Clinical trial NCT02953652
Conditions: Peripheral T-Cell Lymphoma (PTCL)
Sponsor: HUYABIO International, LLC.
Start date: 2016-11-01; Completion date: 2022-02-17
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase 2b, open-label, non-randomized, single arm study to evaluate the safety, efficacy, and pharmacokinetics of HBI-8000 40 mg BIW in patients with relapsed or refractory PTCL (R/R PTCL).

Detailed description:
This is a Phase 2b, open-label, non-randomized, single arm study to evaluate the safety, efficacy, and pharmacokinetics of HBI-8000 40 mg BIW in patients with relapsed or refractory PTCL (R/R PTCL). HBI 8000 will be administered orally approximately 30 minutes after any regular meal twice a week. There will be 3-4 days between dosing. A cycle is defined as consecutive 28 days. HBI-8000 administration will be continued until disease progression or unacceptable toxicities are observed despite appropriate dose reduction or treatment interruption.

Arms: arm 1: Four 10 mg tablets or less twice weekly orally approximately 30 minutes after any regular meal. The treatment will be continuous, with 3-4 days between dosing. Treatment will continue until disease progression in the absence of unacceptable toxicity.
Interventions: intervention 1: HBI-8000
Intervention descriptions: intervention 1: Orally twice weekly

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Page 1 of 83 
 
 
Clinical Study Protocol 
Protocol Title:  
A Phase 2b Open-Label Single Arm Study to 
Evaluate the Efficacy and Safety of Oral HBI-8000 in 
Patients with Relapsed or Refractory Peripheral T-
cell Lymphoma (PTCL) 
Protocol Number:  
HBI-8000-203 
NCT Number: 
NCT02953652 
Version: 
6.0 
Date of Protocol: 
 
 
19 July 2021 
Sponsor: 
HUYABIO International, LLC 
 
 
 
 
 
 
 
 


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HBI-8000-203 Protocol Synopsis 
Name of 
Sponsor/Company: 
HUYABIO International, LLC 
Study Drug: 
HBI-8000 
Title of Study: 
A Phase 2b Open-Label Single Arm Study to Evaluate the Efficacy and 
Safety of Oral HBI-8000 in Patients with Relapsed or Refractory 
Peripheral T-cell Lymphoma (PTCL)   
Protocol No: 
HBI-8000-203 
Study site(s): 
25 to 35 sites in Japan and 10 to 15 sites in South Korea 
Study duration: Approximately 66 months 
Phase: 2b 
Planned study period: 4Q 2016 (first patient in) to 
3Q 2018 (last patient in) 
2Q 2022 study completion 
Objectives: 
Primary: 
• To determine the efficacy of HBI-8000 administered twice a week (BIW) continuously
Secondary: 
• To evaluate the safety and tolerability of HBI-8000 administered BIW continuously
Endpoints: 
Primary: 
• Objective response rate (ORR; Complete Response [CR] + Partial Response [PR])
Secondary: 
• ORR by disease subtype (see inclusion criteria)
• Median duration of progression-free survival (PFS)
• Median duration of response (DOR)
• Safety
Exploratory: 
• Median duration of overall survival (OS)
• Pharmacokinetics (selected sites)
Study Design: 
This is a Phase 2b, open-label, non-randomized, single arm study to evaluate the safety, efficacy, 
and PK of HBI-8000 40 mg BIW in patients with relapsed or refractory PTCL (R/R PTCL).  
HBI-8000 will be administered orally approximately 30 minutes after any regular meal.  The 
treatment will be continuous, with 3-4 days between dosing.  A cycle is defined as 28 days solely 
for the purpose to schedule assessments required by the study.  
The study will continue till the last active Japanese subject initiates administration of the commercial 
product of HBI-8000 after the marketing authorization approval for relapsed or refractory PTCL in 
Japan. If there is no subject who is receiving study treatment at the time of the PTCL approval in 
Japan, the whole study will be completed at the time of the approval. 
In Japan, “Phase 2 study” shall be read as “post-marketing clinical study” and “investigator” shall 
be read as “post-marketing clinical study investigator” in this protocol after the marketing approval. 
In addition, other related terms are to be replaced in accordance with Article 56 of the Ministerial 
Ordinance on the Standards for the Implementation of Clinical Studies on Pharmaceutical Product 
(Japan GCP).  
Treatment-related adverse events (AEs) will be graded according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  In the event of 
unacceptable toxicities, study drug will be held until recovery and dosing will be resumed at 
reduced dose level, following protocol guidelines.  An unacceptable toxicity is defined as the 
following: 


 
 
 
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• Grade 4 afebrile neutropenia > 7 days despite optimal growth factor support 
• Grade ≥ 3 febrile neutropenia or neutropenic infection 
• Grade ≥3 thrombocytopenia with clinically significant bleeding or Grade ≥3 
thrombocytopenia requiring a platelet transfusion 
• Grade ≥3 nausea, vomiting, diarrhea, or electrolyte imbalances lasting greater than 48 hours 
despite optimal prophylactic and curative treatment 
• Grade ≥3 allergic reaction 
• Grade ≥3 other non-hematologic AEs  
• Treatment delay >14 days secondary to recovery from study drugs- related AEs  
 
For determination of efficacy, HBI-8000 administration will be continued until disease progression 
(PD) or unacceptable toxicities are observed despite appropriate dose reduction or treatment 
interruption. Study drug treatment will be discontinued after the PTCL approval when the 
commercial product of HBI-8000 is available at the study sites. 
Number of patients: 
40 patients evaluable for efficacy with approximately 27 from Japan and 
13 from Korea.  To ensure meeting this target, an estimated 50 to 
60 patients would be enrolled in anticipation that some patients may not 
complete study treatment.  
Entry  
Criteria: 
Inclusion   
1. Histological or cytological diagnosis of the following peripheral 
T-cell lymphoma (PTCL) subtypes as defined by the WHO 
classification (2008) may be included: 
a. 
PTCL, NOS  
b. 
Angioimmunoblastic T-cell lymphoma (AITL) 
c. 
Anaplastic large-cell lymphoma (ALCL), ALK+  
d. 
Anaplastic large-cell lymphoma (ALCL), ALK− 
e. 
Enteropathy-associated T-cell lymphoma (EATL)  
f. 
Hepatosplenic T-cell lymphoma 
g. 
Subcutaneous panniculitis-like T-cell lymphoma 
2. Patients for whom at least 1 measurable lesion is confirmed by the 
lesion assessment at baseline; An evaluable lesion is defined 
according to Cheson criteria 2014. 
3. Relapsed or refractory disease after receiving ≥1 prior systemic 
therapy with anti-tumor agent(s) and there is no other standard 
treatment which can be considered appropriate for patients.  
Systemic therapy is defined as frontline chemotherapy or 
immunotherapy administered systemically. 
4. Male or female, age 20 years or older  
5. Eastern Cooperative Oncology Group (ECOG) Performance Status 
of 0 to 2 
6. Life expectancy of greater than 3 months 
7. Meeting the following baseline laboratory criteria for screening:  
a. Absolute Neutrophil Count >1500/µL independent of growth 
factor support within 7 days 
b. Platelets >75,000/µL independent of transfusion within 14 days  
c. Hemoglobin >8 g/dL independent of transfusion within 14 days 
d. Serum creatinine < 1.5 × ULN 
e. Serum 
aspartate 
aminotransferase/glutamyl 
oxaloacetic 
transaminase 
(AST/SGOT) 
and 
alanine 
aminotransferase/glutamyl pyruvic transaminase (ALT/SGPT) ≤ 
3 × ULN 
 


 
 
 
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f. Serum Bilirubin ≤ 1.5 × ULN 
8. Negative serum pregnancy test for females of childbearing 
(reproductive) potential. Female patients of child bearing potential 
must use an effective method of birth control (e.g., hormonal 
contraceptive, intrauterine device, diaphragm with spermicide or 
condom with spermicide) during treatment period and 1 month 
thereafter.  Males must use an effective method of birth control (2 
barrier methods) during treatment period and 3 months thereafter. 
Note: Female patients will be considered to be women of 
childbearing potential unless having undergone permanent 
contraception or postmenopausal.  Postmenopausal is defined as 
at least 12 months without menses with no other medical reasons 
(e.g., chemical menopause because of treatment with anti-
malignant tumor agents) 
9. Signed informed consent 
 
Exclusion  
1. Patients in whom central nervous system lymphoma is recognized 
during screening (if suspected clinically, imaging study should be 
performed to confirm) 
2. Male patients with QTcF >450 msec at screening, female patients 
with QTcF >470 msec at screening or patients with congenital long 
QT syndrome, clinically significant arrhythmia, history of congestive 
heart failure (New York Heart Association Class III or IV) or acute 
myocardial infarction within 6 months of starting the study drug 
3. Patients with known hypersensitivity to benzamide class of 
compounds or any of the components of HBI-8000 tablets, and 
patients with prior exposure of HBI-8000 
4. Patients with a history of second malignancy other than disease under 
study.  The exceptions are diseases (excluding diseases listed below) 
that have been treated with curative intent with no evidence of 
recurrence in past 5 years. Furthermore, if the second malignancy is 
one of the following diseases that were treated with curative intent, it 
is only required that there is no evidence of recurrence in past 2 year. 
a. Basal cell carcinoma of the skin 
b. Squamous cell carcinoma of the skin 
c. Cervical carcinoma in situ 
d. Carcinoma in situ of the breast 
e. An incidental histological finding of prostate carcinoma (TNM 
stage T1a or T1b) 
f. Early-stage gastric cancer treated with endoscopic mucosal 
resection or endoscopic submucosal dissection 
g. Thyroid cancer with differentiated histology (e.g. papillary) 
treated with curative intent  
5. Autologous stem cell transplantation within 12 weeks (84 days) of 
starting the study drug 
6. History of allogeneic stem cell transplantation  
7. Organ transplantation recipients except for autologous hematopoietic 
stem cell transplantation 
8. Uncontrolled inter-current infection  
9. Hepatitis B surface antigen-positive, or hepatitis C virus antibody 
positive.  In case hepatitis B core antibody and/or hepatitis B surface 
antibody is positive even if hepatitis B surface antigen-negative, a 


 
 
 
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hepatitis B virus DNA test (real-time polymerase chain reaction 
(PCR) measurement) should be performed and if positive, the patient 
should be excluded from study 
10. Any history of testing positive for human immunodeficiency virus 
(HIV) or known acquired immunodeficiency syndrome (AIDS) 
11. Uncontrolled diabetes mellitus, hypertension, endocrine disorder, 
bleeding disorder 
12. Major surgery or radiation therapy within 28 days of starting the study 
drug 
13. Receiving investigational agents or anti-cancer therapy, within 28 
days, nitrosourea or mitomycin C within 42 days of starting the study 
drug 
14. Receiving antibody therapy for PTCL within 12 weeks of starting 
the study drug 
15. Women who are breastfeeding or women who are not willing to stop 
breastfeeding during study treatment period and for 30 days after the 
last dose of study drug 
16. Potential for non-compliance or at increased risk based on 
investigator’s judgement 
Excluded Prior or 
Concomitant 
Medications or 
Therapy: 
 
The following drugs are prohibited.  
• 
Drugs known to produce significant QT prolongation and 
ventricular dysrhythmias (see Section 9.6)  
Prohibited from signing informed consent through the EoT 
assessment 
• 
Anti-cancer therapy other than study medication 
Prohibited during the study and within the following time intervals 
prior to the first dose of study drug. 
- 
4 weeks for anti-cancer chemotherapy 
- 
6 weeks for nitrosourea and mitomycin C 
- 
12 weeks for anti-cancer monoclonal antibody therapy 
Corticosteroid prescribed for medical conditions other than lymphoma is 
not considered as an anti-cancer therapy for this study, for example: 
chronic obstructive pulmonary disease, allergy, topical steroids for rash. 
Treatments: 
Study drug is to be taken after any regular meal twice weekly, each dose 
separated by 3-4 days.  Treatment will continue until PD in the absence 
of unacceptable toxicity, whichever is earlier. Study drug treatment will 
be completed when the commercial product of HBI-8000 is available at 
the study sites after the PTCL approval.  
Efficacy Data: 
 
Response and progression for PTCL will be evaluated according to the 
revised criteria for response assessment in lymphoma [Cheson 2014].  To 
be included in final efficacy analyses, the histopathology diagnosis of 
disease will be verified by Central Pathology Review, and disease 
response will be confirmed by Independent Radiology and Independent 
Overall Efficacy Review.   
Safety Data:  
All patients who receive at least one dose of HBI-8000 will be evaluable 
for safety.  Adverse event severity (grade) will be defined according to 
Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.03.  Serial ECGs and clinical laboratory tests will be collected to 
evaluate safety and potential toxicity. Laboratory and other tests, as 
appropriate to the clinical situation, may be obtained more frequently than 
stipulated in the schedules of events.   
All reported AEs will be collected, evaluated and coded using Medical 
Dictionary for Regulatory Activities (MedDRA). 


 
 
 
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Pharmacokinetics 
data from selected 
sites: 
At sites participating in population PK assessments, blood samples for 
plasma HBI-8000 measurement will be taken on Day 1 of Cycle 1 at 
pre-dose, 1 h (± 15 min), 2 h (± 15 min), 3 h (± 15 min), 4 h (± 15 min), 5 
h (± 30 min), 7 h (± 30 min), 24 ± 1 h, 48 ± 1 h and 72 ± 1 h.  On Day 1 
of Cycle 2 (e.g., C2D1) PK samples will be taken at pre-dose and 1 h (± 
15 min), 2 h (± 15 min), 3 h (± 15 min), and 4 h (± 15 min).  On Day 1 of 
Cycles 3 to 6, only pre-dose PK samples will be taken.   
Statistical Procedures: 
Statistical analysis for all safety, efficacy, and PK parameters will be primarily descriptive in nature.  
Categorical variables will be summarized by frequency distributions (number and percentages of 
patients), continuous variables will be summarized by mean, standard deviation, median, minimum, 
maximum, and time-to-event variables will be summarized using Kaplan-Meier methods and 
figures for the estimated median time.  A formal statistical analysis plan will be completed prior to 
database lock and any study-related analyses.  
 
Disease diagnosis including histological subtypes will be confirmed by central pathology review 
conducted by independent pathologists.   
Efficacy should be analyzed using Full analysis set (FAS) and Per protocol set (PPS).  
The FAS is defined as Patients meeting all eligibility criteria and having received at least one dose 
of study medication, and at least one efficacy assessment of disease with either imaging studies or 
clinical examination after receiving study medication. 
 The PPS is defined as Patients meeting all eligibility criteria and having completed Cycle 1 
treatment or discontinued study treatment during cycle 1 due to clinical PD. It should be noted that 
the PPS includes subjects who discontinue within Cycle 1 due to clinical PD without imaging 
studies to assess disease status.  
 In addition, Patients who are assessed as Non-PTCL by the central pathology review committee 
should be excluded from the FAS and PPS for efficacy. The non-PTCL subjects will be included in 
safety analysis for the study. 
The primary efficacy analysis is conducted in the PPS. The Efficacy analysis using the FAS will be 
also reported. 
It is estimated that 40 evaluable patients are adequate to provide efficacy assessment. Assuming a 
30% ORR in this population of 40 evaluable patients, the conclusion would be that there is a 95% 
chance that the ORR in this protocol population would lie between 15.8% and 44.2%. The power 
for showing the response rate >10% at 5% two-sided alpha in 40 patients is 89%.  
 
All patients who have received any amount of study medication will be considered as evaluable for 
safety.  Safety data will be summarized with descriptive statistics and frequency tables and will 
include AEs, hematology, coagulation, serum chemistry, urinalysis, vital signs, and ECG data. 
Laboratory values will be summarized by numerical value and toxicity grade.  


 
 
 
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TABLE OF CONTENTS 
SIGNATURES................................................................................................. 2 
HBI-8000-203 PROTOCOL SYNOPSIS ...................................................... 3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........... 13 
1.0 
INTRODUCTION............................................................................. 15 
 
Background Information ..................................................... 15 
 
Histone Deacetylase as a Therapeutic Target in Cancer ... 15 
 
Rationale for the Use of HBI-8000 for the Treatment of 
Cancer .................................................................................... 16 
 
Immunomodulatory Mechanisms Integrate with 
Cancer Cell Intrinsic Mechanisms of Cell Killing by 
HDACi ...................................................................... 17 
 
Nonclinical Studies ................................................................ 18 
 
Clinical Pharmacology.......................................................... 19 
 
Absorption ................................................................ 19 
 
Distribution ............................................................... 20 
 
Metabolism and Excretion ........................................ 20 
 
Clinical Studies ...................................................................... 20 
 
Rationale for Investigation in Relapsed and Refractory 
Peripheral T-Cell Lymphoma (PTCL) ............................... 21 
 
Dose Selection and Risk Assessment ................................... 21 
2.0 
STUDY OBJECTIVE(S) .................................................................. 23 
 
Primary Objective ................................................................. 23 
 
Secondary Objective ............................................................. 23 
 
Criteria for Evaluation ......................................................... 23 
 
Summary of Study Design .................................................... 24 
 
Safety Determination and Criteria for Dose 
Modification or Interruption ..................................... 24 
 
Selection of Study Population .............................................. 24 
 
Inclusion Criteria ...................................................... 24 
 
Exclusion Criteria ..................................................... 25 
 
Study Procedures Overview ................................................. 26 
 
Screening Assessments (within 28 days prior to start 
of treatment) ............................................................. 27 
 
Baseline Assessments on Cycle 1 Day1 (C1D1) ...... 28 
 
Treatment Phase ....................................................... 28 
 
End of Treatment Safety Follow-up Visit ................ 28 
 
Survival Follow-up ................................................... 29 
 
Patient Withdrawal ................................................... 29 
 
Discontinuation of the Study .................................... 30 


 
 
 
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Management and Dosage Modifications for 
Unacceptable Hematologic and Non-Hematologic 
Adverse Events ......................................................... 30 
 
Management and Dosage Modifications for Non-
Hematologic Adverse Events ................................... 31 
 
Study Drug Administration ................................................. 32 
 
Packaging, Labelling and Storage ....................................... 32 
 
Patient Registration and Subject Number Assignment ..... 32 
 
Concomitant Treatments...................................................... 32 
 
Prohibited Medications and Therapy ........................ 32 
 
Cautioned Medications ............................................. 33 
 
Permitted Medications .............................................. 33 
 
Dietary Restrictions .............................................................. 34 
 
Treatment Compliance ......................................................... 34 
 
Study Medication Accountability ........................................ 34 
3.0 
STUDY ASSESSMENTS ................................................................. 36 
 
Efficacy................................................................................... 36 
 
Primary Efficacy Endpoint ....................................... 36 
 
Secondary Efficacy Endpoints ................................. 36 
 
Exploratory Endpoints .............................................. 36 
 
Safety ...................................................................................... 37 
 
Definitions ................................................................ 37 
 
Adverse Events ....................................... 37 
 
Serious Adverse Event ........................... 37 
 
Period of Observation ............................................... 38 
 
Preexisting Conditions .............................................. 38 
 
Documentation and Reporting of Adverse Events by 
Investigator ............................................................... 38 
 
Assessment of Causal Relationship to Study Drug .. 39 
 
Intensity of Adverse Events ...................................... 40 
 
Events Requiring Immediate Reporting ................... 40 
 
Serious Adverse Events .......................... 40 
 
Pregnancy ............................................... 41 
 
Overdose ................................................. 41 
 
Follow-Up of Adverse Events .................................. 42 
 
Clinical Laboratory Evaluations ............................... 42 
 
Vital Signs, Physical Findings and Other Safety 
Assessments .............................................................. 43 
 
Pharmacokinetics .................................................................. 43 
 
Blood Volume ........................................................................ 44 
 
Independent Review.............................................................. 45 
 
Data Safety Monitoring Board ................................. 45 
 
Independent Radiology Review ............................... 45 
 
Central Pathology Review ........................................ 45 
 
Independent Overall Efficacy Review ...................... 45 


 
 
 
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4.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............. 46 
 
Monitoring ............................................................................. 46 
 
Data Management/Coding ................................................... 47 
 
Retention of Records............................................................. 48 
 
Quality Assurance Audit ...................................................... 48 
 
Site Audits .............................................................................. 48 
5.0 
STATISTICS ..................................................................................... 50 
 
General Statistical Considerations ...................................... 50 
 
Determination of Sample Size .............................................. 50 
 
Treatment Assignment and Blinding .................................. 51 
 
Replacement of Patients ....................................................... 51 
 
Populations for Analysis ....................................................... 51 
 
Safety Population ...................................................... 51 
 
Efficacy Population .................................................. 51 
 
Pharmacokinetic Population ..................................... 52 
 
Patient Disposition .................................................... 52 
 
Patient Characteristics ......................................................... 52 
 
Concomitant Medications .................................................... 52 
 
Treatment Administration ................................................... 53 
 
Efficacy Analysis ................................................................... 53 
 
Safety Analysis ...................................................................... 53 
 
Adverse Events ......................................................... 54 
 
Laboratory Tests ....................................................... 54 
 
ECGs ......................................................................... 54 
 
Vital Signs and Physical Findings ............................ 54 
 
Interim Analysis ....................................................... 54 
 
Pharmacokinetic Analysis .................................................... 55 
6.0 
ETHICS ............................................................................................. 56 
 
Institutional Review Board or Independent Ethics 
Committee .............................................................................. 56 
 
Ethical Conduct of the Study ............................................... 56 
 
Patient Information and Informed Consent ....................... 56 
 
Patient Data Protection ........................................................ 57 
7.0 
STUDY ADMINISTRATION ......................................................... 58 
 
Administrative Structure ..................................................... 58 
 
Data Handling and Record Keeping ................................... 58 
 
Direct Access to Source Data/Documents ........................... 58 
 
Investigator Information ...................................................... 59 
 
Investigator Obligations ........................................... 59 
 
Protocol Signatures ................................................... 59 
 
Publication Policy ..................................................... 59 
 
Financing and Insurance ...................................................... 59 


 
 
 
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8.0 
REFERENCES .................................................................................. 60 
9.0 
APPENDICES ................................................................................... 63 
 
Appendix A:  HBI-8000-203 Schedule of Events ............... 63 
 
Appendix B:  Eastern Cooperative Oncology Group 
(ECOG) Performance Status ............................................... 67 
 
Appendix C: New York Heart Association (NYHA) 
Classification ......................................................................... 68 
 
Appendix D: Method of Efficacy Assessment .................... 69 
 
Evaluation at Screening ............................................ 69 
 
Imaging ..................................................................... 70 
 
Definition of lesion which can be used for 
efficacy assessment (evaluable lesion) ... 70 
 
Definition of lesion which cannot be used 
for efficacy assessment (non-evaluable 
lesion) ..................................................... 70 
 
Definition of Measurable Lesion (common 
with nodal and extranodal lesion) ........... 70 
 
Definition of Non-measurable lesion ..... 71 
 
Nodes or Extranodal Lesions That Split 
When Disease Is Responding ................. 71 
 
Nodes or Extranodal Lesions That Become 
Conﬂuent When Disease Is Progressing . 71 
 
Selection of Target Lesions ...................................... 71 
 
Definition and Selection of Non-target Lesion ........ 72 
 
Evaluation of Skin Lesion ........................................ 72 
 
Evaluation by Modified Severity-Weighted 
Assessment Tool (mSWAT) (Olsen et al. 2011) ...... 72 
 
Presence or absence of splenomegaly ...................... 74 
 
Evaluation of infiltration to bone marrow ................ 74 
 
Postdose Evaluation .................................................. 74 
 
Evaluation of target lesion ...................... 74 
 
Criteria for Response Assessment .......... 75 
 
Evaluation of skin lesion by mSWAT .... 78 
 
Appendix E:  Blood Sample Collection ............................... 79 
 
Appendix F:  Drugs known to produce significant QT 
prolongation and ventricular dysrhythmias ....................... 81 
 
Appendix G:  Signature of Investigator .............................. 83 
 


 
 
 
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List of Tables 
Table 1: HBI-8000 Tablet Dosage Adjustment Guidelines .....................................................31 
Table 2:  Screening Cycle 1 .....................................................................................................44 
Table 3:  Cycles 2 to 6 .............................................................................................................44 
Table 4:  Schedule of Events ...................................................................................................63 
Table 5:  Schedule of Pharmacokinetic Blood Draws .............................................................66 
Table 6:  Modified Severity Weighted Assessment Tool (mSWAT) ......................................73 
Table 7:  Summary of Response Criteria .................................................................................75 
 
List of Figures 
Figure 1:  Molecular and structural formulas for HBI-8000 ....................................................15 
Figure 2:  Proposed manifold anti-tumor mechanisms of chidamide (HBI-8000) ..................17 
Figure 3:  Selection of Lesions ................................................................................................70 
Figure 4:  Percentage BSA of each Part of Human Body ........................................................74 
 


 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
AITL 
Angioimmunoblastic T-cell lymphoma 
ALCL 
Anaplastic large-cell lymphoma 
ALT/SGPT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST/SGOT 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
ATLL 
Adult T-cell leukemia/lymphoma 
AUC 
Area under the curve 
BIW 
Twice a week 
BUN 
Blood urea nitrogen 
CCR4 
CC chemokine receptor 4 
CFDA 
China FDA 
CI 
Confidence interval 
CKMB 
Creatine kinase MB fraction 
Cmax 
Peak plasma drug concentration 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
Cutaneous T-cell lymphoma 
CYP 
Cytochrome P450 
DOR 
Duration of response 
DSMB 
Data safety monitoring board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EoT 
End of treatment 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-colony stimulating factor 
GGT 
Gamma-glutamyl transpeptidase 
GPSP 
Good Post-marketing Study Practice 
HDAC 
Histone deacetylase 
HDACi 
Histone deacetylase inhibitor 
HSP 
Heat shock protein 
IB 
Investigator’s Brochure 
IC 
Inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 


 
 
 
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IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase 
MB 
Muscle band 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labour and Welfare 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin’s lymphoma 
NK 
Natural killer 
NOS 
Not otherwise specified 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Disease progression 
PET 
Positron Emission Tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PMDA 
Pharmaceutical and medical devices agency 
PPS 
Per protocol set 
PR 
Partial response 
PT 
Prothrombin time 
PTCL 
Peripheral T-cell lymphoma 
QTcF 
QT interval corrected by heart rate, using Fridericia’s 
Correction Formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SiRNA 
Small interfering RNA 
SOP 
Standard operating procedures 
TCL 
T-cell lymphoma 
TEAE 
Treatment-emergent adverse event 
TIW 
Three times a week 
ULN 
Upper limit of normal 




 
 
 
Page 16 of 83 
 
 
2006; Glaser et al. 2007; Rasheed, Johnstone, and Prince 2007; Rasheed et al 2008; Haberland, 
Montgomery, and Olson 2009]. 
The activity of Class I HDACs (HDAC isoenzymes 1, 2, 3, and 8) is elevated in acute 
myelogenous leukemia, acute promyelocytic leukemia, non-Hodgkin’s lymphoma (NHL), as 
well as prostate, gastric, colorectal, breast, and cervical cancers [Bolden, Peart, and Johnstone 
2006; Nakagawa et al. 2007; Fritzsche et al. 2008; Weichert et al. 2008a; Weichert et al. 2008b]. 
Small interfering RNA (siRNA)-mediated inhibition of HDAC 1 or 3 resulted in anti-
proliferative effects, and HDAC2 inhibition using siRNA sensitized tumor cells to apoptosis 
[Haberland, Montgomery, and Olson 2009]. 
Class IIb HDACs (HDAC isoenzymes 6 and 10) preferentially target non-histone proteins, 
such as α-tubulin and heat shock protein (HSP) 90.  Heat shock protein 90 has been shown to 
participate in malignant transformation by stabilizing oncoproteins such as Bcr-Abl, mutant 
Flt-3, AKT, c-Raf, estrogen receptors, Her-2, and vascular endothelial growth factor receptor.  
Alpha-tubulin suppresses apoptosis in tumor cells by facilitating lysosomal clearance of 
misfolded proteins.  Deacetylation of HSP90 and α-tubulin by HDAC6 or HDAC10 activates 
these proteins, contributing to the malignant phenotype.  Conversely, inhibition of HDAC6 or 
HDAC10 has been shown to inhibit tumor growth.  The synergy observed with the HSP90 
inhibitor 17-alpha 1-acid glycoprotein and the anti-tumor proteasome inhibitor bortezomib 
further support these proposed mechanisms [Glaser, et al. 2004, Bali et al. 2005, Rodriguez-
Gonzalez et al. 2008, Schemies, Sippl, and, Jung 2009, Park 2008]. 
Several HDAC inhibitors have been approved by the Food and Drug Administration (FDA) 
for the treatment of T-cell lymphoma (TCL), including vorinostat (ZOLINZA®, Merck & Co. 
Inc., October 2006) for the treatment of cutaneous manifestations in patients with cutaneous 
T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease after two 
systemic therapies, romidepsin (ISTODAX®, Celgene Corporation, November 2009) for the 
treatment of CTCL and subsequently for PTCL, and belinostat (BELEODAC®, Spectrum 
Pharmaceuticals, Inc., July 2014) received accelerated approval from FDA for the treatment 
of patients with relapsed or refractory PTCL.  Panobinostat (FARYDAK®, Novartis 
Corporation, February 2015) was approved in combination with bortezomib and 
dexamethasone for the treatment of patients with multiple myeloma.  Several other HDACi are 
under clinical evaluation, including the following different classes: hydroxamic acid (e.g., 
resminostat, pracinostat, abexinostat, quisinostat), cyclic peptide (e.g., FK228/romidepsin), 
short-chain fatty acid (e.g., valproic acid), and benzamide (e.g., entinostat, mocetinostat, HBI-
8000). 
Preliminary results have suggested that HDACi are active in non-small cell lung cancer and 
breast carcinoma when combined with other anti-tumor agents, however, their activity as 
single agent in solid tumors has not been demonstrated in clinical trials [Blumenschein et al 
2008, Crump et al 2008, Modesitt et al 2008, Vansteenkiste et al 2008, Luu 2009]. 
 
Rationale for the Use of HBI-8000 for the Treatment of Cancer 
HBI-8000 inhibits several cancer-associated Class I (HDAC 1, 2, 3) and one Class IIb HDAC 
(isoenzymes 10) HDACs in the nanomolar range and stimulates accumulation of acetylated 


 
 
 
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histones H3 and H4 in tumor cells [Ning et al 2012].  In vitro, HBI-8000 inhibits the growth 
of a wide variety of tumor cell lines, with 50% inhibitory concentrations (IC50s) in the single-
digit micromolar range.  HBI-8000 is non-toxic to non-transformed cells (IC50s ≥ 100 
micromolar) [Ning et al 2012].  In vivo, HBI-8000 has demonstrated dose-dependent anti-
tumor activity against human xenograft models [Ning et al 2012].  Results from pre-clinical 
pharmacokinetics (PK) and toxicology studies in rats and dogs as well as results from a Phase 1 
study conducted to date [Shenzhen Chipscreen Study Report 2008] suggest that HBI-8000 has 
favorable PK and safety profiles.  
Emerging data suggest that there are three major mechanisms underlying the anti-cancer 
activities of HDACi: preferential induction of growth arrest and apoptosis in blood and 
lymphoid-derived tumor cells, enhancement of both NK-mediated and CD8+ Cytotoxic T 
lymphocyte -mediated antigen-specific anti-tumor immunity, and partial reversal of epithelial 
mesenchymal transition and drug resistance of tumor cells as described in Fig. 2. However, the 
activation of natural killer (NK)- and antigen-specific Cytotoxic T lymphocyte -mediated 
cellular anti-tumor immunity appears only to be associated with the benzamide type of 
sel4ctive HDACi such as HBI-8000 (Figure 2). 
Figure 2:  Proposed manifold anti-tumor mechanisms of chidamide (HBI-8000) 
 
 
 
Immunomodulatory Mechanisms Integrate with Cancer Cell Intrinsic 
Mechanisms of Cell Killing by HDACi  
It has been theorized that cancer is caused by genetic defects: gene mutations, abnormal gene 
expression and epigenetic dysregulation, which occur in cancer cells but these mechanisms are 
not limited to cancer cells and could affect immune cell function as well.  Some of these cancer 


 
 
 
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cell intrinsic defects are reversible and the promise of epigenetic regulators like HDACi is that 
they can concurrently target multiple aberrant or compensatory signaling pathways found in 
cancer cells by restoring the genome, and by extension the transcriptome, to more normal-like 
state.  HBI-8000 causes modulation of gene regulation patterns that is consistent with that 
hypothesis.  Genes in several functional clusters were regulated by HBI-8000 [Ning et al 2012, 
Pan et al 2014], including several genes important for cell cycle (CCNA2/Cyclin A2, 
CCNB2/Cyclin B2, CCNE2/Cyclin E2, CDKN1A/p21/WAF1, CHEK1/checkpoint kinase 1), 
apoptosis (DR6/ TNFRSF21/death receptor 6) and the response to antitumor therapies 
(ABCB10, ABCC2/MRP2, RAD23B, UBCH10/ubiquitin-conjugating enzyme E2C).  HBI-
8000 also regulated genes promoting epithelial differentiation (CDH1, KRT8) and reducing 
the epithelial-to-mesenchyme transition, an important process in tumor invasion and metastasis 
(CDH2/N-cadherin).  While these HDACi effects on the cancer cell are important, the effects 
of HDACi are not limited to regulation of cell cycle, cell differentiation and cell death, but also 
affect immune recognition through effects on the cancer cell and immunocytes. 
Notably, HDAC inhibitors increase tumor cell ligands promoting NK cell-mediated tumor cell 
lysis, and NKG2D expression on NK cells involved in tumor cell lysis, thereby promoting 
tumor immunocyte interactions involved in immune surveillance.  For example, in a pancreatic 
cancer model, exposure to valproic acid, an inhibitor of HDAC classes 1 and 2 (but not 6 and 
10), upregulates NKG2D ligands and major histocompatibility complex class I-related chains 
A and B (MICA and MICB) in pancreatic cancer cells, thereby increasing susceptibility of 
tumor cells to NK cell-mediated cell lysis in vitro [Shi et al 2014].  HDAC inhibition by 
entinostat is also associated with enhanced NK cell cytotoxicity against colon carcinoma and 
NK cells associated with increase in MIC expression in tumor cells and NKG2D in primary 
human NK cells [Zhu et al 2015]. 
 
Nonclinical Studies 
HBI-8000 is metabolized, in part, by the cytochrome P450 (CYP) 3A4 pathway, and it inhibits 
CYP3A4 and CYP2C8.  The estimated IC50’s of HBI-8000 for CYP inhibition in pooled human 
liver microsomes were 12.7 μM (CYP2C8) and 1.47 μM (CYP3A4).  Other CYP isoenzymes 
were not significantly inhibited by HBI-8000.  Peak plasma concentrations for HBI-8000 in 
the planned clinical studies are expected to be well below the IC50 for inhibition of CYP3A4 
and CYP2C8, suggesting low potential for significant inhibition of the metabolism of CYP3A4 
or CYP2C8 substrates.  
The findings in toxicology studies conducted in the U.S. and China were consistent.  At dosing 
levels just above the ‘no observed adverse effect level’, the findings across several species 
were gastrointestinal disturbances, loss of appetite, diarrhea, and myeloid and lymphoid 
suppression.  At higher exposure, these effects increased, and oligospermia and mucosal 
hemorrhage in the gastrointestinal tract were also observed.  Sporadic signs of focal myocardial 
inflammation and necrosis were seen in some studies, as were occasional prolonged QT 
intervals in one dog study.  All of these cardiac changes were found only at high exposures, 
were reversible, were inconsistent across studies, and may have been related to the poor 
metabolic condition of animals receiving such high doses of HBI-8000.  Overall, the main 


 
 
 
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target tissue toxicities of HBI-8000 in rats and dogs are in bone marrow, lymphoid tissue, and 
the gastrointestinal tract.   
Further information on non-clinical studies conducted with HBI-8000/chidamide may be found 
in the Investigator’s Brochure [IB 2020].  For the following discussion, the names HBI-8000 
and chidamide are used interchangeably, although chidamide will be used to describe data 
generated by Chipscreen. 
 
Clinical Pharmacology 
 
Absorption 
The single-dose PK of chidamide was evaluated in 33 patients with TCL. After a single oral 
administration of 30 mg of chidamide after any regular meal, the average time to peak plasma 
drug concentration was approximately 4 hours, average peak plasma drug concentration (Cmax) 
60 ng/ml, average area under curve (AUC0-t) 660 ng×h/mL and the average endpoint 
elimination half-life 17 hours.  
The multi-dose PK parameters of chidamide were evaluated in 19 TCL patients administered 
with multiple doses of chidamide. Compared to that of single dose patients, the AUC0-t value 
increased 1.8 folds after the 8th dose, and the differences were statistically significant (p<0.01). 
The correlation between drug exposure and the efficacy and/or safety of chidamide remains to 
be established. 
The effect of dose on PK was evaluated in 21 patients with advanced stage solid tumor or 
lymphoma.  A single dose of 25, 32.5 or 50 mg chidamide tablet was administered, the AUC0-
t were 809±390, 828±509 and 1120±438 ng×h/mL, respectively, indicating non-proportional 
increase of drug exposure versus the increasing dose, and possible dose saturation. 
The bioavailability of chidamide appeared to be higher when taken with food.  The effect of 
food on PK was studied in seven patients with TCL. When 30 mg chidamide was ingested 30 
minutes after any regular meal, the mean plasma drug exposure was 2.3-fold of that when the 
same dose was administered in fasting state.  
It was observed in the clinical trials that administration of drug after any regular meal could 
alleviate gastrointestinal irritation caused by the drug in some patients.  It is thus recommended 
to take the medication at least 30 minutes after any regular meal.  
In clinical studies conducted in China, it was noted that some clinical features were associated 
with drug exposure. The time to Cmax shortened and Cmax increased with increasing age; 
average drug exposure (unit AUClast) for male patients was about 80% of that for females at 
the same dosage.  However, its correlation with the efficacy and safety remained unknown.  
In a Phase 1 trial conducted in the U.S. (Study HBI-8000-101), HBI-8000 was administered 
three times a week (TIW) continuously, significant inter-patient variability was observed.  
There was suggestion of some drug accumulation between Day 1 and Day 19.  On Day 19, 
AUC ranged from 1.3 to 2.2-fold of Day 1 and Cmax ranged from 0.9 to 3.1-fold of Day 1.  Due 


 
 
 
Page 20 of 83 
 
 
to significant variability across doses among 2-3 patients in each dose group, no definitive 
conclusion could be made.  However, no gender difference was observed in this trial. 
In a Phase 1 trial conducted in Japan (Study HBI-8000-201), HBI-8000 was administered two 
times a week continuously. 
 
Distribution 
The apparent volume of distribution of chidamide is relatively large, indicating broad 
distribution in the human body. In vitro studies have shown that in human plasma 89.1 to 
99.3% of chidamide was protein-bound. 
 
Metabolism and Excretion 
Nuclear magnetic resonance and liquid chromatography-tandem mass spectrometry were used 
to investigate the biological conversion and material balance in 4 patients with TCL.  Seven 
days after a single dose of 30 mg, 80.2 ± 9.5% of chidamide was excreted in urine and feces, 
the majority of which occurred within the first 72 hours.  Chidamide was eliminated 
predominantly (67.6 ± 12.7%) through urine, and the remaining 12.6 ± 7.7% through feces.  In 
the excreted chidamide, the parent drug form was 37.6 ± 9.2% of total dosage, of which 39.4% 
was through urine and 86.9% was through feces.  There were also 5 main metabolites, products 
of mono-oxidation at different positions and hydrolysis of benzamide bond through two major 
metabolic pathways. 
Further information on clinical pharmacological studies with HBI-8000/chidamide may be 
found in the Investigator’s Brochure [IB 2020]. 
 
Clinical Studies 
To date, more than 800 patients have been dosed with HBI-8000/chidamide in clinical trials. 
Over 26,000 patients have been prescribed chidamide (Epidaza) in China since marketing 
approval was granted in December 2014. 
Clinical trials with HBI-8000 have shown that HBI-8000 is generally well tolerated in patients 
with advanced solid tumors or relapsed or refractory lymphoma at doses up to 32.5 mg TIW 
and 50 mg BIW administered continuously with or without intermittent breaks (total weekly 
doses of approximately 100 mg in Phase 1 trials).  The Phase 2 registration study in PTCL 
conducted in China demonstrated significant efficacy, with the best response rate of 28% 
(22/79) and a good safety profile. A subgroup analysis of the various histological subtypes 
revealed that the ORR was as high as 44 to 50% [Shi 2013, Shi 2015].  Based on these data, 
the CFDA granted conditional approval on December 23, 2014 for the use of chidamide (HBI-
8000) for the treatment of relapsed or refractory PTCL. 
In Japan, pharmaceutical and medical devices agency (PMDA) was consulted in 2013 to obtain 
advice for the clinical development of HBI-8000 for relapsed or refractory PTCL and ATLL 
in Japan. For a Phase 2 dose selection, a Phase 1 study (HBI-8000-201) in patients with 
relapsed or refractory Non-Hodgkins Lymphoma (NHL) including PTCL and ATLL was 


 
 
 
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initiated in Japan in April, 2014 and has completed. In addition, Phase 2 study in relapsed or 
refractory ATLL was initiated in 2016 and has completed. HUYBIO received approval from 
MLHW for relapsed or refractory ATLL in June 2021. The Phase 2 study in PTCL is this 
protocol. 
 
Rationale for Investigation in Relapsed and Refractory Peripheral T-
Cell Lymphoma (PTCL) 
Peripheral T-Cell Lymphoma (PTCL) s a group of usually aggressive and relatively treatment-
resistant peripheral NHLs that develop from mature T cells (TCL).  Peripheral T-Cell 
Lymphomas  are sub-classified into various subtypes, each of which are typically considered 
to be separate diseases based on their distinct clinical, morphologic, immunophenotypic and 
genetic features [Jaffe 2009]. The 3 most common subtypes of PTCL, not otherwise specified 
(PTCL-NOS), anaplastic large-cell lymphoma (ALCL), and angioimmunoblastic T-cell 
lymphoma (AITL), account for approximately 70% of all PTCLs, although there are 
geographical (North America, Europe and Asia) differences in the prevalence of the different 
subtypes, with ATLL and NK/T-cell lymphoma  being more common in Asia [Vose, Armitage, 
Weisenburger 2008]. 
The frontline therapy for PTCL has been multi-agent chemotherapy. Once disease has relapsed 
or if disease fails to respond to frontline therapy, treatment options are limited.  In Japan, 
mogamulizumab, a humanized monoclonal antibody directed against chemokine (C-C motif) 
receptor 4 (CCR4), has been available for the treatment of relapsed or refractory CCR4+ ATLL 
since 2012 and has been approved by PMDA for PTCL and CTCL based on a Phase 2 clinical 
trial in 2014.  CCR4 is over-expressed on various malignant T cells, including ATLL, PTCL 
and CTCL cells. Approximately 50% of PTCL patients are CCR4+, hence eligible to receive 
mogamulizumab. 
Clinical trials of mogamulizumab have shown that not all patients would respond to treatment.  
In fact, the response rate from the Phase 2 trial in Japan was 34% with a median progression 
free survival (PFS) of 3 months [Ogura et al 2014].  In Phase 1/2 trials conducted in the U.S., 
the overall response rate (ORR) was 37%, while in the EU, the ORR was only 11% with PFS 
of 2.1 months [Zinzani et al 2014].  The low ORR (11 to 37%) suggests that about two thirds 
of mogamulizumab-treated CCR4+ PTCL patients would still require other treatments.  Also, 
clinically significant adverse drug reactions have been observed with mogamulizumab, in 
particular, Stevens-Johnson Syndrome. Thus, treatment with better efficacy and safety is still 
needed. The planned study HBI-8000-203 will be conducted to evaluate the efficacy and safety 
of HBI-8000 in relapsed and refractory PTCL to address an unmet medical need. 
 
Dose Selection and Risk Assessment 
A Phase 1 dose finding study of HBI-8000 was conducted in Japan in NHL patients.  Based 
on the clinical experience from China (Section 1.6) where the CFDA approved dose of 
chidamide (Epidaza) is 30 mg BIW, the starting dose of this study was 30 mg.  Data to date 
have shown that both 30 mg and 40 mg dose levels were well tolerated.  The Grade 3 and 4 


 
 
 
Page 22 of 83 
 
 
toxicities observed at 40 mg in 2 out of 6 patients were transient, and asymptomatic.  The grade 
4 neutropenia was asymptomatic resolved promptly with administration of granulocyte colony 
stimulating factor.  The Grade 3 alanine aminotransferase (ALT) elevation was also 
asymptomatic resolved with dosing interruption.  On the other hand, strong signals of efficacy 
were observed at 40 mg as evidenced by none of the seven patients showing disease 
progression (PD)and five achieving partial response.  Upon review of risk and benefit in 
totality, the 40 mg BIW schedule was selected as the starting dose for the Phase 2. 
In clinical studies, treatment with HBI-8000 has been associated with myelosuppression, 
including thrombocytopenia, neutropenia and/or leukopenia and anemia or decreased 
hemoglobin.  Other adverse drug reactions reported in previous clinical trials include nausea, 
diarrhea, fatigue/lethargy, abdominal pain, vomiting, peripheral edema, pyrexia/fever, 
anorexia, dizziness, decreased appetite and transaminase increase.  Recommendations for the 
management of dose modifications are presented in Sections 2.6.8 and 2.6.9. 
 
. 
 


 
 
 
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2.0 STUDY OBJECTIVE(S)  
 
Primary Objective  
• To determine the efficacy of HBI-8000 administered BIW continuously 
 
Secondary Objective 
• 
To evaluate the safety and tolerability of HBI-8000 administered BIW continuously  
 
Criteria for Evaluation 
Efficacy Endpoints: 
Disease response will be assessed based on evaluation at baseline and postdose evaluations of 
nodal and extranodal lesions by imaging studies every 8 weeks.  Evaluation of nodal lesions 
and extranodal lesions will be performed according to the revised criteria for response 
assessment in lymphoma [Cheson 2014] (see Section 9.4). 
Primary: 
• Objective response rate [ORR; Complete Response (CR) + Partial Response(PR)]  
Secondary: 
• ORR by disease subtype (see Section 2.5.1) 
• Median duration of PFS  
• Median duration of response (DOR)  
Exploratory: 
• Median duration of overall survival (OS) 
• Pharmacokinetics (for selected sites) 
Safety Endpoints: 
Safety and tolerability of HBI-8000 will be measured by the number of patients with adverse 
events (AEs) and severity of AEs as defined by Common Terminology Criteria for Adverse 
Events (CTCAE) v.4.03.  Adverse events reported by the patients or observed during physical 
examination, vital signs assessments, ECGs, and laboratory tests results will be recorded and 
assessed by severity and association with study treatment.  
Population Pharmacokinetic Characterization Study (applicable to participating sites and 
consented patients): 
Population PK will be conducted at selected sites in Japan.  At these sites, only patients that 
consent to this PK study will participate.  To obtain comparable PK database from Japan and 
Korea and to assess regional difference, if any, PK characterization will be required for all 
patients enrolled in Korea.  PK sampling will be performed as detailed in Table 5 of 
Appendix A. 


 
 
 
Page 24 of 83 
 
 
 
Summary of Study Design 
This is a Phase 2b, open-label, non-randomized, single arm study to evaluate the efficacy, 
safety, and PK of HBI-8000 in patients with relapsed or refractory PTCL.  Study patients will 
ingest HBI-8000 approximately 30 minutes after any regular meal BIW.  There will be 3 to 4 
days between dosing.  A treatment cycle is defined as 28 consecutive days.  HBI-8000 
administration will be continued until PD or the occurrence of unacceptable toxicities despite 
optimal supportive care.  
The study will continue till the last active Japanese subject initiates administration of the 
commercial product of HBI-8000 after the marketing authorization approval for relapsed or 
refractory PTCL in Japan. If there is no subject who is receiving study treatment at the time of 
the PTCL approval in Japan, the whole study will be completed at the time of the approval. 
In Japan, “Phase 2 study” shall be read as “post-marketing clinical study” and “investigator” 
shall be read as “post-marketing clinical study investigator” in this protocol after the marketing 
approval. In addition, other related terms are to be replaced in accordance with Article 56 of 
the Ministerial Ordinance on the Standards for the Implementation of Clinical Studies on 
Pharmaceutical Product (Japan GCP).  
Response and progression for PTCL will be evaluated according to the revised criteria for 
response assessment in lymphoma. [Cheson et al 2014] (see Section 9.4). 
 
Safety Determination and Criteria for Dose Modification or Interruption 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
version 4.03 will be used to grade the severity of toxicities.  Abnormalities of laboratory tests 
(investigation) must be evaluated for clinical significance.  Study treatment may be held, and 
dose may be reduced in the event of unacceptable toxicities. (see Section 2.6.8 for Guidelines.) 
 
Selection of Study Population 
 
Inclusion Criteria 
Patients may be entered in the study only if they meet all of the following criteria: 
1. Histological or cytological diagnosis of the following PTCL subtypes as defined by the 
WHO classification (2008) may be included: 
a. PTCL, NOS  
b. Angioimmunoblastic T-cell lymphoma (AITL) 
c. Anaplastic large-cell lymphoma (ALCL), ALK+  
d. Anaplastic large-cell lymphoma (ALCL), ALK− 
e. Enteropathy-associated T-cell lymphoma (EATL)  
f. Hepatosplenic T-cell lymphoma 
g. Subcutaneous panniculitis-like T-cell lymphoma 


 
 
 
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2. Patients for whom at least 1 measurable lesion is confirmed by the lesion assessment 
at baseline; an evaluable lesion is defined according to Cheson Criteria 2014. 
3. Relapsed or refractory disease after receiving ≥1 prior systemic therapy with antitumor 
agent(s) and there is no other standard treatment which can be considered appropriate 
for patients.  Systemic therapy is defined as frontline chemotherapy or immunotherapy 
administered systemically. 
4. Male or female, aged 20 years or older  
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2 
6. Life expectancy of greater than 3 months 
7. Meeting the following baseline laboratory criteria for screening:  
a. Absolute Neutrophil Count >1500/µL independent of growth factor support 
within 7 days 
b. Platelets >75,000/µL independent of transfusion within 14 days  
c. Hemoglobin >8 g/dL independent of transfusion within 14 days  
d. Serum creatinine < 1.5 × upper limit of normal (ULN) 
e. Serum 
aspartate 
aminotransferase/glutamyl 
oxaloacetic 
transaminase 
(AST/SGOT) and alanine aminotransferase/glutamyl pyruvic transaminase 
(ALT/SGPT) ≤ 3 × ULN 
f. Serum Bilirubin ≤ 1.5 × ULN 
8. Negative serum pregnancy test for females of childbearing (reproductive) potential.  
Female patients of child bearing potential must use an effective method of birth control 
(e.g., hormonal contraceptive, intrauterine device, diaphragm with spermicide or 
condom with spermicide) during treatment period and 1 month thereafter.  Males must 
use an effective method of birth control (2 barrier methods) during treatment period 
and 3 months thereafter.   
Note: Female patients will be considered to be women of childbearing potential 
unless 
having 
undergone 
permanent 
contraception 
or 
postmenopausal.  
Postmenopausal is defined as at least 12 months without menses with no other 
medical reasons (e.g., chemical menopause because of treatment with anti-malignant 
tumor agents) 
9. Signed informed consent 
 
Exclusion Criteria 
Patients who meet any of the following criteria are not to be enrolled: 
1. Patients in whom central nervous system lymphoma is recognized during screening (if 
suspected clinically, imaging study should be performed to confirm) 
2. Male patients with QTcF >450 msec at screening, female patients with QTcF 
>470 msec at screening, or patients with congenital long QT syndrome, clinically 
significant arrhythmia, history of congestive heart failure (New York Heart Association 
Class III or IV) or acute myocardial infarction within 6 months of starting the study 
drug  
3. Patients with known hypersensitivity to benzamide class of compounds or any of the 
components of HBI-8000 tablets, and patients with prior exposure of HBI-8000 


 
 
 
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4. Patients with a history of second malignancy other than disease under study. The 
exceptions are diseases (excluding diseases listed below) that have been treated with 
curative intent with no evidence of recurrence in past 5 years. Furthermore, if the 
second malignancy is one of the following diseases that were treated with curative 
intent, it is only required that there is no evidence of recurrence in past 2 years: 
a. Basal cell carcinoma of the skin 
b. Squamous cell carcinoma of the skin 
c. Cervical carcinoma in situ 
d. Carcinoma in situ of the breast 
e. An incidental histological finding of prostate carcinoma (TNM stage T1a or 
T1b) 
f. Early-stage gastric cancer treated with endoscopic mucosal resection or 
endoscopic submucosal dissection 
g. Thyroid cancer with differentiated histology (e.g. papillary) treated with 
curative intent  
5. Autologous stem cell transplantation within 12 weeks (84 days) of starting the study 
drug 
6. History of allogeneic stem cell transplantation 
7. Organ transplantation recipients except autologous hematopoietic stem cell 
transplantation 
8. Uncontrolled inter-current infection  
9. Hepatitis B surface antigen-positive, or hepatitis C virus antibody positive.  In case 
hepatitis B core antibody and/or hepatitis B surface antibody is positive even if hepatitis 
B surface antigen-negative, a hepatitis B virus DNA test (real-time polymerase chain 
reaction measurement) should be performed and if positive, the patient should be 
excluded from study 
10. Any history of testing positive for human immunodeficiency virus  or known acquired 
immunodeficiency syndrome  
11. Uncontrolled diabetes mellitus, hypertension, endocrine disorder, bleeding disorder 
12. Major surgery or radiation therapy within 28 days of starting the study drug 
13. Receiving investigational agents or anti-cancer therapy within 28 days, nitrosourea or 
mitomycin C within 42 days, of starting the study drug 
14. Receiving antibody therapy for PTCL within 12 weeks of starting the study drug 
15. Women who are breastfeeding or women who are not willing to stop breastfeeding 
during study treatment period and for 30 days after the last dose of study drug 
16. Potential for non-compliance or at increased risk based on investigator’s judgement 
 
Study Procedures Overview 
Patients may be treated in this study as long as they receive clinical benefit (stable disease or 
a response) in the absence of unacceptable toxicity.  Disease progression would be determined 
by investigators based on local radiology findings and clinical judgement.  No independent 
radiology review is required prior to designation of PD and treatment discontinuation.  
Independent Radiology Review and Independent Overall Efficacy Review will be performed 
for final efficacy analyses at the completion of this study.   


 
 
 
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To ensure patient safety, a data safety monitoring board (DSMB) will convene to review the 
cumulative safety profiles of study patients at following milestones: first 6 patients completing 
at least 1 cycle, 12, 18, 30 patients have been treated for at least 1 cycle and at end of treatment 
Phase of the study.  Based on the observed safety, dose and regimen of ongoing treatment may 
be modified as needed.  For all patients, weekly safety laboratory tests will be obtained during 
the first 28 days and closely monitored for safety signals, especially for neutropenia and 
transaminase elevation. 
It is estimated that each patient will be on study for up to 42 months after enrollment.  
Assuming that 24 months are needed to meet accrual target, the study period would be of 
66 months to allow efficacy and safety determination. After study drug is discontinued, 
patients will be followed as described in Sections 2.6.4 and 2.6.5.  
Patients will be screened by the study site investigator prior to entry into the study.  Patients 
will receive a detailed explanation of the study design, and the potential risk/benefit of 
treatment will be disclosed to patients prior to the screening process.  Only eligible and 
consenting patients will be enrolled into the study.  Local histopathology report could be used 
to consent patient.  Central pathology review will be completed before efficacy analysis.  The 
investigator will maintain a pre-screening log to record all patients prior to screening.  
Similarly, local radiology reports on disease status will guide investigator’s decision on study 
treatment, including discontinuation.  At end of the study, tumor response of each patient will 
be reviewed by independent radiologists and oncologists in a blinded fashion to obtain best 
response, dates of response and progression.  The data from independent and local assessment 
will be analyzed in parallel in final study report. 
The Schedule of Events is presented in Table 4 of Appendix A (Section 9.1).  The timing of 
PK sampling is provided in Table 5 of Appendix A. 
 
Screening Assessments (within 28 days prior to start of treatment)  
Written informed consent for participation in the study must be obtained before performing 
any study-specific screening tests or evaluations.  Informed Consent Forms (ICFs) for all 
patients screened (whether enrolled or not) will be maintained at the study site. 
All screening and baseline assessments must be completed and reviewed to confirm that 
patients meet all eligibility criteria.  An Eligibility Screening Form (ESF) documenting the 
investigator’s assessment of each screened patient with regard to the protocol’s inclusion and 
exclusion criteria is to be completed and kept at the study site. 
Screening assessments include medical history and concomitant medications, documentation 
of PTCL diagnosis in accordance with the WHO revised classification (WHO 2008) and 
treatment history.  To consent a patient to allow screening procedure, local histology diagnosis 
for PTCL is acceptable.  Unstained tumor pathology slides will be sent to pathology central 
laboratory and stained at the central laboratory.  The images will be captured from the slides 
for central pathology review that is to be completed  before efficacy analysis.  For patients who 
do not have enough tumor tissue archived, a new biopsy will be requested.  However, 
insufficient tumor tissue in archive or inability to perform new biopsy for any reason does not 


 
 
 
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exclude patients from entering this study.  Reasonable efforts should be made to support central 
pathology review.  
Screening assessments will be performed within 28 days prior to Cycle 1 Day 1 (C1D1).  A 
pretreatment bone marrow test (aspiration or biopsy) would be required.  Results of standard-
of-care tests or examinations performed prior to obtaining informed consent and within 28 
days prior to C1D1 may be used (and do not need to be repeated for screening unless they do 
not meet the criteria defined in the protocol).  Similarly, tumor assessment tests <2 weeks 
outside the 28-day window in the absence of clinical evidence of PD, the results may be 
accepted. 
Women of childbearing potential must agree to practice effective contraceptive measures after 
signing informed consent.  A negative serum pregnancy test will be obtained during screening.  
 
Baseline Assessments on Cycle 1 Day1 (C1D1)  
Baseline assessments include a complete physical examination, vital signs, ECOG 
performance status, weight, concomitant medications, laboratory tests (hematology, chemistry, 
coagulation and urinalysis), and safety ECG. Women of childbearing potential must have a 
negative pregnancy status confirmed by serum test before dosing.  If Serum pregnancy test 
result cannot be obtained on the same day before dosing, urine pregnancy test should be 
conducted additionally and the result should be confirmed before dosing (see Section 9.1).  
Some of the pre-dose assessments except vital signs and ECG may be performed 1 day before 
C1D1 to accommodate scheduling requirements in the hospital. 
 
Treatment Phase 
All assessments must be performed as per the Schedule of Events (see Section 9.1. 
Assessments scheduled on the day of study treatment should be performed prior to taking study 
drug, unless otherwise noted in the schedule of assessments.  
Assessment of tumor response will be scheduled by end of the eighth week, then every 8 weeks 
(± 1 week) from C1D1.  However, if a patient develops clinical signs and symptoms of PD, or 
unacceptable toxicity occurs, tumor assessment may be performed sooner as needed.  For the 
patients with skin lesions, decision on treatment discontinuation should be based on computed 
tomography (CT) or positron emission tomography (PET-CT) assessment, not Modified 
Severity Weighted Assessment Tool (mSWAT) scores.  In other words, if imaging studies 
showing SD or PR while mSWAT score increases, treatment will continue. 
 
End of Treatment Safety Follow-up Visit 
All patients receiving at least one dose of HBI-8000 and discontinuing treatment for any reason 
except death will be assessed 30 (± 3) days after the last dosing of study drug, before the 
initiation of new cancer treatment or before the initiation of administration of commercial 
product of HBI-8000, whichever is earlier. Any patient for whom study treatment has been 
discontinued should complete study procedures listed in the EoT visit. At EoT safety visit, 
evaluations will include physical examination, vital signs, body weight, ECOG performance 


 
 
 
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status, hematology, blood chemistry, urinalysis, pregnancy test (if applicable), ECG, and 
assessment of any ongoing adverse events.  If a patient discontinues study treatment before PD 
is recorded, and if the last tumor assessment was >30 days earlier from the EoT visit, tumor 
assessment should be performed at EoT. In these patients, further tumor assessments are to be 
performed approximately every 3 months ± 2 weeks until PD or the start of new cancer therapy 
whichever occurs first, unless consent to study participation is withdrawn or by completion of 
the whole study. If subjects cannot visit at site for this examination due to COVID-19 situation, 
investigators can skip the examination, and the assessment is to be performed approximately 
every 6 months ± 2 weeks. In this case, the investigator should document that fact in the 
medical record.    
Patients with HBI-8000-related AEs of Grade ≥2 observed at the EoT visit should be followed-
up and assessed monthly (phone calls/clinic visits) until the AEs have resolved to Grade ≤1 or 
are determined to be chronic, or patient receives other anti-cancer therapy. 
 
Survival Follow-up 
Follow-up for survival (and tumor status in patients in whom PD has not yet been observed) 
should occur at approximately 3-month intervals after the EoT visit.  Survival status may be 
conducted every 3 months ± 2 weeks by telephone contact or e-mail until death or end of study, 
defined as timing that the last Japanese subject initiates administration of the commercial 
product of HBI-8000. If there is no subject who is receiving study treatment at the time of the 
PTCL approval in Japan, the whole study will be completed at the time of the approval. The 
first subsequent anticancer therapy during this survival follow up period should be recorded 
with regimen and start date in the appropriate Electronic Case Report Form (eCRF).  
 
Patient Withdrawal 
Patients have the right to withdraw from the study at any time for any reason, and the 
investigator should try to ascertain the reason for withdrawal as completely as possible.  The 
investigator also has the authority to determine whether a patient should be discontinued from 
the study.  Study treatment may be discontinued and the patient withdrawn from the study 
under the following circumstances: 
• 
Unacceptable toxicity (AE)  
• 
Progression of the disease under study, except for isolated progression in skin lesion 
• 
Decision by the investigator to permanently discontinue study drug administration  
• 
Intercurrent illness that would, in the judgment of the investigator, affect clinical 
assessments, patient safety, or follow-up significantly 
• 
Significant protocol deviations that jeopardize the usefulness of the data 
• 
Repeated patient noncompliance 
• 
Patient is beginning another anti-cancer treatment protocol  
• 
Patient becomes pregnant  
• 
Patient requests to withdraw informed consent 
• 
Study termination by the sponsor 


 
 
 
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All patients who withdraw from study treatment must complete an EoT visit, to be performed 
30 ± 3 days after the last dosing of the study drug (see Section 9.1), before the initiation of new 
cancer treatment or before the initiation of administration of commercial product of HBI-8000, 
whichever is earlier.  A patient may withdraw consent for treatment but still allow follow-up, 
in which case he/she should be followed for safety, survival, and disease status.  If a patient 
has withdrawn consent to study participation entirely, no subsequent follow-up will be 
performed. 
Patients who are lost to follow up or withdraw consent for study participation prior to receiving 
HBI-8000 or who withdraw before completing Cycle 1 for reasons unrelated to drug AEs or 
PD will be replaced.  
 
Discontinuation of the Study 
The whole study will be discontinued in any of the following cases: 
• 
Sponsor decides to discontinue development of the compound or the study 
• 
In the event of sponsor or regulatory authorities obtain safety information which 
does not allow continuation of the study 
 
Management and Dosage Modifications for Unacceptable Hematologic and 
Non-Hematologic Adverse Events 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 4.03 will be used to grade the severity of toxicities.  An unacceptable toxicity is defined 
as the following treatment-related AEs: 
• Grade 4 afebrile neutropenia >7 days despite optimal growth factor support 
• Grade ≥3 febrile neutropenia or neutropenic infection 
• Grade ≥3 thrombocytopenia with clinically significant bleeding or Grade ≥3 
thrombocytopenia requiring a platelet transfusion 
• Grade ≥3 nausea, vomiting, diarrhea, or electrolyte imbalances lasting greater than 
48 hours despite optimal prophylactic and curative treatment 
• Grade ≥3 allergic reaction 
• Grade ≥3 other non-hematologic AEs  
• Treatment delay >14 days secondary to recovery from study drugs- related AEs  
Table 1 summarizes the guidelines for dosage adjustment in the event of unacceptable AEs.  
Two dose reductions are allowed (from 40 mg to 30mg, or from 30 mg to 20 mg).  If 
unacceptable AEs recur despite 2 dose reductions, the study treatment will be permanently 
discontinued and post-treatment follow-up ensues. However, if the patients are having clinical 
benefit, further treatment may be considered after discussion with the sponsor.  In the event of 
AE, such as hematological AE-uncomplicated, necessitating two treatment interruptions, dose 
will be reduced when treatment resumes.  However, if strongly needed for patient safety, dose 
can be reduced according to the investigator judgement, even if unacceptable hematological 
AE-uncomplicated is occurred once. 


 
 
 
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Table 1: HBI-8000 Tablet Dosage Adjustment Guidelines 
AE Category 
AE Description 
Dosage interruption 
with/without Reduction 
Hematological 
Adverse Events--
Uncomplicated 
• Neutropenia Grade 3 or 4 upon 
observation 
 
 
 
• Thrombocytopenia Grade 3 or 4 upon 
observation 
Hold dose, Initiate G-CSF, once 
resolved to ≤1 within 2 weeks, 
resume at same dose 
 
Hold dose, once resolved to ≤1 
within 2 weeks, resume at same 
dose.  
 
If recovery takes >2 weeks, 
discontinue study drug. 
Hematological 
Adverse Events--
Complicated 
• Grade 4 afebrile neutropenia >7 days 
despite optimal growth factor support 
• Grade ≥ 3 febrile neutropenia or 
neutropenic infection 
• Grade ≥3 thrombocytopenia with 
clinically significant bleeding or Grade 
≥3 thrombocytopenia requiring a 
platelet transfusion 
Hold doses, once resolved to ≤1 
within 2 weeks, resume at 
reduced dose (from 40 mg to 
30 mg, or from 30 mg to 20 mg);  
If recovery takes >2 weeks, 
discontinue study drug. 
Non-Hematological 
Adverse Events 
(excluding 
laboratory values 
without clinical 
significance)  
Grade 3 
Hold doses, once resolved to ≤1 
within 2 weeks, resume at 
reduced dose (from 40 mg to 
30 mg, or from 30 mg to 20 mg) 
with appropriate prophylaxis as 
applicable.  
If recovery takes >2 weeks, 
discontinue study drug. 
Grade 4 
Discontinue study drug 
AE: Adverse Event; G-CSF: granulocyte colony stimulating factor 
G-CSF is recommended to be prescribed when uncomplicated grade 3 or 4 neutropenia is 
observed.  Patient management should follow institution guidelines and be recorded in eCRFs.  
Laboratory tests should be obtained at least once a week to monitor recovery. 
 
Management and Dosage Modifications for Non-Hematologic Adverse 
Events  
In the event of Grade 3 non-hematologic AEs (excluding isolated abnormality of laboratory 
values not associated with clinical significance), study medication should be held.  Appropriate 
treatment should be initiated.  Patients will be closely monitored for recovery and managed 
following the Dose Adjustment Guideline.  If the AEs recur despite two dose reductions as 
applicable, study treatment should be discontinued.  Study treatment should be terminated if 
Grade 4 non-hematologic adverse events occur, following the Dose Adjustment Guideline. 


 
 
 
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Study Drug Administration 
During this trial, patients will receive 40 mg HBI-8000 administered approximately 30 minutes 
after any regular meal as four 10 mg tablets BIW continuously.  The dosing interval would be 
3 to 4 days for a total of 80 mg over 7 days. At each visit when study medication is dispensed, 
the study site staff will contact the Interactive Web Response System (IWRS) before 
dispensing. 
 
Packaging, Labelling and Storage 
HBI-8000 10 mg tablets are packaged in high density polyethylene bottles closed with an 
induction seal and a child-resistant cap and contain a desiccant pack, and a cotton coil.  Each 
bottle contains 26 tablets.  Study drug labels will contain information to meet the applicable 
regulatory requirements.  In case of discontinuation of treatment for any reason unused portion 
of the drug should be returned to hospital pharmacy. 
Drug product will be stored at 2 to 8 ° C at hospital pharmacy until dispensing.  After 
dispensing to patients, the drug will be transported to home in a cooler to maintain refrigerated 
condition.  Once at home, the drug will be kept refrigerated until administration and out of 
reach of children all the time. The study drug shall be read as post-marketing clinical study 
drug in this protocol after the PTCL approval. 
 
Patient Registration and Subject Number Assignment  
Based on medical history, potentially eligible patients will be identified.  After obtaining 
informed consent, the screening procedures will be performed and a 5-digit subject number 
will be assigned.  The first 3 digits are the site number (provided by the sponsor to study sites).  
The last 2 digits are a sequential number within a study site.  If a patient is assigned a subject 
number and later found unable to begin HBI-8000 administration, the patient will be replaced.  
A new subject number will be assigned to the replacement patient. 
 Concomitant Treatments 
All concomitant medications, regardless of whether they are prohibited or not, received after 
signing informed consent must be recorded on the eCRF.  Complete information on all 
concurrent medications (generic name of drugs, reason for use, dosage and duration of 
dosing, etc.) should be documented in the original records and in the eCRF. 
Patients should consult their investigator prior to using medications other than the study drug, 
including over-the-counter medications and supplements. 
 
Prohibited Medications and Therapy 
The following drugs are prohibited.  


 
 
 
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• Drugs known to produce significant QT prolongation and ventricular dysrhythmias (see 
Section 9.6)  
Prohibited from signing informed consent through the EoT assessment 
• Anti-cancer therapy other than study medication 
Prohibited during the study and within the following time intervals prior to the first dose 
of study drug. 
− 4 weeks for anti-cancer chemotherapy 
− 6 weeks for nitrosourea and mitomycin C 
− 12 weeks for anti-cancer monoclonal antibody therapy 
Corticosteroid prescribed for medical conditions other than lymphoma is not considered 
as an anti-cancer therapy for this study, for example: chronic obstructive pulmonary 
disease for allergy, topical steroids for rash. 
Please note that patient use of any prohibited medication is considered a protocol violation.  In 
the event of prohibited medication use, investigator should consult study medical monitor to 
define an appropriate course of action if needed. 
 
Cautioned Medications 
Because the anti-emetic drug Zofran (ondansetron) is well known to prolong QTc, it is 
prohibited on 2 occasions, Cycle 1 Day 1 and Cycle 2 Day 1 when QTc test is scheduled.  
Starting 24 hours before the QTc test until the QTc test is completed on the next day, patient 
must not take Zofran over a 2-day period.  Although anti-emetics are rarely needed for 
HBI-8000, if anti-emetics must be used for other medical reason, alternative drug(s) should be 
used.  If a 5-HT3 antagonist must be used to manage severe emesis refractory to other 
medications, dosing should be postponed until resolution of underlying medical condition.  
In case it is medically necessary to co-administer drugs that could interfere with CYP3A4 
activity, investigators should monitor for toxicities and follow the study drug dose 
modifications for toxicity per study protocol.  Also, St. John’s wort should be used with caution. 
 
Permitted Medications 
Use of supportive care for AEs is permitted.  These treatments may include anti-emetics, 
antipyretics, antidiarrheal, anti-allergy agents, rash reliever, antihypertensive drugs, analgesics, 
antibiotics, hematopoietic growth factors and transfusion with blood products.  
Sulfamethoxazole Trimethoprim use is permitted.  However, when its side effects are observed, 
alternative antibiotics prophylaxis should be considered. 


 
 
 
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 Dietary Restrictions 
Due to potential food-drug interactions for many commonly used medications, grapefruit, 
grapefruit juice, Seville oranges, and any products that contain Seville oranges or grapefruit 
should be avoided when possible. 
 Treatment Compliance 
The prescribed dosage, intervals between doses, and mode of administration, e.g., after meals, 
intact tablet (not crushed) may not be changed without direction by the investigators.  They 
must be recorded in the eCRFs.   
The patient will be provided with a drug log to record date and time of administration, time of 
meal prior to administration, AEs, and missed doses.  To verify compliance, the patient will be 
instructed to bring the drug log and study drug bottles (including any empties) to appointments 
scheduled for Day1 of each cycle starting with Cycle 2 for reconciliation.  
At each visit when study medication is dispensed previously dispensed study drug count will 
be confirmed by the investigator, or authorized designee, and compliance assessed prior to 
dispensing new study medication.  
Patients exhibiting poor compliance as assessed by tablet counts and not following dosing 
schedules should be counseled on the importance of good compliance to the study dosing 
regimen.  Noncompliance to drug amount is defined as taking <75% or >125% of study 
medication during a cycle.  Noncompliance to dosing interval is defined as more than 
2 occurrences of <3 days between doses during a cycle, for example, 1 or 2 days between doses 
#3 and #4 instead of 3 or 4 days according to a BIW schedule.  If in the opinion of investigator 
a patient is unable to follow instruction, study treatment should be discontinued. 
 Study Medication Accountability 
A clinical supplies shipment/receipt verification form will be enclosed with each study drug 
shipment.  The site pharmacist who receives the shipment should complete this form and 
clinical research associate should collect a copy of the form at each pharmacy visit.  If instead 
of the shipment/receipt verification form, a packing list is enclosed with the shipment, 
acknowledgment of the study drug receipt should be done through the IWRS system by the 
site pharmacist or authorized designee. 
The investigator, or authorized designee, must maintain a complete and accurate record of the 
receipt and distribution of all study medication using the Drug Accountability Form.  These 
forms will be described in detail in the pharmacy manual and must be available for inspection 
at any time. 
All study medication supplies should be accounted for at the termination of the study, and a 
written explanation provided for any discrepancies.  All unused study medication supplies and 


 
 
 
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packaging materials are to be inventoried and returned to the local depot by the investigator, 
or authorized designee.  The investigator, or authorized designee, is not permitted to return or 
destroy unused clinical drug supplies or packaging materials unless authorized by the sponsor 
or delegate(s). 


 
 
 
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3.0 STUDY ASSESSMENTS 
 
Efficacy 
 
Primary Efficacy Endpoint 
The primary efficacy endpoint is to establish the ORR, defined as the proportion of patients 
with tumor size reduction of a predefined amount and for a minimum time period, evaluated 
by using the revised criteria for response assessment in lymphoma [Cheson 2014] (see 
Section 9.4). 
Tumor assessments will be performed by imaging modalities. CT, magnetic resonance imaging, 
or PET scanning may be used to evaluate lesions in the neck, chest, abdomen, and pelvis; and 
as a baseline evaluation for patients who may have brain metastases.  The PET-CT is 
encouraged to be performed from baseline.  However, when CT is the routine method to 
monitor patients according to hospital standard of care, PET-CT is not required.  Evaluation of 
nodal lesion and extranodal lesion will be performed according to the revised criteria for 
response assessment in lymphoma [Cheson 2014] (see Section 9.4).  Skin lesions are non-target 
lesions.  Their response will be assessed according to mSWAT, and contribute to overall 
response determination. 
Tumor response based on imaging studies will be confirmed with central review by independent 
radiologists at end of study prior to final efficacy analysis.  The dates of PR, CR and PD will 
be assessed as applicable.  Initial review will be performed by one independent radiologist.  If 
the results differ from those reported by the investigators based on local radiology findings, a 
second independent radiologist will be asked to adjudicate by way of assigning the final disease 
response to the determination made by either the investigators or independent radiologist. The 
overall efficacy review will be done by independent oncologist for final efficacy analysis. 
 
Secondary Efficacy Endpoints 
The secondary efficacy measures are: 
• ORR by disease subtype 
• Median duration of PFS defined as the time from the first dose of study medication to 
objective tumor progression or death. 
• Median DOR defined as the time from the first observation of tumor response to PD. 
 
Exploratory Endpoints 
• Median duration of overall survival  
• Pharmacokinetics  


 
 
 
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Safety 
 
Definitions 
 
Adverse Events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical treatment or procedure.  Assessment 
of the occurrence of an AE will be based on changes in the patient’s physical examination, 
laboratory results, and/or signs and symptoms.  An AE also includes any newly occurring event 
or previous condition that has increased in severity or frequency from signing the informed 
consent.  
Adverse events will be monitored until they are resolved or clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness(es).  Medical care will be provided, 
as defined in the informed consent, for any AE related to study participation. 
 
Serious Adverse Event  
A serious adverse event (SAE) is any untoward medical occurrence resulting in the following: 
• Death 
• Is life-threatening (defined as an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires in-patient hospitalization or causes prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization, but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may require 
intervention [e.g., medical or surgical] to prevent one of the other serious outcomes 
listed in the definition above).  Examples of such events include, but are not limited to, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization. 
Although overdose is not always serious by regulatory definition, this event should be reported 
on an SAE form and sent to the sponsor in an expedited manner. 
All pregnancies, regardless of outcome, must be reported to the sponsor on a pregnancy form, 
not an SAE form. 


 
 
 
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NOTE: 
The following hospitalizations are not considered SAEs in sponsor clinical studies: 
• A visit to the emergency room or other hospital department lasting <24 hours, that does 
not result in admission (unless considered “important medical event” or event that is 
“life-threatening”) 
• Elective surgery planned prior to signing consent 
• Admissions as per protocol for a planned medical/surgical procedure 
• Routine health assessment requiring admission for pretreatment assessment/trending of 
health status (e.g., routine colonoscopy) 
• Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to signing consent.  Appropriate documentation is required in these cases 
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative) 
• Admission for Progressive Disease (PD) 
 
Period of Observation 
All AEs (including SAEs) regardless of the relationship to study drug or study procedure will 
be collected from obtaining informed consent to the EoT assessment. At EoT, AEs Grade ≥2 
considered to be at least possibly related to the study drug must be followed up after the EoT 
assessment until the events have recovered to Grade ≤1, returned to the baseline level, are 
judged by the investigator to be stabilized, or to be given a reason that further follow up will 
not be required (see Section 2.6.4).  However, if the patient begins to receive new cancer 
therapy or withdraws consent to study participation, no further follow-up will be conducted.  
The outcome of the events which do not resolved by that time will be recorded as “ongoing” 
on the eCRF. 
 
Preexisting Conditions 
A preexisting condition will not be reported as an AE unless the condition worsens by at least 
one CTCAE grade during the study.  However, the pre-existing condition must be recorded in 
the screening eCRF as a pre-existing condition, and all concomitant medication administered 
for the condition must be recorded as concomitant medication in the eCRF following 
guidelines for other concomitant medication. 
 
Documentation and Reporting of Adverse Events by Investigator 
Any signs and symptoms that occur after obtaining the informed consent will be described as 
AEs and graded according to the CTCAE in the AE section of the eCRF.   


 
 
 
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Abnormal laboratory values will be recorded on the laboratory section of the eCRF and not in 
the AE section.  Abnormal laboratory results leading to a clinical diagnosis will be reported 
with a clinical term by the investigator and recorded in the AE section of the eCRF in addition 
to the laboratory section.  Abnormal laboratory results that meet the definition of an SAE 
should also be reported on an SAE form.  Relationship (reasonable causal relationship) to drug 
treatment and countermeasures taken will be noted on the eCRF.  Investigators must record in 
the eCRF their opinion concerning the relationship of the AE to study therapy. 
Disease progression should not be recorded as an AE.  Diagnostic and therapeutic non-invasive 
and invasive procedures, such as surgery, will not be reported as an AE, but the procedure 
and/or therapeutic treatment should be recorded on the appropriate eCRF.  The medical 
condition for which the procedure was performed must be reported. 
 
Assessment of Causal Relationship to Study Drug 
The relationship of an AE to the study medication is graded as follows: 
Definite: 
• Distinct temporal relationship with the study drug  
• Stops/improves when the study drug has been stopped 
• Can reasonably be explained by known characteristics of the drug 
Probable: 
• Reasonable temporal sequence from the study drug administration 
• Stops/improves when the study drug has been stopped 
• Event cannot easily be explained by patient’s clinical state or other factors 
Possible: 
• Reasonable temporal relationship with the study drug 
• Event could have been produced by the patient’s clinical state or other factors 
Unlikely: 
• Poor temporal relationship to the study drug  
• Patient’s clinical state is likely to have an association with the effect 
Unrelated: 
• Definitely not associated with the study drug administered 
“Definite”, “Probable” and “Possible” events are regarded as AEs that cannot be denied a 
causal relationship to the study drug, that will be handled as “related to the study drug” for 
reporting purposes, and “Unlikely” and “Unrelated” events are regarded as AEs that can be 
denied a causal relationship to the study drug, that will be handled as “not related to study drug” 
for reporting purposes. 




 
 
 
Page 41 of 83 
 
 
This timeframe also applies to additional new information (follow-up) on previously forwarded 
SAE reports.  For all SAEs, the investigator is obligated to pursue and provide information to 
the sponsor in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by the sponsor to obtain specific additional follow-up 
information in an expedited fashion.  In general, this will include a description of the AE in 
sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality.  Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided.  In the case of death, a summary of 
available autopsy findings must be submitted as soon as possible to the sponsor.  All SAEs 
occurring in this study requiring expedited regulatory reporting will be evaluated, summarized, 
and reported to investigators.  These SAEs must also be submitted in writing by investigators 
to the institutional review board (IRB). 
 
Pregnancy 
If a patient becomes pregnant during treatment or within 1 month following the last dose of 
the study drug, administration (if still ongoing) must be discontinued and the sponsor is notified 
within 24 hours of investigator awareness of the pregnancy.  For the purposes of this study, 
pregnancy of any patient will be considered an AE but not, in itself, an SAE, and should be 
reported to the sponsor on a pregnancy form rather than an SAE form.  However, if pregnancy 
leads to an SAE for example, a spontaneous abortion or miscarriage resulting in medical 
hospitalization, an SAE form should be completed.  Every attempt must be made to follow the 
pregnancy to resolution, which includes birth or termination of the pregnancy.  If the 
information is available, the resolution must be reported to the sponsor on a pregnancy form.  
If possible, births should be followed by the investigator for 8 weeks for observation of any 
congenital abnormalities, and any such abnormalities should be reported within 24 hours of 
investigator awareness of the observation to the sponsor. 
Pregnancy of a male patient’s partner will not be considered an AE, and the male patient should 
not be withdrawn from the study.  If a male patient’s partner becomes pregnant during the 
specified time period (from first dose until 3 months after the last dose), the investigator will 
inform the sponsor within 24 hours of investigator awareness of the pregnancy, as well as the 
IRB, as appropriate, and will provide appropriate medical follow-up, if agreed to by the partner. 
 
Overdose 
Overdose is defined as administration to the patient of a dose of test article that exceeds by 
more than 40 mg/dose or 80 mg/week. 
Any overdose of HBI-8000 should be reported via an SAE form within 24 hours of investigator 
awareness of the overdose to the sponsor, regardless of association with an AE.  In the case 
that the overdose did not result in an AE, the investigator should report this as “overdose, no 
AE” on the SAE form and specify the intended amount, as well as the actual amount, of drug 
administered. 


 
 
 
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Follow-Up of Adverse Events 
Patients should be asked to specifically describe any signs, symptoms, or AEs (regardless of 
relationship to therapy) they may notice prior to the start of the study or thereafter.  At a 
minimum, patients should be asked to report AEs at each visit to the study site.  Conditions 
that the patient experienced prior to informed consent should be recorded in the medical history 
section of the eCRF.   
Follow up of an “overdose” should include continued monitoring of all protocol-specific 
laboratory results, including chemistry and hematology, using the protocol-specified time 
points for laboratory tests, with the exception that an additional full series of chemistry, 
hematology, and coagulation tests, a full physical examination, vital signs, and ECG should be 
conducted within 24 hours of investigator awareness of that the patient received an “overdose”.  
Following this additional ad hoc re-evaluation, the investigator should use his or her medical 
judgment in deciding whether additional supplemental medical treatment is needed to treat 
adverse medical consequences of the overdose.  Also after the ad hoc re-evaluation, the 
investigator should use his or her medical judgment in deciding whether additional 
supplemental monitoring is needed to track resolution of any AEs or other abnormal findings 
to the point of resolution to a CTCAE Grade 1 AE. 
 
Clinical Laboratory Evaluations 
Clinical laboratory tests, fasting or post meal, will be reviewed for results of potential clinical 
significance at all time points throughout the study.  The abnormality will be graded under 
Investigation category of CTCAE version 4.03 independent of clinical significance.  The 
investigator will evaluate any change in laboratory values.   
Hematology testing will include the following parameters: hemoglobin, hematocrit, red blood 
cell count, white blood cell count with differential, platelet count, coagulation, including 
prothrombin time, activated partial thromboplastin time (aPTT), and International Normalized 
Ratio. 
Serum chemistry testing will include the following parameters: blood urea nitrogen, creatinine, 
AST, ALT, gamma-glutamyl transpeptidase, total bilirubin (including direct fraction if total 
bilirubin is abnormal), lipase, amylase, total protein, albumin, alkaline phosphatase, sodium, 
potassium, calcium, magnesium, random blood glucose, lactate dehydrogenase (LDH), 
creatine kinase MB fraction. 
Urinalysis (glucose, protein, occult blood test) will be performed by dipstick method, and in 
the event of abnormal dipstick results, additional test may be required.  
 
The following information will be captured for blood sample collection in each patient’s eCRF: 
• 
Subject number 
• 
Time and date of dose administration  
• 
Time and date of patient’s most recent ingestion of food prior to dose administration 
 


 
 
 
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Vital Signs, Physical Findings and Other Safety Assessments 
Vital signs measurements will include pulse rate and systolic and diastolic blood pressure in a 
seated position of at least 5 minutes. 
Physical examinations will be performed.  A skin assessment will be conducted per the 
standard procedure of the site.  For skin lesions, photograph with an adjacent ruler to indicate 
size will be obtained, if needed. 
ECG are to be 12-lead.  Vital signs measurements should be performed prior to the ECG. 
To assess QTc intervals, 12-lead ECGs in triplicate will be obtained at 3.5 ± 0.5 hours after 
taking study medications on C1D1 and C2D1.  The patient should be in seating position for 5 
minutes before the 1st ECG is obtained, followed by 2nd and 3rd ECGs with 5 ± 2 minutes 
between ECG measurements. 
 
Pharmacokinetics 
Pharmacokinetic sampling for population PK will be performed as detailed in Table 4:   of 
Appendix A. 
Blood samples (2 mL) will be drawn into evacuated tubes containing dipotassium ethylene 
diaminetetra acetic acid.  Each sample will be inverted several times and then placed 
immediately into an ice bath.  Within 30 minutes of sampling, tubes must be centrifuged at 
1,000 × g at 4oC for 5 minutes.  Plasma fractions will then be transferred in 200 μL aliquots 
into 2 cryogenic vials.  The cryogenic vials will be labeled as A or B, plus the unique subject 
number, collection time, and date before being frozen.  Samples will be placed and stored 
at -70oC within 30 minutes of transfer to the cryogenic vial.  The original sample for PK 
analysis (A) and the duplicate sample (B) will be stored at -70°C.  For each patient participating 
PK study, PK (A) samples from Cycles 1 and 2 could be shipped together after Cycle 2 Day 1.  
The site could also ship all samples (Cycles 1 to 6) from each individual patients in one 
shipment.  Samples from several patients could be batched together for shipment as well.  The 
shipment for back-up samples (B) would be handled similarly.  PK samples (A) and samples 
(B) will be shipped to 
. 
Details of sample collection, handling, storage, and transport methodology will be provided to 
the investigator in the laboratory manual. 
The following information will be captured for blood sample collection in each patient’s 
eCRF: 
• 
Subject number 
• 
Time and date of dose administration (as well as time and date of previous dose 
administration for PK samples collected from Cycle 2 onwards) 
• 
Time and date of each blood sample collected for pharmacokinetic analysis 
• 
Time and date of patient’s most recent ingestion of food prior to dose administration 


 
 
 
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Blood Volume 
The total blood volume for each patient to be collected at screening is approximately 20 mL.  
Blood volume collected for safety tests on Days 1, 8, 15, and 22 of Cycle 1 will be 
approximately 30 mL.  Assuming each patients would receive up to 6 Cycles of treatment, 
subsequent cycles will have blood collections for safety tests on Days 1 and 15 of Cycle 2 then 
Day 1 of Cycles 3 to 6.  The total blood collection volume for Cycles 2 to 6 will be 
approximately 58.5 mL.  The total blood collection volume for EoT will be approximately 
6 mL for safety tests.  For patients participating in PK study, blood volume for PK would be 
30 mL for Cycle 1, 15 mL for Cycle 2 and 2 mL pre-dose on Day 1 of Cycles 3 to 6.  For 
patients receiving treatment Cycle 7 and beyond, there will be no PK blood sample except for 
10.5 mL blood for safety tests.  The assumptions are listed in Table 2 and Table 3.  
 
Table 2:  Screening Cycle 1 
PK: pharmacokinetic 
a 
The sample volume of 3 mL includes 1 mL of blood needed for flushing the catheter tubing prior to a 
sample collection. 
 
Table 3:  Cycles 2 to 6 
 
Number of 
Samples 
Sample 
Volume (mL) 
Total Volume 
(mL) 
Hematology 
6 
2 
12 
Serum chemistry 
6 
4 
24 
Coagulation 
5 
4.5 
22.5 
Total (excluding PK) 
 
 
58.5 
Pharmacokinetics cycle 2 day 1 
5 
3a 
15 
Pharmacokinetics cycles 3-6 day 1 
4 
2 
8 
Total (PK participating patients) 
 
 
81.5 
PK: pharmacokinetic 
a   
The sample volume of 3 mL includes 1 mL of blood needed for flushing the catheter tubing prior to a 
sample collection. 
 
Number of 
Samples 
Sample 
Volume (mL) 
Total Volume 
(mL) 
Hematology 
5 
2 
10 
Serum chemistry 
5 
4 
20 
Coagulation 
3 
4.5 
13.5 
Hepatitis B virus tests  
1 
2 
2 
Hepatitis C virus tests 
1 
4 
4 
Total (excluding PK) 
 
 
49.5 
Pharmacokinetics 
10 
3a 
30 
Total (PK participating patients) 
 
 
79.5 


 
 
 
Page 45 of 83 
 
 
 
Independent Review  
 
Data Safety Monitoring Board  
A DSMB has been established to monitor the safety observed during the conduct of this study. 
For all patients, weekly safety laboratory tests should be obtained during the first 28 days and 
closely monitored for safety signals, especially the neutropenia and transaminase elevation.  
DSMB consists of 3 oncologists who are experienced in treating patients with PTCL and are 
not associated with this study.  They are assisted by one DSMB statistician.   
DSMB convenes at planned intervals based on patient accrual (see Section 2.6).  Upon 
reviewing cumulative safety data from the study and taking into consideration of state-of-the-
art medical practice, they will advise sponsor for treatment modification including dose 
adjustment, AE management, and continuation of treatment. 
 
Independent Radiology Review 
To ensure consistent radiology method is applied to assess disease response across the entire 
study, designated radiologists will review sequential imaging studies of individual patients.  
They will assign response outcome including best response, dates of initial response and 
progression when applicable, based on Cheson Critieria. They will be blinded to the local 
radiology findings.  Should discrepancy between assessments by independent radiologist and 
site occur, a 2nd independent radiologist will adjudicate by selecting assessment from either 
site or 1st independent radiologist for final analysis.   
 
Central Pathology Review 
To ensure consistent diagnosis of PTCL subtypes, a panel of pathologists with appropriate 
expertise will review pathology slides from archival tumor specimens or biopsy as applicable.  
The techniques, such as immunohistochemistry staining, will be according to standard of 
practice using agreed methodology, no later than the end of study. 
 
 
Independent Overall Efficacy Review 
To ensure consistent overall efficacy review method is applied to assess disease response 
across the entire study, designated independent oncologists will review sequential clinical data 
of individual patients including radiological assessment provided by the independent 
radiological review. They will assign response outcome including best response, dates of initial 
response and progression when applicable, based on Cheson Criteria 2014. 
 
 




 
 
 
Page 47 of 83 
 
 
During monitoring visits, entries in the eCRFs will be compared with the original source 
documents (source data verification).  For the following items, this check will be 100%:  
• 
Subject number 
• 
Patient consent obtained 
• 
Patient eligibility criteria (inclusion and exclusion criteria) 
• 
Efficacy variables 
• 
Medical record of AE 
 
Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of the 
Data Management and Biostatistics departments of 
. 
Electronic Data Capture (EDC) will be used for this study, meaning that all eCRF data will be 
entered in electronic forms at the study site.  Data collection will be completed by authorized 
study site staff designated by the investigator.  Appropriate training and security measures will 
be completed with the investigator and all authorized study site staff prior to the study being 
initiated and any data being entered into the system for any study patients. 
All data must be entered in English.  The eCRFs should always reflect the latest observations 
on the patients participating in the study.  Therefore, the eCRFs are to be completed as soon as 
possible during or after the patient’s visit.   
The investigator must verify that all data entries in the eCRFs are accurate and correct.  If some 
assessments are not done, or if certain information is not available or not applicable or 
unknown, the investigator should indicate this in the eCRF.  The investigator will be required 
to electronically sign off on the clinical data.   
The monitor will review the eCRFs and evaluate them for completeness and consistency.  The 
eCRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data.  All entries, corrections and alterations are to be made by the responsible 
investigator or his/her designee.  The monitor cannot enter data in the eCRFs.  Once clinical 
data of the eCRF have been submitted to the central server, corrections to the data fields will 
be audit trailed, meaning that the reason for change, the name of the person who performed the 
change, together with time and date will be logged.  Roles and rights of the site staff responsible 
for entering the clinical data into the eCRF will be determined in advance.  If additional 
corrections are needed, the responsible monitor or Data Manager will raise a query in the EDC 
application.  The appropriate study centre staff will answer queries sent to the investigator.  
This will be audit trailed by the EDC application meaning that the name of investigational staff, 
time and date stamp are captured. 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified.  Source documents are all documents used 
by the investigator or hospital that relate to the patient’s medical history, that verify the 
existence of the patient, the inclusion and exclusion criteria and all records covering the 
patient’s participation in the study.  They include laboratory notes, electrocardiogram (ECG) 
results, memoranda, pharmacy dispensing records, patient files, etc. 


 
 
 
Page 48 of 83 
 
 
The investigator is responsible for maintaining source documents.  These will be made 
available for inspection by the study monitor at each monitoring visit.  The investigator must 
submit a completed eCRF for each patient who receives study medication, regardless of 
duration.  All supportive documentation submitted with the eCRF, such as laboratory or 
hospital records, should be clearly identified with the study and patient number.  Any personal 
information, including patient name, should be removed or rendered illegible to preserve 
individual confidentiality. 
eCRF records will be automatically appended with the identification of the creator, by means 
of their unique UserID.  Specified records will be electronically signed by the investigator to 
document his/her review of the data and acknowledgement that the data are accurate.  This will 
be facilitated by means of the investigator’s unique UserID and password; date and time stamps 
will be added automatically at time of electronic signature.  If an entry on an eCRF requires 
change, the correction should be made in accordance with the relevant software procedures.  
All changes will be fully recorded in a protected audit trail, and a reason for the change will be 
required. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 21.1 Concomitant medications will be coded using WHO-DDE.  Concomitant 
diseases/medical history will be coded using MedDRA. 
 
Retention of Records 
Records and documents pertaining to the conduct of this study and the distribution of IMP, 
including eCRFs, ICFs, laboratory test results, and medication inventory records, must be 
retained by the Principal investigator (Japan: Head of study site) for at least 15 years after 
completion or discontinuation of the study, or for the length of time required by relevant 
national or local health authorities, whichever is longer. After that period of time, the 
documents may be destroyed, pertinent to local regulations.  No records may be disposed of 
without the written approval of the sponsor.  Written notification should be provided to the 
sponsor prior to transferring any records to another party or moving them to another location. 
 
Quality Assurance Audit 
Study sites, the study database and study documentation may be subjected to Quality 
Assurance audit during the course of the study by the sponsor or delegate(s) on behalf of the 
sponsor.  In addition, inspections may be conducted by regulatory bodies at their discretion.  
 
Site Audits 
The principal investigator or sub-investigators and institutions involved in the study will permit 
study-related monitoring, audits, IRB review, and regulatory inspection(s) by providing direct 
access to all study records.  In the event of an audit, the principal investigator or sub-
investigator agrees to allow the sponsor, its representatives, or the regulatory agencies access 
to all study records. 


 
 
 
Page 49 of 83 
 
 
The investigator should promptly notify the sponsor or its authorized representative of any 
audits scheduled by any regulatory authorities and promptly forward copies of any audit reports 
received to the sponsor or its authorized representative. 
  


 
 
 
Page 50 of 83 
 
 
5.0 STATISTICS 
 
General Statistical Considerations 
Protocol HBI-8000-203 is an open-label, Phase 2b pivotal study evaluating HBI-8000 for 
regulatory approval in Japan and South Korea for the indication of relapsed or refractory PTCL. 
The main analysis will be conducted for the purpose of regulatory submission of this product. 
The data cut-off (DCO) for the main analysis is set at the time when the last patient completes 
at least one post-efficacy assessment. The eCRF data by the DCO needs to be cleaned to have 
no unresolved queries. All independent reviews (including the Central Pathology Review, the 
independent radiological review, the Independent Overall Efficacy Review and review by the 
Data Safety Monitoring Board) by the DCO need to be completed before the main analysis. 
The data after the main analysis will be provided at the end of the study as a supportive material.  
Statistical analysis for all safety, efficacy, and PK parameters will be primarily descriptive in 
nature. Categorical variables will be summarized by frequency distributions (number and 
percentages of patients), continuous variables will be summarized by mean, standard deviation, 
median, minimum, maximum, and time-to-event variables will be summarized using Kaplan-
Meier methods and figures for the estimated median time.   
All analyses, summaries, and listings will be performed using SAS software (version 9.3 or 
higher) 
A detailed methodology for summary and statistical analysis of the data collected in this trial 
will be documented in a Statistical Analysis Plan (SAP) that will be dated and maintained by 
HUYABIO.  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.  
 
Determination of Sample Size 
For efficacy determination, 40 patients evaluable for efficacy per protocol criteria are required.  
To ensure meeting this target, an estimated 50 to 60 patients would be enrolled in anticipation 
that some patients may not complete study treatment.  Enrolled patients will be treated with 
the starting dose of 40 mg BIW to provide an assessment of tumor response as well as 
additional safety data.  It is planned that 34 to 40 patients (27 evaluable patients) will be 
coming from Japan and 16 to 20 patients (13 evaluable patients) will be coming from Korea. 
The target best ORR for this study is 30%, on the basis of the ORR results that were obtained 
in study TG0902CDM.  The 95% confidence interval (CI) for an ORR of 30% at a sample size 
of N=40 is expected to be between 15.8% and 44.2%. 
The power for showing the response rate >10% at 5% two-sided alpha in 40 patients is 89%. 
The 95% confidence interval for an objective response rate (assumed to be 30%) at various 
sample sizes are shown below: 


 
 
 
Page 51 of 83 
 
 
 
ORR (expected) 
N 
95% CI 
30% 
25 
(12.0 – 48.0) 
30 
(13.6 – 46.4) 
35 
(14.8 – 45.2) 
 
40 
(15.8 – 44.2) 
 
 
Treatment Assignment and Blinding 
This is an open-label, sequential enrollment study; therefore, no randomization or blinding 
procedures will be performed. 
 
Replacement of Patients 
Patients who are lost to follow up or withdraw consent for study participation prior to receiving 
HBI-8000 or who withdraw in Cycle 1 for reasons unrelated to drug toxicity or PD will be 
replaced.   
 
Populations for Analysis 
 
Safety Population 
The safety analyses population will include all patients who receive at least one dose of 
HBI-8000.  The safety analyses population will be the primary population for evaluating 
treatment administration / compliance and safety in the study. 
 
Efficacy Population 
Efficacy should be analyzed using FAS and PPS.  
The FAS is defined as Patients meeting all eligibility criteria and having received at least one 
dose of study medication, and at least one efficacy assessment of disease with either imaging 
studies or clinical examination after receiving study medication. 
The PPS is defined as Patients meeting all eligibility criteria and having completed Cycle 1 
treatment or discontinued study treatment during cycle 1 due to clinical PD. It should be noted 
that the PPS includes subjects who discontinue within Cycle 1 due to clinical PD without 
imaging studies to assess disease status.  
 In addition, Patients who are assessed as Non-PTCL by the central pathology review 
committee should be excluded from the FAS and PPS for efficacy. The non-PTCL subjects 
will be included in safety analysis for the study. 


 
 
 
Page 52 of 83 
 
 
The primary efficacy analysis is conducted in the PPS. The Efficacy analysis using the FAS 
will be also reported. 
 
 
Pharmacokinetic Population 
All patients who have pretreatment baseline and at least 1 blood sample on study providing PK 
data for HBI-8000. 
 
Patient Disposition 
Data tabulations will summarize the following patient numbers: 
• Enrolled 
• HBI-8000 treatment dose received 
• Evaluable for safety and efficacy 
• Protocol violations 
• Protocol completions 
• Withdraw from study due to: 
 Adverse event 
 Physician’s recommendation 
 Withdrew consent 
 Lost to Follow-up 
 Other reasons as collected on the eCRF 
 
Patient Characteristics 
Demographic and baseline characteristics of patients will be summarized using descriptive 
statistics: 
• Age 
• Gender 
• Race 
• Ethnicity 
• ECOG Performance Status 
• Prior therapies 
• Other baseline characteristics as collected on the eCRF 
 
Concomitant Medications 
The number and proportion of patients using different concomitant medications will be 
tabulated and summarized by WHO Drug anatomical therapeutic chemical (ATC) 
classification system and preferred term. 


 
 
 
Page 53 of 83 
 
 
 
Treatment Administration 
Study drug administration will be described in terms of the total number of cycles administered, 
the median (range) of cycles administered, dose intensity, and reasons for the deviations from 
planned therapy. 
 
Efficacy Analysis 
The efficacy endpoints are the following: 
Primary Endpoint:  
• ORR(CR + PR)  
Secondary Endpoint: 
• ORR by disease subtype (see Section 2.5.1) 
• Median duration of PFS  
• Median DOR  
Exploratory Endpoint 
• Median duration of OS 
Response rate endpoints (ORR and ORR by disease subtype) will be summarized by number 
and percentage of patients meeting the definition of ORR along with the corresponding exact 
95% CI.  Tumor response as assessed by imaging studies will be adjudicated by independent 
radiology reviewers.  Tumor lesions, such as skin lesion, that cannot be monitored by imaging 
studies will determined by independent oncology reviewers and contributed to overall disease 
response assessment.  Both investigators reported and independently adjudicated outcomes 
will be reported.  Primary analysis will be based on results from imaging studies and clinical 
data confirmed by Independent Central Review.  Results from investigator assessment will 
also be reported. In addition, the ORR will be analyzed according to histology subtypes of 
PTCL.  The subtypes reported by Central pathology review for each patient will be used for 
such analysis. 
Time-to event endpoints (PFS, DOR, and OS) for entire study population will be summarized 
by Kaplan-Meier methods (median, 95% CI, number of events, number censored and Kaplan-
Meier figures). 
 Safety Analysis 
All patients who receive one dose (any amount) of HBI-8000 will be included in the summaries 
and listings of safety data. Overall safety profile and tolerability will be characterized by type, 
frequency, severity, timing, duration, and relationship of study therapy of AEs and laboratory 
abnormalities. 


 
 
 
Page 54 of 83 
 
 
 
Adverse Events 
Adverse events will be classified using the MedDRA classification system version 19.0 or 
higher.  The severity of the toxicities will be graded according to the NCI CTCAE version 4.03. 
In all summaries, emphasis will be placed on treatment emergent adverse events (TEAEs), 
namely, those with initial onset or that worsen in severity after the first dose of HBI-8000.  
TEAEs will be summarized by the frequency of patients experiencing TEAEs corresponding 
to body systems and MedDRA preferred term and by worst NCI CTCAE (version 4.03) grade.  
Summaries will also be provided of treatment related TEAEs, namely, those judged by the 
investigator to be related or likely related to HBI-8000. 
TEAEs resulting in discontinuation of HBI-8000 treatment or withdrawal from the study, 
Grade 3 or higher, SAEs, and deaths on-study will be tabulated. 
 
Laboratory Tests 
Laboratory data will be summarized for the observed values at each scheduled assessment, 
together with the corresponding changes from baseline (the value obtained prior to dosing on 
Day 1 of Cycle 1) using descriptive statistics.  
For those analyses with CTCAE grades, abnormal laboratory values will be summarized by 
shift tables displaying numerical values and percentages classified by Baseline grade (e.g., 
grade prior to dosing on Day 1 of Cycle 1) and maximum grade on treatment.  All laboratory 
data will be presented in listings.  
 
ECGs 
Serial ECGs will be performed to evaluate the potential effects of the study drug on the heart. 
The ECG parameters (PR interval, QRS duration, QT, QTc and QTcF) will be summarized 
descriptively for each time point for both the observed values and the change from Baseline to 
each post-baseline time point.  The number and percentage of patients with QT or QTc (QTcF) 
outlier values (at any post-baseline time point), as defined in ICH E14, will be summarized. 
 
Vital Signs and Physical Findings 
Vital signs data will be summarized by the observed valued at each scheduled assessment, 
together with the corresponding changes from Baseline using descriptive statistics. 
Physical findings will be presented in data listings.  
 
Interim Analysis 
No interim analysis for efficacy is planned for this Phase 2b study.  


 
 
 
Page 55 of 83 
 
 
 Pharmacokinetic Analysis 
In patients participating in PK study, peripheral blood will be sampled at specified time points.  
Plasma concentration of HBI-8000 will be listed and summarized using descriptive statistics.  
PK data collected in this study will be combined with PK data collected from other studies and 
a population PK analysis will be performed.  Results of the population PK analysis will be 
presented in a report separate from the CSR. 
 


 
 
 
Page 56 of 83 
 
 
6.0 ETHICS 
 
Institutional Review Board or Independent Ethics Committee 
The protocol, ICF and any other written information and/or materials to be provided to the 
patients and the amendments (as required by local regulations) should be reviewed and 
approved by the IRB/Independent Ethics Committee (IEC).  The sponsor’s authorized 
representative should be provided with documentation of IRB/IEC approval of the protocol 
and informed consent before the study may begin at the study center(s). 
The only circumstance in which an amendment may be initiated prior to the sponsor and 
IRB/IEC approval is where the change is necessary to ensure the safety of the patients.  In that 
case, the investigator must document the change and notify the sponsor and IRB/IEC in writing 
immediately after the implementation. 
The investigator should submit written summaries of the study status for review by the 
IRB/IEC annually, or more frequently if requested by the IRB/IEC.  Upon completion of the 
study, the investigator will provide a brief report of the outcome of the study, if required.  The 
sponsor and/or the sponsor’s authorized representative will handle the distribution of any of 
these documents to the national regulatory authorities. 
 
Ethical Conduct of the Study 
This study will be conducted and the informed consent will be obtained according to the ethical 
principles stated in the Declaration of Helsinki (48th General Assembly, Somerset West, 
Republic of South Africa, October 2008 [or current version]), the applicable guidelines for 
GCP (CPMP/ICH/135/95), or the applicable drug and data protection laws and regulations of 
the countries where the study will be conducted. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording and reporting studies that involve the participation of human patients.  
The study will be conducted in compliance with GCP and the applicable national regulations 
so as to assure that the rights, safety and well-being of the participating study patients are 
protected consistent with the ethical principles that have their origin in the Declaration of 
Helsinki. In Japan, the study shall be conducted in accordance with Good Post-marketing Study 
Practice (GPSP) as well as GCP after the PTCL approval. 
 
Patient Information and Informed Consent 
The ICF will be used to explain the risks and benefits of study participation to the patient in 
simple terms before the patient will be entered into the study.  The ICF contains a statement 
that the consent is freely given, that the patient is aware of the risks and benefits of entering 
the study, and that the patient is free to withdraw from the study at any time.  Written consent 
must be given by the patient and/or the legal guardian, after the receipt of detailed information 
on the study. 


 
 
 
Page 57 of 83 
 
 
The investigator is responsible for ensuring that informed consent is obtained from each patient 
or the legal guardian and for obtaining the appropriate signatures and dates on the informed 
consent document prior to the performance of any protocol procedures and prior to the 
administration of study medication.  The investigator will provide each patient with a copy of 
the signed and dated consent form.   
Whenever important new information becomes available that may be relevant to the patient’s 
consent, the approved by the IRB/IEC, revised information will be provided to each patient in 
the trial for signing and dating.  The investigator will explain the changes to the previous 
version. 
 
Patient Data Protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.  
Information about study subjects will be kept confidential and managed according to the 
regulatory requirements. 


 
 
 
Page 58 of 83 
 
 
7.0 STUDY ADMINISTRATION 
 
Administrative Structure 
The administrative structure and study organization is presented in Protocol addendum. 
 
Data Handling and Record Keeping 
It is the investigator’s responsibility to maintain essential study documents (protocol and 
protocol amendments, completed eCRFs, signed ICFs, relevant correspondence, and all other 
supporting documentation).  The study site should plan on retaining such documents for 
approximately 15 years after study completion.  The study site should retain such documents 
until at least 2 years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region or at least 
2 years after the formal discontinuation of clinical development of the investigational product.  
These documents should be retained for a longer period if required by the applicable regulatory 
requirements or the hospital, institution, or private practice in which the study is being 
conducted.  Patient identification codes (patient names and corresponding study numbers) will 
be retained for this same period of time.  These documents may be transferred to another 
responsible party, acceptable to sponsor, who agrees to abide by the retention policies.  Written 
notification of transfer must be submitted to the sponsor and/or the sponsor’s authorized 
representative.  The investigator must contact the sponsor and/or the sponsor’s authorized 
representative prior to disposing of any study records.   
The U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see 
Section 4.9 of the guideline) require that records and documents pertaining to the conduct of 
this study and the distribution of study drug, including eCRFs, consent forms, laboratory test 
results, and medication inventory records, must be retained by the principal investigator for 
15 years after the last marketing application approval in an ICH region or after at least 15 years 
have elapsed since formal discontinuation of clinical development of the investigational drug.   
No records should be disposed of without the written approval of the sponsor and/or the 
sponsor’s authorized representative.  
For studies conducted outside the United States under a U.S.  IND, the principal investigator 
must comply with U.S.  FDA investigational new drug regulations and with those of the 
relevant national and local health authorities. 
 
Direct Access to Source Data/Documents 
The investigator will prepare and maintain adequate and accurate source documents to record 
all observations and other pertinent data for each patient enrolled into the study.   
The investigator will allow the sponsor, the sponsor’s authorized representative(s), and 
authorized regulatory authorities to have direct access to all documents pertaining to the study, 
including individual patient medical records, as appropriate. 


 
 
 
Page 59 of 83 
 
 
 
Investigator Information 
 
Investigator Obligations 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline for 
GCP (GCP, 1997; the US CFR Title 21 parts 50, 56, and 312; European Legislation; and 
Ministerial Ordinance on the Standards for the Implementation of Clinical Studies on 
Pharmaceutical Product [Japan GCP]) and the ethical principles that have their origin in the 
Declaration of Helsinki, and the applicable regulatory requirements of each region. In Japan, 
the study shall be conducted in accordance with GPSP as well as GCP after the PTCL approval. 
The investigator agrees to conduct the clinical study in compliance with this protocol after the 
approval of the protocol by the IEC/IRB in compliance with local regulatory requirements.  
The investigator and the sponsor will sign the protocol to confirm this agreement. 
 
Protocol Signatures 
After reading the protocol, each investigator will sign the protocol signature page and send a 
copy of the signed page to the sponsor or representative (Appendix G).  By signing the protocol, 
the investigator confirms in writing that he/she has read, understands and will strictly adhere 
to the study protocol and will conduct the study in accordance with ICH Tripartite Guidelines 
for Good Clinical Practice and applicable regulatory requirements.  In Japan, the investigator 
will conduct the study in accordance with GPSP as well as GCP after the PTCL approval. The 
study will not be able to start at any site where the investigator has not signed the protocol. 
 
Publication Policy 
The data generated by this study are confidential information of the sponsor.  The sponsor will 
make the results of the study publicly available.  The publication policy with respect to the 
investigator and study site will be set forth in the Clinical Trial Agreement. 
 
Financing and Insurance  
The sponsor has obtained liability insurance, which covers this study as required by local law 
and/or national regulations and/or ICH guidelines whichever is applicable.  The terms of the 
insurance will be kept in the study files. 


 
 
 
Page 60 of 83 
 
 
8.0 
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Page 63 of 83 
 
 
9.0 APPENDICES 
 
 
Appendix A:  HBI-8000-203 Schedule of Events 
Table 4:  Schedule of Events 
 
Screening 
Cycle 1 
Cycle 2 
Cycle 
≥ 3a 
EoTb 
Surviv
al F/Uc 
DAY 
-28 to 0 
1 
8±2 15±2 22±2 
1±4 
15±4 
1±7 
 
 
 
 
Pre-dosep 
3.5 hrs 
 
 
 
Pre-dose 
3.5 hrs 
 
Pre-dose 
 
 
HBI-8000d 
 
BIWe 
BIWe 
BIWe 
 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history, diagnosis and treatment 
history, demographics, height 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, weight 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
 
 
 
 
X 
 
 
X 
X 
 
Vital signsf 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
12 Lead ECG (Safety)  
X 
 
 
 
 
 
 
 
 
X 
X 
 
12 Lead ECG (QTc) 
 
Xg 
Xg 
 
 
 
Xg 
Xg 
 
 
 
 
Hematology h 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Coagulationh 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
Chemistryi 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Urinalysisj 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Hepatitis B/C virus testsk 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (if applicable)l 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Tumor assessment m 
X 
 
 
 
 
 
 
 
 
Xm 
Xm 
Xm 
PK blood samples 
 
Xn 
 
 
 
 
Xn 
 
 
Xo 
 
Patient survival; new cancer therapies 
 
 
 
 
 
 
 
 
 
 
 
X 


 
 
 
Page 64 of 83 
 
 
 
Screening 
Cycle 1 
Cycle 2 
Cycle 
≥ 3a 
EoTb 
Surviv
al F/Uc 
DAY 
-28 to 0 
1 
8±2 15±2 22±2 
1±4 
15±4 
1±7 
 
 
 
 
Pre-dosep 
3.5 hrs 
 
 
 
Pre-dose 
3.5 hrs 
 
Pre-dose 
 
 
Adverse events assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BIW, twice weekly; BUN, blood 
urea nitrogen;  ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EoT, end of treatment; F/U, follow-up; GGT, gamma-glutamyl 
transpeptidase; INR, international normalized ratio; LDH, lactate dehydrogenase; mSWAT, Modified Severity-Weighted Assessment Tool; PET-CT, positron 
emission tomography-computer tomography; PCR, polymerase chain reaction; PK, pharmacokinetic; PT, prothrombin time; 
a 
Cycle/Day designation is based on actual calendar days after the first dose.  All visits and assessments may be performed ± 7 days to 
accommodate unforeseen delays, holidays, or vacations.  
b 
“End of Treatment” visit should be conducted 30 ± 3 days after the last dosing of the study drug, before the initiation of new cancer 
treatment or before the initiation of administration of commercial product of HBI-8000, whichever is earlier.  
c 
Survival data will be collected every 3 months ± 2 weeks after End of Treatment until death or the end of the study, defined as timing 
that the last Japanese subject initiates administration of the commercial product of HBI-8000. 
d 
Drug administration BIW for 4 weeks ; On the days of scheduled visits that is the same as the dosing scheduled day, patient should take 
study drug after receiving confirmation from investigator to continue study treatment.  
e 
Dose adjustments based on hematological and non-hematological criteria.   
f 
Pulse rate, diastolic and systolic blood pressure in seated position of 5 minutes.  On days when ECGs are taken, vital signs to be taken 
shortly prior to ECG recording.  
g 
Pre-dose and post dose at 3.5 ± 0.5 hours in triplicates, 5 ± 2 minutes between 1st and 2nd, 2nd and 3rd ECGs, on Day 1 of Cycles 1 and 
2. 
h 
Hemoglobin, hematocrit, red blood cell count, white blood cell count, differential, platelet count; Coagulation tests (PT, aPTT, and 
INR). 
i 
BUN, creatinine, AST, ALT, GGT, total bilirubin (including direct fraction if total bilirubin abnormal), lipase, amylase, total protein, 
albumin, alkaline phosphatase, sodium, potassium, calcium, magnesium and random blood glucose, LDH, CKMB (creatine kinase MB 
fraction)       
j 
Urinalysis (glucose, protein, occult blood test) will be performed by dipstick method, and  in the event of abnormal dipstick results, 
additional test may be required. 
k 
Hepatitis B surface antigen-positive, or hepatitis C virus antibody positive.  In case hepatitis B core antibody and/or hepatitis B surface 
antibody is positive even if hepatitis B surface antigen negative, a hepatitis B virus DNA test (real-time PCR measurement) should be 
performed and if positive, the patient should be excluded from study. 


 
 
 
Page 65 of 83 
 
 
l 
Only for women of childbearing potential, including those who have had a tubal ligation.  Confirmatory test at the Cycle 1 Day 1 
(C1D1) visit should be done before dosing at the local laboratory.  If Serum pregnancy test result cannot be obtained on the same day 
before dosing, urine pregnancy test should be conducted additionally and the result should be confirmed before dosing.  Only at EoT 
visit, Serum and Urine are both acceptable.  
m 
Complete tumor assessment of all lesions by radiographic or other modality.  Baseline bone marrow test (aspiration or biopsy) is 
required.  Response and progression for PTCL will be evaluated according to the revised criteria for response assessment in lymphoma 
[Cheson 2014], however, PET-CT is not required but encouraged.  Skin lesions, if present, will be assessed by mSWAT and contribute 
to overall tumor response determination by investigators.  Assessment of tumor response will be scheduled by end of the 8th week, then 
every 8 weeks (± 1 week) from C1D1, However, if a patient develops clinical signs and symptoms of disease progression, or 
unacceptable toxicity occurs, tumor assessment may be performed sooner as needed.  If a patient discontinues study treatment before 
disease progression (PD) is recorded, and if their last tumor assessment was >30 days earlier from EoT visit, tumor assessment should 
be performed at EoT.  In these patients, further tumor assessments are to be performed approximately every 3 months ± 2 weeks until 
PD or the start of new cancer therapy whichever occurs first, unless consent to study participation is withdrawn or by completion of the 
whole study. If subjects cannot visit their study site for this examination due to COVID-19 situation, investigators can skip the 
examination, and the assessment is to be performed approximately every 6 months ± 2 weeks. In this case, the investigator should 
document that fact in the medical record. 
n 
PK sampling on C1D1 pre-dose and 1 h (± 15 mins), 2h (± 15 mins), 3h (± 15 mins), 4h (± 15 mins), 5h (± 30 mins), and 7h  (± 30 
mins), then 24 ± 1, 48 ± 1 and 72 ± 1 hours in consenting patients; and C2D1 pre-dose and 1 h (± 15 mins), 2h (± 15 mins), 3h (± 15 
mins), and 4h (± 15 mins). 
o 
Day 1 of cycles 3 to 6 pre-dose PK sample only.  
p 
Some of the pre-dose assessments except vital signs and ECG may be performed one day before C1D1 to accommodate scheduling 
requirements in the hospital. 
 
 
 
 
 
 
 


 
 
 
Page 66 of 83 
 
 
Table 5:  Schedule of Pharmacokinetic Blood Draws 
 
Cycle/Study Day 
 
Measurement Time 
Cycle 1 Day 1 
Predose  
1 hour (± 15 mins) postdose 
2 hours (± 15 mins) postdose 
3 hours (± 15 mins) postdose 
4 hours (± 15 mins) postdose 
5 hours (± 30 mins) postdose 
7 hours (± 30 mins) postdose 
Cycle 1 Day 2 
24 ± 1 hours postdose 
Cycle 1 Day 3 
48 ± 1 hours postdose 
Cycle 1 Day 4 
72 ± 1 hours postdose 
Cycle 2 Day 1 
Predose  
1 hour (± 15 mins) postdose 
2 hours (± 15 mins) postdose 
3 hours (± 15 mins) postdose 
4 hours (± 15 mins) postdose 
Day 1 of  Cycles 3 to 6  
Predose 


 
 
 
Page 67 of 83 
 
 
 
Appendix B:  Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
 
ECOG 
Grade  
ECOG Status  
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 house work, 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 any selfcare. Totally confined to bed or chair  
5  
Dead  
  
Source: Oken, M.M., 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 5:649-655, 
1982. 
 
 


 
 
 
Page 68 of 83 
 
 
 
Appendix C: New York Heart Association (NYHA) Classification 
 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart 
failure at rest.  If any physical activity is undertaken, discomfort increases. 
 
Adapted from Farrell MH et al. JAMA. 2002; 287:890-897 
• 
(1) Raphael C et al. Limitations of the New York Heart Association functional 
classification system and self-reported walking distances in chronic heart failure. 
Heart. 2007;93(4):476-82  
• 
(2) MeReC Bulletin 2008; 18 (3):1-9. 
• 
(3) National Institute for Health and Clinical Excellence (NICE) 2010. Chronic heart 
failure. National clinical guideline for diagnosis and management in primary and 
secondary care 
 
 


 
 
 
Page 69 of 83 
 
 
 
Appendix D: Method of Efficacy Assessment 
Overall response will be assessed according to recommendations for Hodgkin and nonHodgkin 
lymphoma developed in International Conference on Malignant lymphoma in Lugano, 
Switzerland, 2011, and published in 2014 (Cheson 2014).  Patients will have pretreatment 
assessment at screening and postdose evaluations on Day 1 of subsequent cycles.  Imaging 
studies such as CT to evaluate nodal and extranodal lesions will performed at end of the 8th 
weeks, then every 8 weeks (± 1 week) from C1D1.  However, if a patient develops clinical 
signs and symptoms of disease progression, or unacceptable toxicity occurs, tumor assessment 
may be performed sooner as needed.  If a patient discontinues study treatment before disease 
progression (PD) is recorded, and if their last tumor assessment was > 30 days earlier from 
EoT visit, tumor assessment should be performed at EoT.  In these patients, further tumor 
assessments are to be performed approximately every 3 months ± 2 weeks until PD or the start 
of new cancer therapy whichever occurs first, unless consent to study participation is 
withdrawn.  
 
Evaluation at Screening 
At screening, physical examination is not considered quantitative assessment of lesion size.  
Disease lesion(s) will be evaluated by imaging studies (CT or PET-CT), bone marrow test 
(aspiration or biopsy), and skin evaluation.  In case gastrointestinal lesion is suspected, 
endoscopy and biopsy (as needed) will be performed. 
All lesions are categorized into the following: 
• 
lesion which can be used for efficacy assessment (hereinafter, evaluable lesion) 
• 
lesion which cannot be used for efficacy assessment (hereinafter, non-evaluable lesion) 
In addition, evaluable lesions are categorized into the following: 
• 
measurable lesion 
• 
nonmeasurable lesion 
Next, target lesions (up to 6 lesions) are selected from measurable lesions. 
Nonmeasurable lesions and other measurable lesions are deemed as non-target lesions. 
 
 


 
 
 
Page 70 of 83 
 
 
Figure 3:  Selection of Lesions 
 
 
Imaging 
Before the start of study drug administration, evaluation by CT images of neck, chest, abdomen, 
and pelvis that are taken by a pitch of 5 mm preferable (as for neck image, a pitch of 2.5  to 5 
mm will be preferred) will be performed.  Same imaging techniques should be used at baseline 
and on study assessment.  PET-CT is encouraged, but not required. 
 
 
Definition of lesion which can be used for efficacy assessment (evaluable lesion) 
Nodal lesion with the size > 1.5 cm by longest transverse dimension (LDi) on sectional image 
(e.g, enlarged lymph node) at screening and extranodal lesion which can be followed by 
imaging are defined as evaluable lesion. 
 
 
Definition of lesion which cannot be used for efficacy assessment (non-
evaluable lesion) 
Non-evaluable lesion is defined as nodal lesion with LDi ≤ 1.5 cm on sectional image of CT 
at screening and extranodal lesion that cannot be followed by imaging. 
 
 
Definition of Measurable Lesion (common with nodal and extranodal lesion) 
In evaluable lesions, measurable lesion is defined as the lesion that meets both following 
criteria: 


 
 
 
Page 71 of 83 
 
 
• 
The LDi > 1.5 cm on sectional image of CT for nodal lesion; and > 1.0 cm for extranodal 
lesion 
• 
Definitely measurable by 2 perpendicular dimensions (LDi and its perpendicular 
dimension) on sectional image of CT 
 
 
Definition of Non-measurable lesion 
In evaluable lesions, non-measurable lesion is defined as the lesion that meets any of the 
following criteria: 
• 
Enlarged lymph node:  Lesion with the LDi > 1.5 cm on sectional image of CT, but not 
definitely measurable by 2 dimensions (LDi and its perpendicular dimension) 
• 
Extranodal lesion:  All lesions that can be followed by imaging, but do not meet the 
definition of measurable lesion 
 
 
Nodes or Extranodal Lesions That Split When Disease Is Responding  
If a conﬂuent nodal mass splits into several discrete nodes, the individual product of the 
perpendicular diameters (PPDs) of the nodes should be summed together to represent the 
PPD of the split lesion; this PPD is added to the sum of the PPDs of the remaining lesions to 
measure response.  If subsequent growth of any or all of these discrete nodes occurs, the 
nadir of each individual node is used to determine progression (as if each individual node 
was selected as a target lesion at baseline). 
 
Nodes or Extranodal Lesions That Become Conﬂuent When Disease Is 
Progressing  
If a group of target lymph nodes becomes conﬂuent, the PPD of the current conﬂuent mass 
should be compared with the sum of the PPDs of the individual nodes, with more than 50% 
increase in the PPD of the conﬂuent mass compared with the sum of individual nodes necessary 
to indicate progressive disease.  The LDi and shortest diameter are no longer needed to 
determine progression. 
 
Selection of Target Lesions 
Target lesions are selected from measurable lesions, which can be nodal lesion and extranodal 
lesion, along with the following criteria: 
• 
Lesions that is suitable to be measured exactly and continuously by the same method. 
• 
Up to 6 lesions in descending order by LDi length on sectional image of CT.  If measurable 
lesions are less than 6, all measurable lesions are selected. 
• 
Nodes should preferably be from disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas. 
 
The lengths of LDi (cm) and the largest diameter (cm) which is perpendicular to LDi are 
measured, and their product (PPD) is the cross product of LDi and the PPD for the lesion.  The 
sum of PPD of all target lesions (SPD) will be calculated at screening. 


 
 
 
Page 72 of 83 
 
 
 
Definition and Selection of Non-target Lesion 
Measurable lesions that are not selected as target lesion and non-measurable lesions are defined 
as non-target lesions. 
Non-target lesions are separately evaluated as nodal non-target lesions and extranodal 
nontarget lesions.  If any tumor lesions are found through gastrointestinal endoscopy, the lesion 
is to be evaluated as extranodal non-target lesion. 
 
Evaluation of Skin Lesion 
In case tumor lesion on skin exists, the lesion is considered as non-target.  Skin lesion which 
can be monitored for efficacy should be followed.  Investigators can consult dermatologists in 
sites or clinics if needed. 
If it is difficult to determine whether or not skin lesion exist by inspection, biopsy will be 
performed to diagnose histopathologically.   
Skin lesions will be followed according to Severity-Weighted Assessment Tool (Stevens et al 
2002): Revised Edition (mSWAT). 
 
Evaluation by Modified Severity-Weighted Assessment Tool (mSWAT) 
(Olsen et al. 2011) 
A total of body surface area (%BSA) of each part is defined in Table 6and Figure 4 (e.g., head 
7, neck 2, and anterior trunk 13) in which total body surface area of human is defined as 100. 
After %BSA of each type of lesion (patch, plaque, tumor mass, or ulcer) and normal skin is 
assessed by body parts, percentage of total body surface area (%TBSA) of each type of lesion 
will be calculated by adding %BSA of total body by type of lesion.  In addition, mSWAT score 
is defined as summation (0 to 400) of product of %TBSA and each summation factor (see the 
following formula). 
mSWAT score = (%TBSA of patch ×1) + (%TBSA of plaque × 2) + (%TBSA of tumor mass 
and ulcer × 4) 
 
 


 
 
 
Page 73 of 83 
 
 
 
Table 6:  Modified Severity Weighted Assessment Tool (mSWAT) 
 
 
Body Region 
% BSA in 
Body Region 
Assessment of Involvement in Patient’s Skin 
Patch* 
Plaque** 
Tumor*** 
Head 
7 
 
 
 
Neck 
2 
 
 
 
Anterior trunk 
13 
 
 
 
Arms 
8 
 
 
 
Forearms 
6 
 
 
 
Hands 
5 
 
 
 
Posterior trunk 
13 
 
 
 
Buttocks 
5 
 
 
 
Thighs 
19 
 
 
 
Legs 
14 
 
 
 
Feet 
7 
 
 
 
Groin 
1 
 
 
 
Subtotal of lesion % BSA 
 
 
 
 
Weighting factor 
 
 
 
 
Subtotal lesion BSA X 
weighting factor 
 
 
 
 
 
NOTE. mSWAT score equals summation of each column line.  
Abbreviations:  BSA, body surface area 
*Any size lesion without induration or significant elevation above the sur- rounding uninvolved skin; 
poikiloderma may be present. 
**Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present. 
***Any solid or nodular lesion >1 cm in diameter with evidence of deep infiltration in the skin and/or 
vertical growth. 
 
 
 


 
 
 
Page 74 of 83 
 
 
Figure 4:  Percentage BSA of each Part of Human Body 
 
 
 
Presence or absence of splenomegaly  
Presence or absence of splenomegaly which are considered to be caused by infiltration of 
lymphocyte is assessed by CT.  To be considered positive, the vertical length of spleen must 
be >13 cm by CT.  
 
Evaluation of infiltration to bone marrow 
Infiltration to bone marrow will be evaluated by PET-CT or bone marrow aspiration or 
biopsy.  When bone marrow evaluation is selected, the results will be categorized into the 
following: 
• Positive: Presence of apparent malignant findings including infiltration of abnormal 
lymphocyte and abnormality in assembly 
• Undetermined: Increase of lymphocyte aggregation without infiltration of abnormal 
lymphocyte or abnormality in assembly 
• Negative: Absence or minimal findings of lymphocyte aggregation. 
 
Postdose Evaluation  
Imaging studies will be performed by the same method as screening. 
 
 
Evaluation of target lesion 
Efficacy for target lesion will be assessed by calculating reduction rate (A) and growth rate 
(B) of the SPD according to the following formula: 


 
 
 
Page 75 of 83 
 
 
 
(A)＝ 
(C) at screening - (C) at evaluation 
×100 
(C) at screening 
 
(B)＝ 
(C) at evaluation - minimum (C)*1  ×100 
minimum (C) *1 
*1: minimum (C) value obtained during the study including the screening 
 
(C) = SPD 
 
 
Criteria for Response Assessment  
Table 7:  Summary of Response Criteria  
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
 
Lymph 
nodes 
and 
extralymphatic sites 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nonmeasured lesion  
 
Organ enlargement  
 
New lesions  
 
Bone marrow 
Complete metabolic response 
Score 1, 2, or 3* with or without a 
residual mass on 5PS† 
It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with activation 
within spleen or marrow (eg, with 
chemotherapy or myeloid colony-
stimulating factors), uptake may be 
greater than normal mediastinum 
and/or liver. In this circumstance, 
complete metabolic response may be 
inferred if uptake at sites of initial 
involvement is no greater than 
surrounding normal tissue even if the 
tissue has high physiologic uptake  
Not applicable.  
 
Not applicable  
 
None 
No evidence of FDG-avid disease in 
marrow 
Complete radiologic response (all of 
the following) 
Target 
nodes/nodal 
masses 
must 
regress to <1.5 cm in LDi  
No extralymphatic sites of disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
Absent 
 
Regress to normal  
 
None 
Normal 
by 
morphology; 
if 
indeterminate, IHC negative 
Partial 
Lymph nodes and 
extralymphatic sites 
 
 
 
Partial metabolic response 
Score 4 or 5† with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
At interim, these findings suggest 
responding disease 
Partial remission (all of the following) 
≥50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites 
When a lesion is too small to measure 
on CT, assign 5 mm × 5 mm as the 
default value 


 
 
 
Page 76 of 83 
 
 
 
 
 
 
 
Nonmeasured lesions  
 
 
Organ enlargement 
 
 
New lesions  
 
Bone marrow 
 
At end of treatment, these findings 
indicate residual disease 
 
 
Not applicable  
 
 
Not applicable 
 
 
None 
 
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with 
baseline 
(diffuse 
uptake 
compatible with reactive changes 
from chemotherapy allowed). If there 
are persistent focal changes in the 
marrow in the context of a nodal 
response, consideration should be 
given to further evaluation with MRI 
or biopsy or an interval scan. 
When no longer visible, 0mm × 0 mm 
For a node >5 mm × 5 mm, but smaller 
than normal, use actual measurement 
for calculation 
 
Absent/normal, 
regressed, 
but 
no 
increase 
 
Spleen must have regressed by > 50% 
in length beyond normal 
 
None 
 
Not applicable 
No response or stable 
disease 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
 
 
Nonmeasured lesions  
 
Organ enlargement  
 
New lesions 
 
Bone marrow 
No metabolic response 
 
Score 4 or 5 with no significant 
change in FDG uptake from baseline 
at interim or end of treatment 
 
 
Not applicable  
 
Not applicable  
 
None 
 
No change from baseline 
Stable disease 
 
<50% decrease from baseline in SPD of 
up to 6 dominant, measurable nodes and 
extranodal 
sites; 
no 
criteria 
for 
progressive disease are met 
 
No increase consistent with progression  
 
No increase consistent with progression 
  
None 
 
Not applicable 
Progressive disease 
Individual 
target 
nodes/nodal masses 
 
Extranodal lesions 
 
 
 
 
 
 
 
Progressive metabolic disease 
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-
treatment assessment 
 
 
 
 
 
Progressive disease requires at least 
1 of the following PPD progression: 
 
 
An individual node/lesion must be 
abnormal with: LDi >1.5 cm and 
Increase by ;:50% from PPD nadir 
and  
An increase in LDi or SDi from 
nadir 
0.5 cm for lesions < 2 cm 
1.0 cm for lesions > 2 cm 


 
 
 
Page 77 of 83 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nonmeasured 
lesions 
 
New lesions 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
 
 
 
 
 
 
 
 
 
 
 
None 
 
 
New FDG-avid foci consistent with 
lymphoma 
rather 
than 
another 
etiology (eg, infection, inflammation). 
If uncertain regarding etiology of new 
lesions, biopsy or interval scan may be 
considered 
 
 
 
 
 
New or recurrent FDG-avid foci 
In the setting of splenomegaly, the 
splenic length must increase by 
>50% of the extent of its prior 
increase beyond baseline (eg, a 15-
cm spleen must increase to 
>16 cm). If no prior splenomegaly, 
must increase by at least 2 cm from 
baseline 
New or recurrent splenomegaly 
 
 
New or clear progression of 
preexisting nonmeasured lesions 
 
Regrowth of previously resolved 
lesions 
A new node >1.5 cm in any axis 
A new extranodal site >1.0 cm in 
any axis; if <1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size 
unequivocally 
attributable 
to 
lymphoma 
 
New or recurrent involvement 
 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, 
positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis 
perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at 
the time of an interim scan. However, in trials involving PET where de-escalation is investigated, it 
may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured 
dominant 
lesions: Up to 6 of the largest dominant nodes, nodal masses, and extranodal lesions 
selected to be clearly measurable in two diameters. Nodes should 
preferably be from disparate 
regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. 
Nonnodal lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, 
cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not selected as 
measured, dominant disease and truly assessable disease should be considered not measured. These 
sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable 
or that do not meet the requirements for measurability but are still considered abnormal, as well as 
truly assessable disease, which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal 
disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. 
In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be 
greater than in the mediastinum with complete metabolic response, but should be no higher than 
surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy 
or myeloid growth factors). 
 


 
 
 
Page 78 of 83 
 
 
†PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ 
liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new 
areas of uptake unlikely to be related to lymphoma. 
Source: Cheson BD, Fisher RI, Barrington SF, et al. (2014) Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: 
The Lugano Classification. J Clin Oncol 32(27):3059–3067 
 
 
Evaluation of skin lesion by mSWAT 
Criteria for assessment for tumor shrinkage effect on skin lesion by mSWAT are as 
following: 
• CR: 100% clearance  of skin lesion* 
• PR: 50 to 99% clearance of skin disease from baseline without new lesion 
• SD: < 25% increase to < 50% clearance in skin disease from baseline without 
appearance of new lesion. 
• PD: ≥25% increase in skin disease from baseline or New tumor mass** or Loss of 
response: in those with complete or partial response, increase of skin score of greater 
than the sum of nadir plus 50% baseline score.  
* In case distinguish between residual lesion and normal skin tissue is difficult, CR is 
determined after confirming disappearance of skin lesion by biopsy. 
* * tumor mass : at least 1 cm diameter solid or nodular lesion with evidence of depth 
and/or vertical growth 
 


 
 
 
Page 79 of 83 
 
 
 
Appendix E:  Blood Sample Collection 
 
Caution for use concerning vacuum blood-collection tubes 
 
The test kits provided for the clinical study include vacuum blood-collection tubes.  Since reflux may 
occur due to inappropriate handling of a vacuum blood-collection tube resulting in the contents and/or 
contaminants in the blood-collection tube to flow into the patient’s body, the notifications (Notification 
No. 1117001 of PFSB, “Voluntary inspection of caution for use and other relevant information 
concerning vacuum blood-collection tube”, dated 17 November 2003 and Notification No. 0104001 of 
PFSB, “Additional information on the caution for use concerning vacuum blood-collection tubes” dated 
04 January 2005 issued by Director of Safety Division) were released to draw your attention to usage 
of vacuum blood-collection tubes.  Please pay attention to the precautions listed below and use the 
vacuum blood-collection tubes of this study with care. 
 
1. Caution for use of sterile vacuum blood-collection tubes 
o The temperature of the blood-collection tubes prior to blood draw must be equivalent to 
the room temperature (the inner pressure may change, which could cause the blood in the 
blood-collection tube to flow back into the body along with the contaminants). 
o Do not move, or release the pressure applied on the arm of the patient before removing the 
blood-collection needle (moving the position of, or releasing the pressure applied on the 
arm may cause rapid decrease in the venous blood pressure, which could cause the blood 
in the blood-collection tube to flow back into the body along with the contaminants). 
o After the blood starts flowing into the collection tube, do not apply force on the tube that 
could push it into the blood-collection holder (the inner pressure may change, which could 
cause the blood in the blood-collection tube to flow back into the body along with the 
contaminants). 
o Do not remove the tourniquet after the completion of blood draw unless otherwise the 
blood-collection needle is removed first (changes in the pressure due to removal of the 
tourniquet could cause the blood in the blood-collection tube to flow back into the body 
along with the contaminants). 
o The holder is for single-patient use only, and should be disposed of after each use (the 
holder may be contaminated with the blood, which could cause cross infection). 
o Do not draw blood from extracorporeal circuit or central vein (changes in the pressure 
could cause the blood in the blood-collection tube to flow back into the body along with 
the contaminants). 
 
2. Instruction for operation or usage 
o The temperature of the blood-collection tubes should be equivalent to the room temperature. 
o The puncture site should be disinfected after the tourniquet is applied. 
o The blood-collection tube should be pushed into the holder straight and completely. 
o The blood-collection tube should be removed from the holder as soon as the blood flow 
into the tube stops. 
o Consecutive blood draws should be performed with the holder fixed in place and the 
collection tube replaced. 
o Upon completion of the blood draw, the tourniquet should be kept applied until after the 
collection tube is removed from the holder. 
 
3. Basic cautions of importance 


 
 
 
Page 80 of 83 
 
 
The blood-collection tube and the patient’s arm should point downward at all time during the blood 
draw. 
 
When using a winged needle for blood draw, ensure that the blood-collection tube does not move 
up and down. 
 
 
 


 
 
 
Page 81 of 83 
 
 
 
Appendix F:  Drugs known to produce significant QT prolongation 
and ventricular dysrhythmias  
 
The following list includes examples of drugs known to produce significant QT prolongation 
and ventricular dysrhythmias, of which the use is prohibited from signing informed consent 
through the EoT assessment.  This is not an exhaustive list.   
If there are any concerns regarding prohibited medications, please consult the sponsor or 
CRO Medical Monitor. 
<Drugs known to produce significant QT prolongation> 
alendronate sodium 
hydrate 
amiodarone hydrochloride 
apomorphine 
hydrochloride hydrate 
arsenic trioxide 
atazanavir sulfate 
azithromycin hydrate 
bepridil hydrochloride 
hydrate 
cinacalcet hydrochloride 
ciprofloxacin 
clarithromycin 
clofarabine 
clomipramine 
hydrochloride 
dasatinib hydrate 
delamanid 
denosumab 
disopyramide 
donepezil hydrochloride 
droperidol 
ebastine 
erythromycin 
escitalopram oxalate  
famotidine 
fesoterodine fumarate 
fluconazole  
fosfluconazole 
galantamine hydrobromide 
garenoxacin mesilate 
hydrate  
haloperidol  
hydroxyzine hydrochloride 
hydroxyzine pamoate 
ibandronate sodium 
hydrate  
imidafenacin 
imipramine hydrochloride 
isoflurane  
lenvatinib mesilate 
levofloxacin hydrate 
lomefloxacin 
hydrochloride 
maprotiline hydrochloride 
methadone hydrochloride 
mianserin hydrochloride 
miconazole 
minodronic acid hydrate 
mirtazapine 
moxifloxacin 
hydrochloride 
ofloxacin 


 
 
 
Page 82 of 83 
 
 
panitumumab 
pentamidine isetionate 
probucol 
procainamide 
hydrochloride 
propiverine hydrochloride 
prulifloxacin 
quinidine sulfate hydrate 
roxithromycin  
sertraline hydrochloride  
sitafloxacin hydrate 
solifenacin succinate 
sotalol hydrochloride  
sulpiride  
sultopride 
tiapride hydrochloride 
trazodone hydrochloride 
venlafaxine hydrochloride  
voriconazole 
chloroquine 
chlorpromazine 
domperidone 
flecainide 
propafenone 
pimozide 
 
<Drugs known to produce significant ventricular dysrhythmias > 
anagrelide hydrochloride 
hydrate 
arsenic trioxide 
carperitide 
ebastine 
furosemide 
interferon alfa 
miconazole 
oxaliplatin 
pazopanib hydrochloride 
peginterferon alfa 
pentamidine isetionate 
probucol 
ribavirin 
sunitinib malate 
vandetanib 
 
 


 
 
 
Page 83 of 83 
 
 
 
Appendix G:  Signature of Investigator 
 
PROTOCOL TITLE:  A Phase 2b Open-Label Single Arm Study to Evaluate the Efficacy 
and Safety of Oral HBI-8000 in Patients with Relapsed or Refractory Peripheral T-cell 
Lymphoma (PTCL)  
 PROTOCOL NO: HBI-8000-203 
This protocol is a confidential communication of HUYABIO International, LLC.  I confirm 
that I have read this protocol, I understand it, and I will comply with the all the terms and 
requirements of this protocol.  I will also work consistently with the ethical principles that have 
their origin in the Declaration of Helsinki and that are consistent with good clinical practices 
and the applicable laws and regulations.  Acceptance of this document constitutes my 
agreement that no unpublished information contained herein will be published or disclosed 
without prior written approval from HUYABIO International, LLC. 
Instructions to the Investigator:  Please SIGN and DATE this signature page.  PRINT your name, title, and 
the name of the site in which the study will be conducted.  Return the signed copy to 
 
   
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:      
__________________________            Date:  ________ 
Printed Name:                                ___________________________ 
Investigator Title:                           ___________________________ 
 
Name/Address of Site:               
___________________________ 
 
___________________________ 
 
___________________________ 
 


1 / 9 
Protocol：HBI-8000-203 version 6.0 
Protocol Table of Changes（19 July 2021） 
Page 
Change 
Protocol ver. 5.0, 09 October 2019 
Protocol ver. 6.0, 19 July 2021 
Reason 
Applicable 
section 
HUYA International, LLC 
HUYABIO International, LLC 
Company 
name 
change 
Applicable 
section 
IB 2019 
IB 2020 
Information 
update 
Applicable 
section 
tucidinostat 
Addition of 
general 
name 
Applicable 
section 
ATL 
ATLL 
Correction 
1 
CONFIDENTIAL 
The concepts and information contained in this 
document or generated during the study are considered 
proprietary and may not be disclosed, in whole or in 
part, without the expressed written consent of HUYA 
Bioscience International, LLC and 
constitute Confidential Information under the 
Confidential Disclosure Agreement  
(CDA) between the parties.  
The study will be conducted according to the 
International Council for Harmonisation (ICH) 
The concepts and information contained in this document or 
generated during the study are considered proprietary and 
may not be disclosed in whole or in part without the 
expressed written consent of HUYABIO International, LLC 
and constitute Confidential Information under the 
Confidential Disclosure Agreement (CDA) between the 
parties. 
The study will be conducted according to the International 
Council for Harmonisation (ICH) harmonised tripartite 
guideline E6 (R2): Good Clinical Practice (GCP), including 
Confidential 
description 
change 


2 / 9 
Page 
Change 
Protocol ver. 5.0, 09 October 2019 
Protocol ver. 6.0, 19 July 2021 
Reason 
harmonized tripartite guideline E6(R2): Good 
Clinical Practice (GCP), including the archiving of 
essential documents. 
the archiving of essential documents. 
3 
Study duration 
Approximately 60 months 
Approximately 66 months 
Study 
duration 
extension 
3 
Planned study 
period 
4Q 2016 (first patient in) to 
3Q 2018 (last patient in) 
4Q 2021 study completion 
4Q 2016 (first patient in) to 
3Q 2018 (last patient in) 
2Q 2022 study completion 
Study 
duration 
extension 
3 
Study Design 
The study will continue till the last active Japanese subject 
initiates administration of the commercial product of HBI-
8000 after the marketing authorization approval for relapsed 
or refractory PTCL in Japan. If there is no subject who is 
receiving study treatment at the time of the PTCL approval in 
Japan, the whole study will be completed at the time of the 
approval. 
In Japan, “Phase 2 study” shall be read as “post-marketing 
clinical study” and “investigator” shall be read as “post-
marketing clinical study investigator” in this protocol after 
the marketing approval. In addition, other related terms are to 
be replaced in accordance with Article 56 of the Ministerial 
Ordinance on the Standards for the Implementation of 
Clinical Studies on Pharmaceutical Product (Japan GCP). 
Change of 
the study 
design to 
complete the 
study 


3 / 9 
Page 
Change 
Protocol ver. 5.0, 09 October 2019 
Protocol ver. 6.0, 19 July 2021 
Reason 
4 
Study Design 
For determination of efficacy, HBI-8000 
administration will be continued until disease 
progression (PD) or unacceptable toxicities are 
observed despite appropriate dose reduction or 
treatment interruption. 
For determination of efficacy, HBI-8000 administration will 
be continued until disease progression (PD) or unacceptable 
toxicities are observed despite appropriate dose reduction or 
treatment interruption. Study drug treatment will be 
discontinued after the PTCL approval when the commercial 
product of HBI-8000 is available at the study sites. 
Change of 
the study 
design to 
complete the 
study 
6 
Treatments 
Study drug is to be taken after any regular meal twice 
weekly, each dose separated by 3-4 days.  Treatment 
will continue until PD in the absence of unacceptable 
toxicity. 
Study drug is to be taken after any regular meal twice weekly, 
each dose separated by 3-4 days. Treatment will continue 
until PD in the absence of unacceptable toxicity, whichever is 
earlier. Study drug treatment will be completed when the 
commercial product of HBI-8000 is available at the study 
sites after the PTCL approval. 
Change of 
the study 
design to 
complete the 
study 
13 
LIST OF 
ABBREVIATIONS 
AND 
DEFINITIONS OF 
TERMS 
ATL  Adult T-cell lymphoma 
ATLL  Adult T-cell leukemia/lymphoma 
Correction 
13 
LIST OF 
ABBREVIATIONS 
AND 
DEFINITIONS OF 
TERMS 
GPSP 
Good Post-marketing Study Practice 
Addition 
14 
LIST OF 
ABBREVIATIONS 
MHLW  Ministry of Health, Labour and Welfare 
Addition 


4 / 9 
Page 
Change 
Protocol ver. 5.0, 09 October 2019 
Protocol ver. 6.0, 19 July 2021 
Reason 
AND 
DEFINITIONS OF 
TERMS 
15 
1.1 Background 
Information 
Replacement 
15 
1.1 Background 
Information 
molecular weight, 390.41 
molecular weight, 390.42 
Correction 
15 
1.1 Background 
Information 
HBI-8000 was approved by Ministry of Health, Labour and 
Welfare (MHLW) for relapsed or refractory Adult T-cell 
Leukemia/Lymphoma (ATLL) in Japan on June 23, 2021. 
Information 
update 
21 
1.6 Clinical Studies 
To date, more than 300 patients have been dosed with 
HBI-8000/chidamide in clinical trials. Over 1000 
patients have been prescribed chidamide (Epidaza) in 
China since marketing approval was granted in 
December 2014. 
To date, more than 800 patients have been dosed with HBI-
8000/chidamide in clinical trials. Over 26,000 patients have 
been prescribed chidamide (Epidaza) in China since 
marketing approval was granted in December 2014. 
Information 
update 
21 
1.6 Clinical Studies 
Phase 2 clinical trial on going in patients with relapsed 
or refractory PTCL. 
In addition, Phase 2 study in relapsed or refractory ATLL was 
initiated in 2016 and has completed. 
HUYBIO received approval from MLHW for relapsed or 
refractory ATLL in June 2021. The Phase 2 study in PTCL is 
this protocol. 
Information 
update 


5 / 9 
Page 
Change 
Protocol ver. 5.0, 09 October 2019 
Protocol ver. 6.0, 19 July 2021 
Reason 
21 
1.8 Dose Selection 
and Risk 
Assessment 
A Phase 1 dose finding study of HBI-8000 has been 
conducted in Japan in NHL patients.  Based on the 
clinical experience from China (Section 1.6) where the 
CFDA approved dose of HBI-8000 is 30 mg BIW 
A Phase 1 dose finding study of HBI-8000 was conducted in 
Japan in NHL patients.  Based on the clinical experience 
from China (Section 1.6) where the CFDA approved dose of 
chidamide (Epidaza) is 30 mg BIW 
24 
2.4 Summary of 
Study Design 
The study will continue till the last active Japanese subject 
initiates administration of the commercial product of HBI-
8000 after the marketing authorization approval for relapsed 
or refractory PTCL in Japan. If there is no subject who is 
receiving study treatment at the time of the PTCL approval in 
Japan, the whole study will be completed at the time of the 
approval. 
In Japan, “Phase 2 study” shall be read as “post-marketing 
clinical study” and “investigator” shall be read as “post-
marketing clinical study investigator” in this protocol after 
the marketing approval. In addition, other related terms are to 
be replaced in accordance with Article 56 of the Ministerial 
Ordinance on the Standards for the Implementation of 
Clinical Studies on Pharmaceutical Product (Japan GCP). 
Change of 
the study 
design to 
complete the 
study 
27 
2.6 Study 
Procedures 
Overview 
It is estimated that each patient will be on study for up 
to 36 months after enrollment.  Assuming that 24 
months are needed to meet accrual target, the study 
period would be of 60 months to allow efficacy and 
safety determination. 
It is estimated that each patient will be on study for up to 42 
months after enrollment.  Assuming that 24 months are 
needed to meet accrual target, the study period would be of 
66 months to allow efficacy and safety determination. 
Study 
duration 
extension 
28 
2.6.4 End of 
All patients receiving at least one dose of HBI-8000 
All patients receiving at least one dose of HBI-8000 and 
Change of 


6 / 9 
Page 
Change 
Protocol ver. 5.0, 09 October 2019 
Protocol ver. 6.0, 19 July 2021 
Reason 
Treatment Safety 
Follow-up Visit 
and discontinuing treatment for any reason except 
death will be assessed 30 (± 3) days after the last 
dosing of study drug or before the initiation of new 
cancer treatment, whichever is earlier. 
discontinuing treatment for any reason except death will be 
assessed 30 (± 3) days after the last dosing of study drug, 
before the initiation of new cancer treatment or before the 
initiation of administration of commercial product of HBI-
8000, whichever is earlier. 
the study 
design to 
complete the 
study 
29 
2.6.4 End of 
Treatment Safety 
Follow-up Visit 
In these patients, further tumor assessments are to be 
performed approximately every 3 months ± 2 weeks 
until PD or the start of new cancer therapy whichever 
occurs first, unless consent to study participation is 
withdrawn.    
In these patients, further tumor assessments are to be 
performed approximately every 3 months ± 2 weeks until PD 
or the start of new cancer therapy whichever occurs first, 
unless consent to study participation is withdrawn or by 
completion of the whole study. If subjects cannot visit at site 
for this examination due to COVID-19 situation, 
investigators can skip the examination, and the assessment is 
to be performed approximately every 6 months ± 2 weeks. In 
this case, the investigator should document that fact in the 
medical record. 
Change of 
the study 
design to 
complete the 
study and 
COVID-19 
29 
2.6.5 Survival 
Follow-up 
Survival status may be conducted every 3 months ± 2 
weeks by telephone contact or e-mail until death or 
end of study, defined as 12 months after the 
administration of the last dose of the entire study 
Survival status may be conducted every 3 months ± 2 weeks 
by telephone contact or e-mail until death or end of study, 
defined as timing that the last Japanese subject initiates 
administration of the commercial product of HBI-8000. If 
there is no subject who is receiving study treatment at the 
time of the PTCL approval in Japan, the whole study will be 
completed at the time of the approval. 
Change of 
the study 
design to 
complete the 
study 
30 
2.6.6 
Patient 
Withdrawal 
All patients who withdraw from study treatment must 
complete an EoT visit, to be performed 30 ± 3 days 
All patients who withdraw from study treatment must 
complete an EoT visit, to be performed 30 ± 3 days after the 
Change of 
the study 


7 / 9 
Page 
Change 
Protocol ver. 5.0, 09 October 2019 
Protocol ver. 6.0, 19 July 2021 
Reason 
after the last dosing of the study drug (see Section 9.1) 
or before the initiation of new cancer treatment, 
whichever is earlier. 
last dosing of the study drug (see Section 9.1) ,before the 
initiation of new cancer treatment or before the initiation of 
administration of commercial product of HBI-8000, 
whichever is earlier. 
design to 
complete the 
study 
32 
2.8 Packaging, 
Labelling and 
Storage 
The study drug shall be read as post-marketing clinical study 
drug in this protocol after the PTCL approval. 
Change of 
the study 
design to 
complete the 
study 
56 
6.2 Ethical 
Conduct of the 
Study 
In Japan, the study shall be conducted in accordance with 
Good Post-marketing Study Practice (GPSP) as well as GCP 
after the PTCL approval. 
Change 
from study 
to post-
marketing 
study 
59 
7.4.1 Investigator 
Obligations 
In Japan, the study shall be conducted in accordance with 
GPSP as well as GCP after the PTCL approval. 
Change 
from study 
to post-
marketing 
study 
59 
7.4.2 Protocol 
Signatures 
By signing the protocol, the investigator confirms in 
writing that he/she has read, understands and will 
strictly adhere to the study protocol and will conduct 
the study in accordance with ICH Tripartite Guidelines 
By signing the protocol, the investigator confirms in writing 
that he/she has read, understands and will strictly adhere to 
the study protocol and will conduct the study in accordance 
with ICH Tripartite Guidelines for Good Clinical Practice and 
Change 
from study 
to post-
marketing 


8 / 9 
Page 
Change 
Protocol ver. 5.0, 09 October 2019 
Protocol ver. 6.0, 19 July 2021 
Reason 
for Good Clinical Practice and applicable regulatory 
requirements. The study will not be able to start at any 
site where the investigator has not signed the protocol. 
applicable regulatory requirements. In Japan, the investigator 
will conduct the study in accordance with GPSP as well as 
GCP after the PTCL approval. The study will not be able to 
start at any site where the investigator has not signed the 
protocol. 
study 
60 
8.0 STUDY DURATION 
8.0 REFERENCES 
Correction 
60 
8.0 REFERENCES 
IB 2019: Investigator’s Brochure for HBI-8000 
(CS055, chidamide).  HUYA Bioscience 
International, LLC version 9, 08July2019. 
IB 2020: Investigator’s Brochure for HBI-8000 (tucidinostat). 
HUYA Bioscience International, LLC version 10.1, 
18November2020. 
Information 
update 
64 
Table 4:  Schedule 
of Events 
b 
“End of Treatment” visit should be conducted 30 ± 3 
days after the last dosing of the study drug, or before 
the initiation of new cancer treatment, whichever is 
earlier 
“End of Treatment” visit should be conducted 30 ± 3 days 
after the last dosing of the study drug, before the initiation of 
new cancer treatment or before the initiation of 
administration of commercial product of HBI-8000, 
whichever is earlier 
Change of 
the study 
design to 
complete the 
study 
64 
Table 4:  Schedule 
of Events 
c 
Survival data will be collected every 3 months ± 2 
weeks after End of Treatment until death or the end of 
the study, defined as 12 months after the 
administration of the last dose of the entire study 
Survival data will be collected every 3 months ± 2 weeks 
after End of Treatment until death or the end of the study, 
defined as timing that the last Japanese subject initiates 
administration of the commercial product of HBI-8000. 
Change of 
the study 
design to 
complete the 
study 
65 
Table 4:  Schedule 
of Events 
m 
In these patients, further tumor assessments are to be 
performed approximately every 3 months ± 2 weeks 
until PD or the start of new cancer therapy whichever 
occurs first, unless consent to study participation is 
withdrawn. 
In these patients, further tumor assessments are to be 
performed approximately every 3 months ± 2 weeks until PD 
or the start of new cancer therapy whichever occurs first, 
unless consent to study participation is withdrawn or by 
completion of the whole study. If subjects cannot visit their 
Change of 
the study 
design to 
complete the 
study and 


9 / 9 
Page 
Change 
Protocol ver. 5.0, 09 October 2019 
Protocol ver. 6.0, 19 July 2021 
Reason 
study site for this examination due to COVID-19 situation, 
investigators can skip the examination, and the assessment is 
to be performed approximately every 6 months ± 2 weeks. In 
this case, the investigator should document that fact in the 
medical record. 
COVID-19 


1 / 5 
Protocol：HBI-8000-203 version 5.0 
Protocol Table of Changes（09 October 2019） 
Page 
Change 
Protocol ver. 4.0, 31 May 2018 
Protocol ver. 5.0, 09 October 2019 
Reason 
1 
Confidentiality 
Statement 
Confidentiality Statement 
This confidential information in this 
document is provided to you as an 
Investigator or consultant for review by you, 
your staff, and the applicable Institutional 
Review Board/Independent Ethics 
Committee.  Your acceptance of this 
document constitutes agreement that you 
will not disclose the information contained 
herein to others without written 
authorization from the Sponsor. 
CONFIDENTIAL 
The concepts and information contained 
in this document or generated during the 
study are considered proprietary and may 
not be disclosed, in whole or in part, 
without the expressed written consent of 
HUYA Bioscience International, LLC and 
constitute Confidential Information under 
the Confidential Disclosure Agreement 
(CDA) between the parties. 
The study will be conducted according to 
the International Council for 
Harmonisation (ICH) harmonized 
tripartite guideline E6(R2): Good Clinical 
Practice, including the archiving of 
essential documents. 
Template 
update 
2 
Signatures 
 
 
 
 
 
 
 
 
Organization 
change and 
correction 


2 / 5 
Page 
Change 
Protocol ver. 4.0, 31 May 2018 
Protocol ver. 5.0, 09 October 2019 
Reason 
 
 
 
 
3 
HBI-8000-203 Protocol 
Synopsis 
Study duration: Approximately 36 months 
Study duration: Approximately 60 months Study duration 
extension 
3 
HBI-8000-203 Protocol 
Synopsis 
Planned study period: 4Q 2016 (first patient 
in) to 
3Q 2018 (last patient in) 
4Q 2019 study completion 
Planned study period: 4Q 2016 (first 
patient in) to 
3Q 2018 (last patient in) 
4Q 2021 study completion 
Study duration 
extension 
15 
1.1 Background 
Information 
(2-Amino-4-fluorophenyl)-4-[N-[(E)-3-(3-
pyridyl) acryloyl]aminomethyl] benzamide, 
N-(2-Amino-4-fluorophenyl)-4-[N-[(E)-3-
(3-
pyridyl)acryloyl]aminomethyl]benzamide, 
Correction 
# This 
correction is 
English Only 
15 
1.1 Background 
Information 
It is now in the market under the trade name 
Epidaza in China.  HUYA Bioscience 
International, LLC (HUYA) has licensed 
worldwide rights (excluding China) of this 
compound. 
It is marketed under the trade name 
Epidaza® in China.  HUYA Bioscience 
International, LLC (HUYABIO) has 
licensed worldwide rights (excluding 
China) of this compound. 
Information 
update 
17 
1.3 Rationale for the 
Use of HBI-8000 for the 
Treatment of Cancer 
Results from pre-clinical pharmacokinetics 
(PK) and toxicology studies in rats and dogs 
as well as results from a Phase 1 study 
conducted to date [Shenzhen Chipscreen 
Study Report 2008] suggest that HBI-8000 
has favorable PK and safety profiles relative 
Results from pre-clinical 
pharmacokinetics (PK) and toxicology 
studies in rats and dogs as well as results 
from a Phase 1 study conducted to date 
[Shenzhen Chipscreen Study Report 
2008] suggest that HBI-8000 has 
correction 


3 / 5 
Page 
Change 
Protocol ver. 4.0, 31 May 2018 
Protocol ver. 5.0, 09 October 2019 
Reason 
to other HDAC inhibitors. 
favorable PK and safety profiles. 
20 
1.5.1 Absorption 
HBI-8000 is being administered two times a 
week continuously. 
HBI-8000 was administered two times a 
week continuously. 
correction 
20 
1.6 Clinical Studies 
a Phase 1 study (HBI-8000-201) in patients 
with relapsed or refractory Non-Hodgkins 
Lymphoma (NHL) including PTCL and ATL 
was initiated in Japan in April, 2014 and has 
now completed. Phase 2 clinical trials are 
planned in patients with relapsed or 
refractory ATL and relapsed or refractory 
PTCL.   
a Phase 1 study (HBI-8000-201) in 
patients with relapsed or refractory Non-
Hodgkins Lymphoma (NHL) including 
PTCL and ATL was initiated in Japan in 
April, 2014 and has completed. Phase 2 
clinical trials are on going in patients with 
relapsed or refractory ATL and relapsed or 
refractory PTCL.   
Information 
update 
22 
1.8 Dose Selection and 
Risk Assessment 
In clinical studies, treatment with HBI-8000 
has been associated with myelosuppression, 
including thrombocytopenia, neutropenia 
and/or leukopenia and anemia or decreased 
hemoglobin.  Other adverse drug reactions 
reported in previous clinical trials include 
nausea, diarrhea, fatigue/lethargy, abdominal 
pain, vomiting, peripheral edema, 
pyrexia/fever, anorexia, dizziness, and 
decreased appetite and transaminase 
increase. 
In clinical studies, treatment with HBI-
8000 has been associated with 
myelosuppression, including 
thrombocytopenia, neutropenia and/or 
leukopenia and anemia or decreased 
hemoglobin.  Other adverse drug 
reactions reported in previous clinical 
trials include nausea, diarrhea, 
fatigue/lethargy, abdominal pain, 
vomiting, peripheral edema, 
pyrexia/fever, anorexia, dizziness, 
decreased appetite and transaminase 
increase. 
Information 
updat 


4 / 5 
Page 
Change 
Protocol ver. 4.0, 31 May 2018 
Protocol ver. 5.0, 09 October 2019 
Reason 
26 
2.6 Study Procedures 
Overview 
It is estimated that each patient will be on 
study for up to 12 months after enrollment.  
Assuming that 24 months are needed to 
meet accrual target, the study period would 
be of 36 months to allow efficacy and safety 
determination. 
It is estimated that each patient will be on 
study for up to 36 months after 
enrollment.  Assuming that 24 months 
are needed to meet accrual target, the 
study period would be of 60 months to 
allow efficacy and safety determination. 
Study duration 
extension 
47 
4.2 Data 
Management/Coding 
Adverse events will be coded using Medical 
Dictionary for Regulatory Activities 
(MedDRA) Version 19.0. 
Adverse events will be coded using 
Medical Dictionary for Regulatory 
Activities (MedDRA) Version 21.1. 
Information 
update 
59 
8.0 REFERENCES 
IB 2017: Investigator’s Brochure for HBI-
8000 (CS055, chidamide).  HUYA 
Bioscience International, LLC, version 7, 08 
July, 2017 
IB 2019: Investigator’s Brochure for HBI-
8000 (CS055, chidamide).  HUYA 
Bioscience International, LLC, version 9, 
08 July, 2019 
Information 
update 
82 
9.7 Appendix G:  
Signature of Investigator 
This protocol is a confidential 
communication of HUYA Bioscience 
International.  I confirm that I have read 
this protocol, I understand it, and I will work 
according to this protocol.  I will also work 
consistently with the ethical principles that 
have their origin in the Declaration of 
Helsinki and that are consistent with good 
clinical practices and the applicable laws 
and regulations.  Acceptance of this 
document constitutes my agreement that no 
This protocol is a confidential 
communication of HUYA Bioscience 
International, LLC.  I confirm that I have 
read this protocol, I understand it, and I 
will comply with the all the terms and 
requirements of this protocol.  I will also 
work consistently with the ethical 
principles that have their origin in the 
Declaration of Helsinki and that are 
consistent with good clinical practices and 
the applicable laws and regulations.  
Correction 


5 / 5 
Page 
Change 
Protocol ver. 4.0, 31 May 2018 
Protocol ver. 5.0, 09 October 2019 
Reason 
unpublished information contained herein 
will be published or disclosed without prior 
written approval from HUYA Bioscience 
International. 
Acceptance of this document constitutes 
my agreement that no unpublished 
information contained herein will be 
published or disclosed without prior 
written approval from HUYA Bioscience 
International, LLC. 
corresponding 
section 
HUYA 
HUYABIO 
Name change 
corresponding 
section 
HUYA Bioscience International 
HUYA Bioscience International, LLC 
Correction 
corresponding 
section 
 
 
Name change 
corresponding 
section 
IB 2017 
IB 2019 
Information 
update 


Protocol：HBI-8000-203 version 4.0 
Protocol Table of Changes（31 May 2018） 
Page 
Change 
Before (Protocol ver.3.0, 27 Nov 2017) 
After (Protocol ver.4.0, 31 May 2018) 
Reason 
2 
Signatures 
 
 
 
 
 
 
 
 
 
 
 
 
HUYA internal 
organization 
change 
7 
Synopsis 
Statistical 
procedure 
Patients considered evaluable for efficacy must 
meet eligibility criteria and have at least one 
post-baseline assessment of efficacy, or who 
discontinue study early due to clinical PD. 
Efficacy should be analyzed by Full analysis set 
(FAS) and Per protocol set (PPS).  Full 
analysis set is defined as patients having 
received at least one dose of study medication 
and at least one post-baseline assessment. 
Per protocol set is defined as patients in FAS 
having completed Cycle 1 treatment or 
discontinue study early due to clinical PD 
without any deviation from eligibility criteria. 
It should be noted that PPS includes subjects 
Efficacy should be analyzed using Full analysis 
set (FAS) and Per protocol set (PPS). 
The FAS is defined as Patients meeting all 
eligibility criteria and having received at least 
one dose of study medication, and at least one 
efficacy assessment of disease with either 
imaging studies or clinical examination after 
receiving study medication. 
The PPS is defined as Patients meeting all 
eligibility criteria and having completed Cycle 
1 treatment or discontinued study treatment 
during cycle 1 due to clinical PD. It should be 
noted that the PPS includes subjects who 
discontinue within Cycle 1 due to clinical PD 
Clarification 


who discontinue within Cycle 1 due to clinical 
PD without any deviation from eligibility 
criteria. 
It is estimated that 40 evaluable patients are 
adequate to provide efficacy assessment. 
Assuming a 30% ORR in this population of 40 
evaluable patients, the conclusion would be 
that there is a 95% chance that the ORR in this 
protocol population would lie between 15.8% 
and 44.2%. 
without imaging studies to assess disease 
status. 
In addition, Patients who are assessed as 
Non-PTCL by the central pathology review 
committee should be excluded from the FAS 
and PPS for efficacy. The non-PTCL subjects 
will be included in safety analysis for the study. 
The primary efficacy analysis is conducted in 
the PPS. The Efficacy analysis using the FAS 
will be also reported. 
It is estimated that 40 evaluable patients are 
adequate to provide efficacy assessment. 
Assuming a 30% ORR in this population of 40 
evaluable patients, the conclusion would be 
that there is a 95% chance that the ORR in this 
protocol population would lie between 15.8% 
and 44.2%. The power for showing the 
response rate >10% at 5% two-sided alpha in 
40 patients is 89%. 
49 
5.1 General 
Statistical 
Considerations 
5.1  General Statistical Considerations 
Protocol HBI-8000-203 is an open-label, 
Phase 2b pivotal study evaluating HBI-8000 
for regulatory approval in Japan and South 
5.1  General Statistical Considerations 
Protocol HBI-8000-203 is an open-label, 
Phase 2b pivotal study evaluating HBI-8000 
for regulatory approval in Japan and South 
Clarification 


Korea for the indication of relapsed or 
refractory PTCL.  
Korea for the indication of relapsed or 
refractory PTCL. The main analysis will be 
conducted for the purpose of regulatory 
submission of this product. The data cut-off 
(DCO) for the main analysis is set at the time 
when the last patient completes at least one 
post-efficacy assessment. The eCRF data by 
the DCO needs to be cleaned to have no 
unresolved queries. All independent reviews 
(including the Central Pathology Review, the 
independent 
radiological 
review, 
the 
Independent Overall Efficacy Review and 
review by the Data Safety Monitoring Board) 
by the DCO need to be completed before the 
main analysis. The data after the main analysis 
will be provided at the end of the study as a 
supportive material. 
49 
5.2 
Determination 
of Sample Size 
The target best ORR for this study is 30%, on 
the basis of the ORR results that were obtained 
in study TG0902CDM.  The 95% confidence 
interval (CI) for an ORR of 30% at a sample 
size of N=40 is expected to be between 15.8% 
and 44.2%. 
The target best ORR for this study is 30%, on 
the basis of the ORR results that were obtained 
in study TG0902CDM.  The 95% confidence 
interval (CI) for an ORR of 30% at a sample 
size of N=40 is expected to be between 15.8% 
and 44.2%. 
Clarification 


The power for showing the response rate 
>10% at 5% two-sided alpha in 40 patients is
89%. 
50 
5.5.2 
Efficacy 
Population 
Efficacy should be analyzed by FAS and PPS. 
To be evaluable for efficacy analysis, patients 
must meet eligibility criteria and have at least 
one post-baseline assessment of efficacy, or 
who discontinue study early due to clinical PD. 
FAS is defined as Patients having received at 
least one dose of study medication and at least 
one post-baseline assessment. 
PPS is defined as Patients in FAS having 
completed Cycle 1 treatment or discontinue 
study early due to clinical PD without any 
deviation from eligibility criteria.  It should 
be noted that PPS includes subjects who 
discontinue within Cycle 1 due to clinical PD 
without any deviation from eligibility criteria. 
Efficacy should be analyzed using FAS and 
PPS. 
The FAS is defined as Patients meeting all 
eligibility criteria and having received at least 
one dose of study medication, and at least one 
efficacy assessment of disease with either 
imaging studies or clinical examination after 
receiving study medication. 
The PPS is defined as Patients meeting all 
eligibility criteria and having completed Cycle 
1 treatment or discontinued study treatment 
during cycle 1 due to clinical PD. It should be 
noted that the PPS includes subjects who 
discontinue within Cycle 1 due to clinical PD 
without imaging studies to assess disease 
status. 
In addition, Patients who are assessed as 
Non-PTCL by the central pathology review 
committee should be excluded from the FAS 
and PPS for efficacy. The non-PTCL subjects 
Clarification 


will be included in safety analysis for the study. 
The primary efficacy analysis is conducted in 
the PPS. The Efficacy analysis using the FAS 
will be also reported. 
77 
9.4.9.3 
Evaluation of 
skin lesion by 
mSWAT 
PD: Increase in mSWAT score of ≥ 25% from 
baseline or appearance of new lesion 
PD: ≥25% increase in skin disease from 
baseline or New tumor mass** or Loss of 
response: in those with complete or partial 
response, increase of skin score of greater than 
the sum of nadir plus 50% baseline score. 
** tumor mass : at least 1 cm diameter solid or 
nodular lesion with evidence of depth and/or 
vertical growth 
Correction of 
error 


Protocol：HBI-8000-203 version 3.0 
Protocol Table of Changes（27 Nov 2017） 
Page Change 
Before (Protocol ver.2.0, 29May2017) 
After (Protocol ver.3.0, 27Nov2017) 
Reason 
2 
Signature 
 
 
 
 
 
 
HUYA internal 
organization 
change 
4 
Synopsis 
Inclusion 
Criteria 
2. Patients for whom at least 1 measurable
lesion is confirmed by the lesion 
assessment at baseline; an evaluable 
lesion is defined as more than 1.5 cm in 
greatest dimension and can be followed by 
imaging. 
2. Patients for whom at least 1 measurable
lesion is confirmed by the lesion 
assessment at baseline; an evaluable 
lesion is defined according to Cheson 
criteria 2014. as more than 1.5 cm in 
greatest dimension and can be followed by 
imaging. 
Correction of 
error 
4 
Synopsis 
Inclusion 
Criteria 
3.Relapsed or refractory disease after
receiving ≥1 prior systemic therapy with 
anti-tumor agent(s) and there is no other 
available 
treatment 
which 
can 
be 
considered appropriate for patients. 
Systemic therapy is defined as frontline 
3.Relapsed or refractory disease after
receiving ≥1 prior systemic therapy with 
anti-tumor agent(s) and there is no other 
standard 
treatment 
which 
can 
be 
considered appropriate for patients. 
Systemic therapy is defined as frontline 
Clarification 


chemotherapy 
or
immunotherapy 
administered systemically. 
chemotherapy 
or
immunotherapy 
administered systemically. 
5 
Synopsis 
Exclusion 
Criteria 
4. Patients with a history of second
malignancy other than disease under 
study.  The exceptions are disease that 
has been treated with curative intent 
with no evidence of recurrence in past 2 
years including: 
4. Patients with a history of second
malignancy other than disease under 
study. The exceptions are diseases 
(excluding diseases listed below) that 
have been treated with curative intent 
with no evidence of recurrence in past 5 
years. Furthermore, if the second 
malignancy is one of the following 
diseases that were treated with curative 
intent, it is only required that there 
is no evidence of recurrence in past 2 
years: 
Allow PTCL 
patients with 
second 
malignancy who 
had curative 
treatment with 
no evidence of 
recurrence 
6 
Synopsis 
Efficacy data 
Response and progression for PTCL will 
be evaluated according to the revised 
criteria for response assessment in 
lymphoma [Cheson 2014].  To be included 
in final efficacy analyses, the 
histopathology diagnosis of disease will 
be verified by Central Pathology Review, 
and disease response will be confirmed 
by Independent Radiology Review.  
Response and progression for PTCL will 
be evaluated according to the revised 
criteria for response assessment in 
lymphoma [Cheson 2014].  To be included 
in final efficacy analyses, the 
histopathology diagnosis of disease will 
be verified by Central Pathology Review, 
and disease response will be confirmed 
by Independent Radiology and Independent 
Clarification of 
independent 
efficacy 
analysis 


Overall Efficacy Review. 
15 
Introduction 
Background 
Please refer to the Investigator’s 
Brochure for further information on HBI-
8000 [IB 2016] 
Please refer to the Investigator’s 
Brochure for further information on HBI-
8000 [IB 2017] 
IB was update in 
July 2017 
19 
Introduction 
Non-Clinical 
studies 
Further information on non-clinical 
studies conducted with HBI-
8000/chidamide may be found in the 
Investigator’s Brochure [IB 2016]. 
Further information on non-clinical 
studies conducted with HBI-
8000/chidamide may be found in the 
Investigator’s Brochure [IB 2017]. 
IB was update in 
July 2017 
20 
Introduction 
Metabolism 
and Excretion 
Further information on clinical 
pharmacological studies with HBI-
8000/chidamide may be found in the 
Investigator’s Brochure [IB 2016] 
Further information on clinical 
pharmacological studies with HBI-
8000/chidamide may be found in the 
Investigator’s Brochure [IB 2017] 
IB was update in 
July 2017 
24 
2.5.1 
Inclusion 
Criteria 
2. Patients for whom at least 1
measurable lesion is confirmed by the 
lesion assessment at baseline; an 
evaluable lesion is defined as more than 
1.5 cm in greatest dimension and can be 
followed by imaging. 
2. Patients for whom at least 1
measurable lesion is confirmed by the 
lesion assessment at baseline; an 
evaluable lesion is defined according to 
Cheson Criteria 2014. as more than 1.5 
cm in greatest dimension and can be 
followed by imaging. 
Correction of 
error 
24 
2.5.1 
Inclusion 
Criteria 
3.Relapsed or refractory disease after
receiving ≥1 prior systemic therapy with 
anti-tumor agent(s) and there is no other 
available 
treatment 
which 
can 
be 
3.Relapsed or refractory disease after
receiving ≥1 prior systemic therapy with 
anti-tumor agent(s) and there is no other 
standard 
treatment 
which 
can 
be 
Clarification 


considered appropriate for patients. 
Systemic therapy is defined as frontline 
chemotherapy 
or 
immunotherapy 
administered systemically. 
considered appropriate for patients. 
Systemic therapy is defined as frontline 
chemotherapy 
or 
immunotherapy 
administered systemically. 
25 
2.5.2 
Exclusion 
Criteria 
4.Patients with a history of second
malignancy other than disease under 
study.  The exceptions are disease that 
has been treated with curative intent 
with no evidence of recurrence in past 2 
years including: 
4. Patients with a history of second
malignancy other than disease under 
study. The exceptions are diseases 
(excluding diseases listed below) that 
have been treated with curative intent 
with no evidence of recurrence in past 5 
years. Furthermore, if the second 
malignancy is one of the following 
diseases that were treated with curative 
intent, it is only required that there 
is no evidence of recurrence in past 2 
years: 
Allow PTCL 
patients with 
second 
malignancy who 
had curative 
treatment with 
no evidence of 
recurrence 
26 
2.6 
Study 
Procedures 
Overview 
Independent Radiology Review will be 
performed for final efficacy analyses at 
the completion of this study. 
Independent Radiology Review and 
Independent Overall Efficacy Review will 
be performed for final efficacy analyses 
at the completion of this study. 
Clarification of 
independent 
efficacy 
analysis 
27 
2.6 
Study 
Procedures 
At the end of the study, tumor response 
of each patient will be reviewed by 
independent radiologists in a blinded 
At the end of the study, tumor response 
of each patient will be reviewed by 
independent radiologists and oncologists 
Clarification of 
independent 
efficacy 


Overview 
fashion to obtain best response, dates 
of response and progression 
in a blinded fashion to obtain best 
response, dates of response and 
progression 
analysis 
30 
2.6.8 
Management 
and Dosage 
Modifications 
for 
Unacceptable 
Hematologic 
and Non-
hematologic 
Adverse 
Events 
If unacceptable AEs recur despite 2 dose 
reductions, the study treatment will be 
permanently discontinued and post-
treatment follow up ensues. 
If unacceptable AEs recur despite 2 dose 
reductions, the study treatment will be 
permanently discontinued and post-
treatment follow up ensues. However, if 
the patients are having clinical 
benefit, further treatment may be 
considered after discussion with the 
sponsor. 
Change to allow 
treatment 
continuation 
only for 
patients who are 
having clinical 
benefit 
35 
3.1.1 
Primary 
Efficacy 
Endpoint 
a second independent radiologist will be 
asked to adjudicate by way of assigning 
the final disease response to the 
determination made by either the 
investigators or independent radiologist 
for final efficacy analysis. 
a second independent radiologist will be 
asked to adjudicate by way of assigning 
the final disease response to the 
determination made by either the 
investigators or independent radiologist 
for final efficacy analysis. The overall 
efficacy review will be done by 
independent oncologist for final 
efficacy analysis. 
Clarification of 
independent 
efficacy 
analysis 


44 
3.5 
Independent 
Review 
3.5.4 
Independent Overall Efficacy 
Review 
To ensure consistent overall efficacy 
review method is applied to assess 
disease response across the entire 
study, designated independent 
oncologists will review sequential 
clinical data of individual patients 
including radiological assessment 
provided by the independent radiological 
review. They will assign response 
outcome including best response, dates 
of initial response and progression when 
applicable, based on Cheson Criteria 
2014. 
Clarification of 
independent 
efficacy 
analysis 
52 
5.9 
Efficacy 
Analysis 
Tumor response as assessed by imaging 
studies will be adjudicated by 
independent radiology reviewers.  Tumor 
lesions, such as skin lesion, that 
cannot be monitored by imaging studies 
will determined by investigators only 
and contributed to overall disease 
response assessment.  Both investigators 
Tumor response as assessed by imaging 
studies will be adjudicated by 
independent radiology reviewers.  Tumor 
lesions, such as skin lesion, that 
cannot be monitored by imaging studies 
will determined by independent oncology 
reviewersinvestigators only and 
contributed to overall disease response 
Clarification of 
independent 
efficacy 
analysis 


reported and independently adjudicated 
outcomes based on imaging studies will 
be reported.  Primary analysis will be 
based on results from imaging studies 
confirmed by Independent Central Review.  
Results from investigator assessment 
will also be reported.  In patients with 
skin lesion that is assessed by mSWAT, 
response data from imagine studies alone 
will be reported according to 
Independent Review and investigator 
assessment.  Their overall response 
based on imaging studies AND mSWAT 
scores will be reported as 
investigator’s assessment only.  
assessment.  Both investigators reported 
and independently adjudicated outcomes 
based on imaging studies will be 
reported.  Primary analysis will be 
based on results from imaging studies 
and clinical data confirmed by 
Independent Central Review.  Results 
from investigator assessment will also 
be reported.  In patients with skin 
lesion that is assessed by mSWAT, 
response data from imagine studies alone 
will be reported according to 
Independent Review and investigator 
assessment.  Their overall response 
based on imaging studies AND mSWAT 
scores will be reported as 
investigator’s assessment only.  
58 
8.0 
References 
IB 2016: Investigator’s Brochure for 
HBI-8000 (CS055, chidamide).  HUYA 
Bioscience International, version 6, 08 
July, 2016 
IB 2017: Investigator’s Brochure for 
HBI-8000 (CS055, chidamide).  HUYA 
Bioscience International, version 7, 08 
July, 2017 
IB was update in 
July, 2017 


Protocol：HBI-8000-203 
Protocol_Table of Changes（29May2017） 
1 / 21 
Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
All 
pages 
Version. No, 
Date 
（footer） 
Version 1.2, 30 August 2016 
（footer） 
Version 2.0, 29 May 2017 
Change of version 
and date 
All 
pages 
- 
 
 
Information updated 
p.3
Synopsis 
Primary 
objective 
To determine the efficacy of HBI-8000 administered twice every week 
(BIW) continuously. 
To determine the efficacy of HBI-8000 administered twice every a week (BIW) 
continuously 
Change to the same 
word 
p.4
Synopsis 
Inclusion 
Criteria 
3. Progressive disease after receiving ≥ 1 prior systemic therapy with anti-
tumor agent(s). This could include frontline chemotherapy, and
mogamulizumab, or ineligible for mogamulizumab, and there is no other
available treatment with proven efficacy
7. Meeting the following baseline laboratory criteria:
a. Absolute Neutrophil Count >1500/µL independent of growth factor
support within 7 days
b. Platelets >75,000/µL independent of transfusion within 14 days
c. Hemoglobin >8 g/dL independent of transfusion within 14 days
d. Serum creatinine < 1.5 × ULN
e. Serum 
aspartate
aminotransferase/glutamyl 
oxaloacetic 
transaminase (AST/SGOT) or alanine aminotransferase/glutamyl 
pyruvic transaminase (ALT/SGPT) ≤ 3 × ULN 
f.
Serum Bilirubin ≤ 1.5 × ULN
3. Progressive Relapsed or refractory disease after receiving ≥ 1 prior systemic
therapy with anti-tumor agent(s) This could include frontline chemotherapy, and
mogamulizumab, or ineligible for mogamulizumab and there is no other available
treatment with proven efficacy which can be considered appropriate for patients.
Systemic therapy is defined as frontline chemotherapy or immunotherapy
administered systemically 
7. Meeting the following baseline laboratory criteria for screening:
a. Absolute Neutrophil Count >1500/µL independent of growth factor
support within 7 days
b. Platelets >75,000/µL independent of transfusion within 14 days
c. Hemoglobin >8 g/dL independent of transfusion within 14 days
d. Serum creatinine < 1.5 × ULN
e. Serum aspartate aminotransferase/glutamyl oxaloacetic transaminase
(AST/SGOT) 
orand 
alanine 
aminotransferase/glutamyl 
pyruvic
transaminase (ALT/SGPT) ≤ 3 × ULN
f.
Serum Bilirubin ≤ 1.5 × ULN
To clarify the 
definition 
Clarification of the 
contents 
Correction of the 
error 
p.5
Synopsis 
Exclusion 
Criteria 
2. Patients with known hypersensitivity to benzamide class of compounds
or any of the components of HBI-8000 tablets
1. Patients in whom central nervous system lymphoma is recognized during
screening (if suspected clinically, imaging study should be performed to confirm) 
2.3. Patients with known hypersensitivity to benzamide class of compounds or any 
of the components of HBI-8000 tablets, and patients with prior exposure of HBI-
8000 tablets 
Change due to 
reconsideration 
Not to investigate the 
activity of HBI-8000 
in re-treatment 
setting 


Protocol：HBI-8000-203 
Protocol_Table of Changes（29May2017） 
2 / 21 
Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
3. Patients with a second malignancy other than disease under study.  The
exceptions are disease that has been treated with curative intent with no
evidence of recurrence in past 5 years including:
a.
Basal cell carcinoma of the skin
b. Squamous cell carcinoma of the skin
c.
Cervical carcinoma in situ
d. Carcinoma in situ of the breast
e.
An incidental histological finding of prostate carcinoma (TNM
stage T1a or T1b) 
f.
Early-stage gastric cancer treated with endoscopic mucosal
resection or endoscopic submucosal dissection 
5. Allogeneic stem cell transplantation requiring immunosuppressant
treatment within 21 days of starting the study drug or with active Graft
Versus Host Disease (GVHD)
6. Organ transplantation recipients except for hematopoietic stem cell
transplantation 
3.4. Patients with a history of second malignancy other than disease under study. 
The exceptions are disease that has been treated with curative intent with no 
evidence of recurrence in past 5 2 years including: 
a.
Basal cell carcinoma of the skin
b.
Squamous cell carcinoma of the skin
c.
Cervical carcinoma in situ
d.
Carcinoma in situ of the breast
e.
An incidental histological finding of prostate carcinoma (TNM stage T1a or
T1b) 
f.
Early-stage gastric cancer treated with endoscopic mucosal resection or
endoscopic submucosal dissection 
g.
Thyroid cancer with differentiated histology (e.g. papillary) treated with
curative intent 
5.6. Allogeneic History of allogeneic stem cell transplantation requiring 
immunosuppressant treatment within 21 days of starting the study drug or with 
active Graft Versus Host Disease (GVHD) 
6.7. Organ transplantation recipients except for autologous hematopoietic stem 
cell transplantation 
Indolent second 
malignancy with no 
evidence of relapse 
in 2 years is unlikely 
to interfere with the 
treatment of PTCL. 
To allow PTCL 
patients to enter this 
study from Korea 
where indolent 
thyroid cancer is 
common 
The effects of HBI-
8000 on immune 
effector and 
regulatory cells are 
not yet characterized. 
The risks for graft 
rejection or 
exacerbated graft vs 
host disease cannot 
be estimated in 
patients with history 
of allogeneic stem 
cell transplantation. 
To clarify that 
autologous stem cell 
transplantation is not 
considered as an 
organ transplantation 
in this protocol 


Protocol：HBI-8000-203 
Protocol_Table of Changes（29May2017） 
3 / 21 
Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
p.6
Synopsis 
Excluded 
Prior or 
Concomitant 
Medications 
or Therapy: 
Medications 
And Therapy 
Anti-cancer therapy other than study medication is prohibited during the 
study and within the following time intervals prior to the first dose of 
study drug: 4 weeks for anti-cancer chemotherapy and 12 weeks for anti-
cancer monoclonal therapy; 6 weeks for nitrosourea or mitomycin C. 
Drugs known to produce significant QT prolongation or ventricular 
dysrhythmias are prohibited from signing informed consent through the 
EoT assessment. Corticosteroids prescribed for reason other than 
lymphoma is not considered as anti-cancer therapy in this study. 
Concomitant administration of HBI-8000 with drugs that significantly 
induce or inhibit CYP3A4, or are metabolized significantly by CYP3A4, 
and have a narrow therapeutic range, including St. John’s wort, are 
prohibited. 
The following drugs are prohibited. 

Drugs known to produce significant QT prolongation and ventricular
dysrhythmias (see Section 9.6)
Prohibited from signing informed consent through the EoT assessment 

Anti-cancer therapy other than study medication is prohibited
Prohibited during the study and within the following time intervals prior to the
first dose of study drug and 12 weeks for anti cancer monoclonal therapy;
6 weeks for nitrosourea or mitomycin C. Drugs known to produce significant QT 
prolongation or ventricular dysrhythmias are prohibited from signing informed 
consent through the EoT assessment. Corticosteroids prescribed for reason other 
than lymphoma is not considered as anti cancer therapy in this study 
−
4 weeks for anti-cancer chemotherapy Concomitant administration of
HBI 8000 with drugs that significantly induce or inhibit CYP3A4, or 
are metabolized significantly by CYP3A4, and have a narrow 
therapeutic range, including St. John’s wort, are prohibited 
−
6 weeks for nitrosourea and mitomycin C
−
12 weeks for anti-cancer monoclonal antibody therapy
Corticosteroid prescribed for medical conditions other than lymphoma is not 
considered as an anti-cancer therapy for this study, for example: chronic 
obstructive pulmonary disease for allergy, topical steroids for rash. 
Information updated 
p.6
Synopsis 
Treatments 
Study drug is to be taken after any regular meal twice weekly, each dose 
separated by at least 3-4 days. 
Study drug is to be taken after any regular meal twice weekly, each dose 
separated by at least 3-4 days. 
Correction of the 
error 
p.7
Synopsis 
Statistical 
Procedures 
Disease diagnosis including histological subtypes will be confirmed by 
central pathology review conducted by independent pathologists.  A 
patient considered evaluable for efficacy per protocol must have a 
baseline tumor assessment and at least 1 tumor assessment during study 
treatment; have received at least 1 cycle of study drug; and meet all 
eligibility criteria; or have discontinued study early due to clinical PD.  
It is estimated that 40 evaluable patients are adequate to provide efficacy 
assessment. Assuming a 30% ORR in this population of 40 evaluable 
patients, the conclusion would be that there is a 95% chance that the 
ORR in this protocol population would lie between 15.8% and 44.2%. 
Disease diagnosis including histological subtypes will be confirmed by central 
pathology review conducted by independent pathologists.  A patient considered 
evaluable for efficacy per protocol must have a baseline tumor assessment and at 
least 1 tumor assessment during study treatment; have received at least 1 cycle of 
study drug; and meet all eligibility criteria; or have discontinued study early due 
to clinical PD.Patients considered evaluable for efficacy must meet eligibility 
criteria and have at least one post-baseline assessment of efficacy, or who 
discontinue study early due to clinical PD.  Efficacy should be analyzed by Full 
analysis set (FAS) and Per protocol set (PPS).  Full analysis set is defined as 
patients having received at least one dose of study medication and at least one 
post-baseline assessment.  Per protocol set is defined as patients in FAS having 
completed Cycle 1 treatment or discontinue study early due to clinical PD 
without any deviation from eligibility criteria.  It should be noted that PPS 
includes subjects who discontinue within Cycle 1 due to clinical PD without any 
deviation from eligibility criteria.  It is estimated that 40 evaluable patients are 
Clarification of the 
contents 


Protocol：HBI-8000-203 
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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
adequate to provide efficacy assessment. Assuming a 30% ORR in this 
population of 40 evaluable patients, the conclusion would be that there is a 95% 
chance that the ORR in this protocol population would lie between 15.8% and 
44.2%. 
p.13 
List of 
abbreviations 
and 
definitions of 
terms 
 
 
AML 
Acute myelogenous leukemia 
ANC 
Absolute neutrophil count 
APL 
Acute promyelocytic leukemia 
ASCT 
Autologous stem-cell transplant 
 
 
CK 
Creatine kinase 
CNS 
Central Nervous System 
CRA 
Clinical Research Associate 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTL 
Cytotoxic T lymphocyte 
DNA 
Deoxyribonucleic acid 
EATL 
Enteropathy-associated T-cell lymphoma 
EMT 
Epithelial to mesenchymal transition 
 
 
GVHD 
Graft Versus Host Disease 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
 
 
 
 
IND 
Investigational new drug 
K2EDTA 
Dipotassium ethylene diaminetetra acetic acid 
LC-MS/MS 
Liquid chromatography-mass spectrometry 
NKTCL 
NK/T-cell lymphoma 
NMR 
Nuclear magnetic resonance 
NOAEL 
No Observed Adverse Effect Level 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
 
 
 
 
ADL 
Activities of daily living 
AML 
Acute myelogenous leukemia 
ANC 
Absolute neutrophil count 
APL 
Acute promyelocytic leukemia 
ASCT 
Autologous stem cell transplant 
CCR4 
CC chemokine receptor 4 
CK 
Creatine kinase 
CNS 
Central Nervous System 
CRA 
Clinical Research Associate 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTL 
Cytotoxic T lymphocyte 
DNA 
Deoxyribonucleic acid 
EATL 
Enteropathy-associated T-cell lymphoma 
EMT 
Epithelial to mesenchymal transition 
FAS 
Full analysis set 
GVHD 
Graft Versus Host Disease 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC 
Inhibitory concentration 
IND 
Investigational new drug 
K2EDTA 
Dipotassium ethylene diaminetetra acetic acid 
LC MS/MS 
Liquid chromatography mass spectrometry 
NKTCLNK 
NK/Natural killerT cell lymphoma 
NMR 
Nuclear magnetic resonance 
NOAEL 
No Observed Adverse Effect Level 
NSCLC 
Non small cell lung cancer 
NYHA 
New York Heart Association 
PD 
Disease progression 
PMDA 
Pharmaceutical and medical devices agency 
Modifications in 
abbreviation list 


Protocol：HBI-8000-203 
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Reason 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
R/R 
Relapsed or refractory 
SUSAR 
Suspected unexpected serious adverse reaction 
Tmax 
Time to peak plasma drug concentration 
Vd/F 
Apparent volume of distribution 
VEGF-R 
Vascular endothelial growth factor receptor 
WBC 
White blood cell 
WHO 
World Health Organization 
PPS 
Per protocol set 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
R/R 
Relapsed or refractory 
SUSAR 
Suspected unexpected serious adverse reaction 
TCL 
T-cell lymphoma
Tmax 
Time to peak plasma drug concentration 
Vd/F 
Apparent volume of distribution 
VEGF-R 
Vascular endothelial growth factor receptor 
WBC 
White blood cell 
WHO 
World Health Organization 
p.15
1.1 
Background 
Information 
It has been approved by China FDA(CFDA) for the treatment of relapsed 
or refractory peripheral T-cell lymphoma (PTCL) in December 2014.  It 
is now on the market under the trade name Epidaza in China.   
It has been approved by China Food and Drug Administration (CFDA) for the 
treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) in 
December 2014.  It is now onin the market under the trade name Epidaza in 
China.   
Correction in 
grammar 
P16 
1.3 
Rationale for 
the Use of 
HBI-8000 for 
the Treatment 
of Cancer 
HBI-8000 inhibits several cancer-associated Class I (HDAC 1, 2, 3) and 
one Class IIb HDAC (isoenzymes 6 and 10) HDACs in the nanomolar 
range and stimulates accumulation of acetylated histones H3 and H4 in 
tumor cells [Ning 2012]. 
HBI-8000 inhibits several cancer-associated Class I (HDAC 1, 2, 3) and one 
Class IIb HDAC (isoenzymes 6 and 10) HDACs in the nanomolar range and 
stimulates accumulation of acetylated histones H3 and H4 in tumor cells [Ning et 
al 2012]. 
Correction of the 
error 
p.18
1.3.1 
Immunomodu
latory 
Mechanisms 
Integrate with 
Cancer Cell 
Intrinsic 
Mechanisms 
of Cell Killing 
by HDACi 
HBI-8000 causes modulation of gene regulation patterns that is 
consistent with that hypothesis.  Genes in several functional clusters 
were regulated by HBI-8000 [Ning 2013, Pan 2014], including several 
genes important for cell cycle (CCNA2/Cyclin A2, CCNB2/Cyclin B2, 
CCNE2/Cyclin E2, CDKN1A/p21/WAF1, CHEK1/checkpoint kinase 1), 
apoptosis (DR6/ TNFRSF21/death receptor 6) and the response to 
antitumor therapies (ABCB10, ABCC2/MRP2, RAD23B, 
UBCH10/ubiquitin-conjugating enzyme E2C). 
HBI-8000 causes modulation of gene regulation patterns that is consistent with 
that hypothesis.  Genes in several functional clusters were regulated by HBI-
8000 [Ning 2013et al 2012, Pan et al 2014], including several genes important 
for cell cycle (CCNA2/Cyclin A2, CCNB2/Cyclin B2, CCNE2/Cyclin E2, 
CDKN1A/p21/WAF1, CHEK1/checkpoint kinase 1), apoptosis (DR6/ 
TNFRSF21/death receptor 6) and the response to antitumor therapies (ABCB10, 
ABCC2/MRP2, RAD23B, UBCH10/ubiquitin-conjugating enzyme E2C).
Correction of the 
error 
p.20
1.5.3 
Metabolism 
and Excretion 
Nuclear magnetic resonance (19F NMR) and liquid chromatography 
mass spectrometry (LC-MS/MS) were used to investigate the biological 
conversion and material balance in 4 patients with T-cell lymphoma. 
Nuclear magnetic resonance (19F NMR) and liquid chromatography-tandem 
mass spectrometry (LC MS/MS) were used to investigate the biological 
conversion and material balance in 4 patients with TCL. 
Correction of the 
error 
p.20
1.6 Clinical 
Studies 
For a Phase 2 dose selection, a Phase 1 study (HBI-8000-201) in patients 
with relapsed or refractory Non-Hodgkins Lymphoma including PTCL 
For a Phase 2 dose selection, a Phase 1 study (HBI-8000-201) in patients with 
relapsed or refractory Non-Hodgkins Lymphoma (NHL) including PTCL and 
Information updated 


Protocol：HBI-8000-203 
Protocol_Table of Changes（29May2017） 
 
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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
and ATL was initiated in Japan in April, 2014 and is now near 
completion.   
ATL was initiated in Japan in April, 2014 and ishas now near 
completioncompleted.   
p.23 
2.3 Criteria 
for Evaluation 
Population 
Pharmacokine
tic 
Characterizati
on Study 
(applicable to 
participating 
sites and 
consented 
patients): 
To obtain comparable PK data base from Japan and Korea to assess 
regional difference, if any, PK characterization will be required for all 
patients enrolled in Korea.  PK sampling will be performed as detailed 
in Table 2 of Appendix A. 
To obtain comparable PK database from Japan and Korea and to assess regional 
difference, if any, PK characterization will be required for all patients enrolled in 
Korea.  PK sampling will be performed as detailed in Table 2Table 5 of 
Appendix A. 
Information updated 
p.24 
2.4 Summary 
of Study 
Design 
Response and progression for PTCL will be evaluated according to the 
revised criteria for response assessment in lymphoma. [Cheson 2014] 
(see Appendix D).  The rate of overall tumor response (complete 
response [CR], partial response [PR]), stable disease [SD], or progressive 
disease [PD]) will be confirmed with a second assessment repeated at 
least four weeks after the first response observation 
Response and progression for PTCL will be evaluated according to the revised 
criteria for response assessment in lymphoma. [Cheson 2014] (see Appendix D 
Section 9.4).  The rate of overall tumor response (complete response [CR], 
partial response [PR]), stable disease [SD], or progressive disease [PD]) will be 
confirmed with a second assessment repeated at least four weeks after the first 
response observation. 
Correction of the 
error 
p.24 
2.5.1 
Inclusion 
Criteria  
3. Progressive disease after receiving ≥ 1 prior systemic therapy with anti-
tumor agent(s). This could include frontline chemotherapy, and 
mogamulizumab, or ineligible for mogamulizumab, and there is no other 
available treatment with proven efficacy 
 
 
 
7. Meeting the following baseline laboratory criteria: 
a. Absolute Neutrophil Count >1500/µL independent of growth factor 
support within 7 days 
b. Platelets >75,000/µL independent of transfusion within 14 days  
c. Hemoglobin >8 g/dL independent of transfusion within 14 days 
d. Serum creatinine < 1.5 × ULN 
e. Serum 
aspartate 
aminotransferase/glutamyl 
oxaloacetic 
transaminase (AST/SGOT) or alanine aminotransferase/glutamyl 
pyruvic transaminase (ALT/SGPT) ≤ 3 × ULN 
f. Serum Bilirubin ≤ 1.5 × ULN  
3. Progressive Relapsed or refractory disease after receiving ≥ 1 prior systemic 
therapy with anti-tumor agent(s) This could include frontline chemotherapy, and 
mogamulizumab, or ineligible for mogamulizumab and there is no other available 
treatment with proven efficacy which can be considered appropriate for patients. 
Systemic therapy is defined as frontline chemotherapy or immunotherapy 
administered systemically 
 
7. Meeting the following baseline laboratory criteria for screening: 
a. Absolute Neutrophil Count >1500/µL independent of growth factor 
support within 7 days 
b. Platelets >75,000/µL independent of transfusion within 14 days  
c. Hemoglobin >8 g/dL independent of transfusion within 14 days 
d. Serum creatinine < 1.5 × ULN 
e. Serum aspartate aminotransferase/glutamyl oxaloacetic transaminase 
(AST/SGOT) 
orand 
alanine 
aminotransferase/glutamyl 
pyruvic 
transaminase (ALT/SGPT) ≤ 3 × ULN 
f. Serum Bilirubin ≤ 1.5 × ULN  
 
To clarify the 
definition  
 
 
 
Clarification of the 
contents 
Correction of the 
error 


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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
p.25 
2.5.2 
Exclusion 
Criteria 
 
 
 
2. Patients with known hypersensitivity to benzamide class of compounds 
or any of the components of HBI-8000 tablets 
 
 
 
3. Patients with a second malignancy other than disease under study.  The 
exceptions are disease that has been treated with curative intent with no 
evidence of recurrence in past 5 years including: 
a. 
Basal cell carcinoma of the skin 
b. 
Squamous cell carcinoma of the skin 
c. 
Cervical carcinoma in situ 
d. 
Carcinoma in situ of the breast 
e. 
An incidental histological finding of prostate carcinoma (TNM 
stage T1a or T1b) 
f. 
Early-stage gastric cancer treated with endoscopic mucosal 
resection or endoscopic submucosal dissection 
 
 
 
5. Allogeneic stem cell transplantation requiring immunosuppressant 
treatment within 21 days of starting the study drug or with active Graft 
Versus Host Disease (GVHD) 
1. Patients in whom central nervous system lymphoma is recognized during 
screening (if suspected clinically, imaging study should be performed to confirm) 
 
2.3. Patients with known hypersensitivity to benzamide class of compounds or any 
of the components of HBI-8000 tablets, and patients with prior exposure of HBI-
8000 tablets 
 
 
3.4. Patients with a history of second malignancy other than disease under study.  
The exceptions are disease that has been treated with curative intent with no 
evidence of recurrence in past 5 2 years including: 
a. 
Basal cell carcinoma of the skin 
b. 
Squamous cell carcinoma of the skin 
c. 
Cervical carcinoma in situ 
d. 
Carcinoma in situ of the breast 
e. 
An incidental histological finding of prostate carcinoma (TNM stage T1a or 
T1b) 
f. 
Early-stage gastric cancer treated with endoscopic mucosal resection or 
endoscopic submucosal dissection 
g. 
Thyroid cancer with differentiated histology (e.g. papillary) treated with 
curative intent  
 
5.6. Allogeneic History of allogeneic stem cell transplantation requiring 
immunosuppressant treatment within 21 days of starting the study drug or with 
active Graft Versus Host Disease (GVHD) 
Change due to 
reconsideration  
Not to investigate the 
activity of HBI-8000 
in re-treatment 
setting 
Indolent second 
malignancy with no 
evidence of relapse 
in 2 years is unlikely 
to interfere with the 
treatment of PTCL.  
 
To allow PTCL 
patients to enter this 
study from Korea 
where indolent 
thyroid cancer is 
common 
 
The effects of HBI-
8000 on immune 
effector and 
regulatory cells are 
not yet characterized. 
The risks for graft 
rejection or 
exacerbated graft vs 
host disease cannot 
be estimated in 
patients with history 
of allogeneic stem 
cell transplantation. 


Protocol：HBI-8000-203 
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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
6. Organ transplantation recipients except for hematopoietic stem cell
transplantation
6.7. Organ transplantation recipients except for autologous hematopoietic stem 
cell transplantation 
To clarify that 
autologous stem cell 
transplantation is not 
considered as an 
organ transplantation 
in this protocol 
p.26
2.6  Study 
Procedures 
Overview 
No central radiology review is required prior to designation of PD and 
treatment discontinuation.  Independent Radiology Review will be 
performed for final efficacy analyses at the completion of this study. 
No central independent radiology review is required prior to designation of PD 
and treatment discontinuation.  Independent Radiology Review will be 
performed for final efficacy analyses at the completion of this study.   
Change to the same 
word 
p.26
2.6  Study 
Procedures 
Overview 
For the first 6 patients, weekly safety laboratory tests will be obtained 
during the first 28 days and closely monitored for safety signals, especially 
for neutropenia and transaminase elevation. 
Central pathology review is planned at end of study before efficacy 
analysis.  The investigator will maintain a pre-screening log to record 
all patients prior to screening.  
For the first 6 all patients, weekly safety laboratory tests will be obtained during 
the first 28 days and closely monitored for safety signals, especially for 
neutropenia and transaminase elevation. 
Central pathology review is planned at end of study will be completed before 
efficacy analysis.  The investigator will maintain a pre-screening log to record 
all patients prior to screening. 
Correction of the 
error 
p.27
2.6.1. 
Screening 
Assessments 
(within 28 
days prior to 
start of 
treatment) 
Tumor pathology slides will be sent to central laboratory and archived for 
central pathology review that is planned at end of study before efficacy 
analysis.  
Screening assessments will be performed within 28 days prior to Cycle 1 
Day 1 (C1D1). Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 28 days prior to 
C1D1 may be used (and do not need to be repeated for screening unless 
they do not meet the criteria defined in the protocol). 
Tumor Unstained tumor pathology slides will be sent to pathology central 
laboratory and archived stained at the central laboratory.  The images will be 
captured from the slides for central pathology review that is planned at end of 
study to be completed before efficacy analysis.  For patients who do not have 
enough tumor tissue archived, a new biopsy will be requested.  However, 
insufficient tumor tissue in archive or inability to perform new biopsy for any 
reason does not exclude patients from entering this study.  Reasonable efforts 
should be made to support central pathology review. 
Screening assessments will be performed within 28 days prior to Cycle 1 Day 1 
(C1D1).  A pretreatment bone marrow test (aspiration or biopsy) would be 
required.  Results of standard-of-care tests or examinations performed prior to 
obtaining informed consent and within 28 days prior to C1D1 may be used (and 
do not need to be repeated for screening unless they do not meet the criteria 
defined in the protocol).  Similarly, tumor assessment tests <2 weeks outside the 
28-day window in the absence of clinical evidence of PD, the results may be 
accepted. 
Information updated 
Change due to 
reconsideration 


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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
Women of childbearing potential must agree to practice effective 
contraceptive measures after signing informed consent.  A negative 
serum pregnancy test will be obtained during screening.  At the C1D1 
visit, negative pregnancy status will be confirmed verbally before dosing 
and verified with blood test (see Appendix A). 
Women of childbearing potential must agree to practice effective contraceptive 
measures after signing informed consent.  A negative serum pregnancy test will 
be obtained during screening. At the C1D1 visit, negative pregnancy status will 
be confirmed verbally before dosing and verified with blood test (see Appendix 
A). 
Correction of the 
error 
p.28 
2.6.2. 
Baseline 
Assessments 
on Cycle 1 
Day1 (C1D1) 
Women of childbearing potential must have a negative serum pregnancy 
test before dosing (see Appendix A). 
Women of childbearing potential must have a negative serum pregnancy status 
confirmed by serum test before dosing.  If Serum pregnancy test result cannot 
be obtained on the same day before dosing, urine pregnancy test should be 
conducted additionally and the result should be confirmed before dosing (see 
Appendix A Section 9.1).  Some of the pre-dose assessments except vital signs 
and ECG may be performed 1 day before C1D1 to accommodate scheduling 
requirements in the hospital. 
Change due to 
reconsideration 
p.28 
2.6.3 
Treatment 
Phase  
All assessments must be performed as per the Schedule of Events (see 
Appendix A). Assessments scheduled on the day of study treatment should 
be performed prior to administration of study drug, unless otherwise noted 
in the schedule of assessments.  
 
Assessment of tumor response will be scheduled by end of 8 weeks, then 
every 8 weeks (±1 week) from C1D1.  However, if a patient develops 
clinical signs and symptoms of disease progression, or unacceptable 
toxicity occurs, tumor assessment may be performed sooner as needed.  
If a patient discontinues study treatment before disease progression (PD) 
is recorded, tumor assessments are to be performed approximately every 
3 months ± 2 weeks until PD or the start of new cancer therapy 
whichever occurs first, unless consent to study participation is 
withdrawn. 
All assessments must be performed as per the Schedule of Events (see Appendix 
A Section 9.1). Assessments scheduled on the day of study treatment should be 
performed prior to administration of taking study drug, unless otherwise noted in 
the schedule of assessments. 
 
Assessment of tumor response will be scheduled by end of 8 weeks the eighth 
week, then every 8 weeks (± 1 week) from C1D1.  However, if a patient 
develops clinical signs and symptoms of PD, or unacceptable toxicity occurs, 
tumor assessment may be performed sooner as needed.  If a patient discontinues 
study For the patients with skin lesions, decision on treatment before disease 
progression (PD) is recorded, tumor assessments are to discontinuation should be 
performed approximately every 3 months ± 2 weeks until PD based on computed 
tomography (CT) or the start of new cancer therapy whichever occurs first, 
unless consent to study participation is withdrawn positron emission tomography 
(PET-CT) assessment, not Modified Severity Weighted Assessment Tool 
(mSWAT) scores.  In other words, if imaging studies showing SD or PR while 
mSWAT score increases, treatment will continue. 
Change due to 
reconsideration 
p.28 
2.6.4 End Of 
Treatment 
Safety 
Follow-Up 
Visit 
At end of treatment safety visit, evaluations will include physical 
examination, vital signs, body weight, ECOG performance status, 
hematology, blood chemistry, urinalysis, pregnancy test (if applicable), 
ECG, and assessment of any ongoing adverse events. 
At EoT safety visit, evaluations will include physical examination, vital signs, 
body weight, ECOG performance status, hematology, blood chemistry, 
urinalysis, pregnancy test (if applicable), ECG, and assessment of any ongoing 
adverse events.  If a patient discontinues study treatment before PD is recorded, 
and if the last tumor assessment was >30 days earlier from the EoT visit, tumor 
assessment should be performed at EoT.  In these patients, further  tumor 
assessments are to be performed approximately every 3 months ± 2 weeks until 
Change due to 
reconsideration 


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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
PD or the start of new cancer therapy whichever occurs first, unless consent to 
study participation is withdrawn. 
p.29 
2.6.5. 
Survival 
Follow-up 
Follow-up for survival (and tumor status in patients in whom disease 
progression has not yet been observed) should occur at approximately 3-
month intervals after the last dose of study drug.   
Follow-up for survival (and tumor status in patients in whom PD has not yet 
been observed) should occur at approximately 3-month intervals after the last 
dose of study drugEoT visit.  
Correction of the 
error 
p.29 
2.6.6. Patient 
Withdrawal 
Study treatment may be discontinued and the patient withdrawn from the 
study under the following circumstances: 
 
Unacceptable toxicity (adverse event)  
 
Progression of the disease under study 
 
 
Decision by the investigator to permanently discontinue study drug 
administration  
 
Inter-current illness that would, in the judgment of the investigator, 
affect clinical assessments, patient safety, or follow-up significantly 
 
Significant protocol deviations that jeopardize the usefulness of the 
data 
 
Patient noncompliance 
Study treatment may be discontinued and the patient withdrawn from the study 
under the following circumstances: 
 
Unacceptable toxicity (AE)  
 
Progression of the disease under study, except for isolated progression in 
skin lesion 
 
Decision by the investigator to permanently discontinue study drug 
administration  
 
Intercurrent illness that would, in the judgment of the investigator, affect 
clinical assessments, patient safety, or follow-up significantly 
 
Significant protocol deviations that jeopardize the usefulness of the data 
 
Repeated patient noncompliance 
Clarification of the 
contents 
p.30 
2.6.8 
Management 
and Dosage 
Modifications 
for 
Unacceptable 
Hematologic 
and Non-
Hematologic 
Adverse 
Events 
Table 1 summarizes the guidelines for dosage adjustment in the event of 
unacceptable Adverse Events (AEs).  Two dose reductions are allowed 
(from 40 mg to 30mg, or from 30 mg to 20 mg).  If unacceptable 
adverse events recur despite two dose reductions, the study treatment will 
be permanently discontinued and post-treatment follow-up ensues. 
Table 1 summarizes the guidelines for dosage adjustment in the event of 
unacceptable AEs.  Two dose reductions are allowed (from 40 mg to 30mg, or 
from 30 mg to 20 mg).  If unacceptable AEs recur despite 2 dose reductions, the 
study treatment will be permanently discontinued and post-treatment follow-up 
ensues.  In the event of AE, such as hematological AE-uncomplicated, 
necessitating two treatment interruptions, dose will be reduced when treatment 
resumes.  However, if strongly needed for patient safety, dose can be reduced 
according to the investigator judgement, even if unacceptable hematological AE-
uncomplicated is occurred once. 
Change due to 
reconsideration 
p.31 
2.6.8 
Management 
and Dosage 
Modifications 
for 
Unacceptable 
Hematologic 
and Non-
Hematologic 
G-CSF should be prescribed when uncomplicated grade 3 or 4 
neutropenia is observed.  
G-CSF should is recommended to be prescribed when uncomplicated grade 3 or 
4 neutropenia is observed.  
Clarification of the 
contents 


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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
Adverse 
Events 
p.31
2.6.9 
Management 
and Dosage 
Modifications 
for Non-
Hematologic 
Adverse 
Events 
In the event of Grade 3 non-hematologic adverse events (excluding 
isolated abnormality of laboratory values not associated with clinical 
significance), study medication should be held.  Appropriate treatment 
should be initiated.  Patients will be closely monitored for recovery.  If 
the adverse events recur despite two dose reductions as applicable, study 
treatment should be discontinued.  Study treatment should be terminated 
if Grade 4 non-hematologic adverse events occur. 
In the event of Grade 3 non-hematologic AEs (excluding isolated abnormality of 
laboratory values not associated with clinical significance), study medication 
should be held.  Appropriate treatment should be initiated.  Patients will be 
closely monitored for recovery and managed following the Dose Adjustment 
Guideline.  If the AEs recur despite two dose reductions as applicable, study 
treatment should be discontinued.  Study treatment should be terminated if 
Grade 4 non-hematologic adverse events occur, following the Dose Adjustment 
Guideline 
Clarification of the 
contents 
p.32
2.7 Study 
Drug 
Administratio
n 
During this trial, patients will receive 40 mg HBI-8000 administered after 
any regular meal as four 10 mg tablets twice weekly (BIW) continuously. 
During this trial, patients will receive 40 mg HBI-8000 administered 
approximately 30 minutes after any regular meal as four 10 mg tablets BIW 
continuously. 
Clarification of the 
contents 
p.32
2.10 
Concomitant 
Treatments 
All concomitant medications, regardless of whether they are prohibited 
or not, received after signing informed consent must be recorded on the 
eCRF. 
All concomitant medications, regardless of whether they are prohibited or not, 
received after signing informed consent must be recorded on the eCRF.  
Complete information on all concurrent medications (generic name of drugs, 
reason for use, dosage and duration of dosing, etc.) should be documented in the 
original records and in the eCRF. 
Patients should consult their investigator prior to using medications other than 
the study drug, including over-the-counter medications and supplements. 
To move from other 
section 


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Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
p.32 
2.10.1 
Prohibited 
Medications 
And Therapy 
Anti-cancer therapy other than study medication is prohibited during the 
study and within the following time intervals prior to the first dose of 
study drug: 4 weeks for anti-cancer chemotherapy and 12 weeks for anti-
cancer monoclonal therapy; 6 weeks for nitrosourea or mitomycin C. 
Drugs known to produce significant QT prolongation or ventricular 
dysrhythmias are prohibited from signing informed consent through the 
EoT assessment. Corticosteroids prescribed for reason other than 
lymphoma is not considered as anti-cancer therapy in this study. 
 
Concomitant administration of HBI-8000 with drugs that significantly 
induce or inhibit CYP3A4, or are metabolized significantly by CYP3A4, 
and have a narrow therapeutic range, including St. John’s wort, are 
prohibited. 
The following drugs are prohibited.  
 
Drugs known to produce significant QT prolongation and ventricular 
dysrhythmias (see Section 9.6)  
Prohibited from signing informed consent through the EoT assessment 
 
Anti-cancer therapy other than study medication is prohibited 
Prohibited during the study and within the following time intervals prior to the 
first dose of study drug and 12 weeks for anti cancer monoclonal therapy; 
6 weeks for nitrosourea or mitomycin C. Drugs known to produce significant QT 
prolongation or ventricular dysrhythmias are prohibited from signing informed 
consent through the EoT assessment. Corticosteroids prescribed for reason other 
than lymphoma is not considered as anti cancer therapy in this study 
− 
4 weeks for anti-cancer chemotherapy Concomitant administration of 
HBI 8000 with drugs that significantly induce or inhibit CYP3A4, or 
are metabolized significantly by CYP3A4, and have a narrow 
therapeutic range, including St. John’s wort, are prohibited 
− 
6 weeks for nitrosourea and mitomycin C 
− 
12 weeks for anti-cancer monoclonal antibody therapy 
 
Corticosteroid prescribed for medical conditions other than lymphoma is not 
considered as an anti-cancer therapy for this study, for example: chronic 
obstructive pulmonary disease for allergy, topical steroids for rash. 
Information updated 
p.33 
2.10.2 
Cautioned 
Medications 
- 
Because the anti-emetic drug Zofran (ondansetron) is well known to prolong 
QTc, it is prohibited on 2 occasions, Cycle 1 Day 1 and Cycle 2 Day 1 when QTc 
test is scheduled.  Starting 24 hours before the QTc test until the QTc test is 
completed on the next day, patient must not take Zofran over a 2-day period.  
Although anti-emetics are rarely needed for HBI-8000, if anti-emetics must be 
used for other medical reason, alternative drug(s) should be used.  If a 5-HT3 
antagonist must be used to manage severe emesis refractory to other medications, 
dosing should be postponed until resolution of underlying medical condition.  
In case it is medically necessary to co-administer drugs that could interfere with 
CYP3A4 activity, investigators should monitor for toxicities and follow the study 
drug dose modifications for toxicity per study protocol.  Also, St. John’s wort 
should be used with caution. 
Information updated 
p.33 
2.10.3 
Permitted 
Medications 
Complete information on all concurrent medications (generic name of 
drugs, reason for use, dosage and duration of dosing, etc.) should be 
documented in the original records and in the eCRF. 
Sulfamethoxazole Trimethoprim use is permitted.  However, when its side 
effects are observed, alternative antibiotics prophylaxis should be considered. 
Complete information on all concurrent medications (generic name of drugs, 
reason for use, dosage and duration of dosing, etc.) should be documented in the 
original records and in the eCRF. 
Information updated 
To move to other 
section 


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Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
Patients should consult their investigator prior to using medications other 
than the study drug, including over-the-counter medications and 
supplements. 
Patients should consult their investigator prior to using medications other than 
the study drug, including over the counter medications and supplements. 
p.33 
2.11 Dietary 
Restrictions 
Due to potential food-drug interactions, grapefruit, grapefruit juice, 
Seville oranges, and any products that contain Seville oranges or 
grapefruit should be avoided whenever possible. 
Due to potential food-drug interactions for many commonly used medications, 
grapefruit, grapefruit juice, Seville oranges, and any products that contain Seville 
oranges or grapefruit should be avoided whenever when possible. 
Clarification of the 
contents 
p.34 
2.12 
Treatment 
Compliance 
The patient will be provided with a drug log to record date and time of 
administration, time of meal prior to administration, adverse events, and 
missed doses.  The patient will be instructed to bring the drug log and 
study drug bottles (including any empties) to each appointment for 
reconciliation. 
 
 
At each visit, prior to dispensing study medication, previously dispensed 
study drug count will be confirmed by the Investigator, or authorized 
designee, and compliance assessed. 
The patient will be provided with a drug log to record date and time of 
administration, time of meal prior to administration, AEs, and missed doses.  
The To verify compliance, the patient will be instructed to bring the drug log and 
study drug bottles (including any empties) to  each appointment appointments 
scheduled for Day1 of each cycle starting with Cycle 2 for reconciliation.  
 
At each visit prior to dispensing when study medication is dispensed previously 
dispensed study drug count will be confirmed by the investigator, or authorized 
designee, and compliance assessed prior to dispensing new study medication. 
Clarification of the 
contents 
p.35 
3.1.1. Primary 
Efficacy 
Endpoint 
Tumor assessments will be performed by imaging modalities. CT, MRI, 
or PET scanning may be used to evaluate lesions in the neck, chest, 
abdomen, and pelvis; and as a baseline evaluation for patients who may 
have brain metastases.  Evaluation of nodal lesion and extranodal lesion 
will be performed according to the revised criteria for response 
assessment in lymphoma [Cheson 2014] (see Appendix D). 
 
The definition of nodal and extranodal lesion is as following: 
 
Nodal lesion:  lymphoma that developed in lymph node and 
lymphoid tissue (amygdala, thymus, spleen, and Peyer's patch 
in small bowel) 
 
Extranodal lesion: lymphoma that developed in non-lymphoid 
organ or tumor mass 
 
Tumor response will be confirmed by independent radiologists at end of 
study prior to final efficacy analysis.  The dates of PR, CR and PD will 
be assessed as applicable. Initial review will be performed by one 
radiologist.  
Tumor assessments will be performed by imaging modalities. CT, MRI, 
magnetic resonance imaging, or PET scanning may be used to evaluate lesions in 
the neck, chest, abdomen, and pelvis; and as a baseline evaluation for patients 
who may have brain metastases.  The PET-CT is encouraged to be performed 
from baseline.  However, when CT is the routine method to monitor patients 
according to hospital standard of care, PET-CT is not required.  Evaluation of 
nodal lesion and extranodal lesion will be performed according to the revised 
criteria for response assessment in lymphoma [Cheson 2014] (see Appendix D 
Section 9.4).  Skin lesions are non-target lesions.  Their response will be 
assessed according to mSWAT, and contribute to overall response determination. 
The definition of nodal and extranodal lesion is as following: 
 
Nodal lesion:  lymphoma that developed in lymph node and lymphoid 
tissue (amygdala, thymus, spleen, and Peyer's patch in small bowel) 
 
Extranodal lesion: lymphoma that developed in non lymphoid organ or 
tumor mass 
 
Tumor response based on imaging studies will be confirmed with central review 
by independent radiologists at end of study prior to final efficacy analysis.  The 
dates of PR, CR and PD will be assessed as applicable.  Initial review will be 
performed by one independent radiologist.  
Change due to 
reconsideration 
p.35 
3.1.2 
Secondary 
The secondary efficacy measures are: 
 
ORR by disease subtype 
The secondary efficacy measures are: 
 
ORR by disease subtype 
Clarification of the 
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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
Efficacy 
Endpoints 

Median duration of progression-free survival (PFS) defined as
the time from study enrolment to objective tumor progression
or death.

Median duration of PFS defined as the time from the first dose of study
enrolment medication to objective tumor progression or death.
p.36
3.2.1.2 
Serious 
Adverse 
Event 
Suspected transmission of an infectious agent (e.g., any organism, virus, 
or infectious particle, pathogenic or non-pathogenic) via the study drug is 
an SAE and must be reported accordingly. 
Suspected transmission of an infectious agent (e.g., any organism, virus, or 
infectious particle, pathogenic or non-pathogenic) via the study drug is an SAE 
and must be reported accordingly 
Correction of the 
error 
p.39
3.2.7.1 
Serious 
Adverse 
Events 
All suspected unexpected serious adverse reaction (SUSAR) associated 
with the use of HBI-8000 will be reported to the regulatory authorities in 
accordance with the Guideline for Industry International Conference on 
Harmonization (ICH) E2A, Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting.   
All suspected unexpected serious adverse reaction (SUSAR) associated with the 
use of HBI-8000 will be reported to the regulatory authorities in accordance with 
the Guideline for Industry International Conference on HarmonizationCouncil 
for Harmonisation (ICH) E2A, Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting.   
Correction of the 
error 
p.41
3.2.9 Clinical 
Laboratory 
Evaluations 
Serum chemistry testing will include the following parameters: blood 
urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), 
total bilirubin (including direct fraction if total bilirubin is abnormal), 
lipase, amylase, total protein, albumin, alkaline phosphatase, sodium, 
potassium, calcium, magnesium, glucose, LDH, CKMB (creatine kinase 
MB fraction). 
Urinalysis (glucose, protein, occult blood test) will be performed by 
dipstick method followed by microscopic examination in the event of 
abnormal dipstick results. 
Serum chemistry testing will include the following parameters: blood urea 
nitrogen, creatinine, AST, ALT, gamma-glutamyl transpeptidase, total bilirubin 
(including direct fraction if total bilirubin is abnormal), lipase, amylase, total 
protein, albumin, alkaline phosphatase, sodium, potassium, calcium, magnesium, 
random blood glucose, LDH, creatine kinase MB fraction. 
Urinalysis (glucose, protein, occult blood test) will be performed by dipstick 
method followed by microscopic examination, and in the event of abnormal 
dipstick results, additional test may be required. 
Clarification of the 
contents 
Change due to 
reconsideration 
p.42
3.2.10 
Vital Signs, 
Physical 
Findings and 
Other Safety 
Assessments 
The patient should be in seating position for 5 minutes before the 1st ECG 
is obtained, followed by 2nd and 3rd ECGs with 5 minutes between ECG 
measurements. 
The patient should be in seating position for 5 minutes before the first ECG is 
obtained, followed by second and third ECGs with 5 ± 2 minutes between ECG 
measurements. 
Change due to 
reconsideration 
p.44
3.5.1. Data 
Safety 
Monitoring 
Board 
A DSMB has been established to monitor the safety observed during the 
conduct of this study. For the first 6 patients, weekly safety laboratory 
tests should be obtained during the first 28 days and closely monitored 
for safety signals, especially the neutropenia and transaminase elevation 
A DSMB has been established to monitor the safety observed during the conduct 
of this study. For the first 6 all patients, weekly safety laboratory tests should be 
obtained during the first 28 days and closely monitored for safety signals, 
especially the neutropenia and transaminase elevation 
Correction of the 
error 
p.44
3.5.2 
Independent 
Radiology 
Review 
To ensure consistent methodology is applied to assess disease response 
across the entire study, designated radiologists will review sequential 
imaging studies of individual patients. 
To ensure consistent methodology radiology method is applied to assess disease 
response across the entire study, designated radiologists will review sequential 
imaging studies of individual patients. 
Clarification of the 
contents 


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Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
p.44 
3.5.3 Central 
Pathology 
Review 
3.5.3 Independent Pathology Review 
 
To ensure consistent diagnosis of PTCL subtypes, a panel of pathologists 
with appropriate expertise will review pathology slides from archival 
tumor specimens or biopsy as applicable.  The techniques, such as 
immunohistochemistry staining, will be according to standard of practice 
at the end of study. 
3.5.3 Independent Central Pathology Review 
 
To ensure consistent diagnosis of PTCL subtypes, a panel of pathologists with 
appropriate expertise will review pathology slides from archival tumor 
specimens or biopsy as applicable.  The techniques, such as 
immunohistochemistry staining, will be according to standard of practice at using 
agreed methodology, no later than the end of study. 
Change to the same 
word 
Clarification of the 
contents 
p.50 
5.5.2 Efficacy 
Population 
All patients meeting eligibility criteria who receive at least one cycle of 
HBI-8000, have at least one post-baseline assessment of efficacy, or who 
discontinue study early due to clinical PD. 
All Efficacy should be analyzed by FAS and PPS.  To be evaluable for efficacy 
analysis, patients meeting must meet eligibility criteria who receive at least one 
cycle of HBI-8000, and have at least one post-baseline assessment of efficacy, or 
who discontinue study early due to clinical PD.   
 
PK FAS is defined as Patients having received at least one dose of study 
medication and at least one post-baseline assessment. 
 
PPS is defined as Patients in FAS having completed Cycle 1 treatment or 
discontinue study early due to clinical PD without any deviation from eligibility 
criteria.  It should be noted that PPS includes subjects who discontinue within 
Cycle 1 due to clinical PD without any deviation from eligibility criteria. 
Clarification of the 
contents 
p.51 
5.6 Patient 
Characteristic
s 
Demographic and baseline characteristics of patients will be summarized 
using descriptive statistics: 
 
Age 
 
Gender 
 
Race 
 
Ethnicity 
 
ECOG Performance Status 
 
Prior therapies 
 
Stage of Disease 
 
Other baseline characteristics as collected on the eCRF 
Demographic and baseline characteristics of patients will be summarized using 
descriptive statistics: 
 
Age 
 
Gender 
 
Race 
 
Ethnicity 
 
ECOG Performance Status 
 
Prior therapies 
 
Stage of Disease 
 
Other baseline characteristics as collected on the eCRF 
Correction of the 
error 
p.52 
5.9 Efficacy 
Analysis 
Response rate endpoints (ORR and ORR by disease subtype) will be 
summarized by number and percentage of patients meeting the definition 
of ORR along with the corresponding exact 95% confidence intervals.  
Tumor response will be adjudicated by independent reviewers.  Both 
investigators reported and independently adjudicated outcomes will be 
reported. 
 
Response rate endpoints (ORR and ORR by disease subtype) will be summarized 
by number and percentage of patients meeting the definition of ORR along with 
the corresponding exact 95% CI.  Tumor response as assessed by imaging 
studies will be adjudicated by independent radiology reviewers.  Tumor lesions, 
such as skin lesion, that cannot be monitored by imaging studies will determined 
by investigators only and contributed to overall disease response assessment.  
Both investigators reported and independently adjudicated outcomes based on 
imaging studies will be reported.  Primary analysis will be based on results 
from imaging studies confirmed by Independent Central Review.  Results from 
Change due to 
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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
Time-to event endpoints (PFS, DOR, and OS) will be summarized by 
Kaplan-Meier methods (median, 95% CI, number of events, number 
censored and Kaplan-Meier figures). 
investigator assessment will also be reported.  In patients with skin lesion that is 
assessed by mSWAT, response data from imagine studies alone will be reported 
according to Independent Review and investigator assessment.  Their overall 
response based on imaging studies AND mSWAT scores will be reported as 
investigator’s assessment only. 
In addition, the ORR will be analyzed according to histology subtypes of PTCL. 
The subtypes reported by Central pathology review for each patient will be used 
for such analysis. 
Time-to event endpoints (PFS, DOR, and OS) for entire study population will be 
summarized by Kaplan-Meier methods (median, 95% CI, number of events, 
number censored and Kaplan-Meier figures). 
p.54
6.3 Patient 
information 
and informed 
consent 
Written consent must be given by the patient and/or guardian, after the 
receipt of detailed information on the study. 
The investigator is responsible for ensuring that informed consent is 
obtained from each patient or guardian and for obtaining the appropriate 
signatures and dates on the informed consent document prior to the 
performance of any protocol procedures and prior to the administration 
of study medication. 
Written consent must be given by the patient and/or the legal guardian, after the 
receipt of detailed information on the study. 
The investigator is responsible for ensuring that informed consent is obtained 
from each patient or the legal guardian and for obtaining the appropriate 
signatures and dates on the informed consent document prior to the performance 
of any protocol procedures and prior to the administration of study medication. 
Clarification of the 
contents 
p.55
6.4 Patient 
data 
protection 
The ICF will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant 
data protection and privacy legislation. 
Extra precautions are taken to preserve confidentiality and prevent 
genetic data being linked to the identity of the patient.  In exceptional 
circumstances, however, certain individuals might see both the genetic 
data and the personal identifiers of a patient.  For example, in the case 
of a medical emergency, a Sponsor or representative physician or an 
Investigator might know a patient’s identity and also have access to his 
or her genetic data.  Also regulatory authorities may require access to 
the relevant files. 
The ICF will incorporate (or, in some cases, be accompanied by a separate 
document incorporating) wording that complies with relevant data protection and 
privacy legislation.  Information about study subjects will be kept confidential 
and managed according to the regulatory requirements. 
Extra precautions are taken to preserve confidentiality and prevent genetic data 
being linked to the identity of the patient.  In exceptional circumstances, 
however, certain individuals might see both the genetic data and the personal 
identifiers of a patient.  For example, in the case of a medical emergency, a 
Sponsor or representative physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data.  Also regulatory 
authorities may require access to the relevant files. 
Clarification of the 
contents 
p.56
7.1 
Administrativ
e structure 
The administrative structure and study organization is presented in 
Appendix F. 
The administrative structure and study organization is presented in Appendix F 
Protocol addendum. 
Information updated 
p.58
8.0 
References 
Cheson BD, Fisher RI, Barrington SF, et al. (2014) Recommendations 
for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol 
32(27):3059–3067. 
Cheson BD, Fisher RI, Barrington SF, et al. (2014) Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma: The Lugano Classification. J Clin Oncol . 2014;32(27):3059–3067. 
Modifications in the 
references 


Protocol：HBI-8000-203 
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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
 
 
 
 
Oken, M.M., Creech, R.H., Tormey, D.C., et. al. Toxicity and Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982. 
 
 
 
 
 
 
 
 
Piekarz RL, Frye R, Prince HM, et al: Phase 2 trial of romidepsin in 
patients with peripheral T-cell lymphoma. Blood 117:5827-5834, 2011. 
 
Piekarz RL, Frye R, Turner M, et al: Phase II multi-institutional trial of 
the histone deacetylase inhibitor romidepsin as monotherapy for patients 
with cutaneous T-cell lymphoma. J Clin Oncol 27: 5410-5417, 2009. 
 
Schemies J, Sippl W, and Jung M. Histone deacetylase inhibitors that 
target tubulin. Cancer Lett. 2009 Mar 4. [Epub ahead of print] PubMed 
PMID: 19268440. 
 
Shen L and R Pili, Class I histone deacetylase inhibition is a novel 
mechanism to target regulatory T cells in immunotherapy, 
OncoImmunology, 2012, 1(6), 948–950. 
 
 
 
 
 
Shi Y, Dong M, Hong X, Zhang W, et al. Results from a multicentre, 
openlabel, pivotal Phase II study of chidamide in relapsed or refractory 
peripheral T-Cell lymphoma. Annals of Oncology 26, 1766-1771. 
 
Crump M, Coiffier B, Jacobsen ED, et al. Phase II trial of oral vorinostat 
(suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. 
Ann Oncol. 2008 May; 19(5):964-9. PubMed PMID: 18296419. 
 
Oken, M.M.,MM, Creech, R.H., Tormey, D.C., et. al. Toxicity and Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol . 
1982;5:649-655, 1982. 
 
Olsen, EA, Whittaker S, Kim YH, et al.  Clinical end points and response 
criteria in mycosis fungoides and Sezary syndrome: a consensus statement of the 
International Society for Cutaneious Lymphomas, the United States Cutaneous 
Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the 
European Organisation for Research and Treatment Center. J Clin Oncol. 
2011;29:2598-2607.   
 
Piekarz RL, Frye R, Prince HM, et al: Phase 2 trial of romidepsin in patients with 
peripheral T cell lymphoma. Blood 117:5827 5834, 2011.  
 
Piekarz RL, Frye R, Turner M, et al: Phase II multi institutional trial of the 
histone deacetylase inhibitor romidepsin as monotherapy for patients with 
cutaneous T cell lymphoma. J Clin Oncol 27: 5410 5417, 2009.  
 
Schemies J, Sippl W, and Jung M. Histone deacetylase inhibitors that target 
tubulin. Cancer Lett. 2009 Mar 4. [Epub ahead of print] PubMed PMID: 
192684402009 Aug 8;280(2):222-32  
 
Shen L and R Pili, Class I histone deacetylase inhibition is a novel mechanism to 
target regulatory T cells in immunotherapy, OncoImmunology, 2012, 1(6), 948
950. 
 
Shi P, Yin T, Zhou F, et al. Valproic acid sensitizes pancreatic cancer cells to 
natural killer cell-mediated lysis by upregulating MICA and MICB via the 
PI3K/Akt signaling pathway. BMC Cancer. 2014; 14:370. 
 
Shi Y, Dong M, Hong X, Zhang W, et al. Results from a multicentre, openlabel, 
pivotal Phase II study of chidamide in relapsed or refractory peripheral T-Cell 
lymphoma. Annals of Oncology 2015;26, :1766-1771, 2015. 
 


Protocol：HBI-8000-203 
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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
Yamaguchi K. Survey and comprehensive measures of HTLV-1 infection 
and related diseases in Japan (Summary research report 2009). 
Yamaguchi K. Survey and comprehensive measures of HTLV 1 infection and 
related diseases in Japan (Summary research report 2009). 
p.61 
9.1 Appendix 
A:  HBI-
8000-203 
Schedule of 
Events 
 
Table 4 
Schedule of 
Events 
 
Cycle 1 
Cycle 2a 
Cycle 
≥ 3a 
1 
8±2 
15±2 
22±2 
1 
15 
1 
Pre-
dose 
3.5 
hrs 
 
 
 
Pre-
dose 
3.5 
hrs 
 
Pre-
dose 
 
Cycle 1 
Cycle 2a 
Cycle 
≥ 3a 
1 
8±2 
15±2 
22±2 
1±4 
15±4 
1±7 
Pre-
dosep 
3.5 
hrs 
 
 
 
Pre-
dose 
3.5 
hrs 
 
Pre-
dose 
 
Change due to 
reconsideration 
p.61 
9.1 
 
Table 4 
Schedule of 
Events 
 
Cycle 
≥ 3a 
EoTb 
Survival 
F/Uc 
Tumor assessment m 
Xm 
 
 
 
 
Cycle 
≥ 3a 
EoTb 
Survival 
F/Uc 
Tumor assessment m 
Xm 
Xm 
Xm 
Change due to 
reconsideration 
p.62 
9.1 
 
Table 4 
Schedule of 
Events 
Footnote 
Abbreviations: ALT, alanine aminotransferase; aPTT, activated partial 
thromboplastin time; AST, aspartate aminotransferase; BIW, twice 
weekly; BUN, blood urea nitrogen; CNS, central nervous system; CT, 
computed tomography; Disc, discontinuation; ECG, electrocardiogram; 
ECOG- PS, ECOG Performance Status, EoT, end of treatment; F/U, 
follow-up; GGT, gamma-glutamyl transpeptidase; HBsAg, hepatitis B 
surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus;INR, 
international normalized ratio; MRI, magnetic resonance imaging; PK, 
pharmacokinetic; PT, prothrombin time; 
Abbreviations: ALT, alanine aminotransferase; aPTT, activated partial 
thromboplastin time; AST, aspartate aminotransferase; BIW, twice weekly; 
BUN, blood urea nitrogen; CNS, central nervous system; CT, computed 
tomography; Disc, discontinuation; ECG, electrocardiogram; ECOG  PS, ECOG 
Performance Status,, Eastern Cooperative Oncology Group; EoT, end of 
treatment; F/U, follow-up; GGT, gamma-glutamyl transpeptidase; HBsAg, 
hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus;INR, 
international normalized ratio; MRI, magnetic resonance imagingLDH, lactate 
dehydrogenase; mSWAT, Modified Severity-Weighted Assessment Tool; PET-
CT, positron emission tomography-computer tomography; PCR, polymerase 
chain reaction; PK, pharmacokinetic; PT, prothrombin time; 
Correction of the 
error 
p.62 
9.1 
 
Table 4 
Schedule of 
Events 
Footnote 
a. All visits and assessments may be performed ± 5 days to 
accommodate unforeseen delays, holidays, or vacations. 
 
 
d. Drug administration BIW for 4 weeks; On the days of scheduled 
visits, patient  should take study drug after receiving confirmation 
from Investigator to continue study treatment. 
 
 
a. Cycle/Day designation is based on actual calendar days after the first dose.  
All visits and assessments may be performed ± 57 days to accommodate 
unforeseen delays, holidays, or vacations. 
 
d. Drug administration BIW for 4 weeks ; On the days of scheduled visits that 
is the same as the dosing scheduled day, patient  should take study drug 
after receiving confirmation from investigator to continue study treatment. 
 
Change due to 
reconsideration 
Clarification of the 
contents 


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Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
g.
Pre-dose and post dose at 3.5 ± 0.5 hours in triplicates, 5 minutes
between 1st and 2nd, 2nd and 3rd ECGs, on Day 1 of Cycles 1 and 2.
i.
BUN, creatinine, AST, ALT, GGT, total bilirubin (including direct
fraction if total bilirubin abnormal), lipase, amylase, total protein,
albumin, alkaline phosphatase, sodium, potassium, calcium,
magnesium and glucose, LDH, CKMB (creatine kinase MB
fraction).
j.
Urinalysis: dipstick (glucose, protein, occult blood test) followed by
microscopic examination if abnormal results.
l.
Confirmatory test at the Cycle 1 Day 1 (C1D1) visit should be done
before dosing at the local laboratory. Only for women of
childbearing potential, including those who have had a tubal ligation.
Only at EoT visit, Serum and Urine are both acceptable.
m. Complete tumor assessment of all lesions by radiographic or other
modality.  Response and progression for PTCL will be evaluated
according to the revised criteria for response assessment in
lymphoma [Cheson 2014]. Assessment of tumor response will be
scheduled by end of 8 weeks, then every 8 weeks (±1 week) from
C1D1, However, if a patient develops clinical signs and symptoms of
disease progression, or unacceptable toxicity occurs, tumor
assessment may be performed sooner as needed.  If a patient
discontinues study treatment before disease progression (PD) is
recorded, tumor assessments are to be performed approximately
every 3 months ± 2 weeks until PD or the start of new cancer therapy
whichever occurs first, unless consent to study participation is
withdrawn.
g.
Pre-dose and post dose at 3.5 ± 0.5 hours in triplicates, 5 ± 2 minutes
between 1st and 2nd, 2nd and 3rd ECGs, on Day 1 of Cycles 1 and 2.
i.
BUN, creatinine, AST, ALT, GGT, total bilirubin (including direct fraction
if total bilirubin abnormal), lipase, amylase, total protein, albumin, alkaline
phosphatase, sodium, potassium, calcium, magnesium and random blood
glucose, LDH, CKMB (creatine kinase MB fraction).
j.
Urinalysis: dipstick (glucose, protein, occult blood test) followedwill be
performed by microscopic examination ifdipstick method, and  in the event
of abnormal dipstick results, additional test may be required.
l.
Only for women of childbearing potential, including those who have had a
tubal ligation.  Confirmatory test at the Cycle 1 Day 1 (C1D1) visit should
be done before dosing at the local laboratory. Only for women of
childbearing potential, including those who have had a tubal ligation. If 
Serum pregnancy test result cannot be obtained on the same day before 
dosing, urine pregnancy test should be conducted additionally and the result 
should be confirmed before dosing.  Only at EoT visit, Serum and Urine are 
both acceptable. 
m. Complete tumor assessment of all lesions by radiographic or other modality.
Baseline bone marrow test (aspiration or biopsy) is required.  Response and
progression for PTCL will be evaluated according to the revised criteria for
response assessment in lymphoma [Cheson 2014]. ], however, PET-CT is
not required but encouraged.  Skin lesions, if present, will be assessed by
mSWAT and contribute to overall tumor response determination by
investigators.  Assessment of tumor response will be scheduled by end of 8
weeksthe 8th  week, then every 8 weeks (± 1 week) from C1D1, However,
if a patient develops clinical signs and symptoms of disease progression, or
unacceptable toxicity occurs, tumor assessment may be performed sooner as
needed.  If a patient discontinues study treatment before disease progression
(PD) is recorded, and if their last tumor assessment was >30 days earlier
from EoT visit, tumor assessment should be performed at EoT.  In these
patients, further  tumor assessments are to be performed approximately
every 3 months ± 2 weeks until PD or the start of new cancer therapy
whichever occurs first, unless consent to study participation is withdrawn.


Protocol：HBI-8000-203 
Protocol_Table of Changes（29May2017） 
 
 20 / 21 
Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
 
o. Day 1 of cycles 3- 6 pre-dose PK sample only. 
 
o. Day 1 of cycles 3 to 6 pre-dose PK sample only. 
 
p. Some of the pre-dose assessments except vital signs and ECG may be 
performed one day before C1D1 to accommodate scheduling requirements in 
the hospital. 
p.67 
9.4 Appendix 
D 
Appendix D:  Revised Criteria for Response Assessment in Lymphoma 
Appendix D:  Revised Criteria for ResponseMethod of Efficacy Assessment in 
Lymphoma 
Title updated 
p. 67 
Section 9.4 
Appendix D 
Appendix D:  Revised Criteria for Response Assessment in Lymphoma 
The following sections are added in Appendix D 
Preamble 
9.4.1 Evaluation at Screening  
Figure 1:  Selection of Lesions 
9.4.2 Imaging 
9.4.2.1 Definition of lesion which can be used for efficacy assessment (evaluable 
lesion) 
9.4.2.2 Definition of lesion which cannot be used for efficacy assessment (non-
evaluable lesion) 
9.4.2.3 Definition of Measurable Lesion (common with nodal and extranodal 
lesion) 
9.4.2.4 Definition of Non-measurable lesion  
9.4.2.5 Nodes or Extranodal Lesions That Split When Disease Is Responding  
9.4.2.6  
Nodes or Extranodal Lesions That Become Conﬂuent When Disease Is 
Progressing 
9.4.3 Selection of Target Lesions 
Information updated 
Change due to 
reconsideration 


Protocol：HBI-8000-203 
Protocol_Table of Changes（29May2017） 
21 / 21 
Page 
Change 
Before (Protocol ver.1.2, 30Aug2016) 
After (Protocol ver.2.0, 29May2017) 
Reason 
9.4.4 Definition and Selection of Non-target Lesion 
9.4.5 Evaluation of Skin Lesion 
9.4.6 Evaluation by Modified Severity-Weighted Assessment Tool (mSWAT) 
(Olsen et al. 2011) 
Table 1: Modified Severity Weighted Assessment Tool (mSWAT) 
Figure 2: Percentage BSA of each Part of Human Body 
9.4.7 Presence or absence of splenomegaly  
9.4.8 Evaluation of infiltration to bone marrow 
9.4.9 Postdose Evaluation  
9.4.9.1 Evaluation of target lesion 
9.4.9.3 Evaluation of skin lesion by mSWAT 
p. 79
Section 9.6 
Appendix F 
Appendix F: Study Organization 
Appendix F: Study Organization 
New protocol 
addendum is created 
and all the 
information is 
described in. 
p. 79
Section 9.6 
Appendix F 
- 
Appendix F:  Drugs known to produce significant QT prolongation and 
ventricular dysrhythmias 
Information updated