Clinical trial NCT04623996
Conditions: Anemia in Myelodysplastic Syndromes
Keywords: Ph 1/2 Hematologic disease MDS Anemia IPSS-R low IPSS-R intermediate
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2020-12-28; Completion date: 2021-04-27
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate preliminary safety and efficacy of TP-0184 to treat anemia when administered to adult patients with Revised International Prognostic Scoring System (IPSS-R) low or intermediate risk MDS. The recommended Phase 2 dose (RP2D) will be determined by the maximum tolerated dose (MTD) or maximum administered dose (MAD) in the Phase 1 portion of the study.

Detailed description:

Arms: arm 1: TP-0184 is administered orally once a day
Interventions: intervention 1: TP-0184
Intervention descriptions: intervention 1: Oral dose

Protocol documents:
Prot_000.pdf: 
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TP-0184
BBI-TP-0184-102 
A PHASE 1/2, OPEN-LABEL CLINICAL STUDY TO 
EVALUATE SAFETY AND EFFICACY OF TP-0184 TO 
TREAT ANEMIA WHEN ADMINISTERED TO ADULT 
PATIENTS WITH IPSS-R LOW OR INTERMEDIATE 
RISK MYELODYSPLASTIC SYNDROMES  
Study Protocol Number:
BBI-TP-0184-102 
Study Medication Name:
TP-0184 
Developmental Phase: Phase 1/2 
Short Title: 
A Phase 1/2 Study of Oral TP-0184 to Treat 
Anemia in Adults with IPSS-R Low or 
Intermediate Risk MDS 
Indication: Anemia in Myelodysplastic Syndrome (MDS) 
Sponsor: 
Sumitomo Dainippon Pharma Oncology, Inc.
640 Memorial Drive 
Cambridge, MA 02139 
Amendment 3.0 Date
27 May 2021
Confidentiality Statement
The information contained in this document is confidential and the proprietary property of 
Sumitomo Dainippon Pharma Oncology, Inc. Any unauthorized use or disclosure of such 
information without the prior written authorization of Sumitomo Dainippon Pharma Oncology, 
Inc. is prohibited. 




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INVESTIGATOR’S AGREEMENT
I have received and read the Investigator’s Brochure for TP-0184. I have read the protocol for 
Study BBI-TP-0184-102 and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
Printed Name of Investigator 
Signature of Investigator 
Date
























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considered successful. Efficacy as assessed by response rate will be monitored using the Bayesian 
posterior probability to optimize the enrollment with Bayesian stopping rules.


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3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1.
TITLE PAGE................................................................................................................1
SIGNATURE PAGE .......................................................................................................................2
INVESTIGATOR’S AGREEMENT...............................................................................................3
CONTACT INFORMATION ..........................................................................................................4
2.
SYNOPSIS ...................................................................................................................5
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................23
5.
INTRODUCTION ......................................................................................................25
5.1.
Disease Background ...................................................................................................25
5.2.
Rationale for Study .....................................................................................................26
5.3.
Summary of Risks and Benefits in Humans ...............................................................27
5.4.
Investigational Product Background ...........................................................................27
5.4.1. 
Nonclinical Studies .....................................................................................................27
5.4.2. 
Clinical Studies ...........................................................................................................28
5.4.2.1. 
Study TP-0184-101 (Solid Tumor) .............................................................................28
5.4.2.2. 
Study BBI-TP-0184-102 (MDS) ................................................................................28
6.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................30
6.1.
Primary Objectives and Endpoints .............................................................................30
6.2.
Secondary Objectives and Endpoints .........................................................................30
6.3.
Exploratory Objectives and Endpoints .......................................................................33
7.
INVESTIGATIONAL PLAN .....................................................................................35
7.1.
Overall Study Design ..................................................................................................35
7.1.1. 
Phase 1 – Dose Escalation ..........................................................................................35
7.1.2. 
Rationale for Starting Dose ........................................................................................35
7.1.3. 
Phase 2 – Dose Expansion ..........................................................................................36
7.2.
Planned Number of Patients .......................................................................................36
7.2.1. 
Patient Replacement or Addition ................................................................................36
7.3.
Treatment Assignment ................................................................................................37
7.3.1. 
Calculation of Dose ....................................................................................................37


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7.3.2. 
Description of Dose Escalation Study........................................................................37
7.3.1.
Phase 1 Dose Escalation .............................................................................................37
7.3.2.
Determination of RP2D..............................................................................................38
7.3.3. 
Safety Review Committee..........................................................................................38
7.3.4. 
Phase 1 Study Stopping Rules....................................................................................38
7.3.5. 
Phase 1 Individual Patient Stopping Rules.................................................................39
7.4.
Dose Adjustment Criteria ...........................................................................................39
7.4.1.
Management of Nonhematologic and Hematologic Toxicities..................................40
7.4.2. 
Dose-Limiting Toxicities ............................................................................................41
7.5.
Procedures...................................................................................................................42
8.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................47
8.1.
Inclusion Criteria ........................................................................................................47
8.2.
Exclusion Criteria .......................................................................................................49
8.3.
Withdrawal Criteria ....................................................................................................50
8.3.1. 
Reasons for Treatment Discontinuation .....................................................................51
8.3.2. 
Follow-up for Patients Discontinued from Treatment ................................................51
8.3.3. 
Lost to Follow-up .......................................................................................................51
9.
TREATMENT OF PATIENTS..................................................................................52
9.1.
Description of TP-0184 ..............................................................................................52
9.2.
Concomitant Medications...........................................................................................52
9.2.1. 
Prohibited Medications and Therapies .......................................................................52
9.3.
Treatment Compliance................................................................................................53
9.4.
Randomization............................................................................................................53
9.5.
Blinding ......................................................................................................................53
10.
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................54
10.1.
Study Drug ..................................................................................................................54
10.2.
Study Drug Packaging and Labeling ..........................................................................54
10.3.
Study Drug Storage.....................................................................................................54
10.4.
Study Drug Dispensing and/or Administration ..........................................................54
10.5.
Study Drug Accountability .........................................................................................54
10.6.
Study Drug Handling and Disposal............................................................................55
11.
PHARMACOKINETIC, PHARMACODYNAMIC, AND BIOMARKER 
ASSESSMENTS.........................................................................................................56


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11.1.
Pharmacokinetic Assessments....................................................................................56
11.2.
Assessment of Pharmacodynamics and Biomarkers ..................................................57
12.
ASSESSMENTS OF SAFETY AND EFFICACY ....................................................58
12.1.
Assessment of Safety ..................................................................................................58
12.1.1. 
Safety Parameters .......................................................................................................58
12.1.2. 
Assessment for Study Eligibility ................................................................................58
12.1.3.
Informed Consent .......................................................................................................58
12.1.1.
MDS Disease Confirmation........................................................................................58
12.1.2. 
Prior Transfusion History ...........................................................................................59
12.1.3. 
Prior Concomitant Medications and Procedures ........................................................59
12.1.4. 
Pregnancy Testing ......................................................................................................59
12.1.5. 
On-treatment Transfusions .........................................................................................59
12.1.5.1. 
Demographics and Medical/MDS Disease History....................................................59
12.1.5.2. 
Vital Signs ..................................................................................................................59
12.1.5.3. 
Physical Examinations................................................................................................60
12.1.5.4. 
Electrocardiogram.......................................................................................................60
12.1.5.5. 
Clinical Safety Laboratory Assessments ....................................................................60
12.1.6. 
Adverse Events and Serious Adverse Events .............................................................62
12.1.6.1. 
Definitions ..................................................................................................................62
12.1.6.2. 
Procedures for Eliciting, Recording, and Reporting Adverse Events ........................63
12.1.6.3. 
Specific Instructions for Recording Adverse Events on the eCRF.............................65
12.1.6.4. 
Reporting of Expedited Safety Observations by the Investigator Including 
Serious Adverse Events ..............................................................................................67
12.2.
Assessment of Efficacy...............................................................................................69
12.2.1. 
Assessment of MDS Disease......................................................................................69
12.2.2. 
Survival .......................................................................................................................70
12.2.2.1. 
ECOG Performance Status .........................................................................................70
12.2.2.2. 
ECHO/MUGA............................................................................................................70
12.2.2.3. 
MRI Imaging ..............................................................................................................70
12.2.2.4. 
New York Heart Association Classification...............................................................70
12.2.3. 
Patient Reported Outcomes ........................................................................................70
13.
STATISTICS ..............................................................................................................71
13.1.
Statistical Methods......................................................................................................71


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13.1.1. 
Determination of Sample Size....................................................................................71
13.1.2.
Phase 1........................................................................................................................71
13.1.3.
Phase 2........................................................................................................................71
13.1.4. 
Randomization and Stratification ...............................................................................71
13.1.5. 
Analysis Datasets ........................................................................................................71
13.1.6. 
Handling of Missing Data...........................................................................................72
13.1.7.
Demographic and Baseline Characteristics ................................................................72
13.1.8.
Data Analyses .............................................................................................................72
13.1.8.1. 
Phase 1 ........................................................................................................................72
13.1.8.2. 
Determination of Recommended Dose.......................................................................72
13.1.8.3. 
Phase 1 Study Stopping Rule......................................................................................73
13.1.8.4. 
Phase 1 DLT Analysis ................................................................................................73
13.1.9. 
Phase 2 ........................................................................................................................73
13.1.9.1. 
Efficacy Analysis ........................................................................................................73
13.1.9.2. 
Safety Analysis ...........................................................................................................76
13.1.9.3. 
Pharmacokinetics and Biomarkers .............................................................................77
13.1.9.4. 
Patient-reported Outcomes .........................................................................................77
14.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................78
14.1.
Study Monitoring ........................................................................................................78
14.2.
Audits and Inspections................................................................................................78
14.3.
Institutional Review Board/Independent Ethics Committee ......................................79
15.
.........................................80
16.
ETHICS ......................................................................................................................81
16.1.
Ethics Review.............................................................................................................81
16.2.
Ethical Conduct of the Study ......................................................................................81
16.3.
Informed Consent .......................................................................................................81
17.
DATA HANDLING AND RECORDKEEPING.......................................................83
17.1.
Data Protection ...........................................................................................................83
17.2.
Inspection of Records .................................................................................................83
17.3.
Retention of Records ..................................................................................................83
18.
PUBLICATION POLICY ..........................................................................................84
19.
LIST OF REFERENCES............................................................................................85
20.
APPENDICES ............................................................................................................87


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APPENDIX 1. CONSIDERATION OF RESPONSE FOR COMPOSITE ENDPOINT...........88
APPENDIX 2.
BLRM STATISTICAL METHODS..................................................................89
20.1.1.
Dose Escalation Method.............................................................................................89
20.1.1.1. 
Planned Dose Escalation Levels .................................................................................89
20.1.1.2. 
Prior Specifications.....................................................................................................90
20.1.1.3. 
Dose Recommended by the BLRM Method ..............................................................90
APPENDIX 3.
REVISED INTERNATIONAL PROGNOSTIC SCORING SYSTEM 
(IPSS-R)......................................................................................................................99
APPENDIX 4. GUIDELINES RELATED TO MDS CLASSIFICATION..............................101
APPENDIX 5. CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION .............................................................................103
APPENDIX 6. INTERNATIONAL WORKING GROUP RESPONSE CRITERIA 
FOR MYELODYSPLASTIC SYNDROMES, 2006 ...............................................105
APPENDIX 7. ECOG PERFORMANCE STATUS.................................................................107
APPENDIX 8. DRUG INTERACTIONS – CYP3A4 INHIBITORS AND INDUCERS........108
APPENDIX 9. MEDICATIONS WITH KNOWN OR POSSIBLE RISK OF 
.........................111
APPENDIX 10. BRIEF FATIGUE INVENTORY ..................................................................113
APPENDIX 11. NEW YORK HEART ASSOCIATION CLASSIFICATION SCALE .........114


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LIST OF TABLES
Table 1: 
Contact Information......................................................................................................4
Table 2:
Abbreviations and Definitions....................................................................................23
Table 3: 
Planned Dose Escalation Levels .................................................................................37
Table 4
Guide to TP-0184 Dose Adjustments Due to TP-0184 Related 
Non-Hematologic AE .................................................................................................40
Table 5
Guide to TP-0184 Dose Adjustments Due to TP-0184 Related Hematologic 
AE ...............................................................................................................................40
Table 6:
Schedule of Assessments............................................................................................43
Table 7 
Phase 1 PK Sampling Schema with ECG...................................................................56
Table 8
Phase 2 PK Sampling Schema....................................................................................57
Table 9: 
Assessments of Clinical Safety Laboratory Parameters .............................................61
Table 10 
Planned Dose Escalation Levels .................................................................................89
Table 11 
Prior Parameters for Bivariate Normal Distribution of Model Parameters ................90
Table 12 
Prior Distribution Summaries Derived from Priors in Table 11 .................................90
Table13  
True Underlying DLT Probabilities............................................................................92
Table 14: Summary Metrics of the Simulations Performed .......................................................93
Table 15: Hypothetical Dose Allocation Scenarios in Early Cohorts.........................................95


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LIST OF FIGURES
Figure 1: 
Phase 1 and 2 Study Design in Patients with IPSS-R Low or Intermediate 
Risk MDS ...................................................................................................................35


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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Table 2: 
Abbreviations and Definitions 
AE 
adverse event
AESI 
adverse event of special interest 
AML
acute myeloid leukemia
BFI
Brief Fatigue Inventory
BLRM 
Bayesian logistic regression model 
CHF 
congestive heart failure
DLT
dose-limiting toxicities
EAS
efficacy evaluable analysis set
ECG 
electrocardiography 
ECHO 
echocardiography
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EPO
erythropoietin 
ESA
erythropoiesis stimulating agents 
EWOC
escalation with overdose control
FDA 
Food and Drug Administration
GCP 
Good Clinical Practice
GLP
Good Laboratory Practice
HNSTD 
Highest Non-Severely Toxic Dose
ICH 
International Conference on Harmonization
IEC
Independent Ethics Committee 
IPSS-R 
Revised International Prognostic Scoring System 
IRB
Institutional Review Board 
K-M
Kaplan-Meier
LVEF
left ventricular ejection fraction
MAD
maximum administered dose
MDS 
myelodysplastic syndromes
MRI
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 
NYHA
New York Heart Association 
PBMC 
peripheral blood mononuclear cell 
PI
Principal Investigator 
PK
pharmacokinetic 
PTT 
partial thromboplastin time 
RP2D 
Recommended Phase 2 Dose 
SAE
serious adverse event




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5.
INTRODUCTION
5.1.
Disease Background
Myelodysplastic disease syndromes (MDS) is composed of a heterogeneous group of 
hematopoietic stem cell disorders and is characterized by dysplasia in 1 to 3 of the bone marrow 
cell lineages, either myeloid, megakaryocytic and/or erythroid lineages. The abnormal cells seen 
in MDS represent a malignant hematopoietic clone, which represses the remaining normal 
hematopoietic cells in the bone marrow. Patients with MDS have one or more significant 
peripheral blood cytopenias (anemia, leukopenia and/or thrombocytopenia).  
The overall incidence of MDS in the general population is estimated to be 3 to 4 cases per 
100,000 persons per year. Greater than 85% of these patients are older than 60 years at the time 
of diagnosis. It is also generally assumed that the incidence of MDS is underestimated due to the 
complexity of diagnosis. Indolent forms of MDS are often not clinically recognized or not 
evaluated due to patient comorbid conditions. In addition, a number of other disorders, including 
nutritional deficiencies, infections or medications, may cause transient cytopenias, without clonal 
aberrations. Bone marrow aspiration and biopsy including conventional cytogenetics is essential 
for diagnosis. Cytogenetic abnormalities are found in approximately 50% of MDS patients. 
Evaluation of peripheral blood or bone marrow for MDS-associated gene mutations may 
establish the presence of clonal hematopoiesis and help exclude benign causes of cytopenias, 
however do not in isolation establish a diagnosis of MDS. 
The spectrum of MDS ranges from indolent disease in the low to intermediate risk category to 
severe bone marrow failure in those with high-risk disease resulting in life-threatening 
complications. Progression to acute myeloid leukemia (AML) occurs in about 30% of patients. 
The diagnosis is made by review of bone marrow aspirate revealing dysplastic marrow cellular 
changes that may include elevated blast counts and cytogenetic abnormalities. About 30% of 
patients diagnosed with low risk MDS progress to AML. 
Anemia is common in patients with MDS reflecting ineffective erythropoiesis. Proinflammatory 
cytokines have long been implicated in the death of bone marrow progenitors in MDS (Sallman, 
Blood 2019; 133(10):1039-1048). Interleukin-6 and other cytokines of chronic inflammation 
lead to iron-restricted hematopoiesis (Hematologica 2020; 105(2): 1-13). Treatment options for 
anemia in MDS patients are limited (e.g., the administration of erythropoietic agents [EPO]) and 
are only beneficial to a sub-group of patients. As a consequence, ~ 70% of patients with low risk 
MDS require RBC transfusions and subsequently become transfusion dependent.   
Clinical iron overload starts to develop in MDS patients before they become transfusion 
dependent because their ineffective erythropoiesis suppresses hepcidin production in the liver 
leading to unrestrained intestinal iron uptake. (Santini V PLoS ONE: 2011;6(8). However, the 
most important cause of iron overload in MDS is chronic transfusion therapy. While transfusion 
dependency by itself is a negative prognostic factor reflecting poor bone marrow function, the 
ensuing transfusion and dose dependent iron overload have an additional negative impact on the 
survival of patients with low to intermediate risk MDS due to the complications of bone marrow 
failure or acute leukemia (Malcovati L 2011).  
The Myelodysplastic Syndromes (MDS) Event Free Survival With Iron Chelation Therapy trial 
(TELESTO) was the first placebo-controlled study evaluating outcomes using iron chelation 


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therapy in low risk MDS. Results presented in 2018 showed a 36.4% risk reduction in event-free 
survival in chelated patients, fewer cardiac and liver-related events and fewer progression events 
to AML compared with placebo. (Angelucci et al, Blood (2018); 132 Supplement 1: 234.)
There are 3 approved chelating agents for the treatment of iron overload (deferoxamine, 
deferasirox, and deferiprone). However, these agents have limited efficacy and are associated 
with adverse effects.
The management of anemia in MDS remains a challenging issue for hematologists/oncologists.  
This population is primarily elderly with significant co-morbidities making them relatively 
intolerant to therapy. Few therapeutic products have been approved to treat lower risk MDS.  
Revlimid® (lenalidomide) is approved by the United States (US) Food and Drug Administration 
(FDA), but only in subjects with transfusion dependent anemia due to low, or intermediate risk 
MDS and with a 5q deletion abnormality. The approved label for Revlimid bears a black box 
warning due to significant risks associated with its treatment including thrombocytopenia and 
neutropenia, embryofetal toxicity, and incidences of renal and hepatic toxicities (USPI 
Revlimid). Reblozyl® (luspatercept) was recently approved for the treatment of anemia in adult 
patients with very low- to intermediate MDS with ring sideroblasts (MDS-RS) or with 
myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis 
(MDS/MPN-RS-T) who have failed an erythropoiesis stimulating agent (ESA) and require at 
least 2 red blood cell units over 8 weeks. Options for treating anemia in lower risk MDS remains 
an unmet need. 
5.2. 
Rationale for Study 
The ineffective hematopoiesis present in MDS has long been considered to be related to 
inflammatory cytokines, including the TGF-
(Herbertz 2010). The natural inhibitor of the TGF-
suppressed in MDS progenitor cells due to increased miR21 expression, which in turn 
upregulates the TGF-
(Bhagat 2013). This leads to increased expression of myelosuppressive cytokines and decreased 
burst forming unit-erythroid (BFU-E) and colony forming unit- granulocyte, erythrocyte, 
monocyte, megakaryocyte (CFU-GEMM). These same cytokines are immunosuppressive and 
may also contribute to the fatigue seen in MDS patients. Blockade of the TGF-
pathway with an TGF-
-5 inhibitor may improve the ineffective erythropoiesis seen in 
MDS and offer therapeutic benefit for the treatment of MDS. 
TP-0184 is a small molecule dual inhibitor against ALK-2 and ALK-5, affecting both 
ALK-2-SMAD1/5/8 and ALK5-SMAD2/3 signaling pathways, respectively. In pre-clinical 
studies TP-0184 was shown to inhibit downstream signaling from ALK-2 kinase (by reducing 
phospho SMAD1/5 levels) in cancer cells treated with the ALK-2 ligand BMP2, and to block 
expression of hepcidin, an important regulator of iron levels, and thus erythropoiesis. Hepcidin 
was found to be a responsive biomarker to ALK-2 inhibition in cancer cell culture models. 
Hepcidin was also found to be a pharmacodynamic biomarker in in vivo studies with liver tissue 
and blood in the mouse model with acute inflammation or bacteria-induced anemia. Due to the 
lack of an appropriate in vivo model for MDS, the role of hepcidin in the anemia due to MDS is 
unknown.  However, it may or may not play a role as a part of the ALK-2 signaling pathway 
effecting the anemia due to MDS. TP-0184 was also determined to be a potent inhibitor of 


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-5 ex-vivo studies. This was demonstrated by TP-0184 inhibiting downstream 
signaling from ALK-5 kinase by reducing SMAD2/3 phosphorylation in cancer cell lines treated 
with the ALK-5 ligand
differentiation in MDS (Zhou L 2008). TP-0184 was found to inhibit ALK-5 pathways and 
SMAD2/3 phosphorylation in reporter assays at sub-micromolar to single digit micromolar 
concentrations. Activity of TP-0184 with in-vitro cellular models was similar to other known 
ALK-5 inhibitors. Though in vivo studies evaluating ALK-5 inhibition by TP-0184 have not 
been conducted to date, erythroid colony counts in the bone marrow and erythropoietic markers 
such as hemoglobin were found to be responsive biomarkers to ALK-5 inhibition in a transgenic 
mouse model for MDS by other ALK-5 inhibitors (eg, galunisertib) (Zhou L 2014). The in vitro 
and in vivo pharmacology data and the inhibitory activity of TP-0184 towards both the ALK-5 
and ALK-2 signaling pathways supports the proposed evaluation of treatment of anemia in MDS 
patients with TP-0184.
To conclude, the inhibition of both ALK-2 and ALK-5 pathways by TP-0184 presents a potential 
option for the treatment of anemia due to MDS. Treatment with TP-0184 may result in the 
reduction of ineffective erythropoiesis and offer therapeutic benefits of improving anemia and 
lowering the frequency of transfusions. This, in turn, will lower the risk of iron overload. 
5.3. 
Summary of Risks and Benefits in Humans 
A full summary of risks and benefits in humans is included in Section 6, Data and Guidance for 
Investigators, of the Investigator Brochure. 
5.4. 
Investigational Product Background 
5.4.1. 
Nonclinical Studies 
Twenty-eight-day repeat-dose Good Laboratory Practice (GLP) toxicology and toxicokinetic 
studies were conducted in rats and dogs.  
Rats were given TP-0184 orally, once-daily at 0 (vehicle), 20, 50, and 150 mg/kg/day (human 
equivalents of 120, 300 and 900 mg/m2/day, respectively), and following the last dose a subset 
of rats was held for a 14-day post-treatment recovery period. Rats given 150 mg/kg/day lost 
weight (or gained less weight than controls). At the end of the dosing period, rats given 
150 mg/kg/day had slightly higher ALT and AST compared with controls. At necropsy, liver 
weights were higher than controls for rats given 50 or 150 mg/kg/day. All TP-0184-treated 
groups exhibited mild, pan-lobular hepatocellular hypertrophy as well as lymph node sinus 
erythrocytosis; the incidence was dose-related. At the end of the recovery period, chemistry 
parameters as well as liver and lymph node morphology were normal. The Severely Toxic Dose 
in 10% of the animals (STD10) was determined to be greater than 150 mg/kg/day.
Dogs were given TP-0184 orally, once-daily at 0 (empty capsules), 2, 5, and 10 mg/kg/day 
(human equivalents of 40, 100, and 200 mg/m2/day), and following the last dose a subset of dogs 
was held for a 14-day post-treatment recovery period. One dog given 10 mg/kg/day was 
euthanized because of poor condition near the end of the study: it had pronounced clinical signs 
(emesis, mucoid/ soft feces, diarrhea), lost substantial weight and consumed less food, and did 
not respond to veterinary intervention. Emesis occurred in all treatment groups and incidence 
was dose-related; at 5 or 10 mg/kg/day, weight loss as well as diarrhea/ soft feces also occurred 


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along with decreased food consumption. During the recovery period dogs did not exhibit 
treatment-related clinical signs, and weight gain and food consumption were similar among 
control and treated groups. There were no treatment-related gross or microscopic pathologic 
findings. The Highest Non-Severely Toxic Dose (HNSTD) was determined to be greater than 
5 mg/kg/day. 
For additional details regarding these studies, please refer to the TP-0184 Investigator Brochure. 
5.4.2. 
Clinical Studies 
5.4.2.1. 
Study TP-0184-101 (Solid Tumor) 
The first in human clinical study of TP-0184 (Tolero Study No. TP-0184-101) is ongoing in 
adult patients with advanced/refractory solid tumors. Since the study is still ongoing, a complete 
evaluation of the safety of this compound given in escalating doses has not yet been conducted. 
At the start of this study, a Phase 1 first-in-human study exploring escalating dose levels of 
TP-0184 in patients with advanced solid tumors had already been initiated with a starting dose of 
30 
of 60 mg once weekly for 4 weeks (Amendment 2, 12 Sep 2019). The most common side effects, 
regardless of causality, were gastrointestinal (nausea, vomiting) and fatigue. There were no 
clinically significant trends of hepatic or cardiac toxicity and the safety profile was considered 
favorable. Preliminary PK analysis suggested dose-related increases in systemic exposure with 
increasing dose and longer elimination t½ than projected from preclinical PK data. Please refer 
to the TP-0184 Investigational Brochure for additional information.   
Changes in cardiac valve status have been documented in in vivo pre-clinical studies (not 
human) with small molecule kinase inhibitors in the same therapeutic class as TP-0184. 
Following discussion with the US FDA, cardiac toxicity and hepatotoxicity were identified as 
Adverse Events of Special Interest (AESIs) in Study TP-0184-101. While there have been some 
changes in cardiac markers (BNP, NT-proBNP) observed on study, the changes have been either 
Grade 1 or Grade 2 in severity, and none have been associated with clinical symptoms or notable 
changes in ejection fraction. Thus far, no clinically significant trends of hepatic or cardiac 
toxicity have been reported. 
5.4.2.2. 
Study BBI-TP-0184-102 (MDS) 
Patients with MDS related anemia frequently require chronic RBC transfusions, which may 
cause iron overload. The potential for deposition of iron in the heart and liver may lead to organ 
dysfunction. Iron overload has an additional dose dependent negative impact on the survival of 
patients with lower risk MDS. Treatment with an ALK-2/ALK-5 inhibitor could result in 
improvement of anemia, resulting in fewer transfusions and may thereby reduce the risk of iron 
overload. The risk of potential iron deposition and its sequelae on the heart and liver is reduced 
by intensive cardiac and hepatic monitoring as a proactive strategy to avoid undue toxicity.   
Study BBI-TP-0184-102 contains several measures to ensure patient safety, such as defined 
patient selection criteria for participation, judicious and gradual dose escalation rules, 
appropriate safety surveillance measures, and comprehensive dose modification guidelines to be 
implemented in case of treatment toxicity. In addition to physical examinations and routine 
laboratory testing, the medical assessments used in this study to evaluate safety include 


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co
cardiac MRIs for iron quantification, echocardiography/MUGA scans, laboratory markers for 
heart failure (BNP, NT-proBNP), and safety ECGs. Based on the mechanism of action of TP-
0184, cardiac toxicity and hepatotoxicity events will be captured as AESIs in this study. 
Liver monitoring includes liver function testing and hepatic MRIs for iron quantification. Iron 
panels (including ferritin) are performed frequently throughout the study per protocol. 
Blood tests will also be used to explore molecular markers associated with the biology of MDS 
and the mechanism of action of TP-0184. These biomarkers will not be used to make therapeutic 
decisions on dosing or regimen management; they are only conducted for experimental purposes, 
to gain a better understanding of the biology of the treatment at the cellular and molecular levels, 
and to evidence pharmacodynamic action.   
The protocol minimizes currently known risks of TP-0184 by frequent monitoring for early 
detection of AEs. Given the anticipated benefits of TP-0184, the safety profile of TP-0184 in 
patients treated in this study is considered favorable. Results of this study could contribute to a 
better understanding, treatment, evaluation, and management of future patients affected by MDS 
and anemia of cancer.  
More detailed information about the known and expected benefits and risks may be found in the 
Investigator’s Brochure. 












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7.
INVESTIGATIONAL PLAN
7.1.
Overall Study Design
This is a Phase 1/2, open-label clinical study to evaluate preliminary safety and efficacy of 
TP-0184 to treat anemia when administered to adult patients with IPSS-R low or intermediate 
risk MDS. The recommended Phase 2 dose (RP2D) will be determined by the maximum 
tolerated dose (MTD) or maximum administered dose (MAD) in the Phase 1 portion of the 
study. The study structure is summarized in Figure 1. 
Figure 1: 
Phase 1 and 2 Study Design in Patients with IPSS-R Low or Intermediate 
Risk MDS
 
7.1.1. 
Phase 1 – Dose Escalation 
Multiple dose levels of TP-0184, with approximately 1 to 6 patients at each level will be 
evaluated. There must be at least 3 DLT evaluable patients at a specific dose level if there is a 
DLT observed in that level. The first dose cohort will start at 20 mg/day every day. Patients will 
receive their first dose of TP-0184 starting on Cycle 1 Day 1. Dose escalation is planned to 
proceed with patients receiving each provisional dose level of 40 mg, 60 mg, 90 mg, 120 mg, 
160 mg, 210 mg, and 270 mg. Additional dose increments of up to 25% from one dose cohort to 
the next may occur. In order to determine the recommended Phase 2 dose, dose escalation may 
continue until one of the following occurs:  
1. An MTD is determined. 
2. An MAD is determined based on the totality of safety data and medical considerations by 
the SRC and sponsor. 
7.1.2. 
Rationale for Starting Dose 
The initial dose in this study is based on a thorough review of GLP toxicology studies in both rat 
and dog models, as well as review of the initial human data from the solid tumor study. 
In these non-clinical studies, TP-0184 was administered PO daily for 28 days to rats and dogs in 
GLP toxicology studies. The severely toxic dose in 10% of rats (STD10) was greater than 


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150 mg/kg or 900 mg/m2 body surface area (BSA), and in the dogs the HNSTD was 5 mg/kg or 
100 mg/m2 BSA. Given these data, the dog was considered the more sensitive species and per 
FDA and ICH guidance, the recommended safety approach of taking 1/6th of the HNSTD in 
dogs (16.7 mg/m2) was calculated to determine an equivalent starting dose in humans of 
30 mg/day.
At the start of this study, a Phase 1 first-in-human study exploring escalating dose levels of 
TP-0184 in patients with advanced solid tumors had already been initiated with a starting dose of 
30 
of 60 mg once weekly for 4 weeks (Amendment 2, 12 Sep 2019). The most common side effects, 
regardless of causality, were gastrointestinal (nausea, vomiting) and fatigue. There were no 
clinically significant trends of hepatic or cardiac toxicity and the safety profile was considered 
favorable. Preliminary PK analysis suggested dose-related increases in systemic exposure with 
increasing dose and longer elimination t½ than projected from preclinical PK data. Refer to the 
TP-0184 Investigational Brochure for additional information. 
For the current study, a daily dosing regimen of TP-0184 daily for 28 days, without a break, is 
proposed. This is driven by underlying pharmacological considerations of the target which 
suggests continuous drug coverage/inhibition to achieve optimal activity/efficacy. However, 
given the longer elimination t½ observed in an ongoing first in man solid tumor study 
(TP-0184-101 study), a lower starting dose of 20 mg/day is proposed, to allow for continuous 
dosing with a 2.25-fold safety factor built in between the proposed starting dose and the 
60 mg/day dose in TP-0184-101 study in which there was acceptable tolerability. Additionally, 
cardiac and other safety monitoring is included in the protocol for risk mitigation and to ensure 
ultimate safety of the patients (Section 12.1.5.4.2).
In summary, both the preclinical safety data and the ongoing clinical experiences in the 
TP-0184-101 study support the proposed continuous once-daily dosing regimen at 20 mg/day for 
this study. 
7.1.3. 
Phase 2 – Dose Expansion 
Phase 2 will determine the preliminary efficacy of TP-0184 in an expansion phase of up to 
60 patients.  
Preliminary efficacy as assessed by response rate will be monitored using the Bayesian posterior 
probability to optimize the enrollment with Bayesian stopping rules. 
7.2. 
Planned Number of Patients 
Approximately 30 patients are planned to be enrolled in Phase 1, and approximately 
10-60 patients in Phase 2. 
7.2.1. 
Patient Replacement or Addition 
Patients who do not meet either of the criteria for the DLT Analysis Set, as described in 
Section 13.1.5, may be replaced as needed to permit dose escalation. 


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7.3.
Treatment Assignment
7.3.1. 
Calculation of Dose 
In Phase 1, all patients will receive the dose of TP-0184 according to the cohort in which they 
are enrolled (Table 3).  
Table 3: 
Planned Dose Escalation Levels
Dose Level 
Dose (Daily Schedule) 
-1
10 mg
1
20 mg
2
40 mg 
3
60 mg 
4
90 mg 
5
120 mg
6
160 mg 
7
210 mg 
8
270 mg 
Note: An intermediate dose level between the planned dose levels may be explored. In addition, 
based on a safety evaluation during the escalation phase, additional dose schedules than those 
outlined in the table may be explored after discussion and concurrence with SRC members and 
SDP Oncology clinical team.  
Intra-patient dose escalation is not permitted in this protocol.
In Phase 1 and 2, patients will be treated for 24 weeks (6 cycles) and based on assessment of 
response, continue to receive TP-0184 in the absence of MDS disease progression or until loss of 
hematological response or unacceptable toxicity. 
Note: Loss of hematological response (lack of response or refractory to further treatment) will 
follow the guidelines for progression/relapse after hematological improvement by IWG 
Response Criteria for MDS 2006 (Appendix 6). 
7.3.2. 
Description of Dose Escalation Study 
7.3.1. 
Phase 1 Dose Escalation 
Dose escalation will be performed using a design based on a 2-parameter BLRM 
(Neuenschwander 2008). The BLRM method will be applied along with the escalation with 
overdose control (EWOC) principle to control the risk of exposing patients to toxic doses (Babb 
2013). Based on this principle, a dose level will be considered safe if the probability of excessive 
toxicity (ie, the probability of a DLT rate over 33% is no greater than 25%). The MTD with 
estimated posterior probability of a DLT within target toxicity interval (16%, 33%] among the 
admissible doses fulfilling EWOC is determined by BLRM. The MTD is estimated based on 
observed DLTs.
The use of Bayesian adaptive models for Phase 1 studies has been advocated by the European 
Medicines Agency’s guideline on clinical trials in small populations (European Medicines 
Agency, 2016). 


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The actual dose level to be tested in the next cohort will be chosen based on the above risk 
assessment, using the BLRM method. The dose recommended by the BLRM method will be 
treated as guidance and will be integrated with a clinical assessment of the safety adverse event 
information and review of clinical data, including above safety and PK data. Intermediate doses 
between planned dose levels may be SDP Oncology explored based on safety consideration after 
discussion and concurrence with SRC members and SDP Oncology clinical team. The BLRM 
method estimates the MTD by updating the probability of observing a DLT for each dose level in 
the study as DLT information becomes available. An additional cohort with a different dose 
schedule may be considered based on clinical judgment supported by medical observations. 
Procedures for close monitoring of the DLT period and entire study have been established 
(Section 12.1, Section 14.1). In addition, an SRC will conduct scheduled meetings and will 
provide safety oversight of the patients, determine DLTs, and guide escalation and dose 
decisions (Section 7.3.3). 
7.3.2. 
Determination of RP2D 
The RP2D is determined based upon safety, PK, pharmacodynamic, efficacy and other available 
data. Determination of the RP2D will be performed in consultation with the SRC members based 
on safety and other data available at the time of the RP2D decision. In the Phase 2 portion of the 
study, the RP2D, as determined in Phase 1, will be used. 
7.3.3. 
Safety Review Committee
The SRC will consist of the Investigators, the Safety Lead, the Statistician, and the Medical 
Monitor, and a cardiologist consultant. The SRC will conduct scheduled meetings and will 
provide safety oversight of the patients, determine DLTs, and guide escalation and dose 
decisions. The SRC will meet after all patients in the newly escalated cohort have completed the 
DLT evaluation period and before proceeding with the next cohort at a higher dose level.   
The SRC will review and assess all available safety data from each cohort, together with 
available PK and pharmacodynamic data, to determine the escalation to the next dose level 
cohort. The SRC will also conduct unscheduled meetings on an as needed basis to review other 
information that may be relevant to the conduct of this study or safety of the patients. 
7.3.4. 
Phase 1 Study Stopping Rules
Dose escalation can be stopped earlier by a joint decision from the SDP Oncology clinical team 
and the Investigators during a SRC meeting, by considering the model estimations and a global 
assessment of the safety, PK, pharmacodynamics, and preliminary activity data.  
The following safety event will trigger a temporary suspension of patient enrollment to study 
treatment:  
 The posterior probability of target toxicity at each dose level exceeds 50% and is the 
highest among potential dose levels.  
Based on the safety review by the SRC members and the SDP Oncology clinical team, it will be 
determined whether the study may continue (with or without a protocol amendment) or if it must 
be terminated.  


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7.3.5. 
Phase 1 Individual Patient Stopping Rules
The following safety events will trigger individual patient treatment discontinuation:
 Any DLT observed during Phase 1, within 28 days after starting treatment with 
TP-0184 as described in Section 7.4
 Any related AEs that lead to treatment discontinuation per Section 7.4 
 Evidence of disease progression based on IWG Response Criteria for MDS 2006 
7.4. 
Dose Adjustment Criteria 
Dose adjustments may be permitted for patients who experience toxicities. These toxicities will 
be discussed by the Investigators and Medical Monitor to determine if it would be in the best 
interest of the patient to continue to receive a reduced dose of TP-0184. Dose adjustments due to 
study drug related non-hematologic or hematologic AE severity are described in Table 4 and 
Table 5, respectively.   
Decisions to reinstate dosing following a toxicity for which drug was held will be determined by 
the Investigator and Medical Monitor. In patients who receive subsequent and/or multiple 
treatment cycles, the TP-0184 dose may be reduced by one dose level based on the observed AE 
that occurred during the preceding cycle.
If further significant AEs occur during one or more cycles at the new reduced dose level, an 
additional dose reduction may occur (this allows for two dose reductions) EXCEPT in the first 
dose cohort where only one dose reduction (-1) will be permitted. If non-hematologic 
AE(s) > Grade 3 occur at the -1 dose the patient may be discontinued from the study pending 
discussion with the Investigator and Medical Monitor.  
In the Phase 1 portion of the study, no dose re-escalations will be allowed for any patient who 
had a previous dose reduction due to AEs. 
The Phase 2 treatment dosing schedule will be determined by the SRC and SDP Oncology 
clinical team based on the recommended Phase 2 treatment dose, and the MTD or MAD from 
Phase 1 safety data. 
Guidelines for dose adjustments of TP-0184 following Cycle 1 and resolution of a patient’s 
non-
Grade 1 and/or hematologic AE(s) to baseline CTCAE Grade are 
provided in Table 4 and Table 5, respectively. 




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Support with growth factors (eg, filgrastim) is not allowed except in the situation of 
life-threatening infections (eg, a Grade 4 sepsis with life-threatening infection with ongoing 
neutropenia). Whether the patient can continue TP-0184 dosing following treatment with growth 
factor support will be considered following discussion with the Medical Monitor.  
Both onset of new hematologic and non-
 Grade 4 and 
considered related to study drug treatments should be discussed with the Medical Monitor to 
determine whether a dose reduction (Table 4 and Table 5) or treatment discontinuation should 
occur. 
7.4.2. 
Dose-Limiting Toxicities 
A DLT is defined as any one of the following events or abnormal laboratory value not clearly 
unrelated to the study drug observed within 28 days of starting treatment with TP-0184: 
 Any death not clearly due to the underlying progression of disease (such as leukemic 
transformation) 
 
 Grade 3 non hematological toxicity except for Grade 3 of nausea, vomiting, 
diarrhea or clinically not significant lab abnormalities lasting 72 hours or less with 
adequate supportive care 
 New onset cardiac failure or worsening symptomatic cardiac failure based on NYHA 
Functional Classification (Appendix 11) 
 ECHO 
10% 
 Any Grade 4 neutropenia (absolute neutrophil count (ANC) not recovering to 
> 500/µL within 7 days in the absence of myelodysplasia or transformation to acute 
leukemia) 
To determine progression of MDS / transformation to AML, a bone marrow 
biopsy / aspiration and/or peripheral blood can be performed 
 Any Grade 3 thrombocytopenia associated with clinically significant bleeding or 
Grade 4 thrombocytopenia in the absence of myelodysplasia related marrow failure or 
transformation to acute leukemia 
-To determine progression of MDS / transformation to AML, a bone marrow biopsy / 
aspiration and/or peripheral blood can be performed 
 
Grade 3 other than defined above for ANC and 
platelets 
Note: 
 3 neutropenic and Grade 2 thrombocytopenic patients are included in the 
study, any new onset of Grade 4 neutropenia (< 500/uL neutrophils) in a patient with prior 
history of chronic neutropenia with infection or Grade 3 decrease in platelets (< 50K platelets) in 
patients with prior history of MDS-related thrombocytopenia with bleeding, will be evaluated by 
the SRC members and Medical Monitor in consideration as to whether a DLT has occurred. If 
determined that the Grade 3 or 4 hematologic AE is related only to the biology of MDS, no DLT 
will be declared.  
Patients who experience a DLT during Cycle 1 will be discontinued from the study. 


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7.5.
Procedures
The planned schedule of assessments, including all treatments and procedures and their timing, is 
presented in Table 6. Adherence to the study design requirements, including those specified in 
the Schedule of Assessments is essential and required for study conduct. 








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h MRI (iron quantification) of heart and liver is acquired locally and sent to Central Imaging (refer to the study-specific Imaging Manual), and will be performed 
at Screening and Cycle 3 only. MRI may also be performed ad hoc if signs/symptoms of iron overload are noted. For patients continuing on treatment beyond 
Cycle 6, MRI will be performed every 6 cycles for the duration of treatment and at the End of Treatment visit unless performed within 6 weeks of the visit. 
Heart MRI will be performed as secondary monitoring to ECHO/MUGA scans. 
i Pre-treatment counts averages at least 2 measurements, per IWG Criteria. 
j Pregnancy testing (urine or serum) is performed for women of childbearing potential only.  
k Iron panel (serum iron, transferrin, soluble transferrin [STR], and TIBC) is collected by local laboratories and sent to the central laboratory. Ferritin will be 
used as a safety parameter and analyzed by local laboratories and the other iron metabolism parameters will be exploratory. Samples will be collected at 
pre-dose, Cycle 1 Day 8 and Day 22, Cycle 2 Day 1 and Day 15, Cycle 3 Day 1 and Day 15, then Day 1 of subsequent cycles and EOT. 
l CRP and EPO will be collected and analyzed at the local laboratory. IL-6 and TGF-beta1 will be collected by the local laboratory and sent to the central 
laboratory. Samples will be collected pre-dose, Cycle 2 Day 1, Cycle 4 Day1, Cycle 7 Day 1, then Day 1 of every 3 cycles thereafter (Cycle 10, etc.), and EOT. 
m SMAD-1, 2, 3, 5, and 8, in PBMCs and bone marrow biopsy/ aspirates: 1) PBMC’s – using peripheral blood lymphocytes drawn; predose (with biopsy) and 
C1D8. C3D1, C4D1, C6D1, and at EOT; 2) Bone marrow biopsy/aspirate – Pre-dose, Cycle 4 Day 1, and at EOT (if performed for assessment of MDS 
progression); 3) Gene mutations in bone marrow biopsy/aspirates and/or peripheral blood samples – Pre-dose and at EOT. 
n MDS assessments according to IWG MDS 2006 (Appendix 6) include hematology and bone marrow biopsy/aspirate at Pre-dose, Cycle 4 Day 1, and at EOT (if 
performed for assessment of MDS progression). For patients continuing on treatment beyond Cycle 6, response assessments will be performed every 
12 months. NOTE: If the bone marrow biopsy and/or aspirate is nonproductive or not diagnostic, the procedure must be repeated. Six to 8 bone marrow slides 
should be prepared (in addition to fresh bone marrow samples) for study analysis. 
o Adverse events will be assessed according to the NCI CTCAE v5.0. When the grade is not available, refer to Section 12.1.6.2.3. 
p Adverse event will be followed until either resolved, has returned to baseline, or is determined to be a stable or chronic condition.
q Performed in Phase 1 Dose Escalation Only (at 6 hours after dose, and 10 minutes prior to PK collection at 6 hours).
r Holter ECG: Cycle 1 Day 1: Approximately 1 hour prior to TP-0184 dose through Day 2 and Cycle 2 Day 15: Approximately 1 hour prior to TP-0184 dose 
through Day 16. Recordings will continue through 24 hours after the Cycle 1 Day 1 dose and after the Cycle 2 Day 15 dose. 
s Performed in Phase 2 Dose Expansion Only (prior to [but not less than 10 minutes before] any blood sample collection).


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8.
SELECTION AND WITHDRAWAL OF PATIENTS
8.1.
Inclusion Criteria
Each patient must meet the following criteria to be enrolled in this study:
1. A documented diagnosis of lower risk MDS (IPSS-R Low, Intermediate) according to 
WHO 2016 classification, de novo or secondary. 
2. Bone marrow biopsy and/or aspirate performed pre-dose to assess disease status and 
available for review prior to full screening review. If the bone marrow biopsy and/or 
aspirate is nonproductive or nondiagnostic, the procedure must be repeated. Bone marrow 
12 weeks prior to baseline will not need to be repeated if 
results and a minimum of 6 slides are available. 
3. Relapsed, refractory/resistant, intolerant, or inadequate response to ESA treatment, as 
defined by the following:
 Relapse according to IWG 2006 
 Refractory/resistant – documented non-response or response that is no longer 
maintained to prior ESA-containing regimen, either as single agent or combination 
(eg, with G-CSF). ESA regimen must have been either: 
 
 500 IU/wk for at least 8 doses or 
equivalent
OR
 
 
 Intolerant – documented discontinuation of prior ESA containing regimen, either as 
single agent or combination (eg, with G-CSF), at any time after introduction due to 
intolerance or an adverse event. 
 Inadequate response – in the absence of transfusions support, patients under ESA 
treatment for at least 12 weeks that do not show a rise in hemoglobin of greater than 
equal to 1 g/dl.  
4. Patients with 5q deletions are allowed only if they have failed or are intolerant to 
lenalidomide treatment. 
 Failure or intolerance to lenalidomide defined as clinical and cytogenetic responses to 
according to the international working group 2006 MDS: (1) absence of response; 
(2) bone marrow progression during treatment with or without prior response; 
(3) secondary failure (loss of prior hematological response without bone marrow 
progression); or, (4) intolerance (treatment discontinuation due to AEs, with or 
without prior response) based on investigator judgement (Prebet 2017).   
5. Previous treatment for anemia with or without RBC transfusion support: 
a.
Low transfusion burden (LTb), defined as requiring less than 4 red blood cell 
units in the 8 weeks before treatment (and baseline hemoglobin < 9.0 g/dL)


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b. High transfusion burden (HTb), defined as requiring 4 or more red blood cell 
units in the 8 weeks before treatment 
6. At least 12 weeks of transfusion history immediately preceding the first dose of TP-0184. 
This transfusion data must include hemoglobin measured prior to transfusion 
(pre-transfusion Hgb). 
7. Informed consent for trial participation from the patient appropriately in accordance with 
applicable ICH guidelines and local and regulatory requirements prior to the performance 
of any study related procedure. 
8. 
 18 years of age. 
9. 
2.
10. 
3 months (90 days) per the treating investigator. 
11. Adequate major organ function meeting the following criteria on the basis of laboratory 
data within 28 days of first dose, during screening. If multiple data points are available, 
the most recent data acquired during the 28 days screening period will be used. 
a. 
 1.8 x the upper limit of the normal (ULN) range. 
b. 
 1.5 x upper limit of normal (ULN) except in patients with 
Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin 
 2.0 x ULN. Elevated indirect bilirubin due to post-transfusion hemolysis is 
allowed. 
c. 
 2.5 x ULN. 
d. 
 45% by echocardiogram or multigated 
acquisition (MUGA) scan. 
12. All previous therapy with ESAs, G-CSF, and GM-
 14 days 
before Cycle 1 Day 1 dosing. 
13. Twenty-eight-day washout period from prior treatment with cytotoxic chemotherapeutic 
agents, HMAs (hypomethylating agents), ImiDs (immunomodulatory imide drugs), 
luspatercept, and/or investigational drugs before study dosing for the patient begins. 
14. Women of childbearing potential (WOCBP) with a negative serum or urine pregnancy 
test within 5 days prior to the first dose of TP-0184. 
15. Non-fertile or agree to use an adequate method of contraception while on study and for 
7 months after the last dose of TP-0184, and a negative pregnancy test (if female of 
childbearing potential) and not currently nursing; males agree to use an adequate method 
of contraception while on study and for 4 months after the last dose of TP-0184. 
16. Ability to comply with the requirements of the entire study and accessibility for treatment 
and follow-up. 
17. Agreement not to participate in other interventional clinical studies during participation
in this trial, while on study treatment. Patients participating in surveys or observational 
studies are eligible to participate in this study. 


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8.2.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from the study: 
1. IPSS-R high or very high risk MDS. 
2. Presence of concomitant severe cardiovascular disease, congestive heart failure (CHF), 
myocardial infarction, angina, and/ or uncontrolled cardiac arrhythmia as determined by 
the investigator within 180 days of study onset. 
3. Corrected 
 465 msec in men and 
> 480 msec in women. 
4. History of stroke, deep venous thrombosis (DVT), pulmonary or arterial embolism within 
180 days prior to enrollment.  
5. Presence of clinically significant anemia due to iron, vitamin B12, or folate deficiencies, 
or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding. 
a. Iron deficiency to be determined by a bone marrow aspirate stain for iron, 
calculated transferrin 
 20%, or serum 
 15 µg/L. 
b. Iron-chelating agents, except for subjects on a stable or decreasing dose for at 
least 8 weeks prior to enrollment, are excluded. 
6. Prior allogeneic or autologous stem cell transplant. 
7. Known history of diagnosis of AML. 
8. Use of corticosteroids, except for subjects on a stable or decreasing dose (no greater than 
a 10 mg dose of 
 2 weeks prior to enrollment for medical 
conditions other than MDS. 
9. Evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count 
(reticulocyte index) of > 2% with either a positive Coombs’ test or over 50% indirect 
bilirubin. 
10. Patients with a recent diagnosis of malignancy are excluded except for those with in situ 
malignancies treated with curative intent (eg, basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, or carcinoma in situ of the cervix). Patients with more 
advanced malignancies are allowed to enroll, provided they were treated with curative 
 
11. Patients requiring systemic antibiotics or antifungals are not eligible until they have 
completed the prescribed course of antibiotics or antifungals and are clinically stable. 
Topical antibiotics or antifungals are permitted. 
12. Known HIV, active Hepatitis B, and/or active Hepatitis C infection. 
13. Patients with bleeding requiring medical intervention (eg, surgical) in the past month. 
14. Platelet count < 50,000/µL 50 x 109/L) during screening. 
15. Absolute neutrophil count (ANC) < 500 /µL (0.5 x 109/L) during screening.
16. Women who are pregnant or breastfeeding. 


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17. Male patients with partners of childbearing potential who are unwilling to use condoms 
in combination with a second effective method of contraception during the trial and for 
7 months after the last administration of study treatment. 
18. Inability to undergo MRI imaging. 
19. Parenchymal iron overload by screening MRI. 
20. Unwillingness or inability to comply with procedures required in this protocol. 
21. Have undergone recent surgery with potential to cause the impairment of gastrointestinal 
tract absorption or that could cause short bowel syndrome with diarrhea due to 
malabsorption. 
22. Have known hemochromatosis at baseline or a family history of hemochromatosis. 
23. Presence of any psychological, familial, sociological or geographical condition that, in 
the opinion of the investigator, could potentially hinder compliance with the study 
protocol and follow-up schedule. 
24. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from participating in the study. 
25. Live vaccines within 14 days prior to first study drug administration. COVID-19 vaccines 
(non-live) approved by regional health authorities are allowed. 
26. Medications that are known strong to moderate CYP3A4 inducers must be discontinued 
at least 21 days prior to first dose of study drug. Medications that are known strong to 
moderate CYP3A4 inhibitors must be stopped 21 days (or 5 half-lives, whichever is 
shorter) prior to the first dose of study drug.
27. Patients who have received medications with known or possible risk of prolonging the 
 
8.3. 
Withdrawal Criteria 
All patients have the right to withdraw at any time during treatment without prejudice. 
Circumstances may occur under which a patient may be permanently removed from the study. 
The criteria used to justify withdrawal of a patient are described in Section 8.3.1.
An End of Treatment (EOT) visit will be conducted following permanent discontinuation of 
treatment with TP-0184 for any reason, except in the case of consent withdrawal by patient. The 
EOT visit will be conducted within 14 (± 3) days of treatment discontinuation, or within 14 days 
of the decision to discontinue TP-0184 treatment, as detailed in the Schedule of Assessments 
(Table 6).   
If the patient withdraws consent for disclosure of future information, SDP Oncology may retain 
and continue to use any data collected before a withdrawal of consent. If a patient withdraws 
from the study, he/she may request destruction of any samples taken and not tested, and the 
Investigator must document this in the site study records, as well as notify SDP Oncology. 
In the event of a treatment discontinuation, the assessments for the EOT visit and End of Study 
(EOS) visit, as detailed in Table 6, should be completed wherever possible. 


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8.3.1. 
Reasons for Treatment Discontinuation
A patient may be discontinued from TP-0184 treatment for any of the following reasons:
 In Phase 1, patient experiences a DLT during Cycle 1 
 Failure to achieve a hematologic response. Patients not demonstrating evidence of 
hematologic response after the first 6 cycles (24 weeks) of treatment will be 
considered for treatment discontinuation, although with permission of the Medical 
Monitor and Investigator, TP-0184 study treatment may continue if clinically 
indicated and provided there is no evidence of Grade 4 toxicity. 
 Grade 4 toxicity not responding to supportive measures and without a response to 
treatment
 The occurrence of any other AE, concurrent illness or laboratory abnormality which, 
in the opinion of the Investigator, warrants treatment discontinuation 
 Patient noncompliance, defined as refusal or inability to adhere to the study schedule
 At the request of the patient, Investigator, SDP Oncology, or regulatory authority 
 Patient is lost to follow-up
 Patient becomes pregnant while on study 
 Patient begins another treatment for their disease
 Patient death
 Patient withdrawal of consent.
8.3.2. 
Follow-up for Patients Discontinued from Treatment
In the event of a permanent discontinuation of treatment, the patient will be followed up for 
30 (+ 7) days after administration of the last dose of treatment for safety assessments. 
Follow-up for progression of MDS to higher risk and / or transformation to AML and survival 
will continue every 6 months for at least one year from start of treatment (Cycle 1 Day 1) with 
TP-0184.  
8.3.3. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the Investigator or designee. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
study.  
Before a patient is deemed lost to follow up, the investigator or designee must make every effort 
to regain contact with the patient (where possible, 3 telephone calls and, if necessary, a certified 
letter to the patient’s last known mailing address or local equivalent methods). These contact 
attempts should be documented in the patient’s medical record.


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9.
TREATMENT OF PATIENTS
9.1.
Description of TP-0184
Refer to Section 10 for a description of TP-0184, and to Section 7.3 for TP-0184 administration 
details. 
9.2.
Concomitant Medications
Concomitant therapies are any new or existing medications or therapy received by the patient 
including:
 All drugs, including but not limited to, prescription, over-the-counter, birth control 
pills/patches/hormonal devices, and homeopathic preparations.
Note: All previous treatments with ESAs, G-CSF and GM-CSF must be 
 
 Nondrug therapies, including but not limited to, thermal/laser/radiation procedures, 
vitamins, herbal medicines/supplements. 
During the Screening process (within 28 days prior to the anticipated first TP-0184 dose), 
information on all prior and current medications, therapies, and procedures will be recorded. 
Concomitant medications, therapies, and procedures will also be recorded during the study. All 
prior and concomitant treatments will be recorded in the source documents and appropriate 
eCRF along with the diagnosis or reason for use. 
Patients on the study will be permitted to receive non-live COVID-19 vaccinations that are 
authorized for use by the Health Authorities of the country/region. 
The therapies used for the treatment of an AE are to be linked to an AE and documentation of the 
AE must also be completed (refer to Section 12.1.6). 
9.2.1. 
Prohibited Medications and Therapies 
The following medications and therapies are prohibited during the treatment with TP-0184:  
Antileukemic therapy (chemotherapy, radiation therapy, immunotherapy) 
Growth factor support, including G-CSF, -GM-CSF, TPO, ESA’s
Allowing a patient to remain on treatment following administration of growth 
factor for a Grade 4 sepsis with life-threatening infection and ongoing 
neutropenia, will be considered after discussion with the Medical Monitor.
Initiation of iron chelation therapy (oral or injectable) following enrollment.  
Patients receiving iron chelators at stable or decreasing doses for at least 8 weeks 
prior to entering the study will be allowed to continue with this treatment.
Herbal/alternative supplements 
Immune suppressive agents
Live vaccines within 14 days prior to first study drug administration, during the 
study, and for approximately 3 months after the last dose of study drug.
Medications that are known strong or moderate CYP3A4 inhibitors or inducers 
(Appendix 8), as preliminary in vitro reaction phenotyping data suggested that 
TP-0184 is metabolized predominately by CYP3A4.


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Pointes (TdP) one week prior to and during intensive ECG Holter monitoring at both 
Cycle 1 Day 1-Day 2 and Cycle 2 Day 15-16. Refer to Appendix 9 for the list of 
d 
on 31 Mar 2021 from the website, https://crediblemeds.org/new-drug-list/, generated 
on 17 Apr 2021). As the website updates its list periodically, please refer to the 
website (https://crediblemeds.org/new-drug-list/) for a most updated list. 
9.3. 
Treatment Compliance 
The dose of TP-0184 to be dispensed will be determined by the patient’s cohort assignment. 
Patients will receive a pill pack with a 28-day supply of TP-0184 capsules at Day 1 of each 
cycle. The dispensed number of capsules and dose will be recorded in an accountability log to be 
periodically reviewed by SDP Oncology. 
Patients will also be given a Study Drug Dosing Diary and will be asked to record the date, time, 
number of capsules taken, fasting, if a dose was missed, and the reason for any change in dosing. 
Patients will be instructed to bring their diary along with all unused study drug and empty packs 
to each follow-up clinic visit. The diary will be reviewed by the designated study personnel and a 
capsule count will be performed to ensure dosing compliance. 
9.4. 
Randomization 
Not applicable.
9.5. 
Blinding 
Not applicable, as this is an open-label study. 


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10.
STUDY DRUG MATERIALS AND MANAGEMENT
10.1.
Study Drug
The study drug, TP-0184, is supplied by SDP Oncology as a drug/excipient powder blend in hard 
gelatin capsules for oral administration and is manufactured under current Good Manufacturing 
Practices for investigational use.
TP-0184 capsules are formulated in 5, 25, and 125 mg strengths that are color-coded. The 5 mg 
strength comes in a size “3” Swedish orange, hard gelatin capsule. The 25 mg strength comes in 
a size “3” Dark green, hard gelatin capsule. The 125 mg strength comes in a size “0” Brown, 
hard gelatin capsule. They are packaged as follows:
 For 5 mg and 25 mg:
packaged in 200 cc HDPE bottle with approximately 2 g of polyester coil
 For 125 mg: 
packaged in 400 cc HDPE bottle with approximately 2 g of polyester coil
10.2. 
Study Drug Packaging and Labeling 
The label and package for the drug product will be prepared in accordance with current 
regulatory requirements.
10.3. 
Study Drug Storage 
The TP-0184 capsules should be stored as per the storage statement on the investigational 
product label. 
10.4. 
Study Drug Dispensing and/or Administration 
Depending on the assigned dose level, the different combinations of the above-mentioned 
capsule strengths will be dispensed to the patient. To help the patient take the correct dose 
(number of capsules and capsule strength) for their dose level, the authorized staff at the study 
sites will dispense the correct number of capsules and capsule strength from the supplied bottles 
of TP-0184 into a 28-day pill package for each day of the week. 
If there is concern about risk of exposure to SARS-CoV-2, home delivery of TP-0184 may be 
implemented to protect patients from coming to the study sites. In all cases, requirements under 
FDA regulations for maintaining required storage conditions and accountability remain; these 
requirements must be addressed and documented.
Further instructions regarding the dispensing of pill packages to patients is outlined in the 
Pharmacy Manual.
10.5. 
Study Drug Accountability 
An accurate and current accounting of the dispensing of the study drugs for each patient will be 
maintained on an ongoing basis by a member of the study site staff in a drug accountability log 
or equivalent document and will be verified by the SDP Oncology study monitor. All drug 
supplies, including unused study drug, must be accounted for. A final inventory of the total 
amount of drug received at each study site against the amount used and returned must be 


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recorded in the study drug accountability log or an equivalent document. Inventory and dispense 
records must be readily available for inspection by the study monitor and/or auditor, and open to 
government inspection at any time.
10.6.
Study Drug Handling and Disposal
TP-0184 will be provided by SDP Oncology to study sites as an investigational drug. The 
Investigator or designee will inventory and acknowledge receipt of all shipments of study drugs. 
The study drugs must be kept in a locked area with access restricted to designated study 
personnel. Destruction of unused study drug will be handled by the sites or returned to an 
authorized depot for destruction. 


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11.
PHARMACOKINETIC, PHARMACODYNAMIC, AND 
BIOMARKER ASSESSMENTS 
11.1. 
Pharmacokinetic Assessments 
Blood samples will be collected by local laboratories and analyzed by the central laboratory to 
measure plasma concentrations of TP-0184 and possibly its metabolites at the time points 
outlined in Table 6, Table 7, and Table 8. 
Sample preparation and process will be described in this study’s Laboratory Manual. The PK 
parameters to be assessed include:  
 Cmax = maximum observed plasma concentration  
 Ctrough = Trough plasma concentrations 
 tmax = time to Cmax (peak time)
AUC = AUC within a dosing interval
Additional parameters may be determined
Table 7
Phase 1 PK Sampling Schema with ECG
 
Cycle 1
Cycle 2
C1D1 
C1D2 
C1D4a 
(±1) 
C1D8 
(±1) 
C1D15 
(±1) 
C1D22 
(±1)a
C2D1 
C2D8 
(±2) 
C2D15 
(±2) 
C2D16 
(±2, 
same as 
C2D15)a
Intensive 
Holter ECG 
monitor 
Xb
 
 
 
 
 
 
Xb
Safety ECG
Xc
Xc 
Xc
Xc
Xc 
Xc 
Xc
Xc
 
PK Blood Sample Collection Time 
Pre-dose
(-1h)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2-hour post 
(±10 min)
X 
 
X 
X 
 
 
 
 
X 
 
4-hour post 
(±10 min)
X 
 
X 
X 
 
 
 
 
X 
 
6-hour post 
(±15 min)
X
X
X
X
8-hour post 
(±20 min)
X 
 
X 
X 
X 
X 
X 
X 
X 
 
10-hour post
(±20 min)
X 
 
 
X 
 
 
 
 
X 
 
a These assessments are optional.
b Apply the Holter monitor prior to first pre-dose PK blood draw and start recording approximately 1 hour prior to 
the first dose.
c Perform Safety ECG at 6 hours after dose, and 10 minutes prior to PK collection at 6 hours. 
Note: Safety ECGs will be performed prior to PK blood sampling 


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Table 8
Phase 2 PK Sampling Schema
Cycle 1
Cycle 2
Cycle 3
C1D22
(±1)
C2D1
C2D8
(±2)
C2D15
(±2)
C3D1
Safety ECG
X
X
X
X
X
PK Blood Draw Time
Pre-dose
X
X
X
X
X
Note: Safety ECGs should be performed prior to (but not less than 10 minutes) any blood sample 
collection.
Plasma concentrations of TP-0184 and possibly metabolites will be summarized by descriptive 
statistics, including mean, n, standard deviation, coefficient of variation, minimum, maximum, 
and median. TP-0184 and/or metabolite concentration data may also be analyzed in conjunction 
with data from other studies, reported in the associated clinical study report (CSR), other CSRs 
or separately. Prior to analysis of study samples, the assay sensitivity, specificity, linearity, and 
reproducibility will be documented. 
11.2. 
Assessment of Pharmacodynamics and Biomarkers 
Peripheral blood and bone marrow samples will be collected by local laboratories and analyzed 
by the central laboratory at protocol-specific time points (Table 6) to assess the effects of 
TP-0184. The samples will be used to determine any possible correlation between the rate of 
erythropoietic efficacy response, clinically positive bone marrow biopsy/ aspirate results, drug 
plasma concentration and biomarkers for TP-0184.
The types of biomarkers to be analyzed may include, but are not limited to, nucleic acids, 
proteins, lipids or metabolites. Biomarker assessments may be used to assess and generate 
prognostic, predictive, or surrogate biomarker signatures. These assessments may be explored in 
the context of MDS or related conditions or drugs of similar class. The results from these 
analyses are exploratory in nature and may not be included in a CSR. Analyses will include 
evaluating genetic mutations and other biomarkers associated with MDS. 
 Exploratory biomarkers include, but are not limited to: 
 Hepcidin in serum  
 Iron metabolism in serum: (eg, serum iron, transferrin, STR, and TIBC) 
 Cytokine panel including: CRP, EPO, IL-6, TGF-
 
 Signal transduction pathways inhibited by TP-0184, including phosphorylation of 
SMAD-1, 2, 3, 5 and 8, in PBMCs and bone marrow biopsy / aspirate 
mononuclear pellet 
 Gene mutations associated with MDS and/or associated with signal transduction 
pathways inhibited by TP-0184 in bone marrow biopsy / aspirate and/or 
peripheral blood samples 
Additional exploratory analyses may be performed if useful in the interpretation of the data 
and/or to assist SDP Oncology in planning future studies. 


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12.
ASSESSMENTS OF SAFETY AND EFFICACY
12.1.
Assessment of Safety
12.1.1.
Safety Parameters
12.1.2. 
Assessment for Study Eligibility
All screening evaluations must be completed and reviewed with the Medical Monitor to confirm 
that potential patients meet all eligibility criteria. Procedures conducted as part of the patient’s 
routine clinical management and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in Table 6. 
The investigator will maintain a screening log to record details of all patients screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
12.1.3. 
Informed Consent 
Informed consent will be obtained for each participant/potential participant in this trial, in 
accordance with World Medical Association Declaration of Helsinki (DoH) and ICH-Good 
Clinical Practice (GCP) Section 16.3. The investigational site is responsible for ensuring that all 
local policies are followed. 
Additionally, SDP Oncology may require that participants/potential participants be informed of 
any new information that may impact a participant’s/potential participant’s willingness to 
participate in the study. 
Based upon applicable guidelines and regulations, a participating Investigator (as defined on the 
Delegation of Authority list) is ultimately responsible, in terms of liability and compliance, for 
ensuring informed consent has been appropriately obtained. SDP Oncology recognizes that in 
many centers, other personnel (as designated on the Delegation of Authority list) also play an 
important role in this process. It is acceptable for the Principal Investigator to delegate the 
responsibility for conducting the consent discussion. 
SDP Oncology allows the use of translators in obtaining an informed consent. Provision of 
translators is the responsibility of the local investigational site. Investigational sites should 
follow applicable local policies when procuring or using a translator for this purpose.  
If a subject is unable to read, then informed consent may be obtained by having the consent form 
read and explained to the subject. This process must be thoroughly documented. 
12.1.1. 
MDS Disease Confirmation 
MDS diagnosis confirmation at screening requires the collection of peripheral blood, bone 
 12 weeks prior to 
baseline will not need to be repeated if results and a minimum (ie, 6-8) slides are available. If 
> 12 weeks since last bone marrow response assessment, a fresh peripheral blood, bone marrow 
biopsy and/or aspirate sample will be required to confirm the patient’s diagnosis per WHO 
Classification System 2016 (Appendix 3 and Appendix 4). If the bone marrow biopsy and/or 
aspirate is nonproductive or not diagnostic, the procedure must be repeated. Six to 8 bone 


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marrow slides should be prepared in addition to fresh bone marrow samples (see Laboratory 
Manual).  
12.1.2. 
Prior Transfusion History 
Transfusion history must be available and collected for a minimum of 12 weeks immediately 
preceding the first dose of TP-0184. The records must include: the type of transfusion received 
(eg, RBC, platelets), number of units, reason for transfusion, date of transfusion, and 
pre-transfusion Hgb value or, if the patient received platelets, platelet count prior to transfusion. 
12.1.3. 
Prior Concomitant Medications and Procedures
Information on all concomitant therapies, medications, and procedures will be recorded in the 
source documents and appropriate eCRF along with the diagnosis or reason for use.   
12.1.4. 
Pregnancy Testing 
Pregnancy testing is performed at the screening visit and will be repeated at subsequent cycles 
and treatment discontinuation, per institutional standard of care, for WOCBP only.  
WOCPB and males who are enrolled in the trial must be informed of the requirement to use 
contraception as outlined in the eligibility criteria. Investigators are advised to inform the female 
partners of male participants when appropriate and compliant with local policy.  
Contraceptive Guidance and Collection of Pregnancy Information can be found in Appendix 5. 
12.1.5. 
On-treatment Transfusions 
The number of RBC and platelet transfusions received, and the date received will be recorded.  
The hemoglobin and platelet count prior to the transfusion will also be recorded.   
12.1.5.1. Demographics and Medical/MDS Disease History 
The following patient information will be collected: 
 Date of birth, sex, race and ethnicity 
 Relevant medical history (including recent surgical history), as well as other current 
medical conditions 
 MDS disease history (initial histologically confirmed and current diagnosis of MDS, 
signs and symptoms of disease, date of diagnosis, and WHO and /or IPSS-R 
classification at original diagnosis)
 Prior treatments for MDS, including ESAs, HMAs, EMAs (erythroid maturation agents), 
ImiDs, and/or investigational drugs. These therapies will be recorded in the source 
documents and appropriate eCRF.  
12.1.5.2. Vital Signs 
Temperature, heart rate, respiratory rate, height, weight, and systolic and diastolic blood pressure 
will be assessed. Blood pressure and pulse measurements should be preceded by at least 


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5 minutes of rest for the patient in a quiet setting without distractions (eg, television, cell 
phones).
12.1.5.3. Physical Examinations 
Physical examinations will be performed as specified in Table 6. A complete physical 
examination performed during the screening will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems.  
An abbreviated physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). An abbreviated exam may also be 
performed at additional time if an AE- or symptom-directed.
12.1.5.4. Electrocardiogram 
12.1.5.4.1. Intensive ECG Monitoring
An ambulatory 12-Lead ECG recording device (Holter monitor) will be supplied to patients 
receiving TP-0184 in Phase 1 of the study. This device will capture and digitally record 
continuous ECGs.  Please reference study specific Holter ECG Acquisition Manual. 
Patients are to be resting for 10 minutes prior to, and 10 minutes after the designated ECG 
capture windows, which are to precede each PK blood draws, as specified in Table 6. 
The continuous digital ECG data will be stored electronically and transmitted by the study site to 
the ECG central laboratory.   
Up to 10 ECGs will be extracted from the digital recordings by the ECG central laboratory from 
each of the 5-minute time windows preceding each PK blood draw. 
12.1.5.4.2. Safety ECG Assessments 
Triplicate 12-Lead ECGs will be performed at the study site as specified in Table 6. 
The following 
review the results and assess as normal or abnormal.  
12.1.5.5. Clinical Safety Laboratory Assessments 
See Table 9 for the list of clinical laboratory tests to be performed. All protocol-required 
laboratory assessments must be conducted as outlined in Table 6 and in the study specific 
Laboratory Manual. 






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Pregnancy is not an AE; however, if a female patient or partner of a male patient becomes 
pregnant during the conduct of the study, the Investigator must notify SDP Oncology according 
to the procedures provided in Section 12.1.6.4.4
12.1.6.1.2. Adverse Reactions and Suspected Adverse Reactions 
All noxious and unintended responses to an investigational agent related to any dose should be 
considered adverse drug reactions. Suspected adverse reactions are any AEs for which there is a 
reasonable possibility that the investigational agent caused the AE. Adverse reactions may also 
include medication errors and uses outside of what is foreseen in the protocol, including misuse, 
abuse, and overdose (intentional or unintentional) of the investigational agent. 
12.1.6.1.3. Serious Adverse Event
An SAE is any adverse experience occurring at any dose that results in any of the following 
outcomes: 
 Death 
 Life-threatening experience
 Note: “Life-threatening” refers to a situation in which the patient was at risk of 
death at the time of the event as it occurred; it does not refer to an event that 
might have caused death if it were more severe; 
 Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
the hospitalization is for the following:
 Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the ICF (as 
documented as medical history on the eCRF). 
 Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience
 Results in congenital anomaly or birth defect
 Results in persistent or significant disability or incapacity
Is considered to be an important medical event.
Note: Important medical events are those that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient 
or may require intervention to prevent one of the outcomes listed in the definition 
above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
12.1.6.2. Procedures for Eliciting, Recording, and Reporting Adverse Events 
12.1.6.2.1. Eliciting and Recording Adverse Events
Patients will be instructed to report all AEs and will be asked a general health status question at 
each study visit.   
All AEs occurring from the signing of informed consent until 30 days after the last dose of 
investigational therapy will be recorded in the eCRF.  


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An AE will be followed until it is either resolved, has returned to baseline, or is determined to be 
a stable or chronic condition.   
All SAEs occurring from the signing of informed consent through 30 days after the last 
investigational agent administration will be reported to SDP Oncology or designee as outlined in 
Section 12.1.6.3.
At each required visit during the study, all AEs that have occurred since the previous visit must 
be reviewed. The Investigator or appropriate designee must determine if the AE is serious or 
non-serious.   
12.1.6.2.2. Relationship to Investigational Agent 
A medically qualified Investigator must assess the relationship of any AE to the use of the 
investigational agent, as related or not related, based on clinical judgment and using all available 
information, and may include consideration of the following factors: 
 Possible alternative causes of the AE, including the disease under treatment, pre-
existing conditions, concomitant use of other drugs, and presence of environmental or 
genetic factors.
 The temporal association between investigational agent exposure and onset of the AE.
 Whether the manifestations of the AE are consistent with known mechanism of action 
or toxicities associated with the investigational product. 
 Dechallenge: the AE resolved or improved with decreasing the dose or stopping use 
of the investigational agent. Judgment should be used if multiple products are 
discontinued at the same time. 
 Rechallenge: the AE recurred or worsened upon re-exposure to the investigational 
agent. 
The causal relationship between the investigational agent and the AE will be assessed using one 
of the following categories: 
 Not Related: An AE is not associated with the investigational agent if, for example: 
 Temporal relationship is lacking (eg, the event did not occur within a reasonable 
time frame following administration of the investigational agent); or 
 Other causative factors more likely explain the event (eg, a pre-existing condition, 
other concomitant treatments). 
 Related: An AE is attributed to the investigational agent if, for example: 
 There is a positive temporal relationship (eg, the event occurred within a 
reasonable time frame following administration of investigational agent); or 
 The AE is more likely explained by the investigational agent than by another 
cause (ie, the AE shows a pattern consistent with previous knowledge of the 
investigational agent or the class of the investigational agent. 
 The event improved on dechallenge and/or re-occurred upon rechallenge (if 
applicable). 


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12.1.6.2.3. Adverse Event Severity
The severity of AEs will be assessed according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), v5.0. For events not specifically found in 
CTCAE, the following definitions will be used to estimate grade of severity:
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL) 
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe nausea). This is not the same as “serious,” (outlined in 
Section 12.1.6.1.3 which is based on patient/event outcome or action criteria usually associated 
with events that pose a threat to a patient’s life or functioning.  
12.1.6.2.4. Assessment of Expectedness 
The Reference Safety Information for assessing the expectedness of an AE in this study is to be 
the section identified as the Reference Safety Information in the most recent TP-0184 
Investigator’s Brochure.  
12.1.6.3. Specific Instructions for Recording Adverse Events on the eCRF 
12.1.6.3.1. Diagnosis Versus Signs and Symptoms
If a diagnosis is known at the time of reporting, the diagnosis rather than the individual signs and 
symptoms should be recorded in the eCRF (eg, record only hepatitis rather than elevated 
transaminases, bilirubin, jaundice). However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome, each individual event should be 
recorded as an AE or SAE on the eCRF. If a diagnosis is subsequently established, it should be 
reported as follow-up and should replace the individual signs and/or symptoms as the event term 
on the eCRF. 
12.1.6.3.2. Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (eg, clinical sequelae or a cascade of events) 
should be identified by their primary cause. However, medically significant AEs occurring 
secondary to an initiating event that are separated in time should be recorded as independent 
events on the eCRF (eg, dehydration secondary to diarrhea).
12.1.6.3.3. Medication Errors, Misuse and Abuse of Investigational Agent 
Overdose, medication error, misuse and abuse are defined as follows: 


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 Overdose: refers to the administration of a quantity of investigational agent given per 
administration or cumulative, which is above the maximum dose according to the 
protocol. Clinical judgment should always be applied. 
 Medication error: refers to an unintentional error in dispensing or administration of 
the investigational agent not in accordance with the protocol. 
 Off-label use: relates to situations where the investigational agent is intentionally used 
for medical purpose not in accordance with the protocol. 
 Misuse: refers to situations where the investigational agent is intentionally and 
inappropriately used not in accordance with the protocol. 
 Abuse: corresponds to the persistent or sporadic, intentional excessive use of the 
investigational agent, which is accompanied by harmful physical or psychological 
effects. 
 Occupational exposure: refers to the exposure to the investigational agent as a result 
of one’s professional or non-professional occupation.
Overdoses, medication errors, abuse or misuse regardless of whether there was an associated AE 
will be collected as part of investigational agent dosing information and/or as a protocol 
violation, as required.  
Any AE associated with an overdose, medication error, misuse or abuse of study drug should be 
recorded on the AE eCRF with the diagnosis of the AE.   
12.1.6.3.4. Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points. Such events should only be recorded once on the SAE Report Form and/or the AE 
eCRF. If a persistent AE becomes more severe in severity, it should be recorded as a new AE on 
the eCRF.   
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs. Each individual instance of a recurrent AE should be recorded on an SAE 
Report Form and/or AE eCRF. 
12.1.6.3.5. Abnormal Laboratory Values
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 
vital sign should be considered additional information that must be recorded on the relevant 
eCRF. If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis needs 
to be recorded on the SAE Report Form and/or eCRF. Abnormal laboratory values assessed as 
not clinically significant (NCS) should be documented as such in the source document.
Abnormal laboratory values will be reported as an AE if the laboratory result: 
 Requires an adjustment in the investigational agent(s) or discontinuation of treatment
 Meets seriousness criteria 
 Requires additional testing or surgical intervention 
 Is associated with accompanying symptoms 


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12.1.6.3.6. Cancers
The development of cancer (including AML) should be regarded as an AE and will generally 
meet at least one of the serious criteria (see Section 12.1.6.1.3). 
12.1.6.3.7. Adverse Event of Special Interest 
An adverse event of special interest (AESI) is a non-serious AE, SAE, or occurrence that is 
designated to be of special interest and must be reported to SDP Oncology or designee in the 
same manner and on the same timelines as SAEs, as described in Section 12.1.6.4. 
The following events are considered AESIs for this study: 
 Cardiac toxicity 
 Hepatotoxicity 
12.1.6.3.8. COVID-19 
Because much is still unknown about how SARS-CoV-2 affects the human body, patients who 
have tested positive for COVID-19 will be identified and relevant information collected. All 
patients should provide documentation of any testing for COVID-19, if available, along with the 
test results, at screening for enrollment and/or during the study. Prior test results should be 
reported, if available, for any patient who has previously tested positive for COVID-19 
SARS-CoV-2 titers (antiviral immunoglobulin G [IgG] and immunoglobulin M [IgM]). 
(Long 2020) These data will be entered into the patient’s study-specific record. 
Any patient-reported illness of COVID-19 during the study should be recorded as an AE. If a 
patient reports infection with COVID-19, the investigator may discuss with the Medical Monitor 
whether the patient can continue on study. 
12.1.6.3.9. Deaths 
All events leading to the clinical outcome of death occurring during the SAE reporting period 
(from the signing of the informed consent through 30 days after the last investigational agent 
administration) are to be reported to Sponsor or designee as an SAE and recorded on the AE 
eCRF. 
12.1.6.4. Reporting of Expedited Safety Observations by the Investigator Including 
Serious Adverse Events 
12.1.6.4.1. Immediate Reporting of Serious Adverse Events by Investigator to Sponsor 
All SAEs, from the signing of informed consent through 30 days after last dose, including SAEs 
from screen failures, will be reported to the Sponsor or designee within 24 hours of the 
Investigator’s first knowledge of the event, even if the experience does not appear to be related 
to the investigational agent.  


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Serious AEs should be communicated on an SAE report form as follows:
SDP Oncology Pharmacovigilance Department Contacts
Email:
BBISafety@bostonbiomedical.com
Fax:
(617) 674-8660
The initial SAE report must be as complete as possible, including details of the current illness 
and SAE, and an assessment of the causal relationship between the event and the investigational 
product(s). Information not available at the time of the initial report (eg, an end date for the AE, 
laboratory values received after the report, or hospital discharge summary) must be documented 
on a follow-up form. All follow-up information must be reported in the same timelines as initial 
information. 
At any time after completion of the AE reporting period (ie, 30 days post-treatment), if an 
Investigator becomes aware of an SAE that is suspected by the Investigator to be related to the 
investigational agent, the event must be reported to the Sponsor or designee. 
12.1.6.4.2. Immediate Reporting of Occupational Exposure, Adverse Events of Special 
Interest, Overdose, or New Cancers
Cardiac toxicity and hepatotoxicity are AESIs, and therefore immediately reportable events, even 
if the events do not meet SAE criteria.  
All AESIs will be reported to the Sponsor or designee within 24 hours of the Investigator’s first 
knowledge of the event, whether or not the event is serious, even if the experience does not 
appear to be related to investigational agent. Adverse Events of Special Interest should be 
communicated on the SAE Report Form, as described above for SAEs. 
Any occupational exposure or exposure of an individual not enrolled in the study to the 
investigational medicinal product must be reported to the Sponsor or designee within 24 hours 
of the Investigator's first knowledge of the event, even if the exposure does not result in an AE. 
Unintentional exposures should be communicated on the SAE Report Form, as described above 
for SAEs. 
Any overdose to the investigational medicinal product must be reported to the Sponsor or 
designee within 24 hours of the Investigator's first knowledge of the event, even if the overdose 
does not result in an AE. Overdose should be communicated on the SAE Report Form, as 
described above for SAEs. 
Any new cancers must be reported to Sponsor or designee within 24 hours of the Investigator's 
first knowledge of the event. New cancers should be communicated on the SAE Report Form, as 
described above for SAEs. 
12.1.6.4.3. Reporting COVID-19 Infections 
Suspected or confirmed COVID-19 infections, including asymptomatic infections and positive 
COVID-19 tests are AESIs and therefore immediately reportable events, even if the events do 
not meet SAE criteria. 
Serious COVID-19 events will be reported on an SAE Report form within 24 hours of the 
investigator’s awareness, according to Section 12.1.6.4.1. 


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Nonserious COVID-19 events will be reported on a COVID-19 Report form within 5 calendar 
days of the investigator’s awareness, to the same email/fax for reporting SAEs described in 
Section 12.1.6.4.1.
Updates or follow-up information for COVID-19 events should be reported on an SAE Report 
form (serious events) or a COVID-19 Report form (nonserious events) within the same timelines 
as the initial reports.
12.1.6.4.4. Reporting Pregnancies 
If a female patient or the female partner of a male patient becomes pregnant during the course of 
study, the Investigator must report the pregnancy to the Sponsor or designee using the 
Pregnancy Reporting Form within 24 hours of becoming aware of the event. 
If not all information on the Pregnancy Reporting Form is available at the time of the initial 
report, follow-up Pregnancy reports will be completed and submitted within 24 hours of 
becoming aware of the new information. The Investigator is required to follow up on the 
pregnancy until it has completed. The outcome of the pregnancy and the status of the newborn (if 
applicable) will be reported on the Pregnancy Reporting Form within 24 hours of becoming 
aware. SAEs associated with the pregnancy, including fetal death, miscarriage or congenital 
anomalies, must be reported as a serious adverse event according to Section 12.1.6.4.
If the female partner of a male patient becomes pregnant, the Investigator must obtain consent to 
collect pregnancy information from the pregnant partner (including the status of the newborn, if 
applicable). 
12.1.6.4.5. Expedited Reporting by the Sponsor to a Regulatory Health Authority 
The Sponsor will manage the expedited reporting of relevant safety information to concerned 
health authorities, competent authorities, and IRBs/IECs in accordance with local laws and 
regulations. 
12.1.6.4.6. Safety Notifications by the Sponsor to the Investigator 
Investigators will receive prompt notification of any suspected adverse drug reaction that is both 
serious and unexpected, or any finding that suggests a significant risk for patients, in accordance 
with local laws and regulations. The Investigator will promptly inform his/her IRB/IEC of the 
notification and insert the notification in the Investigator’s Regulatory Binder in accordance with 
local regulations. 
12.2. 
Assessment of Efficacy 
12.2.1. 
Assessment of MDS Disease
Assessments of the patient’s MDS disease will be performed by collection of peripheral blood, 
bone marrow biopsy and aspirate samples. If the bone marrow biopsy and aspirate are 
nonproductive or not diagnostic, the procedure must be repeated. Six to 8 bone marrow slides 
should be prepared (in addition to fresh bone marrow samples) and sent to the designated 
pathology laboratory for assessment. The patient’s disease assessment will be done according to 
International Working Group Response Criteria for MDS 2006 (Appendix 6).  


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12.2.2. 
Survival
Survival status will be collected every 6 months for at least one year from the first dose of 
TP-0184 treatment (Cycle 1 Day 1). 
12.2.2.1. ECOG Performance Status 
Standard criteria as defined by the ECOG Scale of Performance Status (Appendix 7) will be 
considered for assessing the patient’s level of activities, mobility, and functioning abilities. 
12.2.2.2. ECHO/MUGA 
ECHO or MUGA scan will be performed as primary cardiac monitoring to assess LVEF, as 
specified in Table 6. If an ECHO or MUGA have been obtained within 6 weeks of EOT, they do 
not need to be repeated. 
12.2.2.3. MRI Imaging 
Cardiac and hepatic imaging by MRI for quantification of iron will be performed as specified in 
the Schedule of Assessments. The MRI may also be performed ad hoc if signs/symptoms of iron 
overload are noted. Please reference study specific MRI Acquisition Manual. 
12.2.2.4. New York Heart Association Classification 
The NYHA (Appendix 11) provides a simple way of classifying the extent of heart failure. It 
classifies patients in 1 of 4 categories based on their limitations during physical activity; the 
limitations/symptoms are with regard to normal breathing and varying degrees in shortness of 
breath and or angina pain. 
12.2.3. 
Patient Reported Outcomes  
The Brief Fatigue Inventory (BFI; see Appendix 10) is a brief participant-reported questionnaire 
that measures the severity of fatigue based on the worst fatigue experienced during the past 
24 hours. The severity of fatigue is assessed using an 11-point numeric scale, with 0 = no fatigue 
and 10 = fatigue as bad (Mendoza 1999). Patients will complete a paper version of this 
questionnaire at screening, Day 1 of each cycle, at EOT and follow-up.  


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13.
STATISTICS
13.1.
Statistical Methods
Detailed methodology for the statistical analyses of the data collected in this study will be 
documented in the statistical analysis plan (SAP), which will be maintained by SDP Oncology. 
The SAP may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol amendment.
13.1.1. 
Determination of Sample Size 
13.1.2. 
Phase 1
The exact sample size for Phase 1 (dose escalation part) cannot be specified in advance due to 
the dynamic features of BLRM study design. Approximately 30 patients are planned to be 
enrolled in Phase 1. 
13.1.3. 
Phase 2
A total of 10 to 60 patients will be enrolled into Expansion Phase 2. After the first 10 enrolled 
patients are evaluable for efficacy (Efficacy Evaluable Analysis Set), response rate monitoring 
using Bayesian posterior probability will be performed. If posterior probability of response rate 
less or equal than 5% is greater t
futility; if posterior probability of response rate greater or equal than 20% is greater than 80% 
enrollment of Phase 2 and trigger subsequent clinical development of TP-0184. If neither 
criterion is met, it will continue to more fully characterize the response rate in a total of 
approximately 60 efficacy evaluable patients. If posterior probability of response rate greater or 
will be considered to be successful. 
13.1.4. 
Randomization and Stratification 
There is no randomization in this study. 
13.1.5. 
Analysis Datasets 
The safety analysis set (SAS) is defined as all patients who receive at least one dose of study 
drug (TP-0184) and will be used for safety analysis and related time to event analyses if 
applicable.  
The DLT analysis set (DAS) is defined as patients evaluable for the determination of dose 
escalation in Phase 1 who met either one of the following criteria: 
1. Experienced a DLT during the first 28 days (the DLT evaluation period) 
2. Completed the DLT evaluation period and received at least 80% of planned doses. 
Patients who did not meet either of the above criteria are not evaluable for the dose escalation 
assessment and may be replaced as needed to permit dose escalation. The DAS will be used for 
DLT related analysis. 


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The efficacy evaluable analysis set (EAS) is defined as all patients who have baseline data of 
Hemoglobin value,  number of transfusions received in previous 12 weeks before study 
treatment, have received at least 1 dose of TP-0184, and have at least 1 available post baseline 
response assessment as per the composite endpoint criteria. The EAS will be used for analyses of 
response rate and related efficacy analyses. 
Pharmacokinetic evaluable analysis set is defined as all treated patients in the trial with sufficient 
and adequate PK sample data as determined by SDP Oncology. 
13.1.6. 
Handling of Missing Data 
All available efficacy and safety data will be included in data listings and tabulations. Data that 
are potentially spurious or erroneous will be examined under the auspices of standard data 
management operating procedures.
In general, missing data will be treated as missing and no data imputation will be applied, unless 
otherwise specified. For patient reported outcomes data, primarily missing data imputation will 
be based on published instrument specific methods. Other missing data imputation method such 
as Last Observation Carry Forward (LOCF) and mixed model may be explored as sensitivity 
analyses for patient reported outcomes data.
13.1.7. 
Demographic and Baseline Characteristics
The demographic and baseline characteristics will be summarized in a descriptive fashion. Data 
to be evaluated will include age, sex, race, weight, baseline disease characteristics, and other 
parameters, as appropriate.
13.1.8. 
Data Analyses 
13.1.8.1. Phase 1
Two-parameter Bayesian logistic regression model (BLRM) with EWOC will be used to guide 
dose escalation and estimate the MTD based on occurrence of DLT during Cycle 1. MTD with 
estimated posterior probability of a DLT within target toxicity interval (16%, 33%] among the 
admissible doses fulfilling EWOC is determined by BLRM. MTD is estimated based on 
observed DLTs.
After completing a given dose escalation cohort, the decision to move up to the next cohort or 
not, or to adjust to a lower or slightly higher dose, will be decided by the SRC based on BLRM 
with EWOC and integration of all available safety data, PK, and other clinical data using the 
BLRM method. The dose recommended using the BLRM method will serve as a guide and will 
be integrated with clinical assessment of the toxicity information and review of other available 
data to determine the actual treatment dosage.
Additional or intermediate dose levels may be explored after the discussion and concurrence of 
SRC and SDP Oncology clinical team. It is possible that potential arm with different dosing 
schedule is added during the Phase I study period based on safety considerations. 
13.1.8.2. Determination of Recommended Dose 
The recommended dose is usually the dose with acceptable toxicity, generally defined as the 
dose level producing a DLT rate within the toxicity interval (16%, 33%]. Determination of the 


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recommended dose will be performed in consultation with the SRC based on safety and other 
data available at the time of the recommended dose decision.  
Once the recommended dose for the expansion arms is identified, the Phase 1 portion of the 
study will progress to Phase 2.  
13.1.8.3. Phase 1 Study Stopping Rule
Dose Escalation can be stopped earlier by a joint decision from SDP Oncology and the 
Investigators during an SRC meeting, by considering the model estimations and a global 
assessment of the safety, PK, pharmacodynamics, and preliminary clinical data.  
The following safety event will trigger a temporary suspension of patient enrollment to study 
treatment if the posterior probability of target toxicity at each dose level exceeds 50% and is the 
highest among potential dose levels. 
Based on the safety review with the SRC, SDP Oncology will determine whether the study may 
continue (with or without a protocol amendment) or if it must be terminated. 
13.1.8.4. Phase 1 DLT Analysis
The DLT will be summarized by dose level using DAS for patients in Phase 1. By-patient listing 
of the DLTs will also be provided. 
13.1.9. 
Phase 2
Bayesian posterior probability of response rate will be estimated continuously. The study may be 
stopped early for futilit
enrollments starting from 10 enrolled efficacy evaluable patients. Study will be considered to be 
13.1.9.1. Efficacy Analysis
13.1.9.1.1. Phase 1 Efficacy Analysis
Phase 1 efficacy endpoints will be analyzed using Phase 1 Efficacy Analysis Set.  
Efficacy analysis at Phase 1 will be conducted using similar methods defined in Phase 2 portion 
unless otherwise specified (details in Section 13.1.9.1.2).
Overall survival for Phase 1 is defined as the time from the date of initial dosing at same dose 
level or one dose level lower than RP2D to the date of death. Patients without documentation of 
death at the time of analysis will be censored at the date last known to be alive. Overall survival 
will be analyzed based on Phase 1 SAS patients. 
13.1.9.1.2. Phase 2 Efficacy Analysis
13.1.9.1.2.1. Response Rate
Response rate is defined as the proportion of patients who achieves response according to the 
composite endpoint criteria for a consecutive period of 8 weeks (Appendix 1). Response rate will 
be estimated with 2-sided 95% exact binomial confidence intervals based on EAS. 


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13.1.9.1.2.2.12-Week Response Rate 
The 12-Week response rate is defined as the proportion of patients who achieves response 
according to the composite endpoint criteria for a consecutive period of 12 weeks (Appendix 1). 
The 12-Week response rate will be estimated with 2-sided 95% exact binomial confidence
intervals based on the EAS. 
13.1.9.1.2.3.Time to RBC transfusion-free analysis
Time to RBC transfusion-free period is defined as the time from the date of initial dosing at 
RP2D to first documentation of a transfusion-free period for patients who have one or more 
transfusion-free periods. Transfusion-free period is defined as the period that a patient becomes 
transfusion-free for consecutive 8 weeks or longer after treatment of TP-0184. Kaplan-Meier 
(K-M) survival curve and K-M median (estimate), along with 2-sided 95% CIs, will be provided. 
13.1.9.1.2.4. Duration of Hemoglobin Response 
Duration of hemoglobin response is defined as the time from the date of first documentation of a 
hemoglobin response to the date of first documentation of progression of hemoglobin response 
for hemato
maintained for a consecutive period of > 8 weeks with no transfusions; hemoglobin progression 
is defined as a change from baseline < 1.5 g/dL of the hemoglobin or the start of one or more 
transfusions.  
The K-M survival curve and K-M median (estimate), along with 2-sided 95% CIs will be 
provided. 
13.1.9.1.2.5. Duration of Reduction in RBC Transfusion for 8 Weeks Analysis 
High transfusion burden patient with reduction in RBC transfusion for 8 weeks is defined as high 
equal or more than 4 units transfusions in consecutive 8 weeks in EAS.  
Duration of reduction in RBC transfusions for 8 weeks is defined as the time from the 
assessment date of consecutive 8 weeks with reduction from baseline of RBC transfusions 
>= 4 units to the assessment date of the reduction from baseline < 4 units or increased 
transfusions frequencies from baseline within a consecutive 8 weeks. For high transfusion 
burden patient with reduction in RBC transfusion. 
The K-M survival curve and K-M median (estimate), along with 2-sided 95% CIs will be 
provided. 
13.1.9.1.2.6. Duration of RBC Transfusion-
 8 weeks 
RBC transfusion-free period  8 weeks patient is defined as a patient who maintains RBC 
transfusion-free during consecutive 8 weeks or longer in EAS. 
Duration of RBC transfusion-
 8 weeks is defined as the time from the assessment 
date of consecutive 8 weeks without any RBC transfusions to the assessment date of the first 
documented transfusion in the following visits for RBC transfusion-
patients. 


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The K-M survival curve and K-M median (estimate), along with 2-sided 95% CIs will be 
provided. 
13.1.9.1.2.7. Changes in Neutrophil Count 
Hematologic improvement in neutrophil count (HI-N) is defined as patients achieving over any 
consecutive 8-week (56-day) period and / or decrease in neutrophil levels in EAS.  
Change in neutrophils analysis will provide summary statistics of the proportion of patients with 
hematologic improvement in neutrophil count with 2-sided 95% exact binomial confidence 
intervals using EAS. 
13.1.9.1.2.8. Changes in Platelet Count 
Hematologic improvement in platelet count (HI-P) is defined as patients achieving hematologic 
improvement in platelets over any consecutive 8-week (56-day) period and / or decrease in 
platelet levels in EAS.  
Change in platelet count analysis will provide summary statistics of the proportion of patients 
with hematologic improvement in platelet count with 2-sided 95% exact binomial confidence 
intervals using EAS. 
13.1.9.1.2.9. Progression to AML 
Progression to AML is defined follow the guidelines by IWG Response Criteria for MDS 2006 
(Appendix 6).
Summary statistics of the proportion of patients progressing to AML will be estimated with 
2-sided 95% exact binomial confidence intervals based on EAS.  
13.1.9.1.2.10. Time to Progression to AML 
Time to progression to AML is defined as the time from the date of initial dosing at RP2D to the 
date of first documented progression to AML using EAS.  
The K-M survival curve and K-M median (if estimable), along with 2-sided 95% CIs will be 
provided.
13.1.9.1.2.11. Overall Survival
Overall survival is defined as the time from the date of initial dosing at RP2D to the date of 
death. Patients without documentation of death at the time of analysis will be censored at the 
date last known to be alive.  Overall survival will be analyzed based on SAS patients whose 
initial dosing is RP2D. 
The KM survival curve and K-M median (if estimable), along with 2-sided 95% Cis will be 
provided.  
13.1.9.1.2.12. Hematopoietic Stem Cell Transplant Analysis 
Hematopoietic stem cell transplant (HSCT) patients are defined as patients achieving a 
hematologic response and an HSCT in EAS. Summary statistics of the proportion of 


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hematopoietic stem cell transplant patients will be estimated with 2-sided 95% exact binomial 
confidence intervals among hematologic response in EAS.
13.1.9.1.2.13. MRI Imaging Analysis
Summary statistics will be provided based on MRI quantitative results by cohort, study, and 
overall patients. By-patient listings will be provided. 
13.1.9.2. Safety Analysis 
13.1.9.2.1. Phase 1 Safety Analysis
All safety analyses will be performed on the safety analysis set in Phase 1. Adverse event listings 
and tabulated summaries of TEAEs will be generated for each dose level, and for all Phase 1 
patients. Treatment-emergent AEs are AEs that occur after administration of the first dose of 
study drug and through 30 days after the last dose of study drug. Additionally, AESIs, SAEs, the 
number of patients enrolled, the number of patients evaluable for dose escalation, number of 
patients with DLTs, and TP-0184 dose interruption and reduction due to TEAEs will be 
described for each dose level and for all Phase 1 patients.   
Descriptive statistics for the actual values and changes from baseline of vital signs, weight, 
ECOG scores will be tabulated by scheduled time point by each dose level, and for all Phase 1 
patients. ECHO or MUGA scans, cardiac markers, and other test results will be analyzed using 
proper statistical methods for each dose level, and for all Phase 1 patients.   
13.1.9.2.2. Phase 2 Safety Analysis 
Safety will be evaluated by the incidence of AEs, severity and type of AEs, SAEs, and by 
changes from baseline in the patient’s vital signs, weight, and clinical laboratory results using the 
safety population. Exposure to study drug and reasons for discontinuation will be tabulated.
Treatment-emergent AEs will be tabulated according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will include the following categories:  
 TEAEs 
 Drug-related TEAEs 
 Grade 3 or higher TEAEs 
 Grade 3 or higher drug-related TEAEs 
 The most commonly reported 
 10% of patients 
in any treatment group)  
 SAEs 
 AESI 
A listing of TEAEs resulting in study drug discontinuation will be provided. 
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) 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 changes from baseline of vital signs, weight, 
ECOG scores will be tabulated by scheduled time point.   


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Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE v.5 
grade from baseline to the worst post baseline value. Graphical displays of key safety 
parameters, such as scatter plots of baseline versus worst post baseline values, may be used to 
understand the TP-0184 safety profile. 
All concomitant medications collected from screening through the study period will be classified 
to preferred terms according to the World Health Organization (WHO) Drug Dictionary. 
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of TP-0184. 
13.1.9.3. Pharmacokinetics and Biomarkers 
Pharmacokinetic parameters including Cmax, Ctrough, tmax, and AUC , will be estimated using 
standard noncompartmental methods. Other parameters may also be computed. Actual sample 
collection times will be used rather than scheduled (nominal) collection times, where available 
(Table 7 and Table 8). Data obtained from the current study may be modeled, either singularly or 
in conjunction with data from other studies (for example, for population PK analyses).  
Exploratory endpoints including biomarker analysis will be summarized using mean, standard 
deviation, median, and minimum/maximum levels of continuous, and frequencies and 
percentages of categorical biomarker measures for the potential biomarker parameters 
(Section 11.2). The correlations of biomarker results with pharmacokinetic parameters and 
measures of efficacy may be explored, if deemed appropriate.
13.1.9.4. Patient-reported Outcomes
Patient-reported outcome assessments using BFI will be analyzed to determine any measurable 
changes in the severity of fatigue based on the worst fatigue score experienced during the past 
24-hours. The analysis will be performed using proper statistical methods for collected scores 
using SAS in Phase 2. Missing items in BFI scores will be handled based on each individual 
assessment and according to the developer’s guidelines. Investigation of missing patterns and 
details of imputation will be discussed in the SAP. Similar analyses will be performed using BFI 
assessments in Phase 1 if data is applicable. 


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14.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
14.1.
Study Monitoring
Before an investigational site can enter a patient into the study, a monitor from SDP Oncology or 
a representative will visit the investigational study site to: 
 Determine the adequacy of the facilities
 Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of SDP Oncology or its representatives. This 
will be documented in a Clinical Study Agreement between SDP Oncology and the 
investigator. 
During the study, a monitor from SDP Oncology or representative will have regular contacts 
with the investigational site, for the following: 
 Provide information and support to the investigator(s) 
 Confirm that facilities remain acceptable
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
 Perform source data verification. This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each patient 
(eg, clinic charts). 
 Record and report any protocol deviations not previously sent to SDP Oncology. 
 Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to SDP Oncology and those SAEs that met criteria for 
reporting have been forwarded to the IRB.
 The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
During the COVID-19 public health emergency, traditional on-site monitoring might be difficult 
for reasons such as: (1) sites may not be able to accommodate monitoring visits (eg, due to 
staffing limitations or site closures) or (2) monitors may not be able to travel to trial sites. When 
planned on-site monitoring visits are not possible, the reason should be documented and 
available for review by SDP Oncology and during FDA inspections. On-site monitoring visits 
may be replaced with remote monitoring visits during the COVID-19 public health emergency 
(Food and Drug Administration, January 2021). 
14.2. 
Audits and Inspections 
Authorized representatives of SDP Oncology, a regulatory authority, an Independent Ethics 
Committee, or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification. The purpose of an SDP Oncology audit or inspection is to 
systematically and independently examine all study-related activities and documents to 


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determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Conference on Harmonization, and any applicable regulatory requirements. The 
investigator should contact SDP Oncology immediately if contacted by a regulatory agency 
about an inspection.
14.3. 
Institutional Review Board/Independent Ethics Committee 
The investigator must obtain IRB or IEC approval for the study. Initial IRB/IEC approval of the 
protocol and all materials approved by the IRB/IEC for this study, including the patient ICF and 
any recruitment materials must be maintained by the study site/investigator and made available 
for inspection by the study monitor or any regulatory authorities with an interest in this study. 


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15.
QUALITY CONTROL AND QUALITY ASSURANCE
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
SDP Oncology may conduct a quality assurance audit. Refer to Section 14.2 for more details 
regarding the audit process.


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16.
ETHICS
16.1.
Ethics Review
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
investigator must submit written approval to SDP Oncology before he or she can enroll any 
patient/subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study. The protocol must be re-approved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. SDP Oncology will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH Good Clinical Practice, applicable 
regulatory requirements and the SDP Oncology’s policy on Bioethics.
16.3. 
Informed Consent 
The Principal Investigator(s) at each site will ensure that the patient is given full and adequate
oral and written information about the nature, purpose, possible risk and benefit of the study. 
Patients must also be notified that they are free to discontinue from the study at any time. The 
patient should be given the opportunity to ask questions and allowed time to consider the 
information provided.
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures. If an informed consent cannot be obtained and documented from a prospective trial 
participant (or legally authorized representative) as signed paper copy, the consent form may be 
provided electronically by the Investigator/designee.  
Where a prospective trial participant (or legally authorized representative) is unable to print the 
informed consent document provided electronically by the Investigator/designee, an electronic 
signature process is not available, and the prospective trial participant must meet time-sensitive 
eligibility criteria, the investigator may consider using the alternative process to satisfy FDA 
requirements for obtaining and documenting informed consent and IRB approved process. (Food 
and Drug Administration, January 2021) 


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The Principal Investigator(s) must maintain the original, signed Informed Consent Form. A copy 
of the signed Informed Consent Form must be given to the patient.


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17.
DATA HANDLING AND RECORDKEEPING
17.1.
Data Protection
Monitors, auditors, and other authorized agents of the Sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the FDA, as well as that of any other applicable 
regulatory agency(ies), will be granted direct access to the study patient’s original medical 
records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the patient to the extent permitted by laws and regulations. In any presentation 
of the results of this study or in publications, the patient’s identity will remain confidential. 
All personal data collected and processed for the purposes of this study should be managed by 
the investigator and his/her staff with adequate precautions to ensure the confidentiality of those 
data, and in accordance with the Health Insurance Portability and Accountability Act and 
applicable national and/or local laws and regulations regarding personal data protection.
17.2. 
Inspection of Records 
SDP Oncology will be allowed to conduct site visits to the investigation facilities for the purpose 
of monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. If on-site monitoring visits are not 
possible SDP Oncology will be allowed to do remote monitoring to maintain oversight of the 
clinical site.
17.3. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for SDP Oncology or 
the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records.


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18.
PUBLICATION POLICY
The publication policy for the study will be described in the clinical study agreement. To avoid 
disclosures that could jeopardize proprietary rights, the investigator agrees to give SDP 
Oncology the right to review all manuscripts, abstracts, and presentations related to this study 
prior to their submission for publication or presentation. SDP Oncology may use these data now 
and in the future for presentation or publication at SDP Oncology’s discretion or for submission 
to government regulatory agencies.  
Authorship among Investigators generally will be based on the extent of significant contribution, 
including scientific and clinical, to the publication.


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19.
LIST OF REFERENCES
Bach DH, Park HJ, Lee SK. The Dual Role of Bone Morphogenetic Proteins in Cancer. Mol 
 
Bhagat TD, Zhou L, Sokol L, et al. miR-21 mediates hematopoietic suppression in MDS by 
activating TGF-
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2008;112(8):3434-43.
Brunning RD, Bennett JM, Flandriin G, et al. Pathology and genetics of tumors and 
hematopoietic and lymphoid tissues. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. 
World Health Organization Classification of Tumors, Lyon (France). IARC Press 2001: 63-73
Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem 
 
Han HJ, Jain P, Resnick AC. Shared ACVR1 mutations in FOP and DIPG: Opportunities and 
challenges in extending biological and clinical implications across rare diseases. Bone 
Herbertz S, Sawyer JS, Stauber AJ, et al. Clinical development of galunisertib (LY2157299 
monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. 
Drug Des Devel Ther. 2015 Aug 10; 9:4479-99
-CoV-2 
in patients with COVID-19. Nature Medicine 2020; 26:845-848 
Fenaux P, Platzbecker U, Mufti G, Garcia-Manero G, Buckstein R, Santini V, Díez-Campelo M, 
Finelli C, Cazzola M, Ilhan O, Sekeres M, Falantes J. Luspatercept in Patients with Lower-Risk 
Myelodysplastic Syndromes. January 9, 2020. N Engl J Med 2020; 382:140-151
Malcovati L, Della Porta MG, Strupp C, et al. Impact of the degree of anemia on the outcome of 
patients with myelodysplastic syndrome and its integration into the WHO classification-based 
Prognostic Scoring System (WPSS). Haematologica. 2011 Oct;96(10):1433-40.   
Martelotto LG, Baslan T, Kendall J, Geyer FC, Burke KA, Spraggon L, et al. Whole-genome 
single-cell copy number profiling from formalin-fixed paraffin-embedded samples. Nat Med 
 
Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et al. The rapid 
assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 
1999;85:1186–96) 
Pacifici M, Shore EM. Common mutations in ALK2/ACVR1, a multi-faceted receptor, have 
roles in distinct pediatric musculoskeletal and neural orphan disorders. Cytokine Growth Factor 
 
Prebet T, Toma A, Cluzeau T, et al. Outcome of patients treated for myelodysplastic syndromes 
without deletion 5q after failure of lenalidomide therapy. Oncotarget 2017; Vol. 8(23):37866-
37874. 
Singh B, Arora S, Agrawal P, Gupta SK. Hepcidin: a novel peptide hormone regulating iron 
metabolism. Clin Chim Acta 2011;412(11-
 


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Sun CC, Vaja V, Babitt JL, Lin HY. Targeting the hepcidin-ferroportin axis to develop new 
treatment strategies for anemia of chronic disease and anemia of inflammation. Am J Hematol  
2012;87
 
Suragani RN, Cadena SM, Cawley SM, et al. Transforming growth factor-
trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014 
Apr;20(4):408-14. 
Taylor KR, Vinci M, Bullock AN, Jones C. ACVR1 mutations in DIPG: lessons learned from 
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization 
(WHO) classification of myeloid neoplasms and acute myeloid leukemia: rationale and 
important changes. Blood 2009;114(5):937-51.
Zhao B, Pritchard JR. Inherited Disease Genetics Improves the Identification of Cancer-
Associated Genes. PLoS Genet 2016;12(6):e1006081. 
Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest 2013;123(
 
Zhou L, McMahon C, Bhagat T, et al. Reduced SMAD7 leads to overactivation of  TGF-beta 
signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. 
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Zhou L, Nguyen AN, Sohal D, Ying Ma J, Pahanish P, Gundabolu K, et al. Inhibition of the 
TGF-
 
 
 


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20.
APPENDICES
 




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APPENDIX 2.
BLRM STATISTICAL METHODS
17.2.1 
Introduction 
In the Dose Escalation part of the study, an adaptive Bayesian logistic regression model (BLRM) 
with EWOC will be used to guide dose escalation and estimate the MTD(s) based on occurrence 
of DLT during Cycle 1. This appendix provides details on the statistical model, prior definition 
and operating characteristics in order to illustrate the performance of the design in estimating the 
MTD under various dose-toxicity relationships through simulations. Finally, hypothetical dose 
escalations scenarios will be presented to illustrate the dose allocation in first cohorts of the 
study. 
20.1.1. 
Dose Escalation Method
17.2.2.1 
Statistical Model 
The DLT-dose relationship in the Dose Escalation part of the study is described by a 2-parameter 
logistic model: 
( ) = log( ) +
log(
) ,
> 0,
> 0
where 
( ) = log
( )
( ) and 
( ) is the probability of a DLT at dose . Doses are rescaled as
 with reference dose 
= 90 
 of TP-0184. As a consequence
toxicity at 
. Note that for a dose equal to zero, the probability of toxicity is zero.
The MTD is the highest drug dosage that is unlikely (< 25% posterior probability) to cause DLT 
in more than 33% of the treated patients in the first cycle of TP-0184 treatment. 
20.1.1.1. Planned Dose Escalation Levels
This study currently plans and expects to complete dose escalation with the following 
provisional dose levels:
Table 10
Planned Dose Escalation Levels
Dose Level
Dose (Daily Schedule) 
-1
10 mg 
1
20 mg 
2
40 mg 
3
60 mg 
4
90 mg 
5
120 mg
6
160 mg
7
210 mg
8
270 mg
Note: An intermediate dose level between the planned dose levels may be explored. In addition, 
based on safety during the escalation phase, additional dose schedules than those outlined in the 


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table may be explored after discussion and concurrence with SRC members and SDP Oncology 
clinical team. 
Intra-patient dose escalation is not permitted in the protocol. 
20.1.1.2. Prior Specifications 
The bivariate normal prior for the BLRM parameters with a reference dose level of 90 mg is 
obtained as follows: 
The following noninform
 
 
-
median DLT rate to be around 1%. 
 
to 0.482, which allows for considerable prior uncertainty for the dose-toxicity profile. 
 
-0.9. 
Table 11 
Prior Parameters for Bivariate Normal Distribution of Model Parameters 
Parameters
Means
Standard Deviations
Correlation 
log( ) , log( )
(-0.847, 0.913)
(1.275, 0.482) 
-0.9 
Table 12 
Prior Distribution Summaries Derived from Priors in Table 11  
TP-0184 
Dose (mg) 
Prior Probabilities Pr(DLT) is in 
Interval:
Mean 
SD 
Quantiles 
(0, 0.16] 
(0.16, 0.33] 
(0.33, 1] 
2.5% 
50% 
97.5% 
20 
0.8685 
0.0744 
0.0571 
0.06784 
0.13677 
0 
0.0101 
0.5253 
40 
0.7191 
0.1414 
0.1395 
0.13674 
0.18611 
0.00026 
0.05436 
0.6946 
60 
0.5463 
0.2089 
0.2448 
0.21414 
0.21583 
0.00324 
0.1354 
0.77793 
90 
0.2602 
0.282 
0.4578 
0.34556 
0.22766 
0.03638 
0.3026 
0.84387 
120 
0.0303 
0.2178 
0.7519 
0.48932 
0.20034 
0.15282 
0.47701 
0.87993 
160
0 
0.0119
0.9881
0.66399
0.14196
0.37032
0.67276
0.91269
210 
0 
1e-04 
0.9999 
0.80101 
0.09715 
0.57776 
0.81558 
0.95098 
270 
0 
0 
1 
0.88234 
0.06829 
0.72003 
0.89404 
0.98476 
Note: Bold doses indicate not meeting the overdose control criterion (more than 25% chance of over-dosing) with the prior 
information only.
Abbreviation: DLT = dose-limiting toxicity.
20.1.1.3. Dose Recommended by the BLRM Method
The dose allocation will start at the dose of 20 mg. Patients will be included by cohort of 1 to 6 
patients. There must be at least 3 DLT evaluable patients at a specific dose level if there is a DLT 
observed in that level. After each cohort of patients is completed, the dose recommendation by 
the model will be based on posterior summaries including the mean, median, standard deviation, 
95% credible interval, and the probability that the true DLT rate for each dose lies in one of the 
following categories: 


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 (0, 16%]: under-dosing  
(16%, 33%]: targeted toxicity
(33%, 100%]: over-dosing
Following the principle of EWOC, after each cohort of patients the recommended dose by the 
model is the one with the highest posterior probability of the DLT rate falling in the targeted 
toxicity interval (16%, 33%] among the admissible doses fulfilling EWOC, i.e., it is unlikely (< 
25% posterior probability) that the DLT rate at the dose falls in the over-dosing interval. 
17.2.2 
Final Recommendation and Stopping Rules 
Dose escalation will continue until identification of the MTD(s) or suitable lower dose for 
recommended phase 2 dose(s) (the RP2D). This will occur when the following conditions are 
met: 
1. At least 6 patients have been treated at this dose. 
2. This dose satisfies one of the following conditions: 
a. The posterior probability of targeted toxicity at this dose exceeds 50% and is the 
highest among potential doses, or  
b. A minimum of 12 patients have already been treated on the trial. 
3. It is the dose recommended for patients, by review of all clinical data by patients of the 
end of cohort meeting. Of note, the Dose Escalation part could be stopped earlier by a 
joint decision from the Sponsor and the Investigators during an SRC meeting, by 
considering the model estimations and a global assessment of the safety, PK, 
pharmacodynamics, and preliminary activity data. 
17.2.3 
Operating Characteristics 
17.2.3.2 
Introduction  
This section presents the operating characteristics illustrating the precision of the design in 
estimating the MTD under various assumed true dose-toxicity relationship. 
17.2.3.3 
True Dose-DLT Scenarios  
Simulations were performed on several true toxicity-dose relationships: 
4. non-decreasing and finally reaching plateau
5. linear increasing (no plateau)
6. constant 
7. increase steadily at the first beginning, and then increase much faster 


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Table13
True Underlying DLT Probabilities
TP-0184 Dose Level (mg) 
Dose-limiting Toxicity 
(DLT) Scenarios
20
40 
60 
90 
120 
160 
210 
270 
A 
0.05 
0.1 
0.2 
0.3 
0.33 
0.45 
0.56 
0.7 
B 
0.05 
0.1
0.2
0.3
0.35 
0.65 
0.8
0.9 
C
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
D
0.05 
0.1 
0.15 
0.2 
0.25 
0.25 
0.35 
0.35 
17.2.3.4 
Simulation Parameters  
For each dose-DLT scenario, 5,000 clinical trial replications were generated using R software 
version 3.6.0 on a x86-64 architecture on a Windows OS. The Markov chain Monte Carlo 
(MCMC) estimation is obtained using R packages rjags and R2WinBUGS with 2,000 burn-in 
and 12,000 iterations on 2 chains (6,000 each). The seed used for MCMC estimation is 1 for 
chain 1 and 2 for chain 2.  
Maximum number of patients of 30 was used. However, during the study, more patients may be 
added. The dose allocation rule used in the simulations is identical to the rule presented in 
Section 20.1.1.3, ie, dose having the highest posterior probability of the DLT rate falling in the 
targeted interval (16%, 33%] among the admissible doses fulfilling EWOC.
20.1.1.3.1. Evaluation Metrics 
Operating characteristics were reviewed for the simulations to compare the relative performance 
of the design under each true dose-DLT relationship. The following metrics were: 
 Probability of recommending as the MTD: 
 An under-toxicity dose level, i.e., a dose with true probability of DLT in the 
under-toxic interval (0%, 16%] (Sponsor risk) 
 A targeted-toxicity dose level, i.e., a dose with true probability of DLT in the 
targeted-toxicity interval (16%, 33%] (correct final decision)
An over-toxicity dose level, i.e., a dose with true probability of DLT in the over 
toxicity interval (33%, 100%] (patient risk)
Average number of patients per trial exposed at:
An under-toxicity dose level, as defined above
A targeted-toxicity dose level, as defined above
An over-toxicity dose level, as defined above
Summary of the total number of patients per trial (mean, first quartile, median, third 
quartile)
Average total number of DLTs observed per trial
20.1.1.3.2. Operating Characteristics of the Design
Operating characteristics of the final design are reviewed to investigate performance of the 
model under each true dose-DLT scenario. 
Table 14 summarizes the results from the simulations performed.


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Table 14: 
Summary Metrics of the Simulations Performed 
DLT 
scenario 
Probability of Recommending 
a Dose with true Pr(DLT) 
No MTD 
Recommended 
Average Number of Patients Per Trial 
Receiving a Dose with True Pr(DLT) 
Average Number of Patients 
(0, 
0.16] 
(0.16, 
0.33] 
(0.33, 1] 
(0, 0.16] 
(0.16, 0.33] 
(0.33, 1] 
Per Trial        
(Q1-Median-
Q3)
Experiencing 
a DLT per 
Trial 
A 
0.038 
0.771 
0 
0.19 
0.3 
10.3 
0 
21.3 (22-22-26) 
5 
B 
0.105 
0.487 
0.201 
0.207 
0.9 
5.2 
1.8 
20.8 (22-22-26) 
5 
C 
0.015 
0 
0 
0.985 
0.3 
0 
0 
26.2 (30-30-30) 
0.1 
D 
0.181 
0.326 
0.303 
0.19 
1.8 
3 
5.4 
21.1 (22-22-26) 
4.7 
Abbreviations: MTD = maximum tolerated dose; P(DLT) 


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17.2.4 Hypothetical Dose Allocation Scenarios in Early Cohorts 
Aside from the overall operating characteristics studied above, the design should make 
reasonable decisions during a study based on the observed DLTs. After completion of a given 
dose level, the dose allocation for the subsequent dose level will depend on the recommendation 
of the model and medical review of all available data. 
Some scenarios to illustrate on-study dose allocation are presented in Table 15. These scenarios 
assume that each dose level has 3 or more evaluable patients and the next recommended dose is 
based on the rule defined in Section 20.1.1.3, with the provisional doses specified in Table 15. 
However, during the study it may be possible to add new provisional dose levels. 
 


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Table 15:
Hypothetical Dose Allocation Scenarios in Early Cohorts
Scenario
Dose (mg)
Npat
Ntox
NDL
P(target) 
at NDL 
P(overtox) 
at NDL 
DLT Rate 
median at 
NDL 
1
20
3 
0 
60 
0.2314 
0.1462 
0.102
2
20, 40
3, 3 
0, 0
90 
0.3905 
0.2312 
0.205
3
20, 40, 60
3, 3, 3
0, 0, 0
90 
0.3571 
0.1501 
0.162
4
20, 40, 60, 90
3, 3, 3, 4
0, 0, 0, 1 
90 
0.5059 
0.1293 
0.193
5
20, 40, 60, 90, 120
3, 3, 3, 3, 4 
0, 0, 0, 0, 1
90 
0.2547 
0.0269 
0.109
6
20, 40, 60, 90, 120
3, 3, 3, 4, 4 
0, 0, 0, 0, 1
90 
0.2426 
0.0194 
0.106
7
20, 40, 60, 90, 120, 160 
3, 3, 3, 3, 3, 4 
0, 0, 0, 0, 0, 1
120
0.6128 
0.1222 
0.207
8
20, 40, 60, 90, 120, 160 
3, 3, 3, 3, 4, 6 
0, 0, 0, 0, 0, 1
120
0.5706 
0.0503 
0.178
9
20, 40, 60, 90, 120, 160 
3, 3, 3, 3, 4, 6 
0, 0, 0, 0, 0, 1
120
0.5706 
0.0503 
0.178
Abbreviations: DLT = Dose-limiting toxicity; EWOC = Escalation with overdose control; NDL = Next dose level; Npat = 
Number of patients; Ntox = Number of toxicities. 
P(target) at NDL: posterior probability that the true DLT rate for the next recommended dose lies in the targeted interval (16%, 
33%]. 
P(overtox) at NDL: posterior probability that the true DLT rate for the next recommended dose lies in the excessive toxicity 
interval (33%, 100%].


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17.2.5 Hypothetical Dose Allocation Scenarios in Early Cohorts:  Visualize Interval 
Probabilities by Dose 
Scenario 1: 
0/3 pts at 20 mg 
 


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Scenario 2: 
1/4 pts at 90 mg
 


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Scenario 3: 
2/4 pts at 90 mg 
In general, when no DLTs are observed in 3 patients at a dose level, the decision is to increase 
the dose. When 1 DLT is observed in 3 patients, the decision is to stay at the current dose level 
or to escalate to the higher provisional dose level. When more than 1 DLT is observed in a 
3-patient cohort, the decision is to decrease the dose level or to stay at the current level. 


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APPENDIX 3.
REVISED INTERNATIONAL PROGNOSTIC SCORING 
SYSTEM (IPSS-R) 


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APPENDIX 4.
GUIDELINES RELATED TO MDS CLASSIFICATION
Myelodysplastic Syndromes World Health Organization 
Classification System 
 


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APPENDIX 5.
CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION 
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
 Premenarchal 
 Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
 For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the patient’s 
medical records, medical examination, or medical history interview. 
 Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
A high follicle stimulating hormone level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one follicle stimulating hormone measurement is required.
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
Contraception Guidance: 
Female patients of childbearing potential (defined as first menarche through post-menopause or 
permanent sterilization) must agree to continued abstinence from heterosexual intercourse or 
2 acceptable methods of birth control, including one highly effective method and one additional 
barrier method at the same time, during the study and for 7 months following the last dose of 
study drug.
Highly effective contraceptive methods are as follows:
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
Oral




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APPENDIX 6.
INTERNATIONAL WORKING GROUP RESPONSE 
CRITERIA FOR MYELODYSPLASTIC SYNDROMES, 
2006 


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APPENDIX 7.
ECOG PERFORMANCE STATUS 
ECOG
Description
0 
Fully active, able to carry on all pre-disease performance without restriction 
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work. 
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on self-care. Totally confined to bed or chair.
Source: Oken MM, et al.., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol (1982) 5:649-
655.
 








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APPENDIX 9.
MEDICATIONS WITH KNOWN OR POSSIBLE RISK OF 
PROLONGING QT OR INDUCING TORSADES DE 
POINTES  
Please check the following website for the most up-to-date information: 
https://crediblemeds.org/new-drug-list/ 


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APPENDIX 10. BRIEF FATIGUE INVENTORY


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APPENDIX 11. NEW YORK HEART ASSOCIATION CLASSIFICATION 
SCALE 
NYHA Classification - The Stages of Heart Failure 
Class 
Functional Capacity 
Objective Assessment 
I
No symptoms and no limitation in 
ordinary physical activity, eg, 
shortness of breath when walking, 
climbing stairs etc. 
A. No objective evidence of 
cardiovascular disease. 
II
Mild symptoms (mild shortness of 
breath and/or angina) and slight 
limitation during ordinary activity. 
B. Objective evidence of 
minimal cardiovascular disease. 
III 
Marked limitation in activity due to 
symptoms, even during less-than-
ordinary activity, eg, walking short 
distances (20-100 m). Comfortable 
only at rest. 
C. Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Severe limitations. Experiences 
symptoms even while at rest. Mostly 
bedbound patients. 
D. Objective evidence of severe 
cardiovascular disease. 
V 
No NYHA class listed or unable to 
determine 
N/A 
Source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. 
Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 

SAP_001.pdf: 
Sumitomo Dainippon Pharma Oncology, Inc. 
                         
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                                                                                  Statistical Analysis Plan  Version 1.0 
 
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STATISTICAL ANALYSIS PLAN 
PHASE I/II 
Date of Plan: 15DEC2021  
 
Based on Protocol Version: BBI-TP-0184-102 Version: 2 
 
STUDY DRUG: TP-0184 
 
STUDY NUMBER: BBI-TP-0184-102 
 
STUDY TITLE: 
A PHASE 1/2, OPEN-LABEL CLINICAL STUDY TO EVALUATE SAFETY 
AND EFFICACY OF TP-0184 TO TREAT ANEMIA WHEN ADMINISTERED 
TO ADULT PATIENTS WITH IPSS-R LOW OR INTERMEDIATE RISK 
MYELODYSPLASTIC SYNDROMES 
 
Sponsor:  
Sumitomo Dainippon Pharma Oncology, Inc. 
640 Memorial Drive 
Cambridge, MA 02139 
Phone: 617-674-6800 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 
 
 
 


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SIGNATURE PAGE
Author: 
Huyuan Yang, PhD
Director, Biostatistics
Sumitomo Dainippon Pharma Oncology, Inc.
Date
Approved by: 
Jie Ding, PhD
Executive Director, Biostatistics
Sumitomo Dainippon Pharma Oncology, Inc.
Date
Gregory Pennock, MD
  Senior Medical Director, Translational Medicine 
Sumitomo Dainippon Pharma Oncology, Inc.


Sumitomo Dainippon Pharma Oncology, Inc. 
                         
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Table of Contents 
1.INTRODUCTION ................................................................................................................ 5 
1.1 
Study Design .......................................................................................................... 5 
1.2 
Study Objectives and Endpoints ............................................................................ 6 
2. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ........................ 12 
3.   STATISTICAL SOFTWARE .......................................................................................... 13 
 
 


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1.     INTRODUCTION 
1.1 
Study Design 
This is a Phase 1/2, open-label clinical study to evaluate preliminary safety and efficacy of 
TP-0184 to treat anemia when administered to adult patients with Revised International 
Prognostic Scoring System (IPSS-R) low or intermediate risk Myelodysplastic Syndrome 
(MDS) who have received prior erythropoiesis stimulating agents (ESA)-containing regimen. 
The recommended phase 2 dose (RP2D) will be determined by the maximum tolerated dose 
(MTD) or maximum administered dose (MAD) in the Phase 1 portion of the study. 
 
Study schematic: from TP-0184-102 protocol 
 
Phase 1 
Dose-escalation for TP-0184 will be performed using a Bayesian logistic regression model 
(BLRM) at a starting dose of 20 mg/day every day, administered in the fasting state (6 hours 
before the dose and 1 hour after the dose).  
 
The BLRM method will be applied along with escalation with overdose control (EWOC) 
principle to control the risk of exposing patients to toxic doses. Based on this principle, a 
dose level will be considered safe if the probability of excessive toxicity, ie, the probability 
of a dose limiting toxicities (DLT) rate greater than 33%, with EWOC is less than or equal to 
25%. After completion of a given dose cohort, a decision will be made to either adjust the 
dose (de-escalate the dose, escalate the dose) or further enroll patients at the same cohort to 
be tested based on a risk assessment using the BLRM method. The dose recommended using 
the BLRM method will be treated as a guide and will be integrated with a clinical assessment 
of the toxicity information and review of other available data. 
The phase 1 portion,  will be conducted in approximately 30 patients due to the dynamic 
feature of BLRM.   
 


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Phase 2 
Phase 2 will determine the preliminary efficacy of TP-0184 in an expansion phase of up to 60 
patients. Preliminary efficacy as assessed by the response rate will be monitored using the 
Bayesian posterior probability to optimize the enrollment with Bayesian stopping rules. 
  
1.2 
Study Objectives and Endpoints 
Phase 1 
 
Primary 
Objectives 
Endpoints 
To assess the safety and tolerability of TP-
0184 
To determine the maximum tolerated dose 
(MTD) or maximum administered dose 
(MAD) and recommended dose for the future 
expansion arms of TP-0184 in the Phase 2 
part of the study 
Assessment of DLTs, treatment-emergent 
adverse events (TEAEs); type, frequency and 
severity of AEs and relationship of AEs to 
TP-0184, TP-0184 dose interruptions and 
dose reductions 
 
Secondary 
Objectives 
Endpoints 
To determine the effect of TP-0184 on the 
treatment and the hematologic improvement 
of anemia in terms of hemoglobin increase, 
reduction in RBC transfusions and RBC 
Transfusion-
 8 weeks 
(Appendix 1: Consideration of Response for 
Composite Endpoint) 
Response rate based on composite response 
criteria: 
ined 
for a consecutive period of 8 weeks with no 
transfusions  
OR 
weeks (consecutive) compared with the 
pretreatment transfusion number in previous 8 
weeks 
OR 
Patients who are RBC transfusion-free over 
any consecutive 8-week (56-day) period  


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Objectives 
Endpoints 
To determine the effect of TP-0184 on the 
treatment and the hematologic improvement 
of anemia in terms of hemoglobin increase, 
reduction in RBC transfusions and RBC 
Transfusion-
 12 weeks 
(Appendix 1 in Protocol: Consideration of 
Response for Composite Endpoint) 
 Response rate based on composite response 
criteria: 
for a consecutive period of 12 weeks with no 
transfusions  
 
OR 
 
Reduction in units of 
12 weeks (consecutive) compared with the 
pretreatment transfusion number in previous 
12 weeks 
 
OR 
 
Patients who are RBC transfusion-free over 
any consecutive 12-week (84-day) period 
Time to RBC transfusion-free period 
Time from first dose of TP-0184 to the first 
onset of a transfusion-free period for 
consecutive 8 weeks  
Median duration of hemoglobin response 
 1.5 g/dL 
maintained for a consecutive period of > 8 
weeks with no transfusions.  
Median duration of reduction in RBC 
transfusions (4 units / 8 weeks) 
transfusions / 8 weeks (consecutive) 
Median duration of RBC-transfusion-free 
 8 weeks  
Duration of RBC transfusion-free period 
To determine the cardiac safety of TP-0184 
Assessment of the presence of symptoms of 
CHF (based on New York Heart Association 
(NYHA) criteria) and 12-Lead ECGs 
abnormalities, intensive ECG recordings 
taken at time of PK draws, cardiac Magnetic 
resonance imaging (MRI), echocardiogram 
(ECHO) or multigated acquisition (MUGA) 
scans, and peripheral blood cardiac markers  
Progression to Acute myeloid leukemia (AML) 
Proportion of patients progressing to AML, 
time to AML progression  
Overall survival 
Time from first dose of TP-0184 to death due 
to any cause  
To establish the pharmacokinetic (PK) profile 
of single agent TP-0184  
PK parameters of TP-0184 as single agent: 
Cmax, Ctrough, tmax, AUC  and possibly others 
 
Exploratory 


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Objectives 
Endpoints 
To determine whether TP-0184 treatment 
modulates hepcidin and iron metabolism 
profiling results in peripheral blood  
Evaluation of iron metabolism including 
hepcidin and other markers of iron regulation1 
with response to treatment with TP-0184 
1iron panel (serum iron, ferritin, transferrin, 
soluble transferrin receptor (STR), and total iron 
binding capacity (TIBC)) 
Correlative biomarkers of therapy  
Evaluation of potential biomarkers in plasma 
and bone marrow samples  
Metabolites of TP-0184 in patients via Phase 
1 data. 
Profile of potential metabolites of TP-0184 
inpatients in Phase 1 
Pharmacodynamic effects of TP-0184 therapy 
Determination of in vivo markers of ALK-2 
/ALK-5 inhibition, not limited to 
SMAD/phospho-SMAD signaling 
Changes in neutrophil counts 
Proportion of patients achieving hematologic 
improvement in neutrophil count (HI-N) over 
any consecutive 8-week (56-day) period and / 
or decrease in neutrophil levels  
Changes in platelet levels  
Proportion of patients achieving hematologic 
improvement in platelets (HI-P) over any 
consecutive 8-week (56-day) period and / or 
decrease in platelet levels  
Change from baseline in the Brief Fatigue 
Inventory (BFI) in RP2D and one dose level 
below RP2D subgroup 
The Brief Fatigue Inventory (BFI) that 
measures the severity of fatigue based on the 
worst fatigue experienced during the past 24-
hours  
 
Phase 2 
 
Primary 


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Objectives 
Endpoints 
To determine the effect of TP-0184 on the 
treatment and the hematologic improvement 
of anemia in terms of hemoglobin increase, 
reduction in RBC transfusions and RBC 
Transfusion-
 8 weeks 
 (TP-0184-102 Protocol Appendix 1: 
Consideration of Response for Composite 
Endpoint) 
Response rate based on composite response 
criteria: 
Hemoglobin incre
for a consecutive period of 8 weeks with no 
transfusions 
OR 
weeks (consecutive) compared with the 
pretreatment transfusion number in previous 8 
weeks 
OR 
Patients who are RBC transfusion-free over 
any consecutive 8-week (56-day) period 
 
Secondary 
Objectives 
Endpoints 
To determine the effect of TP-0184 on the 
treatment and the hematologic improvement 
of anemia in terms of hemoglobin increase, 
reduction in RBC transfusions and RBC 
Transfusion-
 
 (TP-0184-102 Protocol Appendix 1: 
Consideration of Response for Composite 
Endpoint) 
Response rate based on composite response 
criteria: 
for a consecutive period of 12 weeks with no 
transfusions 
 
OR 
 
12 weeks (consecutive) compared with the 
pretreatment transfusion number in previous 
12 weeks 
 
OR 
 
Patients who are RBC transfusion-free over 
any consecutive 12-week (84-day) period 
Time to RBC transfusion- free period 
Time from first dose of TP-0184 to the first 
onset of a transfusion-free period for 
consecutive 8 weeks 
Median duration of hemoglobin response 
 g/dL 
maintained for a consecutive period of > 8 
weeks with no transfusions 
Median duration of reduction in RBC 
transfusions (4 units / 8 weeks) 
transfusions / 8 weeks. (consecutive) 
Median duration of RBC-transfusion-free 
weeks 
Duration of RBC transfusion-free period 


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Objectives 
Endpoints 
Changes in neutrophils 
Proportion of patients achieving HI-N over 
any consecutive 8-week (56-day) period and / 
or decrease in neutrophil levels 
Changes in platelet counts 
Proportion of patients achieving hematologic 
improvement in platelets (HI-P) over any 
consecutive 8-week (56-day) period and / or 
decrease in platelet levels 
To assess the safety and tolerability of TP-
0184 
Assessment of treatment-emergent adverse 
events (TEAEs); type, frequency and severity 
of AEs and relationship of AEs to TP-0184, 
TP-0184 dose interruptions and dose 
reductions 
To determine the cardiac safety of TP-0184 
administered as single agent. 
Assessment of the presence of symptoms of 
CHF (based on NYHA criteria) and 12-Lead 
ECG abnormalities, cardiac MRI, ECHO or 
MUGA scans, and peripheral blood cardiac 
markers 
Steady-state trough PK characterization 
TP-0184 plasma trough concentration data at 
various timepoints.  Specifically, pre-dose 
(trough) samples on Cycle 1 Day 1 of Week 4 
and Cycle 2 Day 1 of each Week 5, 6, 7, and 
9 
Progression to AML 
Proportion of patients progressing to AML, 
time to AML progression 
Overall Survival 
Time from first dose of TP-0184 to death due 
to any cause 
Change from baseline in the Brief Fatigue 
Inventory 
The BFI that measures the severity of fatigue 
based on the worst fatigue experienced during 
the past 24-hours 
Hematopoietic stem cell transplant (HSCT) 
To document the percentage and outcome of 
patients who have achieved a hematologic 
response and a hematopoietic stem cell 
transplant (HSCT) during or following 
treatment with TP-0184 
 
Exploratory 
Objectives 
Endpoints 
Correlative biomarkers of therapy  
Evaluation of potential biomarkers in plasma 
and bone marrow samples 


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Objectives 
Endpoints 
To determine whether TP-0184 treatment 
modulates hepcidin and iron metabolism 
profiling results in peripheral blood 
Evaluation of iron metabolism including 
hepcidin and other markers of iron regulation1 
with response to treatment with TP-0184 
1iron panel (serum iron, ferritin, 
transferrin, soluble transferrin receptor 
(STR), and total iron binding capacity 
(TIBC)) 
Pharmacodynamic effects of TP-0184 therapy 
Determination of in vivo markers of ALK-
2/ALK-5 inhibition, not limited to 
SMAD/phospho-SMAD signaling 
 
 
 
 


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2. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
Per decision of Sumitomo Dainippon Pharma Oncology, Inc., TP-0184-102 is terminated.  
Two patients have been enrolled, dosed, and discontinued in this study. TEAEs will be coded 
preferred terms according to the Medical Dictionary for Regulatory Activities (MedDRA) 
version 24.0. The following data of both patients will be presented in by patient listings: 
 Adverse Events 
 Concomitant Medication 
 Death Listing 
 Demographic and disease characteristics 
 Dosing 
 End of Treatment/Study 
 Laboratory 


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3.    STATISTICAL SOFTWARE  
SAS version 9.4 (or higher) will be used for providing statistical outputs.   
R was used for BLRM monitoring and other modeling work.