A Phase 1 Study to Assess Mass Balance, Pharmacokinetics, and Metabolism of [14C]Subasumstat in Patients With Advanced or Metastatic Solid Tumors
Phase: PHASE1
Conditions: Solid Tumors
Sponsor: Takeda

For non-commercial use only

 
 
PROTOCOL
A Phase 1 Study to Assess Mass Balance, Pharmacokinetics, and Metabolism of 
[14C]Subasumstat in Patients With Advanced or Metastatic Solid Tumors
Sponsor:
Takeda Development Center Americas, Inc. (TDC Americas)
95 Hayden Avenue
Lexington, MA 02421
Please note: Takeda Development Center Americas, Inc. (TDC Americas) may be 
referred to in this protocol as “sponsor” or “Takeda”.
Study Number:
TAK-981-1004
EU Trial Number:
2023-503449-79
Universal Trial 
Number:
Not applicable
Compound:
Subasumstat or TAK-981
Date:
25 April 2023
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed (e)consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event (SAE), pregnancy, and other applicable safety reporting information is 
presented in the study manual, as is information on reporting product complaints.
TDC-Americas–sponsored investigators per individual country requirements will be provided 
with emergency medical contact information cards to be carried by each patient.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
The names and contact information for the medical monitor and responsible medical officer are in 
the study manual.
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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure (IB), 
prescribing information, and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study patients in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events (SAEs) defined in Section 10.0
of this protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
2.0
STUDY SUMMARY ....................................................................................................10
3.0
STUDY REFERENCE INFORMATION ......................................................................13
3.1
Study-Related Responsibilities.................................................................................13
3.2
Coordinating Investigator.........................................................................................13
3.3
List of Abbreviations ...............................................................................................14
3.4
Corporate Identification...........................................................................................15
4.0
INTRODUCTION.........................................................................................................16
4.1
Background .............................................................................................................16
4.1.1
Protein SUMOylation Biology in Cancer.........................................................16
4.1.2
Subasumstat.....................................................................................................16
4.2
Rationale for the Proposed Study.............................................................................19
4.3
Rationale for Dose Selection of Subasumstat ...........................................................19
4.4
Risks and Benefits ...................................................................................................19
4.4.1
Potential Effects Based on Nonclinical Studies ................................................20
4.4.2
Effects Based on Clinical Studies.....................................................................20
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................20
5.1
Objectives................................................................................................................20
5.1.1
Primary Objectives ..........................................................................................20
5.1.2
Secondary Objectives ......................................................................................20
5.1.3
Exploratory Objectives ....................................................................................21
5.2
Estimands ................................................................................................................21
5.3
Endpoints.................................................................................................................21
5.3.1
Primary Endpoints ...........................................................................................21
5.3.2
Secondary Endpoints .......................................................................................21
5.3.3
Exploratory Endpoints .....................................................................................22
6.0
STUDY DESIGN..........................................................................................................22
6.1
Overview of Study Design.......................................................................................22
6.1.1
Part A: Mass Balance/ADME Assessment of Single Agent Subasumstat .........22
6.1.2
Part B: Continued Treatment With Single Agent Subasumstat .........................23
6.2
Number of Patients ..................................................................................................24
6.3
Duration of Study ....................................................................................................24
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6.3.1
Duration of an Individual Patient’s Study Participation....................................24
6.3.2
EOS/Study Completion Definition and Planned Reporting...............................25
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......25
6.3.4
Total Study Duration .......................................................................................26
6.4
Poststudy Access .....................................................................................................27
7.0
STUDY POPULATION................................................................................................27
7.1
Inclusion Criteria .....................................................................................................27
7.2
Exclusion Criteria ....................................................................................................28
8.0
STUDY DRUG .............................................................................................................30
8.1
Study Drug Administration......................................................................................30
8.2
List of European Union Auxiliary Medicinal Products.............................................30
8.3
Dose Modification Guidelines (Part B) ....................................................................31
8.3.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle...................31
8.3.2
Criteria for Dose Interruption or Reduction During a Cycle .............................31
8.3.3
Criteria for Discontinuation of Subasumstat.....................................................35
8.4
Prohibited Concomitant Medications and Procedures...............................................35
8.5
Permitted Concomitant Medications and Procedures................................................36
8.6
Precautions and Restrictions ....................................................................................37
8.7
Management of Clinical Events ...............................................................................37
8.7.1
Nausea or Vomiting.........................................................................................38
8.7.2
Diarrhea...........................................................................................................38
8.7.3
Anemia, Thrombocytopenia, or Neutropenia....................................................38
8.7.4
Infusion Site Care............................................................................................38
8.7.5
Lymphopenia and Opportunistic Infection Prophylaxis....................................39
8.7.6
IRRs ................................................................................................................39
8.7.7
CRS.................................................................................................................39
8.8
Blinding and Unblinding..........................................................................................40
8.9
Description of Investigational Agents ......................................................................41
8.10
Preparation, Reconstitution, and Dispensation..........................................................41
8.11
Packaging and Labeling...........................................................................................41
8.12
Storage, Handling, and Accountability.....................................................................41
8.13
Other Protocol-Specified Materials ..........................................................................42
9.0
STUDY CONDUCT......................................................................................................42
9.1
Study Personnel and Organizations..........................................................................42
9.2
Arrangements for Recruitment of Patients................................................................42
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9.3
Informed Consent ....................................................................................................42
9.4
Treatment Group Assignments.................................................................................42
9.5
Study Procedures.....................................................................................................42
9.5.1
Patient Demographics......................................................................................43
9.5.2
Medical History...............................................................................................43
9.5.3
Confinement....................................................................................................43
9.5.4
Physical Examination ......................................................................................43
9.5.5
Patient Weight .................................................................................................43
9.5.6
Patient Height..................................................................................................43
9.5.7
Vital Signs.......................................................................................................43
9.5.8
Pregnancy Test ................................................................................................43
9.5.9
Concomitant Medications and Procedures........................................................44
9.5.10
AEs .................................................................................................................44
9.5.11
Enrollment.......................................................................................................44
9.5.12
ECG ................................................................................................................44
9.5.13
Clinical Laboratory Evaluations.......................................................................45
9.5.14
ECOG Performance Status...............................................................................46
9.5.15
Disease Assessment by Imaging ......................................................................46
9.5.16
PK Measurements............................................................................................47
9.6
Completion of Study Treatment (for Individual Patients) .........................................47
9.7
Completion of Study (for Individual Patients)..........................................................48
9.8
Discontinuation of Treatment With Study Drug, Patient Withdrawal, and Patient 
Replacement ............................................................................................................48
9.9
Study Compliance....................................................................................................48
10.0
ADVERSE EVENTS ....................................................................................................49
10.1
Definitions...............................................................................................................49
10.1.1
Pretreatment Event Definition..........................................................................49
10.1.2
AE Definition ..................................................................................................49
10.1.3
SAE Definition................................................................................................49
10.1.4
Special Situation Report Definition..................................................................50
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................50
10.2.1
Recording and Reporting AEs and SAEs Related to AxMPs............................51
10.3
Monitoring of AEs and Period of Observation .........................................................52
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........52
10.5
Procedures for Reporting Product Complaints or SSRs (Including Overdose) ..........52
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........53
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11.0
STUDY-SPECIFIC COMMITTEES .............................................................................53
12.0
DATA HANDLING AND RECORDKEEPING............................................................53
12.1
eCRFs......................................................................................................................53
12.2
Record Retention .....................................................................................................54
12.3
Data Protection ........................................................................................................54
13.0
STATISTICAL METHODS..........................................................................................55
13.1
Statistical and Analytical Plans ................................................................................55
13.1.1
Analysis Sets ...................................................................................................56
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................56
13.1.3
Efficacy Analysis.............................................................................................56
13.1.4
PK Analysis.....................................................................................................57
13.1.5
Safety Analysis................................................................................................58
13.2
Interim Analysis and Criteria for Early Termination ................................................59
13.3
Determination of Sample Size..................................................................................59
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................59
14.1
Study-Site Monitoring Visits ...................................................................................59
14.2
Protocol Deviations..................................................................................................59
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................60
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................60
15.1
IRB and/or IEC Approval ........................................................................................60
15.2
Patient Information, Informed Consent, and Patient Authorization...........................61
15.3
Patient Confidentiality .............................................................................................62
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................63
15.4.1
Publication.......................................................................................................63
15.4.2
Clinical Trial Registration................................................................................63
15.4.3
Clinical Trial Results Disclosure......................................................................64
15.5
Insurance and Compensation for Injury....................................................................64
16.0
REFERENCES..............................................................................................................64
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................26
Table 8.a
General Dose Modification Recommendations for Subasumstat 
Nonhematologic Drug-Related AEs ...................................................................32
Table 8.b
Dose Adjustments for Hematologic Toxicities ...................................................33
Table 8.c
TAK-981 Dose Modification Guidelines for CRS ..............................................34
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Table 8.d
CRS Management Recommendations and Subasumstat Dose Modification........40
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................45
Table 9.b
Clinical Urinalysis Tests ....................................................................................46
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................24
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................66
Appendix B
Responsibilities of the Investigator.....................................................................74
Appendix C
Investigator Consent to Use of Personal Information..........................................76
Appendix D
ECOG Scale for Performance Status ..................................................................77
Appendix E
Drugs that Interact With the CYP3A Family of CYPs ........................................78
Appendix F
Examples of Clinical Inhibitors of Pgp...............................................................80
Appendix G
Examples of QTc Interval Prolonging Agents ....................................................81
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2.0
STUDY SUMMARY
Name of Sponsor(s): TDC Americas
Compound: Subasumstat (TAK-981)
Title of Protocol: A Phase 1 Study to Assess Mass 
Balance, Pharmacokinetics, and Metabolism of 
[14C]Subasumstat in Patients With Advanced or Metastatic 
Solid Tumors
EU Trial No.:
2023-503449-79
Study Number: TAK-981-1004
Phase: 1
Study Design:
This is a 2-part, open-label, mass balance and absorption, distribution, metabolism, excretion study in patients with 
advanced or metastatic solid tumors.
Part A is the period assessing the mass balance, pharmacokinetic (PK), metabolism, and excretion of subasumstat in 
this population.
The study will enroll patients diagnosed with locally advanced or metastatic solid tumors with measurable disease. If 
patients drop out, they may be replaced, to ensure approximately 6 PK evaluable patients complete all study 
assessments. Patients will be admitted to the study site for at least 5 days postdose and until all the discharge criteria 
are met for a maximum of 14 days postdose. Samples will be collected and patients confined until 90% or greater of 
the total dose of radioactivity administered is recovered in urine and fecal samples (combined) or until <1% of the 
dosed radioactivity is collected in 2 consecutive intervals when both urine and feces are collected. Patients who meet 
all inclusion criteria and none of the exclusion criteria will be assigned a patient identification number and will be 
admitted to the study site on Day -1 for predose assessments. On Day 1, patients will receive 90 mg [14C]subasumstat 
intravenous (IV) solution containing 100 μCi (approximately 3.7 megabecquerels (MBq); equivalent to 2.74 mrem or 
0.0274 mSv whole body effective dose for human male subjects and 1.41 mrem or 0.0141 mSv whole body effective 
dose for human female subjects) via a 1-hour IV infusion. All samples being assessed for total radioactivity (TRA) 
will be tested in batches. All samples from Day 1 to Day 5 will be assessed at the same time. For patients who do not 
meet the discharge criteria, the samples collected from Day 6 until the time when the TRA is available will be used for 
TRA determination. This process of batch measurement will continue until the discharge criteria are met. Since up to 
a 3-day time lag is anticipated for radioactivity counting of samples, actual patient discharge from the study site may 
occur 3 days after the discharge criteria are met. 
Patients’ safety will be closely monitored, and adverse events (AEs) will be collected throughout the study. Vital 
signs, physical examinations, electrocardiograms (ECGs), and clinical laboratory tests will be captured during the 
confinement (predose, during study, before discharge from study site).
In this clinical study, blood samples will be collected at prespecified time points to analyze subasumstat, TRA in blood 
and plasma, and metabolite profiling in plasma over the confinement. Complete urinary and fecal output will be
collected throughout the confinement period until discharge; urine samples will be analyzed for PK, TRA, and 
metabolite profiling and fecal samples will be analyzed for TRA and metabolite profiling. For patients experiencing 
emesis after drug administration, the full vomitus will be collected as much as possible and assayed for TRA. If a 
subject vomits more than once during a period, vomitus corresponding to each vomiting event will be collected in a 
separate labeled container and separately counted. More detailed information will be provided in the study manual. 
Patients may be provided treatment for constipation if needed, as determined by the investigator.
After completion of Part A, patients will have the opportunity to participate in Part B. Participation in Part B is 
voluntary, and a consent is included in the main study consent form. The patient can withdraw from Part B at any time 
during the study, or the patient can be withdrawn from the study if there is toxicity or there is no evidence of clinical
benefit to the patient at the discretion of the investigator. 
During Part B, the patient will receive subasumstat 90 mg twice daily (on days 1, 4,8, and 11 of the 21-day cycle) for 
3 cycles, followed by weekly maintenance dosing (on days 1 and 8 of the 21 day cycle). The treatment will be up to 1 
year. For patients who have completed 1 year of treatment with subasumstat, the investigator(s) may discuss treatment 
options with the sponsor.
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Safety and disease assessments will be collected in Part B. Investigators will use RECIST 1.1 criteria to assess the 
clinical response. Disease assessments will be conducted using radiological evaluations (computed tomography scan 
or magnetic resonance imaging).
Toxicity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.
Primary Objectives:
The primary objectives are:

To assess the mass balance (ie, cumulative excretion of TRA in urine and feces) of subasumstat following a single 
1-hour infusion of 90 mg [14C]subasumstat IV solution containing 100 μCi (approximately 3.7 MBq) in patients 
with advanced or metastatic solid tumors in Part A.
Secondary Objectives:
The secondary objectives are:

To characterize the PK of subasumstat in whole blood, plasma, and urine, and of TRA in plasma and whole blood 
following a single 1-hour infusion of 90 mg [14C]subasumstat IV solution containing 100 μCi (approximately 3.7 
MBq) in patients with advanced or metastatic solid tumors in Part A.

To evaluate the safety and tolerability of subasumstat in patients with advanced or metastatic solid tumors during 
Part A and Part B.

To collect samples for characterization of the metabolic profile of subasumstat in plasma, urine, and feces 
following a single 1-hour infusion of 90 mg [14C]subasumstat IV solution containing 100 μCi (approximately 3.7 
MBq) in patients with advanced or metastatic solid tumors in Part A.
Patient Population: Adult patients aged ≥18 years old with locally advanced or metastatic solid tumors with 
measurable disease
Number of Patients:
Approximately 10 patients enrolled for approximately 6 PK 
evaluable patients.
Number of Sites: 
Two study sites in Hungary (1 for Part A and 1 for Part 
B).
Dose Level(s):
Part A: Single dose of 90 mg [14C]subasumstat IV solution 
(containing approximately 3.7 MBq of total radioactivity).
Part B (optional): 90 mg subasumstat IV solution on Days 1, 
4, 8, and 11 of a 21 day cycle for 3 cycles, followed by 
weekly maintenance dosing.
Route of Administration:
IV in 1-hour infusion.
Duration of Treatment:
Part A: Single IV infusion.
Part B: Up to 1 year.
Period of Evaluation:
Screening: Within 28 days before the first dose of 
study drug.
Part A: Patients will be required to stay at the study site 
for 5 to 8 days postdose and until the discharge criteria 
are met, with a maximum confinement period of 14 
days postdose. Patients not participating in Part B will 
complete an end of study (EOS) visit 30 days (+10 
days) after the last dose of study drug or before the start 
of the subsequent therapy for the patient’s indication, if 
that occurs sooner.
Part B (optional): The maximum treatment duration is 
1 year. An EOS visit will occur 30 days (+10 days) 
after the last dose of study drug in Part B or before the 
start of subsequent therapy for the patient’s indication, 
if that occurs sooner.
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Main Criteria for Inclusion:
Male or female patients, aged 18 years or older, who (1) have histologically or cytologically confirmed advanced 
(locally regionally recurrent not amenable to curative therapy) or metastatic solid tumors with no standard therapeutic 
option with a proven clinical benefit, are intolerant or have refused them, (2) have a performance status of 0 or 1 on the 
Eastern Cooperative Oncology Group Performance Scale, (3) demonstrate adequate organ function, and (4) have 
recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity established as 
sequela.
Main Criteria for Exclusion:
Patients who (1) have uncontrolled brain metastasis, (2) had a second malignancy within the previous 3 years, except 
treated basal cell or localized squamous skin carcinomas, prostate cancer, cervical carcinoma in situ, resected 
colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the patient is not on active 
anticancer therapies, (3) have an active HIV, hepatitis B, or hepatitis C infection, (4) recent or continued use of 
specific medications or procedures, or (5) has certain types of uncontrolled heart diseases.
Endpoints:
The primary endpoints are:

Cumulative percentage of urinary recovery, fecal recovery, and combined recovery, and percentage of recovered 
TRA in urine and feces for each interval over the entire period of collection.
The secondary endpoints are: 

PK parameters of subasumstat and TRA in plasma and whole blood: maximum observed concentration, time of 
first occurrence of Cmax, and area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration, and as permitted by data, terminal disposition phase half-life, clearance, volume of distribution at 
steady-state, and area under the concentration-time curve from time 0 to infinity, calculated using the observed 
value of the last quantifiable concentration.

PK parameters of subasumstat in urine: cumulative amount of unchanged drug excreted into the urine (Aeurine and 
percentage of dose) and renal clearance.

Safety parameters: AEs, serious adverse events, ECG, and abnormality of laboratory values.

Metabolite profiling and identification in plasma, urine, and feces.
Statistical Considerations:
No formal statistical hypothesis testing will be performed.
Sample Size Justification:
Based on the ALARA principle (As Low [radioactive burden] As Reasonably Achievable) set forth in the 
96/29/EURATOM directive, a sample size of approximately 6 PK-evaluable patients is considered sufficient to 
provide adequate characterization of the mass balance, PK, metabolism, and excretion of subasumstat in patients with 
cancer. 
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform specific 
study-related activities either in full with sponsor oversight or in partnership with the sponsor.
3.2
Coordinating Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol and the study medication, expertise in the therapeutic area and the conduct of clinical 
research, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
ADME
absorption, distribution, metabolism, excretion
AE
adverse event
Aeurine
cumulative amount of unchanged drug excreted into the urine
ALARA
as low (radioactive burden) as reasonable achievable
ASTCT
American Society for Transplantation and Cellular Therapy
AUC∞
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to time of the last quantifiable concentration
AxMP
auxiliary medicinal product
BIW
twice weekly
CL
clearance
CLR
renal clearance
Cmax
maximum observed concentration
CR
complete response
CRO
contract research organization
CRS
cytokine release syndrome
CT
computed tomography
CYP
cytochrome P450
DC
dendritic cell
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOS
end of study
FDA
[United States] Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
IFN
interferon
IMP
investigational medicinal product
IRB
institutional review board
IRR
infusion-related reaction
IV
intravenous
MBq
megabecquerels
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
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MOA
mechanism of action
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
ORR
overall response rate
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamic
PFS
progression-free survival
Pgp
P-glycoprotein
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
PR
partial response
QTcF
QT interval with Fridericia correction method
QW
once weekly
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SOE
schedule of events
SSR
special situation report
SUMO
small ubiquitin-like modifier
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of maximum observed concentration
TRA
total radioactivity
UK
United Kingdom
ULN
upper limit of normal
US
United States
Vss
volume of distribution at steady-state
WHO
World Health Organization
3.4
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
4.1.1
Protein SUMOylation Biology in Cancer
SUMOylation is a posttranslational modification that attaches a small ubiquitin-like modifier 
(SUMO) protein to protein substrates, regulating their activity, subcellular localization, and 
stability (Seeler and Dejean 2017). SUMO pathway components are ubiquitously expressed in 
eukaryotic cells (Geiss-Friedlander and Melchior 2007). 
SUMOylation has been reported to regulate cellular processes important for tumor cell 
proliferation and survival (He et al. 2017; Seeler and Dejean 2017). In addition, SUMOylation has 
also been shown to play a key role in regulating innate immune responses. Inhibition of 
SUMOylation results in induction of type I interferon (IFN) expression, such that inhibiting 
SUMOylation by genetic means resulted in enhanced basal expression levels and sensitization of 
induction of type I IFNs (Decque et al. 2016). Type I IFNs, such as IFN-α and IFN-β, are potent 
immunomodulatory cytokines induced early in the innate immune response which act upon 
multiple cell types to mold both innate and adaptive immunity. They directly enhance natural killer 
(NK) cell cytotoxicity and stimulate interleukin-15 production by dendritic cells (DCs) to promote 
NK cell activation (Lee et al. 2000; Lucas et al. 2007). They also directly act upon T cells to 
stimulate survival, clonal expansion and the development of T cell effector function (Curtsinger et 
al. 2005; Marrack et al. 1999). Importantly, type I IFNs play a central role in propagating adaptive 
immune responses by promoting maturation of DCs and cross presentation of antigens to T cells 
(Diamond et al. 2011; Fuertes et al. 2011). Indeed, innate immune responses have been implicated 
in tumor surveillance, via sensing of tumor DNA through the pattern recognition receptor pathway 
(Woo et al. 2014), activation of which induces production of type I IFNs and propagation of an 
adaptive antitumor response as described above. 
4.1.2
Subasumstat 
4.1.2.1
Mechanism of Action
Subasumstat (TAK-981) is a small molecule inhibitor of the SUMOylation cascade by forming a 
covalent adduct with SUMO, preventing its transfer from SUMO-activating enzyme to the 
SUMO-conjugating enzyme ubiquitin carrier protein 9. 
In vivo treatment with subasumstat resulted in a dose-dependent induction of a type I IFN gene 
signature in peripheral blood mononuclear cells (PBMCs) and upregulation of type I IFNs and 
type I IFN-stimulated genes in mouse splenocytes (Lightcap et al. 2021). In ex vivo assays, 
subasumstat was found to potently activate mouse and human DCs, promoting expression of T cell 
costimulatory markers and production of inflammatory cytokines. In vivo vaccination studies with 
ovalbumin protein demonstrated enhancement of antigen cross-presentation and T cell priming by 
subasumstat (Lightcap et al. 2021).
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In syngeneic mouse tumor models, subasumstat was shown to potently inhibit the growth of 
A20 B-cell lymphoma tumors, with some treated mice achieving complete response (CR). Flow 
cytometry demonstrated increased numbers of activated T and NK cells in A20 tumors responding 
to subasumstat (Lightcap et al. 2021). Blockade of type I IFN signaling by pretreatment with a 
blocking antibody against the type I IFN receptor resulted in complete loss of tumor growth 
inhibition, indicative of a key role for type I IFN signaling in the antitumor mechanism of action 
(MOA) of subasumstat. (Lightcap et al. 2021).
In ex vivo assays evaluating the activity of subasumstat on the function of human monocyte 
derived macrophages and human NK cells (both derived from PBMCs), subasumstat increased the 
phagocytic activity of monocyte derived macrophages and increased the cytotoxicity of NK cells 
in both the absence and presence of the anti-CD20 antibody rituximab (Nakamura et al. 2022). 
These activities were dependent on type I IFN signaling, demonstrating that subasumstat-mediated 
inhibition of SUMO-activating enzymes leads to the functional activation of human macrophages 
and human NK cells via type I IFN signaling ex vivo. Significant antitumor activity was 
demonstrated against OCI-Ly10 xenografts in severe combined immunodeficient mice (lacking B 
and T cells but retaining an intact innate immune system) following administration of single-agent 
subasumstat or the anti-CD20 antibody rituximab. 
4.1.2.2
Nonclinical Pharmacokinetics
Subasumstat has an acceptable nonclinical pharmacokinetic (PK) profile for continuing evaluation 
and development in humans.
In plasma, after single intravenous (IV) administration, subasumstat showed moderate to high 
plasma clearance (CL) and volume of distribution at steady state after IV administration in mice, 
rats, dogs, and monkeys with half-lives varying from 2 to 6 hours among species.
4.1.2.3
Nonclinical Toxicology
Toxicology studies were conducted in rats and dogs because in vitro metabolism, homology, and 
tissue expression data indicated that these species are relevant for evaluation of subasumstat. 
Because intermittent dosing on a once weekly (QW) or twice weekly (BIW) schedule was 
demonstrated to be efficacious in mouse models, both QW and BIW schedules were examined in 
Good Laboratory Practice (GLP)-compliant toxicity studies. QW dosing (5 doses) was associated 
with multiorgan failure in rats at ≥20 mg/kg but was well-tolerated in dogs up to the highest dose 
of 6 mg/kg. BIW dosing (4 doses) was well-tolerated in both species up to the highest dose of 
10 mg/kg in rats and 4 mg/kg in dogs. 
The primary toxicity with BIW dosing was dose-dependent, mild to marked decreases in 
peripheral blood lymphocyte counts that affected T cells, T cell subsets (helper, cytotoxic, 
activated, memory, regulatory), B cells, and NK cells approximately equally. Decreases in 
lymphocyte counts were associated with decreases in lymphoid cellularity in the primary and 
secondary lymphoid organs, including the thymus, spleen, lymph nodes, and gut-associated 
lymphoid tissue. Decreases in other circulating cell types, including neutrophils, monocytes, 
basophils, and/or eosinophils, were also observed but were of decreased severity compared with 
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decreases in lymphocyte counts. Additional effects observed with BIW dosing were limited to 
myeloid hyperplasia in the bone marrow in rats at 10 mg/kg and dogs at 4 mg/kg, injection site 
reactions in rats at ≥0.5 mg/kg, single-cell necrosis in the stomach in dogs at ≥2 mg/kg, and renal 
pelvis inflammation and fibrinoid vascular necrosis (without involvement of the renal parenchyma 
or alterations in renal parameters) in dogs at 4 mg/kg. Additional subasumstat-related effects after 
repeat once daily or QW dosing, often at nontolerated doses only, were noted in the bone marrow, 
liver, kidney, urinary, and bladder (dog only); gastrointestinal tract, heart, musculoskeletal system, 
and lung (rat only); endocrine system (rat only); glandular organs (rat only); and reproductive tract 
(rat only). Injection site reactions have been observed only in rats at all doses tested. All target 
organ toxicities at tolerated doses were considered to be monitorable, except for inflammation and 
vascular necrosis in the renal pelvis in dogs. All target organ toxicities were completely or partially 
reversible.
Subasumstat had no effect on cytokines related to cytokine release syndrome (CRS) in an in vitro 
assay in human whole blood. Subasumstat was not mutagenic; however, it is considered genotoxic 
based on an in vivo micronucleus assay in rats and an in vitro mammalian chromosome aberration 
assay in human peripheral blood lymphocytes, which showed clastogenicity. Subasumstat did not 
demonstrate phototoxic potential in an in vitro assay.
4.1.2.4
Clinical Experience
Subasumstat is currently being evaluated in 4 clinical studies in adult patients with advanced solid 
tumors or hematologic malignancies. These studies include the following:

Study TAK-981-1002 (ongoing): Phase 1/2 dose escalation study with subasumstat as a 
monotherapy in patients with advanced or metastatic tumors or relapsed or refractory 
hematoligic malignancies.

Study TAK-981-1501 (closing): Phase 1/2 clinical efficacy and safety study with a 
combination therapy (subasumstat + rituximab) in patients with relapsed or refractory CD20+ 
non-Hodgkin’s lymphoma.

Study TAK-981-1502 (ongoing): Phase 1b/2 clinical efficacy and safety study with a 
combination therapy (subasumstat + pembrolizumab) in patients with select advanced or 
metastatic solid tumors.

Study TAK-981-1503 (ongoing): Phase 1b/2 clinical efficacy and safety study with a 
combination therapy (subasumstat + anti-CD38 monoclonal antibodies) in patients with 
relapsed refractory multiple myeloma.
Overall, subasumstat has been well-tolerated, with the majority of treatment-emergent adverse 
events (TEAEs) being consistent with the induction of IFN signaling or the patients’ underlying 
cancer. Overall, preliminary efficacy is being observed, and efficacy evaluations are ongoing. 
Study TAK-981-1002 has completed dose escalation and dosing schedule evaluation. The 120 mg 
dose on Days 1, 4, 8, and 11 dosing regimen was determined as the subasumstat single-agent 
maximum tolerated dose. Subasumstat 90 mg (Days 1, 4, 8, and 11 dosing regimen) regimen was 
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determined to be the recommended phase 2 dose (RP2D) and schedule for the subsequent phase 2 
portion of the single-agent study. Dose finding and schedule evaluation are continuing in the other 
3 ongoing studies.
Refer to the current TAK-981 IB for additional details.
4.2
Rationale for the Proposed Study
Part A of this study is intended to provide a quantitative characterization of the mass balance, rates 
and routes of excretion, and metabolic profiles of subasumstat in humans. Such definitive 
characterization will help guide understanding of the potential for the intrinsic (eg, renal and 
hepatic impairment) or extrinsic (eg, concomitant medications with potential to affect drug 
metabolism and disposition) factors to affect subasumstat PK and, thereby, is important to inform 
the need for future clinical pharmacology studies (eg, special population studies in patients with 
organ impairment). Part B of this study is intended to provide opportunity for the patients with 
advanced or metastatic solid tumors to receive treatment with single agent subasumstat.
4.3
Rationale for Dose Selection of Subasumstat
Based on the totality of data (safety, tolerability, efficacy, PK, pharmacodynamic (PD) and PK/PD 
modeling) from Study TAK-981-1002 (single agent), 90 mg BIW has been selected as RP2D for 
subasumstat single agent study. Thus, patients will receive a single dose of 90 mg 
[14C]subasumstat in Part A. In Part B, patients will receive 90 mg BIW dosing for 3 cycles 
(21-days), followed by 90 mg weekly maintenance dosing for the remainder of Part B.
4.4
Risks and Benefits
Subasumstat is currently being evaluated in 4 clinical studies (see Section 4.1.2.4) and, as such, the 
clinical benefits and risks are still emerging. The only serious adverse reaction considered 
expected for safety reporting purposes across the ongoing TAK-981 studies is pyrexia. 
Preliminary safety information is described in Sections 4.4.1 and 4.4.2.
Objective responses in clinical studies have been observed. Though additional data are needed to 
characterize the clinical benefit of subasumstat either alone or in a relevant combination, the 
emerging data support ongoing development of subasumstat.
The salient MOA of subasumstat in vivo is sensitization of the innate immune response, promoting 
production of type I IFNs. However, effects on SUMOylation-dependent cellular processes, other 
than a type I IFN signaling pathway, are possible in immune and nonimmune cells and may give 
rise to additional toxicities other than those related to increased type I IFN signaling.
During this study, risk mitigation strategies include but are not limited to the following: strict 
application of the study inclusion and exclusion criteria, frequent monitoring of clinical and 
laboratory results, guidelines for management and prophylaxis of potential toxicities, criteria for 
dose modification, and regular monitoring of TEAEs and serious adverse events (SAEs) by the 
sponsor.
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Further details for subasumstat administration, safety events, and management can be found in 
Section 8.0 and the Guidance for Investigator section of the IB.
4.4.1
Potential Effects Based on Nonclinical Studies
The potential risks listed below are based on findings from GLP repeat-dose nonclinical 
toxicology studies with QW or BIW dosing in rats and dogs, and a single-dose safety 
pharmacology study in dogs. These events may or may not develop in human patients treated with 
subasumstat. The potential risks identified from nonclinical studies include infusion-related 
reactions (IRRs), potential for CRS, hematologic effects, kidney effects, injection site reactions, 
and reproductive and developmental toxicity.
Further details for subasumstat administration and safety event management can be found in the 
Guidance for Investigator section of the IB.
4.4.2
Effects Based on Clinical Studies
Clinical study protocols for subasumstat include monitoring for the potential adverse events (AEs) 
specified for this compound using routine laboratory evaluations, urinalysis, cardiac monitoring, 
physical examinations, and disease assessment. The timing of these tests and evaluations is 
detailed in the schedule of events (SOE) (Appendix A). Additional tests and evaluations will be 
considered based on symptoms and findings observed in the study. It is possible that 
administration of subasumstat will result in toxicities that were not observed or predicted from the 
completed nonclinical studies conducted in animals. Potential risks based on clinical studies 
include IRRs, potential for CRS, hematologic effects, and injection site reactions.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objectives are:

To assess the mass balance (ie, cumulative excretion of total radioactivity (TRA) in urine and 
feces) of subasumstat following a single 1-hour infusion of 90 mg [14C]subasumstat IV 
solution containing 100 μCi (approximately 3.7 megabecquerels [MBq]) in patients with 
advanced or metastatic solid tumors in Part A.
5.1.2
Secondary Objectives
The secondary objectives are:

To characterize the PK of subasumstat in whole blood, plasma, and urine, and of TRA in 
plasma and whole blood following a single 1-hour infusion of 90 mg [14C]subasumstat IV 
solution containing 100 μCi (approximately 3.7 MBq) in patients with advanced or metastatic 
solid tumors in Part A.
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
To evaluate the safety and tolerability of subasumstat in patients with advanced or metastatic 
solid tumors during Part A and Part B.

To collect samples for characterization of the metabolic profile of subasumstat in plasma, 
urine, and feces following a single 1-hour infusion of 90 mg [14C]subasumstat IV solution 
containing 100 μCi (approximately 3.7 MBq) in patients with advanced or metastatic solid 
tumors in Part A.
5.1.3
Exploratory Objectives
The exploratory objective is:

To evaluate efficacy of subasumstat in patients with advanced or metastatic solid tumors 
during Part B.
5.2
Estimands
Not applicable. 
5.3
Endpoints
5.3.1
Primary Endpoints
The primary endpoints are: 

Cumulative percentage of urinary recovery, fecal recovery, and combined recovery, and 
percentage of recovered TRA in urine and feces for each interval over the entire period of 
collection.
5.3.2
Secondary Endpoints
The secondary endpoints are:

PK parameters of subasumstat and TRA in plasma and whole blood: maximum observed 
concentration (Cmax), time of first occurrence of Cmax (tmax), and area under the 
concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast), 
and as permitted by data, terminal disposition phase half-life (t1/2z), CL, volume of distribution 
at steady-state (Vss), and area under the concentration-time curve from time 0 to infinity 
(AUC∞), calculated using the observed value of the last quantifiable concentration.

PK parameters of subasumstat in urine: cumulative amount of unchanged drug excreted into 
the urine (Aeurine and percentage of dose) and renal clearance (CLR).

Safety parameters: AEs, SAEs, electrocardiogram (ECG) and abnormality of laboratory 
values.

Metabolite profiling and identification in plasma, urine, and feces.
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5.3.3
Exploratory Endpoints

Efficacy parameters: overall response rate (ORR), progression-free survival (PFS), best 
response (CR, partial response [PR], etc.) and duration of response (DOR).
6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a 2-part, open-label, mass balance and absorption, distribution, metabolism, excretion 
(ADME) study in patients with advanced or metastatic solid tumors. 
6.1.1
Part A: Mass Balance/ADME Assessment of Single Agent Subasumstat
Part A is the period assessing the mass balance, PK, metabolism, and excretion of subasumstat in 
this population.
The study will enroll patients diagnosed with locally advanced or metastatic solid tumors with 
measurable disease. If patients drop out, they may be replaced, to ensure approximately 6 PK 
evaluable patients complete all study assessments. Patients will be confined to the study site for 
5 to 8 days postdose and until the discharge criteria are met (Section 6.1.1.1) for a maximum of 
14 days postdose. Patients who sign an informed consent form (ICF) will be assigned a patient 
identification number, and those who meet all inclusion criteria and none of the exclusion criteria 
will be admitted to the study site on Day -1 for predose assessments. On Day 1, patients will 
receive 90 mg [14C]subasumstat IV solution containing 100 μCi (approximately 3.7 MBq; 
equivalent to 2.74 mrem or 0.0274 mSv whole body effective dose for human male subjects and 
1.41 mrem or 0.0141 mSv whole body effective dose for human female subjects) via a 1-hour IV 
infusion. All samples being assessed for TRA will be tested in batches. All samples from Day 1 to 
Day 5 will be assessed at the same time. For patients who do not meet the discharge criteria, the 
samples collected from Day 6 until the time when the TRA is available will be used for TRA 
determination. This process of batch measurement will continue until the discharge criteria are 
met. Since up to a 3-day time lag is anticipated for radioactivity counting of samples, actual patient 
discharge from the study site may occur 3 days after the discharge criteria are met.
Patients’ safety will be closely monitored, and AEs will be collected throughout the study. Vital 
signs, physical examinations, ECGs, and clinical laboratory tests will be captured during the 
confinement (predose, during study, before discharge from study site).
In this clinical study, blood samples will be collected at prespecified time points to analyze 
subasumstat, TRA in blood and plasma, and metabolite profiling in plasma over the confinement. 
Complete urinary and fecal output will be collected throughout the confinement period until 
discharge; urine samples will be analyzed for PK, TRA, and metabolite profiling and fecal samples 
will be analyzed for TRA and metabolite profiling. For patients experiencing emesis after drug 
administration, the full vomitus will be collected as much as possible and assayed for TRA. If a 
subject vomits more than once during a period, vomitus corresponding to each vomiting event will 
be collected in a separate labeled container and separately counted. More detailed information will 
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be provided in the study manual. Patients may be provided treatment for constipation if needed, as 
determined by the investigator.
6.1.1.1
Part A Discharge Criteria
Samples will continue to be collected and patients confined until 90% or greater of the total dose of 
radioactivity administered is recovered in urine and fecal samples (combined) or until <1% of the 
dosed radioactivity is collected in 2 consecutive intervals when both urine and feces are collected. 
Patients will be confined for a minimum of 5 days postdose and up to a maximum of 14 days 
postdose.
6.1.2
Part B: Continued Treatment With Single Agent Subasumstat
After completion of Part A, patients will have the opportunity to participate in Part B. Participation 
in Part B is voluntary, and a consent is included in the main study consent form. The patient can 
withdraw from Part B at any time during the study, or the patient can be withdrawn from the study 
if their medical condition changes and there is no clear evidence of clinical benefit to the patient at 
the discretion of the investigator. 
During Part B, the patient will receive subasumstat 90 mg BIW (on days 1, 4, 8, and 11 of the 
21 day cycle) for 3 cycles, followed by weekly maintenance dosing (on days 1 and 8 of the 21 day 
cycle). The treatment will be up to 1 year. For patients that complete 1 year of subasumstat 
treatment and experience clinical benefit in the opinion of the investigator, the investigator may 
discuss treatment options with the sponsor. 
Safety and disease assessments will be collected in Part B. Disease assessments will be conducted 
using radiological evaluations (computed tomography [CT] scan or magnetic resonance imaging 
[MRI]) to evaluate the response. Investigators will use Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 criteria to assess the clinical response.
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 5.
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Figure 6.a
Schematic of Study Design
BIW: twice weekly; EOS: end of study; IV: intravenous; PK: pharmacokinetic; QW: once weekly.
a Screening assessments will be performed within 28 days before administration of [14C]subasumstat.
b Patients will receive a single dose of [14C]subasumstat 90 mg as a 1-hour IV infusion on Day 1. The clinic will be 
supplied with vials containing approximately 100 μCi (approximately 3.7 MBq) of [14C] subasumstat as the 
radioactive tracer.
c Discharge criteria for Part A are in Section 6.1.1.1. Patients will be discharged between Days 6 and 14, given that the 
discharge criteria have been met. Discharge assessments are done only once on the day of discharge. Since up to a 
3-day time lag is anticipated for radioactivity counting of samples, actual patient discharge from the study site may 
occur 3 days after the discharge criteria are met.
d The maximum treatment will be for 1 year. Patients will have at least 3 cycles (21 days each) on a BIW schedule on 
days 1, 4, 8, and 11) followed by maintenance with the QW schedule.
e Patients will attend an EOS visit 30 days (+10 days) after the last dose of study drug in Part B or before the start of 
subsequent therapy for the patient’s indication, if that occurred sooner.
6.2
Number of Patients
Approximately 10 patients will be enrolled in this study to get approximately 6 PK-evaluable 
patients. All enrolled patients will complete Part A at 1 study site in Hungary, with any participants 
in Part B completing Part B at a second study site. Enrollment is defined as the time of initiation of 
the first dose of study drug.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Study screening will last up to 28 days before the first dose of the study drug, during which the 
patient’s eligibility and baseline characteristics will be determined.
Patients will be required to stay at the study site in Part A for 5 to 8 days postdose and until the 
discharge criteria are met (Section 6.1.1.1), with a maximum estimated confinement of 14 days 
postdose. Since up to an approximate 3-day time lag is anticipated for radioactivity counting of 
samples, actual participant release from the CRU may occur 3 days after discharge criteria are met. 
Patients will have the option to continue to receive treatment during Part B of the study. Patients 
who do not continue into Part B will have an end of study (EOS) visit when they are released from 
confinement in Part A. 
-1
[14C]Subasumstat(b)
6 to 14
OR
Subasumstat 90 mg BIW
(Days 1, 4, 8, 11 of 21 day cycle)
for 3 cycles, then QW dosing
Discontinue study (no Part B)
End of 
Study(e)
1
2
3
4
5
Confinement
Study Day
Discharge(c)
Screening(a)
Part A: Mass Balance / PK
Part B (Optional): Continued 
Treatment With Subasumstat(d)
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Patients who choose to continue with Part B of the study will continue to receive subasumstat for 
up to 1 year or until the discontinuation criteria are met (see Section 9.8). Patients in Part B will 
complete an EOS visit 30 days (±10 days) after the last dose of study drug in Part B or at the start 
of subsequent therapy for the patient’s indication, whichever occurs first.
6.3.2
EOS/Study Completion Definition and Planned Reporting
Primary Completion/Study Completion
Patients who have completed Part A, defined as completing the Part A EOS visit for patients not 
participating in Part B and the first dose of Part B for patients who do participate in Part B, will be 
considered to have completed the study. 
The analyses for the clinical study report will be conducted after 6 PK-evaluable patients complete 
Part A. The estimated time frame for study completion, defined as the time from the first patient 
being enrolled until the last PK-evaluable patient completes Part A, is approximately 12 months.
Other Planned Analyses
A clinical study report addendum is planned when all enrolled patients who participate in Part B of 
the study complete 1 year of treatment or discontinue the study. The estimated time frame for the 
completion of Part B for all participating patients is approximately 24 months.
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
Primary: Cumulative percentage of 
urinary recovery, fecal recovery, and 
combined recovery, and percentage 
of recovered TRA in urine and feces 
for each interval over the entire 
period of collection
Cumulative amount of 
[14C]-radioactivity excreted in urine up 
to the last sampling interval
Cumulative amount of 
[14C]-radioactivity excreted in feces up 
to the last sampling interval
Total cumulative excretion of 
[14C]-radioactivity from the body
Up to 14 days postdose
Secondary: PK parameters of 
subasumstat and TRA in plasma and 
whole blood
Cmax, tmax, AUClast
as permitted by data: t1/2z, CL, Vss, 
AUC∞
Up to 14 days postdose
Secondary: PK parameters in of 
subasumstat in urine
Aeurine, CLR
Up to 14 days postdose
Secondary: Safety parameters: AEs, 
SAEs, ECG, and abnormal 
laboratory values
Abnormal laboratory values are those 
outside of normal range
See Section 10.1 for AE and SAE 
definitions
AEs will be recorded from the start 
of study drug administration 
through 30 days (+10 days) after 
the last dose of the study drug
SAEs, including serious 
pretreatment events will be 
reported from signing the ICF 
through 30 days (+10 days) after 
the last dose of the study drug
Laboratory tests up to EOS or 
early termination visit
Secondary: Metabolite profiling and 
identification in plasma, urine, and 
feces
Determination of relative percentage of 
circulatory and excretory metabolites 
Up to 14 days postdose
AE: adverse event; Aeurine: cumulative amount of unchanged drug excreted into the urine; AUClast: area under the 
concentration-time curve from time 0 to time of the last quantifiable concentration; AUC∞: area under the 
concentration-time curve from time 0 to infinity; CL: clearance; CLR: renal clearance; Cmax: maximum observed 
concentration; ECG: electrocardiogram; EOS: end of study; ICF: informed consent form; PK: pharmacokinetic; 
SAE: serious adverse event; t1/2z: terminal disposition half-life; tmax: time of first occurrence of Cmax; TRA: total 
radioactivity; Vss: volume of distribution at steady-state.
6.3.4
Total Study Duration
It is anticipated that Part A of this study for all patients will last for approximately 12 months. Part 
B, which is optional, is anticipated to last for approximately 24 months for all patients.
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6.4
Poststudy Access
Treatment with subasumstat will be administered as a part of this study for up to 1 year. For 
patients that complete 1 year of subasumstat treatment and experience clinical benefit in the 
opinion of the investigator, the investigator may discuss treatment options with the sponsor.
7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Adult male or female patients aged 18 years or older.
2. Be willing and able to provide written informed consent for the study.
3. Have histologically or cytologically confirmed advanced (local regionally recurrent not 
amenable to curative therapy) or metastatic solid tumors with no standard therapeutic option 
with a proven clinical benefit, are intolerant or have refused them.
4. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Scale. 
5. Demonstrate adequate organ function as described below:
a) Platelet count ≥75.0 × 109/L. 
b) Absolute neutrophil count ≥1.0 × 109/L. 
c) Calculated creatinine CL ≥30 mL/min using the Cockcroft-Gault formula. 
d) Aspartate aminotransferase, glutamic-oxaloacetic transaminase, and alanine 
aminotransferase, glutamic-pyruvic transaminase ≤3.0 times the upper limit of normal 
(ULN), <5.0 times the ULN if liver enzyme elevations are due to liver metastases; bilirubin 
≤1.5 times the ULN. Patients with Gilbert’s syndrome may have a bilirubin level >3.0 
times the ULN, per discussion between the investigator and the medical monitor.
6. Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy or 
have the toxicity established as sequela.
Note: Neuropathy Grade ≤2, any grade alopecia, or autoimmune endocrinopathies with stable 
replacement therapy are permitted.
7. Women of childbearing potential must have a negative serum or urine pregnancy test within 
72 hours before receiving the first dose of study medication.
8. Female patients must meet 1 of the following:
a) Postmenopausal for at least 1 year before the screening visit, or
b) Surgically sterile, or
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c) If they are of childbearing potential, agree to practice 1 highly effective method and 
1 additional effective (barrier) method of contraception at the same time, from the time of 
signing of the ICF through 6 months after the last dose of study drug, or
d) 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.)
9. Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:
a) Agree to practice effective barrier contraception during the entire study treatment period 
and through 6 months after the last dose of study drug, or
b) 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.)
10. Must be willing and able to comply with clinic visits and procedures outlined in the study 
protocol.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Received treatment with systemic anticancer treatments or investigational products within 
14 days before the first dose of study drug or 5 half-lives, whichever is shorter.
Note: Low-dose steroids (oral prednisone or equivalent ≤10 mg per day), hormonal therapy for 
prostate cancer or breast cancer (as adjuvant treatment), and treatment with bisphosphonates 
and receptor activator of nuclear factor kappa-Β ligand inhibitors are allowed.
2. Received treatment with radioisotopes within 5 half-lives before the first dose of the study 
drug
3. Received radiolabeled substances, were exposed to radiation sources within 12 months of the 
first dose in this study, or is likely to receive radiation exposure or radioisotopes within 
12 months of the first dose in this study such that participation in this study would increase 
their total exposure beyond the recommended safe levels (ie, weighted annual limit 
recommended by the International Commission on Radiological Protection). 
4. Received extended field radiotherapy ≤4 weeks before the start of treatment (≤7 days for 
limited field radiation for palliation outside the chest or brain).
5. Uncontrolled brain metastasis (evidence of progression by imaging over a period of 4 weeks 
and/or neurologic symptoms that have not returned to baseline). Patients with treated brain 
metastases are allowed provided they are radiologically stable, without evidence of 
progression for at least 4 weeks by repeat imaging, clinically stable, and without requirement 
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of steroid treatment for at least 14 days before first dose of study treatment. Note: For 
asymptomatic patients, screening brain imaging is not required.
6. Second malignancy within the previous 3 years, except treated basal cell or localized 
squamous skin carcinomas, prostate cancer, cervical carcinoma in situ, resected colorectal 
adenomatous polyps, breast cancer in situ, or other malignancy for which the patient is not on 
active anticancer therapy.
7. Major surgery ≤14 days from the first dose of study drug and not recovered fully from any 
complications from surgery.
8. Prior treatment with subasumstat.
9. Hypersensitivity to subasumstat or any component of the drug product.
10. Baseline prolongation of the QT interval when corrected using Fridericia’s formula (QTcF) 
(eg, repeated demonstration of QTcF interval >480 ms, history of congenital long QT 
syndrome, or torsades de pointes).
11. Receiving or requires the continued use of medications that are known to be strong or moderate 
inhibitors and inducers of cytochrome P450 (CYP) 3A4/5 and strong P-glycoprotein (Pgp) 
inhibitors. To participate in this study, such patients should discontinue using CYP inducers 
for at least 2 weeks, and CYP/Pgp-inhibitors for 1 week before receiving a dose of 
subasumstat.
12. Has active noninfectious pneumonitis or interstitial lung disease that required steroids.
13. History of allogeneic tissue or solid organ transplant.
14. Has active bacterial infection requiring systemic therapy <14 days before the start of treatment.
15. Active HIV infection or any other relevant congenital or acquired immunodeficiency.
16. Active hepatitis B or hepatitis C infection. Note: Patients who have positive hepatitis B core 
antibody or hepatitis B surface antigen antibody can be enrolled but must have an undetectable 
hepatitis B viral load.
17. Any of the following uncontrolled heart diseases: congestive heart failure New York Heart 
Association Grade III or IV, unstable angina, myocardial infarction, unstable symptomatic 
ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, 
ongoing symptomatic cardiac arrhythmias >Grade 2, pulmonary embolism or symptomatic 
cerebrovascular events, or any other serious cardiac condition (eg, pericardial effusion or 
restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy is 
allowed.
18. Psychiatric illness/social circumstances that would limit compliance with study requirements 
and substantially increase the risk of AEs or has compromised ability to provide written 
informed consent.
19. Female patients who are pregnant or lactating and breastfeeding.
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8.0
STUDY DRUG
Patients enrolled in the study will receive [14C]subasumstat in Part A and subasumstat in Part B.
8.1
Study Drug Administration
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). All patients will receive
subasumstat as specified in the SOE (Appendix A).
Subasumstat will be provided as a solution for infusion containing 0.9 mg/mL [14C]subasumstat 
drug substance for Part A and 10 mg/mL subasumstat drug substance for Part B (refer to the 
pharmacy manual). Subasumstat will be administered as 60 (±10) minute IV infusion. In case 
infusion reactions are observed, the length of the infusion can be extended up to 2 hours for all 
patients without requiring a protocol amendment.
Subasumstat administration should occur in area with resuscitating equipment and medications 
such as antihistamines, acetaminophen, corticosteroids, epinephrine, and bronchodilators readily 
available. Patients’ vital signs must be monitored before, during the, and at the end of 
administration of subasumstat. Treatment must be stopped if the patient experiences symptoms 
compatible with an infusion reaction of Grade 2 or greater. The management of infusion reactions 
and CRS is detailed in Sections 8.7.6 and 8.7.7, respectively.
As with other potentially toxic compounds, caution should be exercised in handling this drug. The 
use of gloves is recommended. Following topical exposure, events could include redness or 
blistering. Given the possibility of extravasation, it is advisable to closely monitor the infusion site 
for possible infiltration during drug administration. Administration through a central port if 
available is always preferred versus a peripheral line.
Patients will be asked to maintain adequate hydration (1.5-2 L/day) 48 hours before initiating 
therapy, and IV fluid administration is recommended for those who cannot maintain adequate oral 
hydration.
Patients in Part A will receive 90 mg [14C]subasumstat IV solution containing 100 μCi 
(approximately 3.7 MBq; equivalent to 2.74 mrem or 0.0274 mSv whole body effective dose for 
human male subjects and 1.41 mrem or 0.0141 mSv whole body effective dose for human female 
subjects) on Day 1.
Patients continuing with Part B will receive subasumstat IV 90 mg BIW (on days 1, 4,8, and 11 of 
a 21-day cycle), starting on day 14 of the study. Patients will receive a total of 3 cycles(21-days) of 
subasumstat, followed by weekly maintenance dosing for up to 1 year.
8.2
List of European Union Auxiliary Medicinal Products
Auxiliary medicinal products (AxMPs) may be used in this study. Tocilizumab is an interleukin-6 
(IL-6) receptor antagonist. Tocilizumab is an authorized AxMP in the European Union, and in this 
study, it is indicated for the management of CRS, which is a potential adverse event of the study 
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drug Subasumstat. Tocilizumab for intravenous infusion injection comes as: 80 mg/4 mL, 
200 mg/10 mL, 400 mg/20 mL as a clear, colorless to pale yellow solution in 20 mg/mL 
single-dose vials for further dilution prior to intravenous infusion. The recommended dose of 
tocilizumab to treat CRS is 12 mg/kg for body weight <30 kg and 8 mg/kg for body weight 
≥30 kg. The dose will be given as 60-minute intravenous infusion. For information on the 
preparation and administration of tocilizumab, refer to the individual product label.
8.3
Dose Modification Guidelines (Part B)
8.3.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Treatment with subasumstat in Part B will use a cycle length of 21 days. To initiate a new cycle of 
subasumstat treatment, the patient must meet the following dosing criteria:

Absolute neutrophil count ≥1.0 × 109/L.

Platelet count ≥75.0 × 109/L.
Additionally, subasumstat–related AEs or laboratory abnormalities must have returned to 
≤Grade 1/baseline (other than those stated above). If the patient fails to meet the above-cited 
criteria for retreatment, initiation of the next cycle of treatment should be delayed for 1 week. At 
the end of that time, the patient should be re-evaluated to determine whether the criteria for 
retreatment have been met. Should the start of the next cycle need to be delayed for more than 
2 weeks because of incomplete recovery from treatment-related toxicity, the patient may be 
withdrawn from treatment unless there is clinical benefit as assessed by the investigator, with 
agreement by the sponsor’s medical monitor. If clinical benefit for the individual patient is 
confirmed, recovery period can be extended or retreatment at the same or reduced dose can be 
started without complete recovery. 
8.3.2
Criteria for Dose Interruption or Reduction During a Cycle
All toxicities that occur during the study will be actively managed following the standard of care 
unless otherwise specified in the protocol. Patients with AEs attributed to subasumstat may 
continue study treatment, may have subasumstat treatment withheld, or may be permanently 
discontinued from the study. Patients who have study drug withheld because of treatment-related 
or possibly related AEs should resume study drug treatment after resolution of the AE to Grade ≤1 
or baseline (or Grade 2 for some specified hematological AEs as shown in Table 8.b).
Dosing of subasumstat should be interrupted or reduced to 60 mg according to the dose 
modification recommendations listed in Table 8.a for nonhematologic toxicity, Table 8.b for 
hematologic toxicities, and Table 8.d for CRS events. When the dose of subasumstat is withheld 
based on the listed criteria, clinical and laboratory reevaluation should be repeated at least weekly 
or more frequently, depending on the nature of the toxicity observed, until the toxicity resolves to 
the Grade specified in Table 8.a, Table 8.b and Table 8.d. If indicated, TAK-981 dose should be 
reduced to 60 mg. 
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If subasumstat cannot be administered in a 48-hour window because of an AE, the dose will be 
missed, and the patient will be scheduled for the next administration per the SOE (Appendix A).
In general, after a dose is reduced, it should not be re-escalated even if there is minimal or no 
toxicity with the reduced dose. However, if further evaluation reveals that the AE that led to the 
dose reduction was not study drug-related, or there were other circumstances contributing to the 
AE that are unlikely to recur, the dose may be re-escalated to the original dose level. If the dose of 
subasumstat would need to be reduced below 60 mg to manage subasumstat-related AEs, 
treatment with subasumstat should be discontinued.
Table 8.a
General Dose Modification Recommendations for Subasumstat 
Nonhematologic Drug-Related AEs
Criteria
Action
Grade 1 AEs
No dose reductions or interruptions.
Grade 2 AEs
Treat according to local practice. 
Patients experiencing Grade 2 AEs considered related to study treatment that are 
not easily managed or corrected and are not tolerable to the patient, or AEs that are 
not acceptable in the investigator’s judgment, should have study treatment 
interrupted until the AE resolves to Grade ≤1 or baseline and then restarted at the 
same dose or, depending on the toxicity, at 60 mg.
Grade 3 and Grade 4 non–
life-threatening AEs
Hold subasumstat until resolution to Grade ≤1 or baseline, and then resume 
treatment at 60 mg.
Note: Permanently discontinue treatment if Grade ≥3 QTcF prolongation occurs.
Grade 4 life-threatening AEs
Permanently withdraw the patient from the study.
AEs of all grades
If treatment has been held for >14 consecutive days without resolution of the 
toxicity (to baseline or Grade ≤1 or if considered a sequela), consider permanently 
discontinuing study treatment unless there is clinical benefit for the patient as 
assessed by the investigator and with sponsor’s approval. Treatment should be 
resumed at 60 mg after resolution of AEs to Grade ≤1 or baseline.
AE: adverse event; CRS: cytokine release syndrome; QTcF: QT interval with Fridericia correction method.
For specific instructions in case of CRS, refer to Table 8.d.
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Table 8.b
Dose Adjustments for Hematologic Toxicities
Criteria
Action
Neutropenia (ANC)
Grade 1 (ANC < LLN- 1.5 × 109 cells/L)
Continue subasumstat at the same dose.
Grade 2 (ANC 1.0- <1.5 × 109 cells/L)
Continue subasumstat at the same dose.
Grade 3 (ANC 0.5- <1 × 109 cells/L) without fever
Withhold dose until resolved to ≤Grade 2 or baseline, then:
If resolved in ≤7 days, resume treatment at the same dose.
If resolved in >7 days, resume treatment at 60 mg.
Grade 4 (ANC <0.5 × 109 cells/L) without fever
Withhold dose until resolved to ≤Grade 2 or baseline, then if 
resolved in ≤7 days, resume treatment at the same dose. If 
recovered in >7 days, second Grade 4 neutropenia event, ANC 
>0.1 × 109/L, or concomitant occurrence of mucositis or 
thrombocytopenia, resume treatment at 60 mg.
Febrile neutropenia (ANC <1.0 × 109 cells/L, with a single 
temperature of >38.3°C or sustained temperature of ≥38°C for 
more than 1 hour)
Withhold dose until fever/infection have recovered and ANC 
≤Grade 2 or baseline, then resume treatment at 60 mg.
Thrombocytopenia (PLT)
Grade 1 (PLT < LLN- 75.0 109 cells/L)
Grade 2 (PLT <75.0 - 50.0 × 109 cells/L)
Grade 3 (PLT <50.0 - 25.0 × 109 cells/L) without 
bleeding 
Continue subasumstat at the same dose.
Continue subasumstat at the same dose.
Withhold dose until resolved to ≤Grade 1 or baseline, then:
If resolved in ≤7 days, resume treatment at the same dose.
If resolved in >7 days, resume treatment at 60 mg.
Grade 4 (PLT <25.0 × 109 cells/L) without bleeding
Withhold dose until resolved to ≤Grade 1 or baseline, then if 
resolved in ≤7 days, resume treatment at the same dose, if 
resolved in >7 days, then resume treatment at 60 mg.
PLT <10.0 × 109 cells/L, thrombocytopenia ≥Grade 3 
associated clinically significant bleeding, second event of Grade 
4 thrombocytopenia >7 days
Consider permanently withdrawing the patient from the study, 
except when the investigator determines that the patient is 
obtaining clinical benefit and has discussed this with the 
sponsor, then resume treatment at 60 mg.
ANC: absolute neutrophil count; LLN: lower limit of normal; PLT: platelet.
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Table 8.c
TAK-981 Dose Modification Guidelines for CRS
ASTCT Grade
TAK-981 Dose Modification
Grade 1:
Fever a (≥38°C)
Continue subasumstat at the same dose.
Grade 2:
Fever a (≥38°C)
with hypotension not requiring 
vasopressors; 
and/or b hypoxia requiring low-flow c
nasal cannula
Withhold dose until resolved to Grade ≤1, then:

If resolved in ≤14 days, maintain dose.

If resolved in >14 days or repeat event, reduce dose to 60 mg.

If >2 consecutive doses of subasumstat are skipped due to CRS, 
permanently discontinue treatment with subasumstat.
Grade 3:
Fever a (≥38°C)
with hypotension requiring a 
vasopressor with or without 
vasopressin; 
and/or b hypoxia requiring high-flow c
nasal cannula, facemask, nonrebreather 
mask, or Venturi mask
Withhold dose until resolved to Grade ≤1, then:

If resolved in ≤14 days, reduce dose and if toxicity does not recur, 
consider re-escalating to original dose.

If resolved in >14 days or repeat event, reduce dose to 60 mg.

If >2 consecutive doses of subasumstat are skipped due to CRS, 
permanently discontinue treatment with subasumstat.
Grade 4:
Fever a (≥38°C)
with hypotension requiring multiple 
vasopressors (excluding vasopressin); 
and/or b hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, intubation, 
and mechanical ventilation)
Permanently discontinue subasumstat.
ASTCT: American Society for Transplantation and Cellular Therapy; BiPAP: bilevel positive airway pressure; CPAP: 
continuous positive airway pressure; CRS: cytokine release syndrome; DL: dose level.
ASTCT consensus grade adapted from Lee et. Al. 2019 (Lee et al. 2019); CRS management recommendations are 
adapted from Neelapu et al, 2018 (Neelapu et al. 2018) and should be implemented at the investigator’s discretion.
a Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive 
antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent 
CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow 
nasal cannula is classified as Grade 3 CRS.
c Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. High-flow nasal cannula is defined as oxygen 
delivered at >6 L/minute.
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8.3.3
Criteria for Discontinuation of Subasumstat
In the event of discontinuation of study therapy, patients will undergo the early termination visit. 
Patients should discontinue treatment with subasumstat if they meet the criteria listed below. 
Treatment with subasumstat must be discontinued for any of the following reasons:

Occurrence of drug-related AEs that require study drug discontinuation per dose modification 
guidelines in Section 8.3.2.

If subsequent cycle is delayed by >21 days for treatment-related AEs despite supportive 
treatment per standard clinical practice. (Exceptions to this criterion may be made after 
discussion and agreement between the investigator and the sponsor based on the benefit-risk 
assessment.)

If more than 1 dose-level reductions of TAK-981 are required for a patient. (Exceptions to this 
criterion may be made after discussion and agreement between the investigator and the sponsor 
based on the benefit-risk assessment.)

Occurrence of AEs resulting in discontinuation of study drug that is desired or considered 
necessary by the investigator and/or the patient (if applicable).
8.4
Prohibited Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Strong and moderate CYP3A4/5 inhibitors and inducers (see list in Appendix E). During the 
study, should patients require the use of medications that are known to be strong and moderate 
inhibitors/inducers of CYP3A4/5, they should temporarily discontinue the use of subasumstat. 
Patients can resume treatment with subasumstat approximately 2 weeks or 5 times the half-life 
(whichever is shorter) after discontinuing the use of these strong and moderate inhibitors and 
inducers of CYP3A4/5.

Concomitant corticosteroid administration of >20 mg of prednisone or equivalent unless given 
as treatment or prophylaxis for IRRs, as premedication for administration of certain blood 
products (80 mg methylprednisolone is accepted) or short courses (<96 hours) for 
exacerbations of respiratory tract disorders or for acute control of emerging tumor pain.

Strong inhibitors of Pgp (see list in Appendix F).

Initiation of prophylactic use of myeloid growth factors (eg, granulocyte-colony stimulating 
factor) are not allowed in the first cycle, but may be administered to manage patients who 
experience Grade 4 and/or febrile neutropenia if clinically indicated in accordance with 
American Society of Clinical Oncology guidelines and/or institutional practices. For the first 
episode of neutropenia, dose reduction is preferred. 

Patients currently on chronic erythropoietin support for anemia may continue to receive 
erythropoietin, but initiation of new erythropoietin therapy is not allowed during the first cycle.

Any investigational agent other than subasumstat.
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
Any concurrent antineoplastic therapy (eg, chemotherapy, hormonal therapy, immunotherapy, 
radiation therapy except for palliative radiation therapy and once progressive disease is ruled 
out) or standard or investigational agents for treatment of cancer.

Drugs known to prolong QTc interval (see list in Appendix G).

Because the safety of immunization with live viral vaccines following subasumstat therapy has 
not been studied, vaccination with live virus vaccines is prohibited while the patient is being 
treated on study.
8.5
Permitted Concomitant Medications and Procedures
All prescription and over-the-counter medications, including influenza vaccines, taken by a patient 
as of the first study drug administration through the EOS visit or before initiation of new 
anticancer therapy (whichever comes first) will be recorded in the designated electronic case 
report form (eCRF). Patients must be instructed not to take any medications, including 
over-the-counter medications and herbal supplements, without first consulting with the 
investigator.
The following medications and procedures are permitted while the patient is receiving the study 
drug:

Topical or inhaled steroids (eg, for the treatment of asthma) are permitted.

Patients should be transfused with red blood cells (RBCs) and platelets as clinically indicated.

Concomitant treatment with bisphosphonates or receptor activator of nuclear factor kappa-Β 
ligand inhibitors will be allowed for patients with evidence of lytic destruction of bone or with 
osteopenia, according to the American Society of Clinical Oncology Clinical Practice 
guidelines or institutional practice in accordance with the product label, unless specifically 
contraindicated. 

Narrow therapeutic range Pgp substrates such as digoxin or dabigatran may be used with 
caution, and patients requiring use of these drugs will be closely monitored.

Coronavirus disease 2019 (COVID-19) vaccination is generally allowed for patients enrolled 
in the study with the exception of live attenuated vaccines, which must be completed at least 4 
weeks before treatment initiation. COVID-19 vaccination should follow local guidances and 
regulations. Ideally, patients will have completed vaccination before treatment initiation. 
Vaccination should be avoided within ±3 days of subasumstat administration and should be 
administered after the last dose of subasumstat of a given cycle; study treatment may be 
delayed for up to 7 days to accommodate a vaccine dose administration after discussion with 
the sponsor. COVID-19 vaccine should be captured as a concomitant medication. 
Additional concomitant medications and procedures are permitted during the study to prevent and 
actively manage AEs. Treatment of AEs with prohibited concomitant medications (except 
anticancer treatments) is allowed per the investigator’s judgment. In this situation, treatment with 
subasumstat must be interrupted. Treatment with subasumstat may be resumed, if the patients 
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meets criteria for resuming treatment with subasumstat, once treatment with the prohibited 
medication is stopped and a washout period (7 days or 5 half-lives whichever is shorter) is 
completed. This situation requires discussion between the investigator and the medical monitor. 
Supportive measures consistent with optimal patient care may be given throughout the study.
8.6
Precautions and Restrictions
Precautions and requirements for a safe subasumstat administration are detailed in Section 8.1.
It is not known what effects subasumstat has on human pregnancy or development of the embryo 
or fetus; therefore, patients participating in this study should avoid becoming pregnant or avoid 
impregnating a partner. Nonsterilized female patients of reproductive age with a uterus and/or 
ovaries and patients with testes/testis should use effective methods of contraception through 
defined periods during and after study treatment as specified below.
Reproductively female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method and 
1 additional effective (barrier) method of contraception at the same time, from the time of 
signing of the ICF through 6 months 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.)
Reproductively male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 
1 of the following:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 6 months 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.)
Before starting treatment, patients should be advised to seek counseling on sperm or egg storage.
8.7
Management of Clinical Events
Therapies that are required to manage AEs and control cancer symptoms are allowed based on 
standard clinical practice, unless specifically excluded. Supportive care agents, such as 
erythropoietin, granulocyte-colony stimulating factor, blood products (RBC and platelet 
transfusions), and pain medications are permitted as needed per American Society of 
Hematology/American Society of Clinical Oncology guidelines or local institutional practice. 
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However, these agents should not be used in this study in a manner that would either help establish 
eligibility for the study. If dose alterations are necessary as a result of the events detailed below, 
refer to Section 8.3.
AxMP identified in the protocol as those that may be administered to patients when the effect of 
the investigational medicinal product (IMP) is likely to cause a hazard to the patient, or to manage 
an emergency situation. 
In the sections below is guidance for the management of some expected AEs based on 
observations in nonclinical toxicology or other AEs that have not been substantiated in these 
experiments but that could be expected because of the MOA of TAK-981. This guidance is not 
expected to replace investigator judgment in the management of AEs.
8.7.1
Nausea or Vomiting
This study will not initially employ prophylactic antiemetics before the first dose of the study drug. 
However, a patient who develops nausea or vomiting will be actively managed by employing 
optimal antiemetic treatment based on local standard practice. Additionally, antiemetics may be 
used prophylactically as clinically indicated following the occurrence of a first event of study 
drug-related or possibly related nausea and/or vomiting. An optimal antiemetic regimen is defined 
as one that employs both a 5-hydroxytryptamine 3 serotonin receptor antagonist and a short course 
of corticosteroid given in standard doses and according to standard schedules. If these are 
inadequate, an NK-1 antagonist may be added.
8.7.2
Diarrhea
This study will not initially employ prophylactic antidiarrheals; however, there is no prohibition 
against their use in the management of a patient who develops diarrhea. Patients will be instructed 
to take antidiarrheal medication(s) at the physician’s discretion until they are diarrhea-free for at 
least 12 hours. Fluid intake should be maintained to avoid dehydration.
8.7.3
Anemia, Thrombocytopenia, or Neutropenia
Please refer to Table 8.b for dose delay and reduction recommendations for hematologic toxicities. 
Subasumstat should be held if a significant treatment-emergent cytopenia or bleeding is suspected 
to be related to, or can be worsened by, study treatment. Precautionary measures should be taken to 
prevent bleeding and overwhelming infections. Blood transfusions (RBCs or platelet) and 
hematopoietic or thrombopoietic stimulating factors may be used to treat 
cytopenia/thrombocytopenia at the discretion of the investigator per standard clinical practice. In 
case of a first event, a dose reduction is preferred over the usage of myeloid growth factors.
8.7.4
Infusion Site Care
Skin lesions, which may include inflammation or necrosis, represent a potential risk and were 
observed at the injection site in rats. Local institutional guidelines must be applied to stress proper 
administration and prevention of accidental extravasation of subasumstat. Usage of IV ports is 
highly recommended. The IV line should be flushed at the end of the infusion accordingly to local 
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procedures. Monitoring at the beginning and during infusion must be ensured. If extravasation 
occurs, the infusion must be discontinued immediately, and institutional guidelines applied. 
Treatment and monitoring of patients until symptoms resolve should be consistent with 
institutional standards and guidelines as appropriate. Patients should be instructed to report any 
discomfort, pain or swelling at the infusion site.
8.7.5
Lymphopenia and Opportunistic Infection Prophylaxis
Because lymphopenia is an expected AE, patients may be at an increased risk of opportunistic 
pathogens. Subasumstat lymphopenia is expected to be fully reversible and limited in time, 
therefore no antibiotic or antiviral primary prophylaxis is indicated. It is also not known if all 
lymphocyte populations or just a subset are affected. Follow-up with standard hemograms and 
serial CD4/8 counts will help to make clinical decisions about the risk of immunosuppression. 
However, in the event of long-lasting lymphopenia, pneumocystis, or herpes zoster infection, 
prophylaxis can be started at investigator’s discretion.
8.7.6
IRRs
Although subasumstat is not a biological, its immune activating properties may produce AEs in the 
category of IRRs. If they were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypotension or hypertension, bronchospasm, or other symptoms. Treatment 
and monitoring of patients until symptoms resolve should be consistent with institutional 
standards and guidelines as appropriate. The patient should be closely monitored until recovery of 
symptoms. The patient will be permanently discontinued from the trial in case of a Grade 4 
life-threatening reaction. All Grade 3 or 4 infusion reactions should be reported within 24 hours to 
the medical monitor and communicated as an SAE if criteria are met. Concomitant medications 
administered for infusion reaction treatment should be collected in the eCRF. If a patient presents 
signs and symptoms compatible with infusion reaction, and at investigator discretion, 
premedication can be instituted for the rest of the treatment.
8.7.7
CRS
CRS is a disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, 
and/or hypoxia caused by the release of cytokines. CRS should be diagnosed and managed 
following institutional guidelines. CRS should be graded following the American Society for 
Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS (Lee et al. 2019). 
Investigators should try to differentiate CRS syndrome from other IRRs. Recommendations for 
management of CRS are shown in Table 8.d and can be implemented at the investigator’s 
discretion.
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Table 8.d
CRS Management Recommendations and Subasumstat Dose Modification
ASTCT Consensus Grade 
CRS Management Recommendations and TAK-981 Dose Modification
Grade 1:
Fever a (≥38°C) 

Monitor fluid status.

Supportive care: antipyretics, analgesics. 
Subasumstat dosing

Continue subasumstat at the same dose level.
Grade 2:
Fever a (≥38°C)
with hypotension not requiring 
vasopressors; 
and/or b requiring low-flow c nasal 
cannula 
As per Grade 1 and:

Closely monitor all organ functions, including cardiac function.

IV fluid bolus.

Supportive care.
Subasumstat dosing

Withhold subasumstat until recovers to ≤Grade 1.

Once recovered, restart subasumstat at the same dose level.
A maximum of 2 consecutive subasumstat doses can be skipped; otherwise 
TAK-981 must be permanently discontinued.
Grade 3:
Fever a (≥38°C)
with hypotension requiring a 
vasopressor with or without vasopressin; 
and/or b requiring high-flow c nasal 
cannula, facemask, nonrebreather mask, 
or Venturi mask 
As Grade 2 and:

Closely monitor all organ functions, including cardiac function.

Tocilizumab (8 mg/kg IV; maximum dose 800 mg) can be repeated after 6 hours.

If refractory to tocilizumab, dexamethasone 10 mg IV every 6 hours; if refractory, 
increase to 20 mg every 6 hours or equivalent methylprednisone.

Vasopressors as needed.

Supplemental oxygen as needed for hypoxia (including high-flow O2 and CPAP).

Transfer to ICU.
Subasumstat dosing

Withhold subasumstat until recovers to ≤Grade 1.

If recovered within 2 weeks, reduce subasumstat by 1 dose level.
A maximum of 2 consecutive subasumstat doses can be skipped; otherwise 
subasumstat must be permanently discontinued.
Grade 4:
Fever a (≥38°C)
with hypotension requiring multiple 
vasopressors (excluding vasopressin); 
and/or b requiring positive pressure (eg, 
CPAP, BiPAP, intubation and 
mechanical ventilation)
As per Grade 3 and:

Substitute dexamethasone with methylprednisone 1 g IV per day. 

Mechanical ventilation.
Subasumstat dosing

Permanently discontinue subasumstat.
ASTCT: American Society for Transplantation and Cellular Therapy; BiPAP: bilevel positive airway pressure; CPAP: continuous 
positive airway pressure; CRS: cytokine release syndrome; ICU: intensive care unit; IV: intravenous; O2: supplemental oxygen.
ASTCT consensus grade adapted from (Lee et al. 2019); CRS management recommendations are adapted from (Neelapu et al. 
2018) and should be implemented at the investigator’s discretion.
a Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or 
anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, 
CRS grading is driven by hypotension and/or hypoxia.
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a 
patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is 
classified as grade 3 CRS.
c Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. High-flow nasal cannula is defined as oxygen delivered at 
>6 L/minute.
8.8
Blinding and Unblinding
This is an open-label study.
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8.13
Other Protocol-Specified Materials
Information on supplies required by the site for drug administration is provided in the pharmacy 
manual. Clinical supplies other than study drug to be provided by the sponsor or designee are 
specified in the study manual.
9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the project clinician for this study, the central laboratory and any 
additional clinical laboratories, the coordinating investigator for each member state/country, and 
other vendors, such as the interactive response technology provider and the contract research 
organization (CRO) team may be found in the study manual. A full list of investigators is available 
in the sponsor’s investigator database.
For 24-hour contact information, please refer to the study manual or equivalent.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board (IRB)/ 
independent ethics committee (IEC). Prisoners (or other populations that might be subject to 
coercion or exploitation) will not be enrolled into this study.
9.3
Informed Consent
Each patient must provide written or electronic informed consent before any protocol-directed 
procedures are conducted unless those procedures are performed as part of the patient’s standard 
care.
The requirements of informed consent are described in Section 15.2.
9.4
Treatment Group Assignments
This is not a randomized study. All patients will receive the same study treatment.
9.5
Study Procedures
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow. Unless otherwise noted, evaluations during the treatment 
period must occur before drug administration on scheduled visits. Tests and procedures should be 
performed on schedule for all visits.
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9.5.1
Patient Demographics
The age, race, ethnicity, and sex of the patient are to be recorded during screening. 
9.5.2
Medical History
During the screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it. In addition, concomitant medications will be recorded as 
specified in Section 8.5.
9.5.3
Confinement
In Part A, patients will check into the clinic on Day -1 and be confined from Day -1 to Day 5 as 
specified in the SOE (Table A-1, Appendix A). Patients will be required to stay at the study site 
through Day 5 or until the discharge criteria are met (Section 6.1.1.1), with a maximum estimated 
confinement period of 14 days. 
9.5.4
Physical Examination
A full or symptom-directed physical examination will be completed per standard of care at the 
times specified in the SOE (Appendix A).
9.5.5
Patient Weight
Weight will be measured at screening, before and after dosing at the Day 1 visit and at the start of 
each cycle. If the weight measurement that occurs during screening occurs within 3 days of Day 1, 
this measurement can also be used as predose evaluations, and it does not need to be repeated.
9.5.6
Patient Height
Height will be measured only during screening (within 28 days before the first dose of 
subasumstat).
9.5.7
Vital Signs
Vital signs include measurements of systolic and diastolic blood pressure, heart rate, and body 
temperature. All vital signs are measured with the patient in a sitting or supine position. On days 
when subasumstat is administered, vital signs will be measured 20 minutes (±10 minutes) before 
the infusion, 30 minutes (±10 minutes) after the start of the infusion, 1 hour (±10 minutes) and 
3 hours (±30 minutes) after end of the infusion. When the timing of the vital signs assessment 
coincides with the timing of a blood draw, vital signs will be measured before blood sample 
collection.
9.5.8
Pregnancy Test
A serum or urine pregnancy test will be obtained for women of childbearing potential as indicated 
in the SOEs (Table A-1 and A-2, Appendix A). 
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The result of the pregnancy test performed at screening must be negative before dosing. If the 
screening pregnancy test is performed within 3 days of Day 1, this test result can be used as the 
predose evaluation and does not need to be repeated.
Pregnancy tests are required for women of childbearing potential at the start of every cycle. Urine 
pregnancy tests are typically performed on Day 1 of the cycle. However, if a serum pregnancy test 
is used, this can be performed up to 3 days before Day 1. The negative results of the pregnancy test 
must be available before the first dose of the cycle is administered. A pregnancy test will also be 
performed for women of childbearing potential at the EOS/early termination visit. For women of 
childbearing potential, if menstrual period is delayed during the study, absence of pregnancy must 
be confirmed by serum pregnancy test. Pregnancy tests will be repeated during the study if 
requested by an IEC/IRB or if required by local regulations.
9.5.9
Concomitant Medications and Procedures
Concomitant medications and therapeutic procedures received by the patient will be recorded in 
the eCRF from the start of study drug administration through 30 days (+10 days) after the last dose 
of the study drug. See Section 8.4 and Section 8.5 for a list of medications and therapies that are 
prohibited or allowed during the study.
9.5.10
AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the SOE. Refer to Section 10.0 for details regarding definitions, documentation, and reporting of 
AEs and SAEs.
9.5.11
Enrollment
A patient is considered to be enrolled in the study when they receive the first dose of the study 
drug.
Procedures for completing enrollment information are described in the study manual.
9.5.12
ECG
A 12-lead ECG will be performed at the time points specified in the SOEs in Table A-1 and Table 
A-2 for Part A and B, respectively (Appendix A). ECGs are to be performed with the patient rested 
for 5 minutes.
ECGs will be performed before administration within 3 hours before and within 10 minutes 
(±30 minutes) after the subasumstat infusion on Day 1 in Part A and on Day 1 of Cycles 1 and 2 in 
Part B. From Cycle 3 onward, pre-subasumstat infusion and post-subasumstat infusion ECGs will 
be performed on Day 1 of every other cycle. Starting in Cycle 3, the post-subastumstat infusion 
ECG can be performed within 1 hour of the end of infusion.
When the timing of the ECG measurements coincides with the timing of a blood draw, the ECG 
should be completed before the blood sample collection, with the exception of the end of infusion 
PK sample, which will be collected before the ECG is completed.
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9.5.13
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Handling and shipment of clinical 
laboratory samples will be outlined in the study manual. Clinical laboratory evaluations will be 
performed as outlined below. 
9.5.13.1
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematologic parameters are shown in 
Table 9.a and urine samples for analysis of the parameters shown in Table 9.b will be obtained as 
specified in the SOE (Appendix A). 
Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Coagulation
Hematocrit
Hemoglobin
Leukocytes with differential
ANC
Platelets (count)
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Bilirubin (total)
(Blood) Urea nitrogen (BUN)
Corrected calcium
Bicarbonate (HCO3-) or Carbon 
dioxide (CO2)
Creatinine 
Chloride
Glucose
Lactate dehydrogenase (LDH)
Magnesium
Phosphate
Potassium
Sodium
Protein (total)
Urate
Activated partial thromboplastin time 
(aPTT)
Prothrombin time (PT)
Fibrinogen
ANC: absolute neutrophil count.
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Table 9.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
If creatinine CL is to be estimated, the Cockroft-Gault formula will be employed as follows:
	
 
	
 
		
 
= [(140 −
) ∗	() ] / [72 ∗
! 
	
(/")] 
For female patients, the result of the formula above should be multiplied by 0.85.
For transgender patients, use the sex at birth for patients not using hormone therapy or for patients 
who have used hormone therapy for <6 months; use the current gender for patients who have used 
hormone therapy for ≥6 months.
9.5.14
ECOG Performance Status
Performance status is to be assessed using the ECOG scale (see Appendix D for a description of 
the scale) at the times specified in the SOEs (Appendix A).
9.5.15
Disease Assessment by Imaging
Patients will undergo CT and/or MRI scans imaging to assess disease response and progression, 
using RECIST v1.1 criteria for solid tumors (Eisenhauer et al. 2009). The disease response will be 
assessed by the same radiological measurement throughout the study. For this study CT and/or 
MRI scans should be acquired with at least IV contrast. CT scans of the chest, abdominal cavity, 
and pelvis will be obtained at screening. The imaging modalities used for a patient should remain 
consistent throughout the study. If contrast-enhanced CT scans are contraindicated for a particular 
patient, a noncontrast CT of the chest, in addition to contrast-enhanced abdomen and pelvis MRIs 
should be acquired, if possible. Anatomical measurements (summed across target lesions) will be 
collected at baseline and each subsequent evaluation. In addition, nonmeasurable disease and new 
lesions will be documented and their status evaluated. Objective assessments of the disease burden 
(target, nontarget, and potential new lesions) will be performed at each time point as described in 
the SOE (Appendix A). Radiographic images will be maintained at the site and can be requested 
by the sponsor at a later date for centralized review of the images.
Bone scans should be collected as clinically indicated.
Imaging tests performed before the screening consent date, if of diagnostic quality, may be used as 
screening tests if Day 1 of the study is planned within the 28 days after the date of the test.
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9.5.16
PK Measurements
Details regarding the preparation, handling, and shipping of samples are provided in the study and 
laboratory manuals. Any necessary actions will be taken to comply with the applicable rules and 
regulations regarding the collection, storage, and future use of biological samples from clinical 
trial subjects, where applicable.
9.5.16.1
Blood Sampling
During Part A, blood samples for TRA and PK assessments in whole blood (approximately 6 mL) 
and plasma (approximately 7 mL) will be drawn at the time points specified in Table A-1-a 
(Appendix A). Additional blood samples will be collected at each time point for metabolite 
profiling in plasma (approximately 10 mL).
The exact date and time of each sample collection and the actual start and stop times of the infusion 
should be recorded accurately, with particular care given to the recording of blood sampling times 
that occur close to the infusion. If the IV infusion is interrupted for more than 10 minutes, 2 
additional PK samples (1 sample drawn when the infusion is stopped and 1 sample drawn when the 
infusion is restarted) should be collected so that the patient may be considered evaluable. The 
exact date and time of each additional sample collection and the actual start and stop times of the 
infusion should be recorded accurately. 
Blood/plasma samples should be collected from the contralateral arm (not the arm which was used 
for drug infusion) if a peripheral line is used. If only a single arm is available, blood should be 
drawn as distal to the infusion site as feasible, and the site of the blood draw should be 
documented.
9.5.16.2
Urine and Fecal Sampling
In Part A, urine and fecal output will be collected over the minimum 5-day confinement period or 
until the discharge criteria are met (Section 6.1.1.1). Urine samples will be analyzed for PK, TRA, 
and metabolite profiling. Fecal samples will be analyzed for TRA, and metabolite profiling as 
specified in Table A-1-b (Appendix A). 
9.5.16.3
Vomitus Sampling
For patients experiencing emesis after drug administration, the full vomitus will be collected as 
much as possible and assayed for TRA. If a subject vomits more than once during the period, 
vomitus corresponding to each vomiting event will be collected in a separated labeled container 
and separately counted.
9.6
Completion of Study Treatment (for Individual Patients)
Patients will be considered to have completed study treatment if they discontinue study drug for 
any of the reasons outlined in Section 9.8.
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9.7
Completion of Study (for Individual Patients)
Based on the study purpose and endpoints, patients have completed Part A will be considered to 
have completed the study.
Patients who are not participating in Part B will be considered to have completed Part A if they 
received the single dose of [14C]subasumstat, have completed the protocol-specified assessments, 
and finished the EOS visit. Patients who are participating in Part B will be considered to have 
completed Part A when they receive the first dose of Part B.
9.8
Discontinuation of Treatment With Study Drug, Patient Withdrawal, and Patient 
Replacement
Study drug can be permanently discontinued for patients meeting any of the following criteria:

AE.

Major protocol deviation.

Progressive disease. 

Symptomatic deterioration. 

Unsatisfactory therapeutic response. 

Pregnancy (patient must be discontinued). 

Study terminated by sponsor.

Withdrawal by patient.

Lost to follow-up.

Death.

Other.
If a patient is withdrawn from the study during Part A, all study procedures outlined in the EOS 
visit will be completed as specified in the SOE. The primary reason for study drug discontinuation 
will be recorded on the eCRF. These patients will be replaced.
If a patient discontinues study drug treatment during Part B, all study procedures outlined in the 
early termination visit will be completed as specified in the SOE. The primary reason for study 
drug discontinuation will be recorded on the eCRF. A phone call, 14 days postdischarge phone 
call, will be arranged 14 days postdischarge for AE collection purposes. These patients will not be 
replaced.
9.9
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient who has provided informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation.
10.1.2
AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3
SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life-threatening, or require hospitalization, but may be considered serious when, 
on the basis of appropriate medical judgment, it may jeopardize the patient, require medical or 
surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
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development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, version 5.0, effective 27 November 2017 
(ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referen
ce_8.5x11.pdf, CTCAE, Accessed 27 February 2023), except for CRS events, which will be 
graded according to the ASTCT Consensus Grading for CRS (Lee et al. 2019).
Clarification should be made between an SAE and an AE that is considered severe in intensity 
(Grade 3 or 4) because the terms serious and severe are NOT synonymous. The general term 
severe is often used to describe the intensity (severity) of a specific event; the event itself, 
however, may be of relatively minor medical significance (such as a Grade 3 headache). This is 
NOT the same as serious, which is based on patient/event outcome or action criteria described 
above and is usually associated with events that pose a threat to a patient’s life or ability to 
function. A severe AE (Grade 3 or 4) does not necessarily need to be considered serious. For 
example, a white blood cell count of 1000/mm3 to less than 2000/mm3 is considered Grade 3 
(severe) but may not be considered serious. Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
10.1.4
Special Situation Report Definition
A special situation report (SSR) is defined as any of the following events:

Abuse: persistent or sporadic, intentional excessive use of medicinal products which is 
accompanies by harmful physical or psychological effects.

Misuse: situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the prescribed or authorized dose, route of administration, and/or the 
indication(s) or within the legal status of its supply.

Medication Error: an unintentional error in the drug treatment process (prescribing, dispensing 
or administration, including incorrect dose or poor quality administration) of a medicinal 
product while in the control of a health care provider, patient, or consumer, which leads to 
harm or has the potential to lead to harm.

Overdose: the administration of a quantity of medicinal product given per administration or per 
day, which is above the maximal dose according to protocol.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as a single comprehensive event.
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Regardless of causality, SAEs must be reported (see Section 10.3 for the period of observation) by 
the investigator to the Takeda Global Pharmacovigilance department or designee within 24 hours 
of becoming aware of the event. This will be done by transmitting an electronic data capture 
(EDC) SAE report. If transmission of an EDC SAE report is not feasible, then a facsimile of the 
completed Takeda paper-based SAE form will be sent. A sample of the paper-based SAE form and 
processing directions are in the Study Manual. Information in the SAE report or form must be 
consistent with the data provided on the eCRF.
If information not available at the time of the first report becomes available at a later date, then the 
investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an EDC 
SAE report is not feasible) or provide other documentation immediately within 24 hours of receipt. 
Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the study are not to be considered AEs unless the condition deteriorated in 
an unexpected manner during the study, eg, surgery was performed earlier or later than planned.
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug and AxMP administration. 
Severity (toxicity grade) for each AE, including any laboratory abnormality and excluding CRS 
events, will be determined using the NCI CTCAE, version 5.0. The criteria are provided in the 
study manual. The severity of CRS events will be graded according to the ASTCT Consensus 
Grading for CRS (Lee et al. 2019).
Relationship of the event to study drug administration or AxMP (ie, its causality) will be 
determined by the investigator responding yes (related) or no (unrelated) to this question: Is there a 
reasonable possibility that the AE is associated with the study drug?
10.2.1
Recording and Reporting AEs and SAEs Related to AxMPs
The use of AxMPs is required in this study for the management of CRS (Section 8.2). The 
investigator must report nonserious AEs related to an AxMP (ie, adverse drug reactions) within 
7 calendar days of awareness by transmitting an EDC report and provide a causality assessment for 
each SAE as it relates to an AxMP, and report the SAE to Takeda Global Pharmacovigilance 
within 24 hours of awareness. If transmission of the EDC report is not feasible, a paper SAE report 
form must be sent.
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10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows: 

AEs will be reported from the signing of informed (e)consent through 30 days (+/-5 days 
[where +/-5 days is the possible collection window]) after administration of the last dose of 
study drug and recorded in the eCRFs. 

SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from 
the signing of informed (e)consent through 30 days (+/-5 days [where +/-5 days is the possible 
collection window]) after administration of the last dose of study drug and recorded in the 
eCRF. After this period, only related SAEs must be reported to the Takeda Global 
Pharmacovigilance department or designee. SAEs should be monitored until they are resolved 
or are clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es).

AEs of special interest will be reported and monitored as stated in the SAE section.
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a patient becomes pregnant or suspects pregnancy while participating in this study, the patient 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by sending a completed pregnancy form to the Takeda Global 
Pharmacovigilance department or designee. The pregnancy must be followed for the final 
pregnancy outcome.
If a patient impregnates a partner during participation in this study, the sponsor must also be 
contacted immediately by sending a completed pregnancy form to the Takeda Global 
Pharmacovigilance department or designee. Every effort should be made to follow the pregnancy 
for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or SSRs (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, device, or 
combination product. Individuals who identify a potential product complaint situation should 
immediately report this via the contact information provided in the study manual.
SSRs are defined as medication errors and uses outside of what is foreseen in the protocol, 
including overdose, misuse, and abuse of the product. SSRs may or may not be associated with an 
AE/SAE. SSRs must be reported to Takeda Global Patient Safety Evaluation (Takeda Global 
Pharmacovigilance department or designee) using a paper SSR form within 7 calendar days of 
awareness via the contact information provided in the study manual. If an SSR is associated with 
an SAE, the SAE must be reported to Takeda Global Patient Safety Evaluation within 24 hours of 
awareness.
Product complaints and SSRs in and of themselves are not AEs. If a product complaint or SSR
results in an SAE, the SAE should be reported.
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10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
and any other applicable SAEs to regulatory authorities, including the European Medicines 
Agency, investigators, and IRBs and IECs, as applicable, in accordance with national regulations 
in the countries where the study is conducted. Relative to the first awareness of the event by/or 
further provision to the sponsor or sponsor’s designee, suspected unexpected serious adverse 
reactions will be submitted to the regulatory authorities as expedited reports within 7 days for fatal 
and life-threatening events and within 15 days for other serious events, unless otherwise required 
by national regulations. The sponsor will also prepare an expedited report for other safety issues 
where these might materially alter the current benefit-risk assessment of an IMP or that would be 
sufficient to consider changes in the IMP’s administration or in the overall conduct of the study. 
The investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations. 
11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, adjudication committee, or clinical 
endpoint committee will be used in this study
12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, medical history, and concurrent conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization (WHO) Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each patient who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designee) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for the change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
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eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor (or designee) will be permitted to review the patient’s medical and 
hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs are 
the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated informed (e)consent forms, patient authorization forms 
regarding the use of personal health information (if separate from the ICFs), electronic copies of 
eCRFs including the audit trail, and detailed records of drug disposition to enable evaluations or 
audits from regulatory authorities and the sponsor (or designees). Any source documentation 
printed on degradable thermal-sensitive paper should be photocopied by the site and filed with the 
original in the patient’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 
requires the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 
2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the clinical study site agreement between the investigator 
and sponsor.
Refer to the clinical study site agreement for the sponsor’s requirements for record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
Should the sponsor request a longer retention period, the head of the institution should discuss how 
long and how to retain those documents with the sponsor. In addition, the investigator and the head 
of the institution should retain the essential relevant documents until the receipt of a 
sponsor-issued notification to state the retention is no longer required. 
When proceeding to a local post-marketing study, the investigator and the head of the institution 
are required to retain essential relevant documents until the later of the end of the re-examination 
or re-evaluation. However, if the sponsor requests a longer time period for retention, the head of 
the institution should discuss how long and how to retain those documents with the sponsor.
12.3
Data Protection
The confidentiality of records that may be able to identify patients will be protected in accordance 
with applicable laws, regulations, and guidelines. 
After patients have consented to take part in the study, the sponsor and/or its representatives 
reviews their source documents and data collected during the study. These records and data may, 
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in addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; national or local regulatory authorities; and the IRB(s)/IEC(s) that
gave approval for the study to proceed. The sponsor and/or its representatives accessing the 
records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of patients’ identities. Patients are 
assigned a unique identifying number; however, their initials and date of birth may also be 
collected, if permitted under local laws governing privacy. 
The results of studies containing participants’ unique identifying number, relevant source 
documents, and possibly initials and dates of birth, where allowed per local law, may be 
transferred to, and used in, other countries that may not afford the same level of protection applied
within the countries where this study is conducted. The purpose of any such transfer would 
include: to support regulatory submissions, to conduct new data analyses to publish or present the 
study results, or to answer questions asked by regulatory or health authorities. 

Patients will be assigned a unique identifier by the sponsor. Any patient records or datasets that 
are transferred to the sponsor will contain the identifier only; patient names or any information 
that would make the patient identifiable will not be transferred.

The patient must be informed that their personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient, who will be required to give consent for their data to be used as described in the 
ICF.

The patient must be informed that their source documents may be examined by Clinical 
Quality Assurance auditors or study monitors, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities. 
In the event that a serious data breach affecting personal data is detected, the sponsor or its
designee and the investigator (as applicable) will take appropriate corrective and preventive 
actions in response. These actions will be documented, and the relevant regulatory agency(ies) will 
be notified as appropriate. Where appropriate, the relevant individuals materially affected by the 
breach would also be notified; in the case of study patients, this would be done through the 
investigator.
Takeda applies certain measures to protect participants’ personal data and prevent data breaches, 
detailed in a separate document (Compliance with National Requirements on Data Protection). 
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized before database lock. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives.
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13.1.1
Analysis Sets
The analysis sets are:

Safety analysis set: Patients who have received at least 1 dose of study drug, even if 
incomplete. This set will be used for all safety analyses and some efficacy analyses.

PK analysis set: Patients with sufficient dosing and PK data to reliably estimate at least 1 PK 
parameter. This set will be used for PK analyses.

Tumor response-evaluable analysis set: Patients who have received at least 1 dose of study 
drug, with measurable disease at baseline, and have at least 1 postbaseline disease assessment, 
or was discontinued due to symptomatic deterioration or death before a postbaseline 
evaluation occurs. This set will be used for analyses of response. 
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized descriptively. Variables to be 
analyzed include sex, age, race, medical history, baseline disease characteristics, prior 
medications/therapies, ECG findings, and other parameters as appropriate. For continuous 
variables, descriptive statistics (number, mean, standard deviation, median, minimum, and 
maximum) will be provided. For categorical variables, patient counts and percentages will be 
provided. Categories for missing data will be presented as needed. 
13.1.3
Efficacy Analysis
All efficacy analyses may be performed depending upon data availability. 
13.1.3.1
Primary Efficacy Analysis
Efficacy is not a primary objective for this study.
13.1.3.2
Secondary Efficacy Analysis
Efficacy is not a secondary objective for this study.
13.1.3.3
Exploratory Efficacy Analysis
ORR is defined as the proportion of patients who achieve CR and PR (determined by the 
investigator) during the study and estimates of the ORR (CR + PR) will be presented with 2-sided 
90% exact binomial CIs.
Response assessments are based on RECIST v1.1 for solid tumors.
Other exploratory efficacy endpoints for Part B include PFS, best response (CR, PR, etc.) and 
DOR. 
PFS is defined as the time from the date of the first dose administration to the date of first 
documentation of progressive disease or death due to any cause, whichever occurs first. Patients 
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without documentation of progressive disease will be censored at the date of the last response 
assessment that is SD or better.
DOR is the time from the date of the first documentation of PR or better to the date of first 
documentation of progressive disease for responders (PR or better). Responders without 
documentation of progressive disease will be censored at the date of the last response assessment 
that is SD or better.
Best response is defined as the best response recorded after the first dose of the study drug until 
subsequent anti-cancer therapy or end of treatment, whichever is earlier. Responses assessed after 
disease progression will not be considered in determination of the best response.
PFS and DOR will be summarized descriptively using the Kaplan-Meier method. ORR and best 
response will be analyzed using the tumor response-evaluable analysis set.
13.1.4
PK Analysis
All data will be summarized using descriptive statistics and will be listed and summarized in 
tabular and/or graphical form. The following PK parameters will be calculated by 
noncompartmental analysis and tabulated for each individual:

TRA in plasma and whole blood: Cmax, tmax, AUClast, and as permitted by data, t1/2z and AUC∞.

TRA in urine: amount of [14C]-radioactivity excreted into urine per sampling interval 
(Aeurine,14
C,t1-t2 in ng-eq and percentage of dose) and cumulative amount of [14C]-radioactivity 
excreted in urine up to the last sampling interval (Aeurine,14
C in ng-eq and percentage of dose).

TRA in feces: amount of [14C]-radioactivity excreted into feces per sampling interval 
(Aefeces,14
C,t1-t2 in ng-eq and percentage of dose) and cumulative amount of [14C]-radioactivity 
excreted in feces up to the last sampling interval (Aefeces,14
C in ng-eq and percentage of dose).

The total cumulative excretion of [14C]-radioactivity per interval and over the total collection 
period will be calculated as the sum of the cumulative excretion in urine and feces: total 
cumulative excretion of [14C]-radioactivity from the body (Aetotal,14
C = Aeurine,14
C + Aefeces,14
C) 
(in ng-eq and percentage of dose).

Subasumstat in plasma and whole blood: Cmax, tmax, AUClast, and as permitted by data, t1/2z, 
AUC∞, CL, and Vss.

Subasumstat in urine (per sampling interval and total): cumulative amount excreted in urine 
(Aeurine and percentage of dose) and CLR.
Additionally, one of the secondary objectives of this study is to collect plasma, urine, and feces for 
metabolite profiling and identification. While the results of the PK of subasumstat and TRA, time 
course of excretion of TRA in urine and feces, and overall mass balance will be included in the 
clinical study report, the metabolite profiling and identification results will be reported separately. 
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13.1.5
Safety Analysis
Safety will be evaluated by the frequency of AEs, severity and types of AEs, and by changes from 
baseline in patients’ vital signs, weight, and clinical laboratory results using the safety analysis set. 
All safety analyses will be performed based on data availability.
Exposure to study drug and reasons for discontinuation will be tabulated.
TEAEs that occur after administration of the first dose of the study drug and through 30 days after 
the last dose of the study will be tabulated.
AEs will be tabulated according to the MedDRA coding system and will include the following 
categories:

TEAEs.

Study drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher study drug-related TEAEs.

The most commonly reported TEAEs (ie, those reported by ≥10% of all patients).

SAEs.

Study drug-related SAEs.

On-study deaths (ie, death that occurs between the first dose of any study drug and within 
30 days of the last dose of any study drug).

TEAE leading to study dose modification and discontinuation.
Descriptive statistics for the actual values of clinical laboratory parameters and/or change from 
baseline in clinical laboratory parameter will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters.
Descriptive statistics for the actual values and/or the changes from baseline of vital signs and 
weight will be tabulated by scheduled time point. ECOG performance statuses will be summarized 
using a shift table.
Shift tables for laboratory parameters will be generated for changes in NCI CTCAE grade from 
baseline to the worst postbaseline value. Graphical displays of key safety parameters, such as 
scatter plots of baseline versus worst baseline values may be used to understand the subasumstat 
safety profile. The number and percentage of patients with clinically significant abnormal 
laboratory values will also be tabulated as appropriate. 
All concomitant medications collected from the first dose of study drug throughout the study 
period will be classified to preferred terms according to the WHO Drug Dictionary.
Additional safety analyses may be performed to clearly enumerate rates of toxicities and to further 
define the safety profile of subasumstat.
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13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
The sample size for this study is not based on statistical considerations. On the basis of the As Low 
(radioactive burden) As Reasonable Achievable (ALARA) principle set forth in the 
96/29/EURATOM directive, a sample size of approximately 6 PK-evaluable patients is considered 
sufficient to provide adequate characterization of the mass balance, PK, metabolism and excretion 
of subasumstat in patients with cancer. Patients will be replaced if they are not evaluable for PK.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Where permitted by local and country regulations, alternative 
approaches such as remote source data review via phone or video may be used to ensure data 
quality and integrity and patient safety. Additional details are in the monitoring plan. Source 
documents will be reviewed for verification of data recorded on the eCRFs. Source documents are 
defined as original documents, data, and records. The investigator and institution guarantee access 
to source documents by the sponsor or its designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
including, but not limited to, the investigator’s binder, study medication, patient medical records, 
informed consent documentation, documentation of patient authorization to use personal health 
information (if separate from the ICFs), and review of eCRFs and associated source documents. It 
is important that the investigator and other study personnel are available during the monitoring 
visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the patient’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of the primary study 
assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a patient or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP or the protocol. In the event that a 
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protocol deviation has been identified as being a serious breach of GCP or the protocol, the serious 
breach shall be documented and reported to the appropriate regulatory authorities. Appropriate 
corrective and preventive actions shall be taken in response to any serious breach of GCP or the 
protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the United States [US] Food and Drug Administration [FDA], 
the United Kingdom [UK] Medicines and Healthcare products Regulatory Agency [MHRA], the 
Pharmaceuticals and Medical Devices Agency of Japan [PMDA]). If the study site is contacted for 
an inspection by a regulatory body, the sponsor should be notified immediately. The investigator 
and institution guarantee access for quality assurance auditors to all study documents as described 
in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (herein 
“patients”) according to the protocol, the ethical principles that have their origin in the Declaration 
of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the responsibilities of the investigator that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, patient recruitment materials and advertisements and other documents required by all 
applicable laws and regulations must be submitted to a central or local IRB or IEC for approval. 
The IRB’s or IEC’s written approval of the protocol and patient informed consent must be 
obtained and submitted to the sponsor or designee before commencement of the study, ie, before 
shipment of the sponsor-supplied drug or study-specific screening activity. The IRB or IEC 
approval must refer to the study by its exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. If required by country 
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or regional regulations or procedures, approval from the competent regulatory authority will be 
obtained before commencement of the study or implementation of a substantial amendment. The 
sponsor will ship drug/notify site once the sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the sponsor has received permission from the competent 
authority to begin the trial. Until the site receives drug/notification, no protocol activities, 
including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by patients, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor (or 
designee).
Patient incentives should not exert undue influence for participation. Payments to patients must be 
approved by the IRB or IEC and sponsor.
15.2
Patient Information, Informed Consent, and Patient Authorization
Written and electronic consent documents will embody the elements of informed consent as 
described in the Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance 
with all applicable laws and regulations. The ICF, patient authorization form (if applicable), and 
patient information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study, including the use of electronic devices and associated technologies (if applicable). The 
ICF and the patient information sheet (if applicable) further explain the nature of the study, its 
objectives, and potential risks and benefits, and the date informed consent is given. The ICF will 
detail the requirements of the participant and the fact that he or she is free to withdraw at any time 
without giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the patient authorization form. The ICF, patient authorization form (if 
applicable), and patient information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. Information should 
be given in both oral and written form whenever possible and in the manner deemed appropriate by 
the IRB or IEC. If the patient is not capable of rendering adequate written or electronic informed 
consent, then the patient’s legally acceptable representative may provide such consent for the 
patient in accordance with applicable laws and regulations.
The patient, or the patient’s legally acceptable representative, must be given ample opportunity to 
(1) inquire about details of the study and (2) decide whether to participate in the study. If the 
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patient, or the patient’s legally acceptable representative, determines that he or she will participate 
in the study, then the ICF and patient authorization form (if applicable) must be signed and dated 
by the patient, or the patient’s legally acceptable representative, at the time of consent and before 
the patient enters into the study. The patient or the patient’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using a ballpoint pen with 
either blue or black ink in the case of written informed consent. The investigator must also sign and 
date the ICF and patient authorization (if applicable) at the time of consent and before the patient 
enters into the study; however, the sponsor may allow a designee of the investigator to sign to the 
extent permitted by applicable law.
Once signed, the original ICF, patient authorization form (if applicable), and patient information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the informed consent in the patient’s medical record. Copies of the signed 
ICF, the signed patient authorization form (if applicable), and patient information sheet (if 
applicable) shall be provided to the patient.
All revised ICFs must be reviewed and signed by relevant patients or the relevant patient’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
revised (e)consent was obtained should be recorded in the patient’s medical record, and the patient 
should receive a copy of the revised ICF.
15.3
Patient Confidentiality
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or date 
of birth, and patient initials may be used to verify the patient and accuracy of the patient’s unique 
identification number. In the event that a serious data breach is detected, the sponsor or its 
designee and the investigator (as applicable) will take appropriate corrective and preventive 
actions in response. These actions will be documented, and the relevant regulatory agency(ies) will 
be notified as appropriate. Where appropriate, the relevant individuals materially affected by the 
breach would also be notified; in the case of study patients, this would be done through the 
investigator.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, US FDA, UK MHRA, Japan PMDA), the sponsor’s designated auditors, 
and the appropriate IRBs and IECs to review the patient’s original medical records (source data or 
documents) including, but not limited to, laboratory test result reports, ECG reports, admission and 
discharge summaries for hospital admissions occurring during a patient’s study participation, and 
autopsy reports. Access to a patient’s original medical records requires the specific authorization 
of the patient as part of the informed (e)consent process (see Section 15.2).
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Copies of any patient source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, patient name, address, and other identifier fields not 
collected on the patient’s eCRF.
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study site agreement. In the event of any discrepancy between the 
protocol and the clinical study site agreement, the clinical study site agreement will prevail.
15.4.2
Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations, and guidance, Takeda will, at a minimum, register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined by Takeda policy/standards. Takeda contact 
information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods preferred by callers requesting trial information. Once patients 
receive investigator contact information, they may call the site requesting enrollment into the trial. 
The investigative sites are encouraged to handle the trial inquiries according to their established 
patient screening process. If the caller asks additional questions beyond the topic of trial 
enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
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15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov, clinicaltrialsregister.eu, and 
other publicly accessible websites (including the Takeda corporate site) and registries, as required 
by Takeda policy/standards, applicable laws, and/or regulations.
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.5
Insurance and Compensation for Injury
Each patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study patients. 
Refer to the clinical study site agreement regarding the sponsor’s policy on patient compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
16.0
REFERENCES
Curtsinger, J. M., Valenzuela, J. O., Agarwal, P., Lins, D. and Mescher, M. F. 2005. Type I IFNs 
provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J 
Immunol, 174(8), 4465-9.
Decque, A., Joffre, O., Magalhaes, J. G., Cossec, J. C., Blecher-Gonen, R., Lapaquette, P., et al. 
2016. Sumoylation coordinates the repression of inflammatory and anti-viral 
gene-expression programs during innate sensing. Nat Immunol, 17(2), 140-9.
Diamond, M. S., Kinder, M., Matsushita, H., Mashayekhi, M., Dunn, G. P., Archambault, J. M., et 
al. 2011. Type I interferon is selectively required by dendritic cells for immune rejection of 
tumors. J Exp Med, 208(10), 1989-2003.
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., et al. 2009. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 
1.1). Eur J Cancer, 45(2), 228-47.
Fuertes, M. B., Kacha, A. K., Kline, J., Woo, S. R., Kranz, D. M., Murphy, K. M., et al. 2011. Host 
type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ 
dendritic cells. J Exp Med, 208(10), 2005-16.
Geiss-Friedlander, R. and Melchior, F. 2007. Concepts in sumoylation: a decade on. Nat Rev Mol 
Cell Biol, 8(12), 947-56.
He, X., Riceberg, J., Soucy, T., Koenig, E., Minissale, J., Gallery, G., et al. 2017. Probing the roles 
of SUMOylation in cancer cell biology by using a selective SAE inhibitor. Nature 
Chemical Biology, 13, 1164-73.
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Lee, C. K., Rao, D. T., Gertner, R., Gimeno, R., Frey, A. B. and Levy, D. E. 2000. Distinct 
requirements for IFNs and STAT1 in NK cell function. J Immunol, 165(7), 3571-7.
Lee, D. W., Santomasso, B. D., Locke, F. L., Ghobadi, A., Turtle, C. J., Brudno, J. N., et al. 2019. 
ASTCT consensus grading for cytokine release syndrome and neurologic toxicity 
associated with immune effector cells. Biol Blood Marrow Transplant, 25(4), 625-38.
Lightcap, E. S., Yu, P., Grossman, S., Song, K., Khattar, M., Xega, K., et al. 2021. A
small-molecule SUMOylation inhibitor activates antitumor immune responses and 
potentiates immune therapies in preclinical models. Sci Transl Med, 13(611), eaba7791.
Lucas, M., Schachterle, W., Oberle, K., Aichele, P. and Diefenbach, A. 2007. Dendritic cells 
prime natural killer cells by trans-presenting interleukin 15. Immunity, 26(4), 503-17.
Marrack, P., Kappler, J. and Mitchell, T. 1999. Type I interferons keep activated T cells alive. J 
Exp Med, 189(3), 521-30.
Nakamura, A., Grossman, S., Song, K., Xega, K., Zhang, Y., Cvet, D., et al. 2022. The 
SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent 
macrophage and NK cell stimulation. Blood, 139(18), 2770-81.
Neelapu, S. S., Tummala, S., Kebriaei, P., Wierda, W., Gutierrez, C., Locke, F. L., et al. 2018. 
Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat 
Rev Clin Oncol, 15(1), 47-62.
Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. T., et al. 1982. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. American 
Journal of Clinical Oncology, 5(6), 649-55.
Seeler, J. S. and Dejean, A. 2017. SUMO and the robustness of cancer. Nat Rev Cancer, 17(3), 
184-97.
Woo, S. R., Fuertes, M. B., Corrales, L., Spranger, S., Furdyna, M. J., Leung, M. Y., et al. 2014. 
STING-dependent cytosolic DNA sensing mediates innate immune recognition of 
immunogenic tumors. Immunity, 41(5), 830-42.
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Appendix A
Schedule of Events
Table A-1
Schedule of Study Procedures: Part A
ADME Assessment Period
EOS c
Screening a
Week 1
Confinement
Week 2
Discharge b
Day -1 
Predose
Day 1 
Predose
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Between Days 
6 and 14
Confinement d
X
X
X
X
X
X
X
Study Drug Administration
Single [14C]subasumstat IV solution 
administration e
X
Study Procedures
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history/prior therapy
X
Full physical examination
X
X
X
Symptom-directed physical examination
X
X
Height
X
Weight
X
X f
X
Vital signs g
X
X
X
X
X
ECOG performance status
X
X
X
12-lead ECG h
X
X f
X
X
Disease assessment by imaging
X
Monitoring of concomitant medications, 
therapies, and procedures
Recorded from start of study drug administration through 30 days (+/-5 days [where +/-5 days is the possible collection window]) after 
the last dose of study drug
AE reporting i
Recorded from start of study drug administration through 30 days (+/-5 days [where +/-5 days is the possible collection window]) after 
the last dose of study drug 
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Table A-1
Schedule of Study Procedures: Part A
ADME Assessment Period
EOS c
Screening a
Week 1
Confinement
Week 2
Discharge b
Day -1 
Predose
Day 1 
Predose
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Between Days 
6 and 14
SAEs will be reported from signing of the ICF through 30 days (+/-5 days [where +/-5 days is the possible collection window]) after the 
last dose of study drug.
Samples/Laboratory Assessments
Pregnancy test
X
X f
X
Hematology/
chemistry j, k
X
X f
X f
X
X
X
Urinalysis 
X
X f
X f
X
X
Blood sample collection
See Table A-1-a for Blood Sampling Schedule
Urine sample collection
See Table A-1-b for Urine Collection Sample Schedule
Fecal sample collection l
See Table A-1-b for Fecal Collection Sample Schedule
Vomitus 
Vomitus to be collected if event occurred during first 24 hours after dosing and at any other vomiting events afterward
ADME: absorption, distribution, metabolism, excretion; AE: adverse event; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOS: end of study; IV: 
intravenous; PK: pharmacokinetic; SAE: serious adverse event.
a Unless otherwise noted, the screening visit must occur within 28 days before the day of the first dose of study drug in Part A.
b Discharge criteria for Part A can be found in Section 6.1.1.1. Patients will be discharged between Days 6 and 14 given the discharge criteria has been met. Discharge assessments are 
done only once on the day of discharge.
c An EOS visit is needed in Part A only if the patient did not continue into Part B, and will occur 30 days (+/-5 days [where +/-5 days is the possible collection window]) after the last 
dose of study drug or before the start of subsequent therapy for the patient’s indication, if that occurred sooner.
d During Part A, patients are required to stay at the Part A study site for at least 5 days postdose and until the discharge criteria are met, with a maximum estimated confinement period 
of 14 days postdose.
e Patients will receive a single dose of [14C]subasumstat 90 mg given as a 1-hour IV infusion on Day 1. The clinic will be supplied with vials containing approximately 100 µCi 
(approximately 3.7 MBq) of [14C]subasumstat as the radioactive tracer.
f Procedures conducted during screening that are performed within 3 days of Day 1 could also be used as the Day 1 predose evaluation and would not need to be repeated, with the 
exception of an ECG that was required to be repeated predose on Day 1.
g On days when subasumstat is administered, vital signs will be measured predose (20 minutes [±10 min]) before the infusion of subasumstat; 30 minutes (±10 min) after the start of 
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subasumstat dosing; and 1 hour (±10 min) and 3 hours (±30 min) after the completion of subasumstat dosing. All vital signs are measured with the patient in the sitting or supine 
position. When the timing of vital signs assessment coincides with the timing of a blood draw, vital signs will be measured before blood sample collection.
h A 12-lead ECG will be performed during screening and before administration (within 3 hours) of subasumstat on Day 1 and immediately after the subasumstat infusion is completed 
(±20 min) on Day 1. When the timing of ECG measurements coincide with the timing of a blood draw, the ECG should be completed before the blood sample collection, with the 
exception of the end of infusion PK sample, which will be collected before the ECG is completed.
i Including pretreatment serious adverse events; see Section 10.1.1.
j Hematology samples will be collected during screening and before dosing with study drug on Day 1. It is permitted that these samples may be drawn up to 1 day before dosing. If 
dosing falls on a Monday, the collection window could be extended to collect samples on the previous Friday. In addition, samples will be collected on Day 1 predose and postdose, 
at the time of discharge, and at the EOS visit.
k Clinical chemistry samples will be collected during screening, before dosing with study drug, and 3 hours (±30 min) after completion of the subasumstat infusion. Predose samples 
can be drawn within 24 hours predose. If dosing falls on a Monday, the collection window can be extended to collect samples on the previous Friday. In addition, samples will be 
collected on Day 1 predose and postdose, at the time of discharge, and at the EOS visit.
l Patients may be provided treatment for constipation if needed, as determined by the investigator.
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Table A-1-a
Blood Sampling Schedule: Part A
Study Day
Time Point (hour)
Whole Blood Sample 
Collection
Plasma Sample 
Collection
Plasma Sample 
Collection
Blood 1 a
Blood 2 a
Plasma 1 b
Plasma 2 b
Plasma 3 b
Day 1
Predose c
X2
X2
X
Day 1
EOI d (-5 to +1 min)
X2
X2
X
Day 1
0.5 hour post-infusion e (±5 min)
X2
X2
X
Day 1
1 hour post-infusion e (±15 min)
X2
X2
X
Day 1
2 hours post-infusion e (±15 min)
X2
X2
X
Day 1
4 hours post-infusion e (±45 min)
X2
X2
X
Day 1
8 hours post-infusion e (±1 hour)
X2
X2
X
Day 2
24 hours post-dose f (±1 hour)
X2
X2
X
Day 3
48 hours post-dose f (±2 hours)
X2
X2
X
Day 4
72 hours post-dose f (±3 hours)
X2
X2
X
Day 5
96 hours post-dose f (±4 hours)
X2
X2
X
Day 6
120 hours post-dose f (±4 hours)
X2
X2
X
Day 7
144 hours post-dose f (±4 hours)
X2
X2
Day 8
168 hours post-dose f (±4 hours)
X2
X2
X
Day 9-14
g
X2
X2
ADME: absorption, distribution, metabolism, excretion; EOI: end of infusion; IV: intravenous; X2: 2 samples will be collected; X: 1 sample will be collected.
a For determination of TRA (Blood 1) and subasumstat (Blood 2).
b For determination of TRA (Plasma 1), subasumstat (Plasma 2), and metabolite profiling (Plasma 3).
c The sample will be collected within 1 hour before the start of subasumstat infusion on Day 1.
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d The window for collection of the EOI time point is between 5 minutes before completion of infusion and 1 minute after completion of infusion. If, during Part A, 
IV infusion of study drug is interrupted or slowed, the project clinician or designee will be contacted as soon as possible for consideration of patient replacement, as 
appropriate. If the IV infusion is interrupted, 2 additional PK samples (1 sample will be drawn when the infusion is stopped and 1 sample will be drawn when the 
infusion is restarted) will be collected so that the patient will be considered evaluable. The exact date and time of each additional sample collection and the actual 
start and stop times of the infusion will be recorded accurately.
e Samples will be collected after completion of subasumstat IV infusion on Day 1.
f Samples will be collected after initiation of the subasumstat IV infusion on Day 1. 
g Samples will be continued to be collected at 24-hour intervals until discharge criteria has been met (ie, 90% or greater of the total dose of radioactivity 
administered is recovered from urine and fecal samples or until <1% of the dosed radioactivity is collected in 2 consecutive intervals when both urine and feces are 
collected).
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Table A-1-b
Urine and Fecal Sample Collection Schedule: Part A
Study Day
Time Interval (hour) a
Urine Sample Collection
Feces Sample Collection
Matrix
Urine b
Fecal c
Day -1
0 (pre-dose)
X
X
Day 1
0-6 hours
X
X (0-24 hours)
Day 1
6-12 hours
X
Day 2
12-24 hours
X
Day 3
24-48 hours
X
X
Day 4
48-72 hours
X
X
Day 5
72-96 hours
X
X
Day 6-14
d
X
X
ADME: absorption, distribution, metabolism, excretion; IV: intravenous; TRA: total radioactivity; X: 1 sample will be collected.
a Sampling times are relative to the initiation of the IV infusion on Day 1.
b For determination of TRA, metabolite profiling, and subasumstat (urine).
c For determination of TRA and metabolite profiling (feces).
d Samples will be continued to be collected at 24-hour intervals until discharge criteria has been met (ie, 90% or greater of the total dose of radioactivity 
administered is recovered from urine and fecal samples or until <1% of the dosed radioactivity is collected in 2 consecutive intervals when both urine and feces are 
collected).
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Table A-2
Schedule of Study Procedures: Part B
Single Agent Subasumstat Treatment
21-Day Cycle, Cycles 1-3 a
Single Agent Subasumstat Treatment
21-Day Cycle, Cycles 4+ a
EOS/
Early Termination c
Day 1 
Predose b
Day 1
Day 4
Day 8
Day 11
Day 1 Predose b
Day 1
Day 8
Study Drug Administration
Subasumstat administration d
X
X e
X
X e
X
X
Study Procedures
Full physical examination 
X
X
Symptom-directed physical examination
X
X e
X
X e
X
X
ECOG performance status
X f
X f
X
X f
X f
X
Weight
X
X
Vital signs g
X
X
X e
X
X e
X
X
X
X
12-Lead ECG h
X
X
X
X
Tumor assessments i
To be completed before dosing in Part B, end of Cycle 2, and every 3 cycles thereafter 
X
Monitoring of concomitant medications, 
therapies, and procedures
Recorded from start of study drug administration in Part A through 30 days (+/-5 days [where +/-5 days is the 
possible collection window]) after the last dose of study drug in Part B
AE reporting 
Recorded from start of study drug administration in Part A through 30 days (+/-5 days [where +/-5 days is the 
possible collection window]) after the last dose of study drug in Part B
SAEs reported from signing of the ICF in Part A through 30 days (+/-5 days [where +/-5 days is the possible 
collection window]) after the last dose of study drug in Part B
Samples/Laboratory Assessments
Pregnancy test j
X
X
X
Hematology/chemistry k 
X
X 
X e
X
X e
X
X
X
X
Urinalysis 
X
X
X
AE: adverse event; BIW: twice weekly; CT: computed tomography; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOS: end of study; ICF: informed 
consent form; IV: intravenous; MRI: magnetic resonance imaging; PK: pharmacokinetic; QW: once weekly; SAE: serious adverse event.
Tests and procedures are to be performed on schedule, but occasional changes are allowable (±2 days) for holidays, vacations, and other administrative reasons.
a Patients will receive subasumstat 90 mg in an induction treatment period of at least 3 cycles with BIW schedule (on days 1, 4, 8, and 11 of the 21-day cycle) schedule followed by 
maintenance with the QW schedule. From Cycle 4 onwards, patients can continue to receive treatment for up to 1 year. 
b For patients to be eligible for dosing with subasumstat (Part B), they should meet certain entry criteria (see Section 7.0).
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c If the patient continues into Part B, the EOS visit will occur 30 days (+/-5 days [where +/-5 days is the possible collection window]) after the last dose of study drug in Part B or 
before the start of subsequent therapy for the patient’s indication, if that occurred sooner. A 14 days postdischarge phone call will be arranged for AE collection purpose.
d The infusion of subasumstat can be slowed or stopped and restarted for any associated infusion-related reactions. The dose of subasumstat can be reduced because of toxicities, in 
accordance with Section 8.3.2.
e Subasumstat administration, symptom-directed physical examination, vital signs, and hematology and chemistry samples only need to be collected if the patient is on the BIW 
dosing schedule(the first 3 cycles).
f If ECOG performance status is measured at screening, it does not need to be repeated on Day 1 predose and Day 1. Only one ECOG measurement is needed on Day 1 predose and 
Day 1.
g On days when study drug is administered, vital signs will be measured predose (20 minutes [±10 min]) before the infusion of subasumstat; 30 minutes (±10 min) after the start of 
subasumstat dosing; and 1 hour (±10 min) after the completion of subasumstat dosing. All vital signs will be measured with the patient in the sitting or supine position. When the 
timing of vital signs assessment coincides with the timing of a blood draw, vital signs will be measured before blood sample collection.
h A 12-lead ECG will be performed on Day 1 within 3 hours of administration and within 10 minutes (±30 minutes) after the subasumstat infusion. When the timing of ECG 
measurements coincides with the timing of a blood draw, the ECG will be completed before the collection of the blood sample, with the exception of the end of infusion PK sample, 
which will be taken before the ECG is completed. From Cycle 3 onwards, ECGs will be collected on Day 1 of every other cycle before the subasumstat dosing and within 1 hour of 
finishing the infusion. Additional ECGs may be obtained as clinically indicated at the discretion of the investigator. ECG assessments are to be performed with the patient rested for 
5 minutes.
i Contrast enhanced Radiological evaluations (CT scan or MRI) (unless contrast is contraindicated) of the chest, abdomen, and pelvis (and any other known suspected disease area) are 
required as entry criteria for Part B to assess the status of the patient’s underlying disease. If the patient has had appropriate imaging scans performed within 28 days of Cycle 1 Day 
1 of Part B, then the results of those scans could be used. During the study, CT scans or MRIs encompassing the known sites of disease will be performed at the end of Cycle 2 and 
every 3 cycles thereafter. An EOS/early termination CT scan is not needed to be completed/repeated if a scan was performed within the previous 28 days. Same technique with 
appropriate contrast usage (CT or MRI) used at screening should be utilized throughout the study.
j A pregnancy test is required to be performed for women of childbearing potential at every cycle (typically performed on Day 1 of the cycle; however, if a serum pregnancy test is 
used, this could be performed up to 3 days before Day 1) with negative results available before the first dose is administered in that cycle. A pregnancy test will also be performed for 
women of childbearing potential at the EOS/early termination visit. Pregnancy tests will be repeated during the study if requested by an independent ethics committee/institutional 
review board or if required by local regulations.
k Hematology and chemistry samples will be collected as part of the entry criteria for Part B. Hematology, chemistry, and urinalysis may be taken up to 3 days before the Day 1 visit. 
Hematology and chemistry assessments on Days 4, 8, and 11 (Cycle 1) and Days 1 and 8 (Cycle 2 and onwards) are to be performed on dosing days depending on treatment schedule.
If dosing falls on a Monday, the collection window can be extended to collect samples on the previous Friday.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those study-related duties and functions and should implement 
procedures to ensure the integrity of the study-related duties and functions performed and any 
data generated.
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments, are NOT performed on potential patients before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
ICH and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to patients. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed (e)consent, as outlined in ICH and local regulations, are 
met.
9. Obtain valid informed (e)consent from each patient who participates in the study, and 
document the date of (e)consent in the patient’s medical chart. Valid informed (e)consent is the 
most current version approved by the IRB/IEC. Each ICF should contain a patient 
authorization section that describes the uses and disclosures of a patient’s personal information 
(including personal health information) that will take place in connection with the study. If an 
ICF does not include such a patient authorization, then the investigator must obtain a separate 
patient authorization form from each patient or the patient’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other identifying personal information. In addition, the investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
UK, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
The investigator’s personal information may be retained, processed, and transferred by Takeda 
and these other parties for research purposes including the following:

Assessment of the suitability of the investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details, and results on publicly accessible 
clinical trial registries, databases, and websites.
The investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in the investigator’s 
own country.
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above.
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Appendix D
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
Source: Oken MM, 1982 (Oken et al. 1982).
ECOG: Eastern Cooperative Oncology Group.
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Appendix E
Drugs that Interact With the CYP3A Family of CYPs
Drugs listed in the table that are strong or moderate inducers or inhibitors of the CYP3A family of 
CYPs are prohibited as concomitant medications with subasumstat. This list is not intended to be 
exhaustive, and a similar restriction will apply to other agents that are known to strongly modulate 
CYP3A activity. Appropriate medical judgment is required. Please contact the sponsor’s medical 
monitor with any queries.
Drugs Inducing or Inhibiting CYP3A Metabolism That Are Prohibited Concomitant 
Medications With Subasumstat
Strong CYP3A Inducers a
Strong CYP3A Inhibitors b
apalutamide
carbamazepine
enzalutamide
mitotane
phenytoin
rifampin
St John’s wort
boceprevir
cobicistat
danoprevir and ritonavir
elvitegravir and ritonavir
grapefruit juice
indinavir and ritonavir
itraconazole
ketoconazole
lopinavir and ritonavir
paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir)
posaconazole
ritonavir
saquinavir and ritonavir
telaprevir
tipranavir and ritonavir
telithromycin
troleandomycin
voriconazole
clarithromycin
idelalisib
nefazodone
nelfinavir
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Drugs Inducing or Inhibiting CYP3A Metabolism That Are Prohibited Concomitant 
Medications With Subasumstat
Moderate CYP3A Inducers a
Moderate CYP3A Inhibitors b
bosentan
efavirenz
etravirine
phenobarbital
primidone
aprepitant
ciprofloxacin
conivaptan
crizotinib
cyclosporine
diltiazem
dronedarone
erythromycin
fluconazole
fluvoxamine
imatinib
tofisopam
verapamil
CYP: cytochrome P450.
a Reference: 
fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-in
ducers#table3-3 (accessed 13 October 2021).
b Reference: 
fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-in
ducers#table3-2 (accessed 13 October 2021).
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Appendix F
Examples of Clinical Inhibitors of Pgp
Drugs listed below that are inhibitors of Pgp are prohibited as concomitant medications with
subasumstat. 
Transporter
Gene
Inhibitor
Pgp
ABCB1
amiodarone
carvedilol
clarithromycin
dronedarone 
itraconazole
lapatinib
lopinavir and ritonavir 
propafenone
quinidine
ranolazine
ritonavir
saquinavir and ritonavir
telaprevir
tipranavir and ritonavir
verapamil
Source: 
fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-in
ducers#table5-2 (accessed 13 October 2021).
Pgp: P-glycoprotein.
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Appendix G
Examples of QTc Interval Prolonging Agents
The use of the following drugs known to prolong QTc interval are prohibited.
Drug Class
Examples of Drugs that Increase the Risk of TdP, 
Name (Brand name)
Antiarrhythmic
amiodarone (Cordarone, Pacerone)
bepridil (Vascor)
disopyramide (Norpace)
dofetilide (Tikosyn)
flecainide (Tambocor)
ibutilide (Corvert)
procainamide (Pronestyl, Procan)
quinidine (Cardioquin, Quinaglute)
sotalol (Betapace)
Antibiotic
azithromycin (Zithromax)
clarithromycin (Biaxin)
erythromycin (Erythrocin, EES)
moxifloxacin (Avelox)
pentamidine (NebuPent, Pentam)
sparfloxacin (Zagam)
Anticancer
arsenic trioxide (Trisenox)
vandetanib (Caprelsaa)
Antidepressant
citalopram (Celexa)
Antiemetic
domperidone (Motilium)
droperidol (Inapsine)
Antihistamine
astemizole (Hismanal)
terfenadine (Seldane)
Antilipemic/hypercholesterolemia
probucol (Lorelco)
Antimalarial
chloroquine (Aralen)
halofantrine (Halfan)
Antipsychotic
chlorpromazine (Thorazine)
haloperidol (Haldol)
mesoridazine (Serentil)
pimozide (Orap)
thioridazine (Mellaril)
Gastrointestinal stimulant/heartburn
cisapride (Propulsid)
Opiate agonist
levomethadyl (Orlaam)
methadone (Dolophine, Methadose)
TdP: torsade de pointe.
For non-commercial use only

For non-commercial use only