer treatment are 
allowed prior to Cycle 1].
For consistency
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Section 4.2.3
CNS prophylaxis and 
treatment
Previous language stating 
specific details regarding 
CNS prophylaxis and 
treatment. 
It included 
statement “CNS 
prophylaxis with 
intrathecal methotrexate, 
and/or intrathecal 
cytarabine is permitted, at 
the discretion of the 
investigator.”
Statement updated to include 
intrathecal 
steroids 
and 
timing and dosing will be per 
Pi discretion.
Also added language:
Specifically, IV HD-MTX for 
up to 4 doses is allowable 3 
weeks after the completion 
of 6 cycles of Nivo-R-
CHOP.  Dosing and 
schedule of HD-MTX is up to 
the discretion of the treating 
physician and should be 
carried out per institutional 
guidelines.
For increased clarity
Section 4.5.1
Required concomitant 
medications
.
Language regarding 
required ancillary drugs
Modified the section heading 
to Required/Permitted 
medication.
Added language regarding 
permitted steroids. Steroids 
for anti-cancer treatment are 
permitted prior to cycle 1
Moved topical steroid use 
language to permitted 
concomitant medication 
section from the prohibited 
section
For clarity and 
consistency
Section 4.5.2
Prohibited Concomitant 
Medications
 Language included 
steroids
Removed language 
regarding steroids, since 
modified steroid related 
language has now been 
added to the permitted 
concomitant medications 
section(4.5.1)
For clarity and 
consistency
Section 5.1 and 5.2 
Study procedure tables 
for patients with “On 
and off study R-CHOP 
schedules”
The Study treatment 
period at the top of the 
table was stated as 
“1 cycle=21 days, each 
visit +/-3 days “.
Footnote 16 of both tables 
Had language regarding 
cardiologic assessment for 
Added language clarifying 
that this statement is 
applicable “ unless otherwise 
stated in footnotes”(specific 
instructions that may differ)
Added language to state that 
the C4D1 echo can be done 
within a window of (-7days) 
but prior to dosing. Also, 
For increased clarity
and flexibility
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toxicity.
Footnote 17 of both tables 
had language stating 
details regarding T-cell 
panel. 
timeline for echo at EOT has 
been clearly stated.
One of the components,  
Total B-cell (CD3)(/uL) has 
been corrected to Total T 
cell(CD3)(uL)
Updated position of ‘X’ s in 
both tables for increased 
clarity
Correction of error
Section 8.1.8 
Incompatibilities 
Language regarding 
treatment with steroids 
and statement regarding 
anti-neoplastic therapy 
during study treatment. 
Both statements removed.
To align with the rest of 
the protocol and to 
remove redundant 
language
Section 11.7
Adherence to protocol
Term Promptly reportable 
non-compliance used
Updated to RNI (Reportable 
New Information)
To align with current IRB 
requirements
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Amendment 4 dated 4.3.2020
Section(s) Affected
Prior Version
Amendment 4 Changes
Rationale
Title page 
List of Sub-Investigators at 
NU
Listed Denise Scholtens, 
PhD as Biostatistician
Removed list of Sub-
Investigators at NU
Removed Denise Scholtens, 
PhD and added 
Masha Kocherginsky, PhD
as biostatistician , along with 
her contact email address
Administrative update
[since it is not a 
mandatory requirement to 
list sub-investigators]
Change in biostatistician   
assignment.
Section 3.1.8
Inclusion criteria
Criterion listing  the 
laboratory values to 
assess adequate organ 
and bone marrow function
A note added, stating: 
“Cytopenias felt to be 
disease related will not be 
excluded from the trial.”
For flexibility and clarity
Section 3.1.2
Inclusion criteria
Patients may have 
completed the first cycle of 
R-CHOP (off study not 
combined with TAK-659) ≤ 
21 days prior to the first 
dose of TAK-659 or plan to 
receive the first cycle of R-
CHOP after registration
The ≤ 21 days has been 
changed to ≤ 30 days
Correction of 
discrepancy. To align 
with Section 5 footnote
Throughout
Language stating that 
patients may have 
completed the first cycle of 
R-CHOP (off study not 
combined with TAK-659) 
≤ 21 days prior to the first 
dose of TAK-659
The ≤ 21 days has been 
changed to ≤ 30 days
For consistency
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Section 3.2.1
Exclusion criteria 
Patients with exposure to 
chemotherapy or 
immunotherapy ≤ 30 days 
prior to starting study 
treatment are not eligible 
Note: Patients may receive 
at most 1 cycle of R-
CHOP, rituximab, or 
systemic corticosteroids 
within this timeframe
Language in the note has 
been re-worded to state: 
“Patients may receive a 
bridge of rituximab or 
steroids prior to C1 of R-
CHOP.  Additionally, 
patients can receive their 
first cycle of R-CHOP prior 
to enrolment on trial (off 
study).”  
For increased clarity
Section 3.2.10
Exclusion
criteria
Patients who have 
received systemic 
anticancer treatment 
(including investigational 
agents) or radiotherapy 
less than 3 weeks before 
the first dose of study 
treatment (≤ 5 times half-
life for large molecule 
agents or ≤4 weeks with 
evidence of disease 
progression if 5 times half-
life is > 4 weeks) are not 
eligible.
Note exception: Patients 
may receive R-CHOP 
Cycle 1 as outlined in 
section 4.1 or systemic 
corticosteroids or rituximab 
as specified in section 
3.2.1
The language in the note 
has been reworded to state: 
“This does not apply to C1 
dosing of R-CHOP: it is 
expected that all patients will 
receive R-CHOP for C1 
either on or off study.  
Patients will also be allowed 
to receive rituximab and/or 
steroids as a bridge to C1 of 
R-CHOP as an exception as 
outlined in section 3.2.1”
For increased clarity
To align with section 3.2.1
Table 4.5 
TAK-659 Dose 
Adjustments for Non-
hematologic Toxicities
Table for dose 
adjustments for non-
hematologic toxicities. 
But attribution was not 
clearly stated 
Other asymptomatic Grade 3 
laboratory abnormalities that 
the investigator considers not 
clinically significant
Added language to 
appropriate columns:
“If attribution to TAK-659 is 
felt to be possible, probable 
or definite.”
“If there is question of relation to 
TAK-659, discuss with PI to 
determine appropriate course of 
action.”
Modified to add other clinical 
findings (including HTN) 
along with grade 3 
laboratory abnormalities, 
which the investigator 
considers not clinically 
significant
For increased clarity and 
flexibility
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Table 4.6
R-CHOP dose 
adjustments for non-
hematologic toxicities
Previous directives
for Sensory neuropathy:
Grade 3 neuropathy :
“Reduce vincristine by 25-
50%, per investigator 
discretion. If symptoms 
improve, doses may be 
increased to previous 
levels”
There was no Grade 2
Added grade 2 directives:
“Grade 2 sensory 
neuropathy-
Can maintain or reduce 
vincristine by 25-50%, per 
investigator discretion “
Grade 3 directive remains 
the same
For accuracy
Section 4.4.3
Criteria for 
Discontinuation of 
Study Drug(s)
Previous instructions
Added language:
Patients exceeding delays of 
>21 days for TAK-659 
related toxicities may be 
considered on a case-by-
case for continuing dosing 
with TAK-659. PI and DSMC 
approval should be obtained 
prior to continuing dosing 
with TAK-659
For flexibility
Section 4.4.4
Management of Clinical 
events
Prophylaxis against 
infections
Previous language which 
included the statement 
that 
PJP prophylaxis should be 
considered at the start of 
study treatment
Reworded and modified 
some of the previous 
language for prophylaxis 
against infections. 
The PJP 
prophylaxis is now required 
to be as follows:
“PJP prophylaxis should be 
initiated with C2 (first dose of 
combination treatment).”
For accuracy and clarity
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Section 4.5.5
Required/permitted 
concomitant 
medications
Previous list
Added language 
“PJP prophylaxis should be 
initiated with C2 (first cycle 
of combination therapy)”
To be consistent with 
Section 4.4.4
Section 5.1 and Section 
5.2
Study procedure
tables
PET/CT should be 
obtained ≤ 30 days prior to 
first cycle of R-CHOP (on- 
or off-study)
The baseline ECHO 
window as 30 days like 
other screening 
procedures
The window for PET/CT 
scan has been increased 
from ≤ 30 to ≤ 60 days.
The window for baseline 
ECHO has been increased 
from 30 to 60 days. 
Footnote 16 now states: “For 
baseline ECHO, a window of 
60 days prior to registration is 
acceptable.”
For increased flexibility 
and to avoid additional 
testing
Section 5.2 Study 
procedures table
[Off-study R-CHOP]
The Screening procedures 
window was ≤ 21 days
The screening procedures 
window has been increased 
to ≤ 30 days
For consistency and 
convenience
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Section 11
Study management
Previous template 
language 
Updated with most current 
version of NU protocol 
template language
Administrative update
IRB #: STU00207880-CR0003 Approved by NU IRB for use on or after 4/11/2022 through 4/10/2023.