Clinical trial NCT02955589
Conditions: Adult T-Cell Lymphoma (ATL)
Sponsor: HUYABIO International, LLC.
Start date: 2016-11-01; Completion date: 2019-11-01
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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

Detailed description:
This is a Phase 2b, open-label, non-randomized, single arm study to evaluate the safety, and efficacy of HBI-8000 40 mg BIW in patients with relapsed or refractory ATL (R/R ATL). HBI 8000 will be administered orally approximately 30 minutes after any regular meal twice a week. 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 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: Oral, twice weekly

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
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 Adult T Cell Lymphoma (ATL) 
Protocol Number: 
HBI-8000-210 
Version: 
5.0 
Date of Protocol: 
21 September 2018 
Replaced Protocol: 
17 July 2018 / Version 4.0 
Product: 
HBI-8000 
Study Phase: 
2b 
Sponsor: 
HUYA Bioscience International, LLC 
12531 High Bluff Drive, Suite 138 
San Diego, CA 92130 
United States of America 
 
 
 
 
 
 
 
 
 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
HBI-8000-210 Protocol Synopsis 
Name of 
Sponsor/Company: 
HUYA Bioscience 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 Adult 
T-Cell Lymphoma (ATL) 
Protocol No: 
HBI-8000-210 
Study site(s): 
25 to 35 sites in Japan 
Study duration: Approximately 36 months 
Phase: 2b 
Planned study period: 4Q 2016 (first patient in) to 
4Q 2018 (last patient in) 
4Q 2019 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 twice a week (BIW) 
continuously 
Endpoints: 
Primary: 
• 
Objective response rate (ORR; Complete Response [CR] + Unconfirmed CR [CRu) + 
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) 
Study Design: 
This is a Phase 2b, open-label, non-randomized, single-arm study to evaluate the safety and 
efficacy of HBI-8000 40 mg BIW in patients with relapsed or refractory ATL (R/R ATL). 
HBI-8000 will be administered orally approximately 30 minutes after any regular meal. The 
treatment will be continuous, with 3 to 4 days between dosing. A cycle is defined as 28 days 
solely for the purpose to schedule assessments required by the study. 
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: 
• 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 or unacceptable toxicities are observed despite appropriate dose reduction or 
treatment interruption. 
Number of 
patients: 
Eighteen Japanese patients with relapsed or refractory ATL evaluable for 
efficacy. To ensure meeting this target, an estimated 22 patients would 
be enrolled in anticipation that some patients may not complete study 
treatment. 
Entry 
Criteria: 
Inclusion 
1. Histopathological or cytological diagnosis of ATL confirmed as 
seropositive for anti-Human T-lymphotrophic Virus type-I (HTLV-1) 
antibody 
2. Acute, lymphoma or unfavorable chronic types. The unfavorable 
chronic type is defined by the presence of at least 1 of the following: 
serum albumin <3.5 g/dL, lactic dehydrogenase (LDH) >300 U/L, or 
blood urea nitrogen (BUN) >25 mg/dL.   The patient must have  
at least 1 of measurable lesion, or evaluable lesion in either of 
peripheral blood or skin 
3. Relapsed or refractory disease after receiving prior systemic therapy 
with mogamulizumab, or ≥1 prior systemic therapy with cytotoxic 
chemotherapy 
in 
case 
of 
intolerance/contraindication 
for 
mogamulizumab. And there is no other standard treatment which 
can be considered appropriate for patients 
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-cancer 
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 
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 
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  intercurrent 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 deoxyribonucleic acid (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 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 
 
 


 
 
 
 
 
2 8 d a ys, nitr os o ur e a or mit o m y ci n C wit hi n 4 2 d a ys of st arti n g t h e 
st u d y dr u g 
1 4.  R e c ei vi n g a nti b o d y t h er a p y f or A T L wit hi n 4 w ee ks of st arti n g t h e 
st u d y dr u g  
1 5.  W o m e n  w h o  ar e br e astf e e di n g or  w o m e n  w h o  ar e  n ot  willi n g  t o st o p 
br e astf e e di n g d uri n g st u d y tr e at m e nt peri o d a n d f or 3 0 d a ys aft er  t he 
last d os e  of  st u d y dr u g  
1 6.  P ot e nti al   f or   n o n -c o m pli a n ce   or   at   i n cr e as e d   ris k   bas e d   o n  
i n vesti gat or’s j u d ge me nt 
E x cl u d e d P ri o r o r 
C o n c o mit a nt 
M e di c ati o ns o r 
T h e r a p y:  
T h e f oll o wi n g dr u gs ar e pr o hi bit e d;  
 Dr u gs  k n o w n  t o pr o d u c e  si g nifi c a nt Q T  pr ol o n gati o n  a n d  v e ntri c ul ar 
d ysr h yt h mias  (se e A p p e n di x  E) 
Pr o hi bit e d fr o m si g ni n g i nf or m e d c o ns e nt t hr o u g h t h e e n d of 
tr e at m e nt ( E o T) ass ess m e nt 
 A nti -c a n c er  t her a p y ot h er  t h a n st u d y m e di c ati o n  
Pr o hi bit e d d uri n g t h e st u d y a n d wit hi n t h e f oll o wi n g ti m e i nt er v als 
pri or t o t h e first d os e of st u d y dr u g;  
- 
4 w e e ks  f or a nti-c a nc er  c h e m ot h er a p y  
- 
6 w e e ks  f or nitr os o ur e a  or  mit o m yci n  C 
- 
4 w ee ks f or a nti -c a n cer m o n o cl o n al a nti b o d y t h er a p y 
C orti c ost er oi ds  pr es cri be d  f or m e di cal  c o n diti o ns  ot h er  t ha n l y m p h o m a is 
n ot  c o nsi d er e d  as  a nti -ca n c er  t h er a p y f or t his st u d y, f or e x a m pl e:  c hr o nic 
o bstr u cti v e  p ul m o n ar y  dis e as e,  all er g y,  t o pi cal st er oi ds f or r as h. 
T r e at m e nts:  
St u d y dr u g is t o b e t a k e n aft er a n y r e g ul ar m e al t wi c e w e e kl y, e a c h d os e 
s e par at e d b y  3 t o 4 d a ys.  Tr e at m e nt  will  c o nti n u e  u ntil  P D  i n t h e a bse nce 
of  u n a cc e pt a bl e  t o xi cit y. 
Effi c a c y D at a:  
R es p o ns e a n d pr o gr essi o n f or A T L will be e v al u at e d a c c or di n g t o t h e 
criteri a  of  t h e  I nt er n ati o n al  C o nse ns us  M e eti n g  [ Ts u kas a ki  2 0 0 9 ] 
( m o difi e d). 
S af et y D at a:  
All  p ati e nts  w h o  r ec ei v e at l e ast 1  d os e  of  H BI -8 0 0 0  will  b e  e v al u a bl e  f or 
s af et y.  A E  s e v erit y  ( Gr a d e)  will  b e  d efi n e d  ac c or di n g  t o  C o m m o n  
T er mi n ol o g y Crit eria f or A d v ers e E v e nts ( C T C A E) V ersi o n 4. 0 3. S eri al 
el e ctr o c ar di o gr a ms ( E C Gs) a n d cli ni c al l a b or at or y t ests will b e  c oll e ct e d 
t o e val u ate s af et y a n d p ot e ntial t oxi cit y. L a b or at or y a n d ot h er t ests, as 
a p pr o pri at e  t o t h e cli ni cal  sit u ati o n, m a y  b e  o btai n e d  m or e  fr e q u e ntl y t h a n 
sti p ul ate d i n t h e s c h e d ule of  e v e nts.  
All r e p ort e d A Es will b e c olle ct e d, e v al u at e d, a n d c o d e d usi n g M e dic al 
Di cti o n ar y f or R e g ul at or y A cti viti es ( M e d D R A).  
St atistic al Pr oce d ures:  
St atisti c al a n al ysis f or all s af et y a n d effi c a c y p ar a m et ers will b e pri m aril y d es cri pti v e i n n at ur e. 
C at e g ori c al  vari a bl es  will  b e  s u m m ari z e d b y  fr e q u e n c y distri b uti o ns  ( n u m ber a n d  p er c e nt a ges  of 
p ati e nts),  c o nti n u o us  v ari a bles  will  b e  s u m m ariz e d  b y  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  
mi ni m u m, a n d m a xi m u m, a n d ti m e -t o-e v e nt v aria bl es will b e s u m m ari ze d usi n g Ka pl a n -M eier 
m et h o ds a n d fi g ur es f or t h e esti m at e d m e di a n ti m e. A f or m al st atistic al a n al ysis pl a n will be 
c o m pl et e d  pri or  t o d at a bas e  l o c k a n d  a n y  st u d y-r el at e d a n al ys es.  
 
Effi c ac y s h o ul d b e a n al y z e d b y F ull a nal ysis s et ( F A S) a n d P er pr ot o c ol s et ( P P S). T h e F A S is 
d efi n e d as P atie nts m e eti n g all eli gi bilit y crit eri a a n d h a vi n g r e c ei v e d at l e ast o ne d os e of st u d y 
m e di c ati o n,  a n d  at l e ast o n e  effic a c y  ass ess m e nt  of  dis e as e  wit h  eit her  i m a gi n g st u di es or  cli ni c al 
e xa mi nati o n  aft er  r e c ei vi n g st u d y m e di cati o n.  
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. For efficacy determination, 18 patients evaluable for 
efficacy per protocol criteria are required. To ensure meeting this target, 22 patients would be 
enrolled if 20% of patients are assumed not to complete required study treatment or evaluations 
for efficacy determination. 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. 
The target best ORR for this study is 30%, on the basis of the ORR results that were obtained in 
study TG0902CDM. The power for showing the response rate >5% at 5% two-sided alpha in 18 
patients is 80%. 
Any patient that has 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. 


 
 
 
 
TABLE OF CONTENTS 
SIGNATURES..........................................................................................................................2 
HBI-8000-210 PROTOCOL SYNOPSIS ...............................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................13 
1.0        INTRODUCTION......................................................................................................15  
1.1 
Background  Information ..............................................................................15  
1.2 
Histone Deacetylase as a Therapeutic Target  in Cancer............................15 
1.3 
Rationale for the Use of HBI-8000 for the Treatment  of 
Cancer  .............................................................................................................16  
1.3.1 
Immunomodulatory Mechanisms Integrate with  Cancer 
Cell Intrinsic Mechanisms of Cell Killing by HDACi  ......................17  
1.4 
Non-clinical  Studies .......................................................................................18  
1.5 
Clinical  Pharmacology...................................................................................19  
1.5.1 
Absorption  .........................................................................................19  
1.5.2 
Distribution........................................................................................20  
1.5.3 
Metabolism  and Excretion.................................................................20  
1.6 
Clinical   Studies...............................................................................................20  
1.7 
Rationale for Use in Disease under Study – Adult  T-Cell 
Lymphoma (ATL) ..........................................................................................21 
1.8 
Dose Selection and Risk Assessment  ............................................................21  
 
2.0        STUDY OBJECTIVE(S) ...........................................................................................22  
2.1 
Primary   Objective..........................................................................................22  
2.2 
Secondary  Objective ......................................................................................22  
2.3 
Criteria  for  Evaluation ..................................................................................22  
2.4 
Summary  of  Study Design.............................................................................22  
2.4.1 
Safety Determination and Criteria for Dose  Modification 
or  Interruption....................................................................................23  
2.5 
Selection  of  Study Population .......................................................................23  
2.5.1 
Inclusion  Criteria ...............................................................................23  
2.5.2 
Exclusion   Criteria:.............................................................................24  
2.6 
Study  Procedures  Overview..........................................................................25  
2.6.1 
Screening Assessments (within 28 days prior to start of 
treatment)...........................................................................................25  
2.6.2 
Baseline Assessments on Cycle 1 Day  1 (C1D1)..............................26 
2.6.3 
Treatment  Phase ................................................................................26  
2.6.4 
End of Treatment Safety Follow-up  Visit .........................................26 
2.6.5 
Survival  Follow-up ............................................................................27  
2.6.6 
Patient  Withdrawal ............................................................................27  
 
 


 
 
 
 
 
 
 
2.6.7 
Discontinuation of the Study  .............................................................28  
2.6.8 Management and Dosage Modifications for Unacceptable Hematologic  
and Non-hematologic Adverse Events  ........................28  
2.6.9 Management and Dosage Modifications for Non- 
Hematologic  Adverse  Events ............................................................29  
2.7 
Study  Drug  Administration ..........................................................................30  
2.8 
Packaging, Labeling, and Storage  ................................................................30  
2.9 
Patient Registration and Subject  Number Assignment..............................30 
2.10 
Concomitant  Treatments...............................................................................30  
2.10.1     Prohibited Medications and Therapy.................................................30  
2.10.2     Cautioned Medications ......................................................................31  
2.10.3      Permitted Medications.......................................................................31  
2.10.4     Dietary Restrictions ...........................................................................31  
2.11 
Treatment  Compliance ..................................................................................32  
2.12 
Study  Medication  Accountability .................................................................32  
 
3.0 
STUDY  ASSESSMENTS ..........................................................................................33  
3.1 
Efficacy............................................................................................................33  
3.1.1 
Primary Efficacy Endpoint  ................................................................33  
3.1.2 
Secondary  Efficacy  Endpoints ..........................................................33  
3.1.3 
Exploratory   Endpoints.......................................................................33  
3.2 
Safety...............................................................................................................33  
3.2.1 
Definitions  .........................................................................................33  
3.2.1.1 
Adverse  Events ................................................................33  
3.2.1.2 
Serious Adverse Event  ....................................................34  
3.2.2 
Period  of Observation........................................................................35  
3.2.3 
Pre-existing  Conditions .....................................................................35  
3.2.4 
Documentation and Reporting of Adverse Events  by 
Investigator  ........................................................................................35  
3.2.5 
Assessment of Causal Relationship to Study  Drug ...........................36 
3.2.6 
Intensity of  Adverse Events...............................................................36  
3.2.7 
Events Requiring  Immediate Reporting ............................................37  
3.2.7.1 
Serious Adverse Events ...................................................37  
3.2.7.2 
Pregnancy  ........................................................................38  
3.2.7.3 
Overdose..........................................................................38  
3.2.8 
Follow-Up of Adverse Events  ...........................................................38  
3.2.9 
Clinical  Laboratory  Evaluations........................................................39  
3.2.10 Vital Signs, Physical Findings and Other Safety 
Assessments.......................................................................................39  
3.3 
Blood  Volume .................................................................................................40  
3.4 
Independent  Review.......................................................................................41  
3.4.1 
Data Safety Monitoring Board  ..........................................................41  
3.4.2 
Independent  Radiology  Review ........................................................41  
3.4.3 
Independent  Overall  Efficacy Review...............................................41  
 
 


 
 
 
 
 
 
 
4.0 
QALITY CONTROL AND QUALITY   ASSURANCE..........................................42  
4.1 
Monitoring  ......................................................................................................42  
4.2 
Data  Management/Coding ............................................................................43  
4.3 
Retention  of Records......................................................................................44  
4.4 
Quality  Assurance  Audit ...............................................................................45  
4.5 
Site   Audits.......................................................................................................45  
 
5.0 
STATISTICS  ..............................................................................................................46  
5.1 
General  Statistical  Considerations ...............................................................46  
5.2 
Determination  of  Sample Size.......................................................................46  
5.3 
Treatment Assignment and  Blinding ...........................................................46  
5.4 
Replacement  of  Patients ................................................................................47  
5.5 
Populations  for  Analysis................................................................................47  
5.5.1 
Safety  Population...............................................................................47  
5.5.2 
Efficacy  Population ...........................................................................47  
5.5.3 
Patient  Disposition.............................................................................47  
5.6 
Patient  Characteristics ..................................................................................48  
5.7 
Concomitant  Medications .............................................................................48  
5.8 
Treatment  Administration ............................................................................48  
5.9 
Efficacy  Analysis ............................................................................................48  
5.10 
Safety  Analysis ...............................................................................................49  
5.10.1     Adverse Events ..................................................................................49  
5.10.2      Laboratory Tests ................................................................................49  
5.10.3      ECGs..................................................................................................49  
5.10.4     Vital Signs and Physical Findings .....................................................50  
5.10.5     Interim Analysis ................................................................................50  
 
6.0 
ETHICS   ......................................................................................................................51  
6.1 
Institutional Review Board or Independent Ethics  Committee ................51 
6.2 
Ethical Conduct of the  Study ........................................................................51  
6.3 
Patient Information  and Informed Consent................................................51 
6.4 
Patient  Data  Protection .................................................................................52  
 
7.0 
STUDY   ADMINISTRATION...................................................................................53  
7.1 
Administrative  Structure ..............................................................................53  
7.2 
Data Handling and Record Keeping  ............................................................53  
7.3 
Direct Access to Source  Data/Documents ....................................................53 
7.4 
Investigator  Information ...............................................................................54  
7.4.1 
Investigator  Obligations ....................................................................54  
7.4.2 
Protocol  Signatures............................................................................54  
7.4.3 
Publication  Policy..............................................................................54  
7.5 
Financing  and  Insurance...............................................................................54  
 
 
 


 
 
 
 
 
 
 
8.0 
REFERENCES...........................................................................................................55  
 
9.0 
APPENDICES  ............................................................................................................59  
9.1 
Appendix A:   HBI-8000-210 Schedule of Events ........................................59  
9.2 Appendix B: Eastern Cooperative Oncology Group  (ECOG) 
Performance   Status........................................................................................62  
9.3 Appendix C: New York Heart Association  (NYHA) 
Classification ..................................................................................................63 
9.4 
Appendix D: Tumor Response  Criteria .......................................................64  
9.4.1 
Method of Efficacy  Assessment ........................................................64  
9.4.2 
Evaluation at Screening  .....................................................................64  
9.4.2.1 
Evaluation of Nodal Lesion and Extranodal 
Lesion ..............................................................................65 
9.4.2.2 
Evaluation of Skin  lesion.................................................67  
9.4.2.3 
Evaluation of peripheral  blood lesion..............................69 
9.4.2.4 
Presence or absence of hepatic enlargement 
and  splenomegaly ............................................................69  
9.4.2.5 
Evaluation of infiltration  to bone-marrow.......................69 
9.4.3 
Post-dose  Evaluation .........................................................................70  
9.4.3.1 
Evaluation of nodal and extranodal lesion  ......................70  
9.4.3.2 
Evaluation of skin lesion  by mSWAT.............................71 
9.4.3.3 
Evaluation of peripheral blood lesion 
(Abnormal  lymphocyte) ..................................................72  
9.4.3.4 Evaluation of hepatic enlargement and 
splenomegaly...................................................................72  
9.4.3.5 Evaluation  of  bone-marrow infiltration...........................72  
9.4.3.6 
Presence or absence of new lesion  ..................................73  
9.5 Appendix E:  Drugs known to produce significant  QT 
prolongation  and  ventricular dysrhythmias................................................74  
9.6 
Appendix F:   Signature of Investigator .......................................................76  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
List of Tables 
Table 1: HBI-8000 Tablet Dosage Adjustment Guidelines .....................................................29 
Table  2:  Screening-Cycle 1......................................................................................................40  
Table 3: Cycle 2-Cycle 6   .........................................................................................................40  
Table 4:   Schedule of Events  ...................................................................................................59  
Table 5: Eastern Cooperative Oncology Group (ECOG) Performance Status .......................62 
Table 6: New York Heart Association (NYHA) Classification..............................................63 
Table 7: BSA in Body Region   .................................................................................................68  
Table 8:  Response Criteria for Adult T-Cell Leukemia-Lymphoma  (Tsukasaki 
2009)  ................................................................................................................73  
Table 9: Drugs Known To Produce Significant QT Prolongation..........................................74 
Table 10:  Drugs Known To Produce Significant Ventricular  Dysrhythmias .........................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  ................................................................................................65  
Figure 4:   %BSA of each part of human  body.........................................................................69  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALT/SGPT 
Alanine aminotransferase/glutamyl pyruvic 
transaminase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
ASCT 
Autologous stem cell transplant 
AST 
Aminotransferase/glutamyl  oxaloacetic transaminase 
AST/SGOT 
Aminotransferase/glutamyl  oxaloacetic transaminase 
ATL 
Adult T-cell leukemia/lymphoma 
AUC 
Area under the curve 
BIW 
Twice a week 
BUN 
Blood urea nitrogen 
CFDA 
China FDA 
CI 
Confidence interval 
CKMB 
Creatine kinase MB fraction 
Cmax 
Peak plasma drug concentration 
CNS 
Central Nervous System 
CR 
Complete response 
CRA 
Clinical Research Associate 
CRO 
Contract research organization 
CRu 
Unconfirmed complete response 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse  Events 
CTCL 
Cutaneous T-cell lymphoma 
CTL 
Cytotoxic T-lymphocyte 
CYP 
Cytochrome P450 
DNA 
Deoxyribonucleic acid 
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 
HDAC 
Histone deacetylase 
 
 


 
 
 
 
 
 
 
HDACi 
Histone deacetylase inhibitor 
HSP 
Heat shock protein 
IC50s 
inhibitory concentrations 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LC-MS/MS 
Liquid chromatography-tandem mass  spectrometry 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
mSWAT 
Modified Severity-Weighted Assessment Tool 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin’s lymphoma 
NK 
Natural killer cell 
NKG2D 
Natural killer group 2D 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
PPS 
Per protocol set 
PT 
Prothrombin time 
PTCL 
Peripheral T-cell lymphoma 
QTcF 
QT interval corrected by heart rate, using  Fridericia’s 
Correction Formula 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SiRNA 
Small interfering RNA 
SOP 
Standard operating procedures 
TEAE 
Treatment-emergent adverse event 
TIW 
Three times a week 
Tmax 
Time to peak plasma drug concentration 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
1.0 INTRODUCTION 
1.1 
Background Information 
HBI-8000 
(CS055, 
chidamide), 
N-(2-Amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridyl) 
acryloyl]aminomethyl] benzamide, is a member of the benzamide class  of  histone  
deacetylase inhibitors (HDACi) designed to block primarily the catalytic pocket of Class I 
HDACs. It was discovered by Shenzhen Chipscreen Biosciences Co., Ltd. (Chipscreen) in 
Shenzhen, China, using a computer-aided rational drug design [Yin 2004]. 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 on the market 
under the trade name Epidaza in China. HUYA Bioscience International, LLC (HUYA) has 
licensed worldwide rights (excluding China) of this compound.  The development programs   
in solid tumors and hematologic malignancies are underway. The terms HBI-8000 and 
chidamide (CS055) are used interchangeably throughout this  document. 
The molecular and structural formulas for HBI-8000 are shown below (Figure  1). 
Figure 1:  Molecular and structural formulas for  HBI-8000 
 
O 
 
N 
NH2 
H 
H 
N 
N 
 
O 
F 
HBI-8000 (C22H19FN4O2; molecular weight,  390.41) 
HBI-8000 is an orally bioavailable, low-nanomolar inhibitor of cancer-associated histone 
deacetylase (HDAC) enzymes with favorable pharmacology and safety profiles relative to 
existing benzamide and non-benzamide HDACi. Please refer to the Investigator’s Brochure  
for further information on HBI-8000 [IB  2017]. 
1.2 
Histone Deacetylase as a Therapeutic Target in Cancer 
Histone acetylation and deacetylation play important roles in the modulation of chromatin 
topology and the regulation of gene transcription. The HDACi inhibit the proliferation of 
tumor cells by inducing cell-cycle arrest, differentiation, and/or apoptosis in culture. Three 
classes of HDAC enzymes (I, IIa/IIb, and IV) utilize a zinc-catalyzed mechanism to 
deacetylate histones and non-histone proteins [Bolden 2006; Minucci 2006; Glaser 2007; 
Rasheed 2007; Rasheed 2008; Haberland 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  2006;    Nakagawa 
 
 


 
 
 
 
 
 
 
2007; Fritzsche 2008; Weichert 2008a; Weichert 2008b]. Small interfering RNA (siRNA)-
mediated inhibition of HDAC isoenzyme 1 or 3 resulted in anti-proliferative effects, and 
HDAC2 inhibition using siRNA sensitized tumor cells to apoptosis [Haberland  2009]. 
Class IIb HDACs (isoenzymes 6 and 10) preferentially target non-histone proteins, such as α-
tubulin and heat shock protein (HSP) 90. The HSP90 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 R. The α-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-  
AAG and the anti-tumor proteasome inhibitor bortezomib further support these proposed 
mechanisms [Glaser 2004, Bali 2005, Rodriguez-Gonzalez 2008, Schemies 2009, Park  2008]. 
Several HDAC inhibitors have been approved by the FDA for the treatment of T-cell 
lymphoma, 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 2 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 2008, 
Crump 2008, Modesitt 2008, Vansteenkiste 2008, Luu  2009]. 
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 1 Class IIb HDAC 
(isoenzyme 10) HDACs in the nanomolar range and stimulates accumulation of acetylated 
histones H3 and H4 in tumor cells [Ning 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 2012]. In vivo HBI-8000 has demonstrated dose-dependent anti-tumor activity against 
human xenograft models [Ning 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 2008] suggest that HBI-8000 has favorable PK and safety profiles relative to other 
HDAC inhibitors. 
 
 
 


 
 
 
 
 
 
 
Emerging data suggest that there are 3 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 natural killer cell (NK)-mediated and 
CD8+ Cytotoxic T-lymphocyte (CTL) -mediated antigen-specific anti-tumor immunity, and 
partial reversal of epithelial mesenchymal transition and drug resistance of tumor cells as 
described in Figure 2. However, the activation of NK- and antigen-specific CTL-mediated 
cellular anti-tumor immunity appears only to be associated with the benzamide type of 
selective HDACi such as HBI-8000 (Figure 2). 
Figure 2:  Proposed manifold anti-tumor mechanisms of chidamide  (HBI-8000) 
 
1.3.1 
Immunomodulatory Mechanisms Integrate with Cancer Cell Intrinsic 
Mechanisms of Cell Killing by HDACi 
It has been theorized that cancer 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 immunocyte function as well. Some of these 
cancer 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 2012, 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 anti-tumor 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 NK group 2D (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 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  2015]. 
1.4 
Non-clinical 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 1 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 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 2017]. For the following discussion, the names HBI-
8000 and chidamide are used interchangeably, although chidamide will be used to describe 
data generated by Chipscreen. 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
1.5 
Clinical Pharmacology 
1.5.1 
Absorption 
The single-dose pharmacokinetics of chidamide was evaluated in 33 patients with T-cell 
lymphoma. After a single oral administration of 30 mg of chidamide after any regular meal,  
the average time to peak plasma drug concentration (Tmax) 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 pharmacokinetic parameters of chidamide were evaluated in 19 T-cell 
lymphoma patients administered with multiple doses of chidamide.  Compared to that of  
single dose patients, the AUC0-t value increased 1.8-fold after the eighth 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 pharmacokinetics 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 pharmacokinetics was studied in seven patients with T-cell lymphoma. 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 potential 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 to significant variability across doses among 2 to 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 is being administered  
2 times a week continuously. 
 
 
 
 


 
 
 
 
 
 
 
1.5.2 
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. 
1.5.3 
Metabolism and Excretion 
Nuclear magnetic resonance and liquid chromatography-tandem mass spectrometry (LC- 
MS/MS) were used to investigate the biological conversion and material balance in 4 patients 
with T-cell lymphoma.  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 2 major metabolic  pathways. 
Further information on clinical pharmacological studies with HBI-8000/chidamide may be 
found in the Investigator’s Brochure [IB  2017]. 
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. 
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  23 December 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 
ATL in Japan. For a Phase 2 dose selection, a Phase 1 study (HBI-8000-201) in patients with 
relapsed or refractory 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. 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
1.7 
Rationale for Use in Disease under Study – Adult T-Cell Lymphoma 
(ATL) 
Adult T-cell leukemia/lymphoma (ATL) is a PTCL caused by  latent  infection  of  human T-
cell lymphotropic virus type 1 (HTLV-1). There is a long latency period, up to 4 decades, 
between infection and the onset of ATL, and only 5% of HTLV-1 infected  individuals  
develop ATL [Tobinai 2009]. There are an estimated 1.2 million HTLV-1 carriers in Japan. 
The annual incidence of ATL among HTLV-1 carriers ranges from 0.05%  to  0.1%.  
According to a 2009 survey, there were approximately 1100 new ATL cases diagnosed 
annually in Japan. Approximately 700 to 1,000 patients die yearly in Japan from ATL 
[Yamaguchi 2002, Yamaguchi 2009]. 
The outcome for ATL patients in general is poor. The 3-year overall survival has been 
approximately 24% with conventional chemotherapy. There is an unmet need for efficacious 
treatment [Yoshimitsu 2015]. Over the last decade, the outcome of autologous hematopoietic 
stem cell transplantation has been disappointing.  Allogeneic stem cell transplantation has   
been considered as potential approach to achieve long term disease remission. However, it is 
only applicable to a small fraction of patients who are younger, having achieved sufficient 
disease control, and with an appropriate stem cell donor [Utsunomyia  2001,  Hishizawa  2010]. 
In Japan, Mogamulizumab (an anti-CCR4 monoclonal antibody) was approved in 2012 based 
on a multicenter Phase II study in 28 patients with relapsed, aggressive CCR4+ATL.  However, 
despite initial response, albeit in a fraction of patients, the disease invariably  relapsed or 
became refractory [Ishida 2003, Ishida 2012]. Therefore, it is of  critical  importance to 
develop additional new therapies for ATL, especially for relapsed or refractory ATL (R/R 
ATL). 
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, 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 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 (G-CSF).  The Grade 3 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 and  5  
achieving partial response (PR). Furthermore, 4 of the 5 patients with R/R ATL enrolled in  
this Phase 1 study achieved PR, 1 had stable disease (SD). Although the sample size is small 
and firm conclusion must not be made, it is worth pointing out that the 4 PRs were observed   
in ATL patients initially treated at 40 mg while the SD patient were treated at 30 mg.   Thus,   
it was felt that such an efficacy signal in patients with strong unmet medical needs warrants 
further investigation.  Upon review of risk and benefit in totality, the 40 mg BIW schedule   
was selected as the starting dose for the Phase 2. The current study is designed to further 
evaluate the efficacy of HBI-8000 in R/R  ATL. 
 
 


 
 
 
 
 
 
 
 
2.0 STUDY  OBJECTIVE(S) 
2.1 
Primary Objective 
• To determine the efficacy of HBI-8000 administered BIW  continuously 
2.2 
Secondary Objective 
• To evaluate the safety and tolerability of HBI-8000 administered BIW  continuously 
2.3 
Criteria for Evaluation 
Efficacy Endpoints: 
Disease response will be assessed based on evaluation at baseline and post-dose evaluations   
of peripheral  blood,  skin  lesions,  nodal  and  extranodal  lesions  by  imaging  studies  every 
8 weeks.  Evaluation of nodal lesions and extranodal lesions will be performed according to  
the  criteria  of   the   International   Consensus   Meeting   [Tsukasaki   2009]   (modified)   
(See Appendix D). 
Primary: 
• Objective response rate (ORR; Complete Response [CR] + Unconfirmed CR [CRu] + 
PR 
Secondary: 
• ORR by disease subtype (see inclusion  criteria) 
• Median duration of progression-free survival  (PFS) 
• Median duration of response (DOR) 
Exploratory: 
• Median duration of overall survival (OS) 
Safety Endpoints: 
Safety and tolerability of HBI-8000 will be measured by the number of patients with  AEs   
and severity of AEs as defined by Common Terminology Criteria for Adverse Events 
(CTCAE) version. 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. 
2.4 
Summary of Study Design 
This is a Phase 2b, open-label, non-randomized, single-arm study to evaluate the safety, and 
efficacy of HBI-8000 40 mg BIW in patients with relapsed or refractory ATL (R/R ATL). 
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. 
 
 
 
 


 
 
 
 
 
 
 
Response and progression for ATL will be evaluated according to the criteria of the 
International Consensus Meeting [Tsukasaki 2009] (see Appendix  D). 
2.4.1           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.) 
2.5 
Selection of Study Population 
2.5.1 
Inclusion Criteria 
Patients may be entered in the study only if they meet all of the following  criteria: 
1. Histopathological, or cytological diagnosis of ATL confirmed as seropositive for anti-
Human T-lymphotrophic Virus type-I (HTLV-I)  antibody 
2. Acute, lymphoma or unfavorable chronic types. The unfavorable chronic  type  is  
defined by the presence of at least 1 of the following: serum albumin <3.5 g/dL, lactic 
dehydrogenase (LDH) >300 U/L or blood urea nitrogen (BUN)  >25  mg/dL.  The  
patient must have at least 1 of measurable lesion, or evaluable lesion in either of 
peripheral blood or skin. 
3. Relapsed or refractory disease after receiving prior systemic therapy with 
mogamulizumab, or ≥1 prior systemic therapy with cytotoxic chemotherapy in case of 
intolerance/contraindication for mogamulizumab. And there is no other standard 
treatment which can be considered appropriate for  patients. 
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 
2.5.2 
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 at screening. 
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  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 
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 intercurrent 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 ATL within 4 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 
2.6 
Study Procedures Overview 
Patients may be treated in this study as long as they receive clinical benefit (SD  or  a  
response) in the absence of unacceptable toxicity.  Progressive disease 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. 
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 (EoT) 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 the neutropenia and transaminase  elevation. 
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. 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 in the study.  The investigator will maintain a screening  
log to record all patients screened. 
Local radiology reports on disease status will guide investigator’s decision  on-study  treatment, 
including discontinuation. At the 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). 
2.6.1 
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 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 ATL diagnosis in accordance with the WHO revised classification [WHO 2008] and 
treatment history. 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 contraceptive measures after signing 
informed consent.  A negative serum pregnancy test will be obtained during  screening. 
2.6.2 
Baseline Assessments on Cycle 1 Day 1 (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 Appendix A). 
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. 
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 taking 
study drug, unless otherwise noted in the schedule of  assessments. 
Assessment of tumor response will be scheduled  by end of the fourth  week, eighth week,  
then every 8 weeks (± 1 week) from C3D1. However, if a patient develops clinical signs and 
symptoms of PD, or unacceptable toxicity occurs, tumor assessment may be  performed  
sooner as needed. 
2.6.4 
End of Treatment Safety Follow-up Visit 
All patients receiving at least 1 dose of HBI-8000 and discontinuing treatment for any reason 
except death will be evaluated approximately 30 (± 3) days after the last dosing of study drug 
or before the initiation of new cancer treatment, 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 status, hematology, blood chemistry,  urinalysis, pregnancy test  (if 
applicable), ECG, and assessment of any ongoing AEs.          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. 
Patients with HBI-8000-related AEs of Grade ≥ 2 observed at the EoT visit should be 
followed-up and monitored 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. 
2.6.5 
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 12 months after the administration of the last dose of the entire study. The first 
subsequent anti-cancer therapy during this survival follow-up period should be recorded with 
regimen and start date in the appropriate Electronic Case Report Form  (eCRF). 
2.6.6 
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 decide 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 
• 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 non-compliance 
• Patient is beginning another anti-cancer treatment  protocol 
• Patient becomes pregnant 
• Patient requests to withdraw informed consent 
• Study termination by the sponsor 
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 Appendix A) or before the initiation   of 
 
 


 
 
 
 
 
 
 
new cancer treatment, 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. 
 
2.6.7 
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 
2.6.8 
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 2  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. 
 
 
 


 
 
 
 
 
 
 
 
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 
Grade 3 
Hold doses, once resolved to ≤1 
Adverse Events 
within 2 weeks, resume at 
(excluding 
reduced dose (from 40 mg to 
laboratory values 
30 mg, or from 30 mg to 20 mg), 
without clinical 
with appropriate prophylaxis as 
significance) 
applicable. 
If recovery takes >2 weeks, 
discontinue study drug. 
Grade 4 
Discontinue study drug 
The 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. 
2.6.9 
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 2 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 (Table 1). 
 
 


 
 
 
 
 
 
 
2. 7  
St u d y Dr u g  A d mi nist r ati o n 
D uri n g t his t he trial, patie nts will recei ve 4 0 m g of H BI - 8 0 0 0    a d mi nistere d  a p pr o xi matel y     
3 0 mi n utes after a n y re g ular meal as f o ur 1 0 m g ta blets BI W c o nti n u o usl y.  T he  d osi n g 
i nter val w o ul d be 3 t o 4 da ys f or a t otal of 8 0 m g o ver 7 da ys. At eac h visit w he n st u d y 
me dicati o n  is  dis pe nse d,  t he  st u d y  site  staff  will  c o ntact  t he  I nteracti ve  We b   Res p o nse   
S yste m (I W R S) bef ore   dis pe nsi n g. 
2. 8  
P ac k a gi n g, L a b eli n g, a n d St or a g e 
H BI -8 0 0 0 1 0 m g ta blets are pac ka ge d i n hi g h de nsit y p ol yet h yle ne b ottles cl ose d wit h a n 
i n d ucti o n seal a n d a c hil d-resista nt ca p a n d c o ntai ni n g a desicca nt pac k, a n d a c ott o n c oil.  
Eac h b ottle c o ntai ns 2 6 ta blets. I n case of disc o nti n uati o n of treat me nt f or a n y reas o n u n use d 
p orti o n of t he dr u g s h o ul d be ret ur ne d t o h os pital  p har mac y. 
Dr u g  pr o d uct  will  be  st ore d  at  2  t o  8 ⁰C  at  h os pital  p har mac y  u ntil  dis pe nsi n g.   After   
dis pe nsi n g  t o  patie nts,  t he  dr u g  will  be  tra ns p orte d  t o  h o me  i n  a  c o oler  t o   mai ntai n   
refri gerate d c o n diti o n. O nce at h o me, t he dr u g will be ke pt refri gerate d u ntil a d mi nistrati o n 
a n d o ut of reac h of c hil dre n all t he  ti me. 
2. 9  
P atie nt Re gistr ati o n a n d S u bj ect N u m ber Assi g n m e nt 
Base d  o n  me dical  hist or y,  p ote ntiall y  eli gi ble  patie nts  will  be  i de ntifie d.  After  o btai ni n g  
i nf or me d c o nse nt, t he scree ni n g pr oce d ures will be perf or me d a n d a 5-di git s u bject n u m ber  
will be assi g ne d.  T he first 3 di gits are t he site n u m ber ( pr o vi de d b y t he s p o ns or t o st u d y   
sites). T he last 2 di gits are a se q ue ntial n u m ber wit hi n a st u d y site. If a patie nt is assi g ne d a 
s u bject n u m ber a n d later f o u n d u na ble t o be gi n H BI-8 0 0 0 a d mi nistrati o n, t he patie nt will be 
re place d.  A ne w s u bject n u m ber will be assi g ne d t o t he re place me nt  patie nt.  
2. 1 0  C o nc o mit a nt Tre at m e nts 
All c o nc o mita nt me dicati o ns, re gar dless of w het her t he y are pr o hi bite d or n ot, recei ve d after 
si g ni n g i nf or me d c o nse nt m ust be rec or de d o n t he e C R F. C o m plete i nf or mati o n o n all 
c o nc urre nt me dicati o ns ( ge neric na me of dr u gs, reas o n f or use, d osa ge a n d d urati o n of  
d osi n g, etc.) s h o ul d be d oc u me nte d i n t he ori gi nal rec or ds a n d i n t he  e C R F. 
Patie nts s h o ul d c o ns ult t heir i n vesti gat or pri or t o usi n g me dicati o ns ot her t ha n t he st u d y dr u g, 
i ncl u di n g o ver-t he-c o u nter me dicati o ns a n d  s u p ple me nts. 
2. 1 0. 1  
Pr o hi bite d Me dic ati o ns a n d  T her a p y  
T he f oll o wi n g dr u gs are pr o hi bite d. 
 Dr u gs k n o w n t o pr o d uce si g nifica nt Q T pr ol o n gati o n a n d ve ntric ular d ysr h yt h mias 
(see A p pe n di x  E) 
Pr o hi bite d fr o m si g ni n g i nf or me d c o nse nt t hr o u g h t he E o T  assess me nt 
 A nti -ca ncer t hera p y ot her t ha n st u d y  me dicati o n  
 
 
 
 


 
 
 
 
 
 
 
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 
- 4 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. 
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. 
2.10.3 
Permitted Medications 
Use of supportive care for AEs is permitted. These treatments may include anti-emetics, 
antipyretics, anti-diarrheal, anti-allergy agents, rash reliever, anti-hypertensive 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. 
2.10.4 
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. 
 
 
 
 
 
 


 
 
 
 
 
 
 
2.11 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 dates and times 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 Day 1 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. Non-compliance to drug amount is defined as taking <75% or >125% of study 
medication  during  a  cycle.   Non-compliance  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 the 
investigator, a patient is unable to follow instruction, study treatment should be   discontinued. 
2.12 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 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). 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
3.0 STUDY  ASSESSMENTS 
3.1 
Efficacy 
3.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the ORR, evaluated using the criteria of the International 
Consensus Meeting [Tsukasaki 2009] (modified) (see Appendix  D). 
Tumor response will be confirmed with central review by independent radiologist at end of 
study based on imaging studies prior to final efficacy analysis. The dates of PR, CR and PD 
will be assessed as applicable. Initial review will be performed by 1 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 
3.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy measures are: 
• ORR by disease subtype (acute, lymphoma, and unfavorable chronic  type) 
• 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. 
3.1.3 
Exploratory Endpoints 
 
• Median duration of OS 
3.2 
Safety 
3.2.1 
Definitions 
3.2.1.1 
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. 
3.2.1.2 
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 1 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 dyscrasia 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. 
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 PD 
3.2.2 
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, Grade ≥2 AEs 
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 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 resolve by that time will be recorded as “ongoing” on the 
eCRF. 
3.2.3 
Pre-existing Conditions 
A pre-existing condition will not  be  reported  as  an  AE unless  the  condition  worsens  by  
at least 1 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. 
3.2.4 
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. 
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. 
Progressive disease 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. 
 
 
 


 
 
 
 
 
 
 
3.2.5 
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. 
3.2.6 
Intensity of Adverse Events 
The intensity of adverse changes in clinical signs  or symptoms  will  be graded according to 
the CTCAE. For all other AEs not described in the CTCAE criteria, the intensity will be 
assessed by the investigator using the following  categories: 
 
Grade 1: 
• Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
 
 
 




 
 
 
 
 
 
 
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). 
3.2.7.2 
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. 
3.2.7.3 
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. 
3.2.8 
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. 
3.2.9 
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, 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, LDH, creatine kinase MB fraction. 
 
Urinalysis (glucose, protein, occult blood) 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. 
3.2.10 
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 for safety 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 pre-dose and 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 first ECG is obtained, followed by second and third ECGs 
with 5 ± 2 minutes between ECG  measurements. 
3.3 
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. The sum of Screening and Cycle 1 is shown in  Table 2.  Assuming  
each patient would receive up to 6 Cycles of treatment, subsequent cycles will have blood 
collections for safety tests on Day 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 60 mL (Table  3).  For  
patients receiving treatment  Cycle 7 and beyond, 10.5 mL blood will be drawn for safety  tests.  
The total blood collection volume for EoT will be approximately 6 mL for safety   tests. 
Table 2: Screening-Cycle 1 
 
Number of Samples 
Sample Volume (mL) 
Total Volume (mL) 
Hematology 
5 
2 
10 
Serum chemistry 
5 
4 
20 
Coagulation 
3 
4.5 
13.5 
HTLV-1 antibodies 
1 
1 
1 
Hepatitis B virus tests 
1 
2 
2 
Hepatitis C virus tests 
1 
4 
4 
Total 
50.5 
Table 3: Cycle 2-Cycle 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 
58.5 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
3.4 
Independent Review 
 
3.4.1 
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   ATL and are 
not associated with this study.  They are assisted by 1 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. 
3.4.2 
Independent Radiology Review 
To ensure consistent radiology method is applied to assess disease response cross 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 Tsukasaki Criteria. They will be blinded to the local 
radiology findings. Should discrepancy between assessments by independent radiologist (s) 
and site occur, a second independent radiologist will adjudicate by selecting assessment from 
either site or first independent radiologist for final  analysis. 
 
3.4.3 
Independent Overall Efficacy Review 
To ensure consistent overall efficacy determination, 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 
Tsukasaki Criteria. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
4.0 QALITY CONTROL AND QUALITY ASSURANCE 
According to the Guidelines of Good Clinical Practice (GCP) (CPMP/ICH/135/95), the 
sponsor is responsible for implementing and maintaining quality assurance  and  quality  
control systems with written Standard Operating Procedures  (SOPs). 
Quality control will be applied to each stage of data  handling. 
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
• Clinical laboratory parameters 
• Study site initiation visit 
• Early site visits post-enrollment 
• Routine site monitoring 
• Ongoing site communication and training 
• Data management quality control checks 
• Continuous data acquisition and cleaning 
• Internal review of data 
• Quality control check of the clinical study report  (CSR) 
In addition, sponsor may conduct periodic audits of the study processes, including, but not 
limited to study site, site visits, clinical laboratories, vendors, clinical  database, and final   
CSR. When audits are conducted, access must be authorized for all study-related documents 
including medical history and concomitant medication documentation  to  authorized  
sponsor’s representatives and regulatory  authorities. 
4.1 
Monitoring 
The sponsor has engaged the services of a contract research organization (CRO), 
, 
to perform all monitoring functions within this clinical study. 
’ monitors will 
work in accordance with 
’ SOPs and have the same rights and responsibilities as 
monitors from the sponsor organization. Monitors will establish and maintain regular contact 
between the investigator and the  sponsor. 
Monitors will evaluate the competence of each study site, informing the sponsor about any 
problems relating to facilities, technical equipment or medical staff. During the study,  
monitors will check that written informed consent has been obtained from all  patients  
correctly and that data are recorded correctly and completely. Monitors are also entitled to 
compare entries in eCRFs with corresponding source data and to inform the investigator of  
any errors  or omissions.   Monitors will also  control  adherence to  the  protocol  at  the  study 
 
 


 
 
 
 
 
 
 
site. They will arrange for the supply of investigational product and  ensure  appropriate  
storage conditions are maintained. 
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards. Regular monitoring visits will be made to each site while patients are enrolled in  
the study. The monitor will  make written reports to the  sponsor on each occasion  contact  
with the investigator is made, regardless of whether it is by phone or in  person. 
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. 
4.2 
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 site  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, ECG results, memoranda, 
pharmacy dispensing records, patient files,  etc. 
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. 
The eCRF records will be automatically appended with the identification of the creator, by 
means of their unique User ID. 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  User  ID  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. 
AEs will be coded  using Medical  Dictionary for Regulatory Activities  (MedDRA)     version 
19.0. 
Concomitant 
medications 
will 
be 
coded 
using 
WHO-DDE. 
Concomitant  
diseases/medical history will be coded using  MedDRA. 
4.3 
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. 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
4.4 
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. 
4.5 
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. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
5.0 STATISTICS 
5.1 
General Statistical Considerations 
Protocol HBI-8000-210 is a Phase 2b Open-Label Single-Arm Study to Evaluate the Efficacy 
and Safety of Oral HBI-8000 in Patients with Relapsed or Refractory Adult  T-Cell  
Lymphoma (ATL). 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 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, and efficacy 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 Statistical Analysis System 
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 
HUYA Biosciences. 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. 
5.2 
Determination of Sample Size 
For efficacy determination, 18 patients evaluable for efficacy per protocol criteria  are  
required. To ensure meeting this target, 22 patients would be enrolled if 20% of patients are 
assumed not to complete required study treatment or evaluations for efficacy determination. 
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. 
 
 
The target best ORR for this study is 30%, on the basis of the ORR results that were obtained 
in study TG0902CDM. The power for showing the response rate >5% at 5% two-sided alpha  
in 18 patients is 80%. 
5.3 
Treatment Assignment and Blinding 
This is an open-label, sequential enrollment study; therefore, no randomization or blinding 
procedures will be performed. 
 


 
 
 
 
 
 
 
5.4 
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. 
5.5 
Populations for Analysis 
5.5.1 
Safety Population 
The safety analyses population will include all patients who receive at least 1 dose of HBI-
8000. The safety analyses population will be the primary population for evaluating treatment 
administration / compliance and safety in the  study. 
5.5.2 
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. 
5.5.3 
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: 
▪ AE 
▪ Physician’s recommendation 
▪ Withdrew consent 
▪ Lost to follow-up 
▪ Other reasons as collected on the eCRF 
 
 
 


 
 
 
 
 
 
 
5. 6  
P atie nt C h ar acteristics 
De m o gra p hic a n d baseli ne c haracteristics of patie nts will be s u m marize d usi n g descri pti ve 
statistics: 
 A ge  
 Ge n der  
 Race  
 Et h nicit y  
 E C O G Perf or ma nce  Stat us  
 Pri or  t hera pies 
 Ot her baseli ne c haracteristics as c ol lecte d o n t he  e C R F. 
5. 7  
C o nc o mit a nt Me dic ati o ns 
T he  n u m ber  a n d  pr o p orti o n  of  patie nts  usi n g  differe nt  c o nc o mita nt  me dicati o ns  will  be  
ta b ulate d  a n d  s u m marize d  b y  W H O  Dr u g  a nat o mical  t hera pe utic  c he mical  classificati o n  
s yste m a n d preferre d ter m. 
5. 8  
Tre at m e nt A d mi nistr ati o n 
St u d y  dr u g  a d mi nistrati o n  will  be  descri be d  i n  ter ms  of  t he  t otal  n u m ber  of  c ycles  
a d mi nistere d, t he me dia n (ra n ge) of c ycles a d mi nistere d, d ose i nte nsit y, a n d reas o ns f or t he 
de viati o ns fr o m pla n ne d t hera p y.  
5. 9  
Effic ac y A n al ysis 
T he efficac y e n d p oi nts are t he f oll o wi n g: 
Pri mar y E n d p oi nt: 
 O R R ; C R + C R u + P R 
Sec o n dar y  E n d p oi nts:  
 O R R b y disease s u bt y pe (ac ute, l y m p h o ma, a n d u nfa v ora ble c hr o nic  t y pe) 
 Me dia n d urati o n of P F S  
 Me dia n D O R 
E x pl orat or y  E n d p oi nt  
 Me dia n d urati o n of O S  
Res p o nse rate e n d p oi nts ( O R R a n d O R R b y disease s u bt y pe) will be s u m marize d b y n u m ber 
a n d perce nta ge of patie nts meeti n g t he defi niti o n of O R R al o n g wit h t he c orres p o n di n g   e xact 
 


 
 
 
 
 
 
 
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. 
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). 
5.10 Safety Analysis 
All patients who receive 1 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. 
5.10.1 
Adverse Events 
AEs 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. 
5.10.2 
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. 
5.10.3 
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. 
5.10.4 
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. 
5.10.5 
Interim Analysis 
No interim analysis for efficacy is planned for this Phase 2b  study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
6.0 ETHICS 
6.1 
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. 
6.2 
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. 
GCP 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. 
6.3 
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. 
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. 
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. 
Information about study subjects will be kept confidential and managed according to the 
regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
7.0 STUDY  ADMINISTRATION 
7.1 
Administrative Structure 
The administrative structure and study organization is presented in protocol  addendum. 
7.2 
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. investigational new drug (IND), 
the principal investigator must comply with U.S. FDA IND regulations and with those of the 
relevant national and local health authorities. 
7.3 
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. 
 
 


 
 
 
 
 
 
 
7.4 
Investigator Information 
7.4.1 
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. 
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. 
7.4.2 
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 F). 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 GCP and applicable regulatory requirements. The study will not be able to start at any site 
where the investigator has not signed the  protocol. 
7.4.3 
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. 
7.5     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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
8.0 REFERENCES 
 
Bali P, Pranpat M, Bradner J, et al. Inhibition of histone deacetylase 6 acetylates and disrupts 
the chaperone function of heat shock protein 90: a novel basis for antileukemia  
activity of histone deacetylase inhibitors. J Biol Chem. 2005  Jul 
22;280(29):26729-34. Epub 2005 Jun 2. PubMed PMID:  15937340. 
Blumenschein GR Jr, Kies MS, Papadimitrakopoulou VA, et al. Phase II trial of the histone 
deacetylase inhibitor vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in 
patients with recurrent and/or metastatic head and neck cancer. Invest New  Drugs. 
2008 Feb;26(1):81-7. Epub 2007 Oct 25. PubMed PMID:  17960324. 
Bolden JE, Peart MJ, and Johnstone RW. Anticancer activities of histone deacetylase 
inhibitors. Nat Rev Drug Discov. 2006; 5(9):769-84. Review. PubMed PMID: 
16955068. 
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. 
Fritzsche FR, Weichert W, Roske A, et al. Class I histone deacetylases 1, 2 and 3 are highly 
expressed in renal cell cancer.BMC Cancer. 2008;8:381. doi:  10.1186/1471-2407- 
8-381. 
Glaser KB, Li J, Pease LJ, et al. Differential protein acetylation induced by novel histone 
deacetylase inhibitors. Biochem Biophys Res Commun. 2004 Dec 17;325(3):683-90. 
PubMed PMID: 15541343. 
Glaser KB. HDAC inhibitors: clinical update and mechanism-based potential. Biochem 
Pharmacol. 2007; 74(5):659-71. Epub 2007 Apr 7. PubMed PMID:  17498667. 
Haberland M, Montgomery RL, and Olson EN. The many roles of histone deacetylases in 
development and physiology: implications for disease and therapy. Nat Rev Genet. 
2009; 10(1):32-42. Review. PubMed PMID:  19065135. 
Hishizawa M, Kanda J, Utsunomiya A, et al. Transplantation of allogeneic hematopoietic 
stem cells for adult T-cell leukemia: A nationwide retrospective study. Blood (2010) 
116:1369–1376. 
IB 2017: Investigator’s Brochure for HBI-8000 (CS055, chidamide). HUYA Bioscience 
International, version 7, 08 July, 2017. 
Ishida T, Joh T, Uike N, et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) 
for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin 
Oncol. 2012 Mar 10;30(8):837-42. 
 
 
 


 
 
 
 
 
 
 
Ishida T, Utsunomiya A, Iida S, Inagaki H. Clinical Significance of CCR4 Expression in 
Adult T-Cell Leukemia/Lymphoma Its Close Association with Skin Involvement and 
Unfavorable Outcome. Clin Cancer Res. 2003 Sep 1;9(10 Pt  1). 
Luu TH, Morgan RJ, Leong L, et al. A phase II trial of vorinostat (suberoylanilide  
hydroxamic acid) in metastatic breast cancer: California Cancer Consortium study. 
Clin Cancer Res. 2008 Nov 1;14(21):7138-42. Erratum in: Clin Cancer Res. 2009 Jan 
1;15(1):416. PubMed PMID: 18981013. 
Minucci S and Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and 
more) treatments for cancer. Nat Rev Cancer 2006; 6(1):38-51. Review. PubMed 
PMID: 16397526. 
Modesitt SC, Sill M, Hoffman JS, et al; Gynecologic Oncology Group. A phase II study of 
vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary 
peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2008 
May; 109(2):182-6. Epub 2008 Mar 4. PubMed PMID:  18295319. 
Nakagawa M, Oda Y, Eguchi T, et al. Expression profile of class I histone deacetylases in 
human cancer tissues. Oncol Rep. 2007; 18(4):769-74. PubMed PMID:  17786334. 
Ning ZQ, Li ZB, Newman MJ, et al. Chidamide (CS055/HBI-8000): a new histone 
deacetylase inhibitor of the benzamide class with antitumor activity and the ability to 
enhance immune cell-mediated tumor cell cytotoxicity.  Cancer Chemother 
Pharmacol.  2012; 69(4):901-9. 
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. 
Pan DS, Yang QJ, Fu X, et al. Discovery of an orally active subtype selective HDAC 
inhibitor, chidamide, as an epigenetic modulator for cancer treatment. Med. Chem. 
Commun., 2014, 5:1789-96. 
Park JH, Kim SH, Choi MC, et al. Class II histone deacetylases play pivotal roles in heat 
shock protein 90-mediated proteasomal degradation of vascular endothelial growth 
factor receptors. Biochem Biophys Res Commun. 2008 Apr 4; 368(2):318-22. Epub 
2008 Jan 22. PubMed PMID: 18211808. 
Rasheed W, Bishton M, Johnstone RW, et al. Histone deacetylase inhibitors in lymphoma 
and solid malignancies. Expert Rev Anticancer Ther. 2008; 8(3):413-32. Review. 
PubMed PMID: 18366289. 
Rasheed WK, Johnstone RW, and Prince HM. Histone deacetylase inhibitors in cancer 
therapy. Expert Opin Investig Drugs. 2007; 16(5):659-78. Review. PubMed PMID: 
17461739. 
Rodriguez-Gonzalez A, Lin T, Ikeda AK, et al. Role of the aggresome pathway in cancer: 
targeting histone deacetylase 6-dependent protein degradation. Cancer Res. 2008 Apr 
15; 68(8):2557-60. Review. PubMed PMID:  18413721. 
 


 
 
 
 
 
 
 
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. 
Shenzhen Chipscreen Biosciences Co. L. A Phase I Clinical Trial of the Tolerance and 
Pharmacokinetics (PK) of Chidamide. Clinical study report for Protocol No 
TG0702CDM. 2008; June. 
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 YK, Dong M, Hong XN, et al. Phase II study of chidamide (CS055), a new subtype- 
selective oral histone deacetylase inhibitor, in patients with relapsed or refractory 
peripheral T-cell lymphoma.  J Clin Oncol 2013; 31(suppl): abstr  8525. 
Shi Y, Dong M, Hong X, 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, 2015. 
Tobinai, K. Current Management of Adult T-Cell Leukemia/Lymphoma. Oncology. 2009 
Dec;23(14):1250-62013) 
Tsukasaki K, Hermine O, Bazarbachi A, et al. Definition, prognostic factors, treatment, and 
response criteria of adult T-cell leukemia-lymphoma: a proposal from an international 
consensus meeting. J Clin Oncol. 2009 Jan 20;27(3):453-9. doi:  10.1200/JCO.2008. 
Utsunomiya A, Miyazaki Y, Takatsuka Y, et al. Improved outcome of adult T cell 
leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation. Bone 
Marrow Transplant (2001) 27:15–20. 
Vansteenkiste J, Van Cutsem E, Dumez H, et al. Early phase II trial of oral vorinostat in 
relapsed or refractory breast, colorectal, or non-small cell lung cancer. Invest New 
Drugs. 2008 Oct;26(5):483-8. Epub 2008 Apr 19. PubMed PMID:  18425418. 
Weichert W, Denkert C, Noske A, et al. Expression of class I histone deacetylases indicates 
poor prognosis in endometrioid subtypes of ovarian and endometrial  carcinomas. 
Neoplasia. 2008; 10(9):1021-7. PubMed PMID: 18714364; PubMed Central PMCID: 
PMC2517648. (a) 
Weichert W, Röske A, Gekeler V, et al. Histone deacetylases 1, 2 and 3 are highly expressed 
in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time 
after radical prostatectomy. Br J Cancer 2008; 98(3):604-10. Epub 2008 Jan  22. 
PubMed PMID: 18212746. (b) 
WHO (2008) Swerdlow, Steven H; International Agency for Research on Cancer; World 
Health Organization. WHO Classification of Tumours of Haematopoietic and 
Lymphoid Tissues. 4th ed. Lyon, France: IARC Press;  2008. 
Yamaguchi K. Survey and comprehensive measures of HTLV-1 infection and related 
diseases in Japan (Summary research report  2009) 
 


 
 
 
 
 
 
 
Yamaguchi, K. and Watanabe T. Human T lymphotropic virus type-I and adult T-cell 
leukemia in Japan. Int. J. Hematol. 2002 Aug; 76 Suppl  2:240-245 
Yin Z-H, Wu Z-W, Lan Y-K, et al. Synthesis of chidamide, a new histone deacetylase 
(HDAC) inhibitor.  Chinese Journal of New Drugs. 2004;  13:536-8. 
Yoshimitsu M, Arima N. Mogamulizumab for the treatment of adult T-cell 
leukemia/lymphoma. Blood and Lymphatic Cancer: Targets and Therapy, 2015:5   17–23 
Zhu S, Denman CJ, Cobanoglu ZS, et al. The narrow-spectrum HDAC inhibitor entinostat 
enhances NKG2D expression without NK cell toxicity, leading to enhanced 
recognition of cancer cells. Pharm Res.  2015;32:779-92. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
\ 
 
 
 
9.0 APPENDICES 
9.1 
Appendix A:  HBI-8000-210 Schedule of  Events 
Table 4:  Schedule of Events 
 
Screening 
Cycle 1 
Cycle 2 
Cycle ≥3 a 
EoTb 
Survival 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,e 
BIWf 
BIWf 
BIWf 
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 signsg 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG (Safety) 
X 
X 
X 
12 Lead ECG (QTc)h 
X 
X 
X 
X 
Hematology i  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation j 
X 
X 
X 
X 
X 
Chemistry k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis l 
X 
X 
X 
Hepatitis B/C virus, and HTLV-I 
Antibody tests m 
X 
Serum pregnancy test (if applicable)n 
X 
X 
X 
Tumor assessment o 
X 
X 
Xo 
Xo 
Xo 
Patient survival; new cancer therapies 
X 
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/Uh, follow-up;  GGT, 
gamma-glutamyl transpeptidase; INR, international normalized ratio; LDH, lactate dehydrogenase; mSWAT, Modified Severity-Weighted 
Assessment Tool; PCR, polymerase chain reaction; 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, or before the initiation of new cancer treatment, 
whichever is earlier. 
c 
Survival data will be collected every 3 months ± 2 weeks after EoT until death or the end of the study, defined as 12 months after the administration of the 
last dose of the entire study. 
d 
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 
Drug administration BIW for 4 weeks 
f 
Dose adjustments based on hematological and non-hematological criteria. 
g 
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. 
h 
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 C1D1 and C2D1    
i 
Hemoglobin, hematocrit, red blood cell count, white blood cell count, differential, platelet  count. 
j 
Coagulation tests (PT, aPTT, and INR). 
k 
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 
l 
Urinalysis (glucose, protein, occult blood) will be performed by dipstick method, and in the event of abnormal dipstick results, additional test may be 
required.. 
m 
Hepatitis B surface antigen, hepatitis B core antibody, hepatitis B surface antibody and hepatitis C virus antibody will be analyzed at screening. Hepatitis  
B surface antigen-positive or hepatitis C virus antibody positive patients are excluded from the study. 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 the study. 
n 
Only for women of childbearing potential, including those who have had a tubal ligation.  Confirmatory test at the 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. 
o 
Complete tumor assessment of all lesions by radiographic or other modality. Response and progression for ATL will be evaluated according to the 
International Consensus Meeting [Tsukasaki 2009]. CT or MRI of the chest, abdomen, and pelvis to evaluate disease in these locations. CT/MRI of the 
head at screening for patients who are suspected to have CNS metastases.  Assessment of tumor response will be scheduled by end of the 4th week, the   
8th week, then every 8 weeks (± 1 week) from C3D1. 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 treatment before 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. 
 


 
\ 
 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
9.2 
Appendix B: Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
Table 5:  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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
9.3 
Appendix C: New York Heart Association (NYHA) Classification 
Table 6:  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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
9.4 
Appendix D: Tumor Response Criteria 
 
9.4.1 
Method of Efficacy Assessment 
Overall response will be assessed based on evaluation at screening and post-dose evaluation 
including complete tumor response assessments (peripheral blood, skin lesions, nodal and 
extranodal lesions) and on Day 1 of subsequent cycles for peripheral blood and skin lesions. 
Imaging studies such as CT to evaluate nodal and extranodal lesions will  performed by end    
of the 4th week, the eighth week, then every 8 weeks (± 1 week) from C3D1 . 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 treatment  
before 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. 
 
9.4.2 
Evaluation at Screening 
At screening, lesion will be evaluated by imaging (CT), hematology test (white blood cell 
[WBC] count, absolute lymphocyte count, and abnormal lymphocyte count (% and absolute 
count) and bone-marrow test (bone-marrow aspiration or biopsy). 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 
• non-measurable lesion 
Next, target lesions (up to 6 lesions) are selected from measurable  lesions. 
Non-measurable lesions and other measurable lesions are deemed as non-target  lesions. 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Figure 3:  Selection of Lesions 
 
 
9.4.2.1 
Evaluation of Nodal Lesion and Extranodal  Lesion 
 
Evaluation of nodal lesion and extranodal lesion will be performed according to the Criteria  
for Adult T-Cell Leukemia-Lymphoma (Tsukasaki  2009). 
The definition of nodal and extranodal lesion is as  following: 
• Nodal lesion: lymphoma that developed in lymph node and lymph tissue (amygdala, 
thymus, spleen, and Peyer's patch in small bowel) 
• Extranodal lesion:  lymphoma that developed in non-lymphoid organ or tumor  mass. 
 
9.4.2.1.1 
Imaging 
Before the start of study drug administration, evaluation by CT images of neck, chest, 
abdomen, and groin that are taken by a pitch of 1 cm or less (as for neck image, a pitch of        
5 mm or less will be preferred) will be performed. As a general rule, contrast enhanced CT 
should be used. However, in case contrast enhanced CT cannot be performed because the 
subject has a history of adverse drug reaction caused by contrast agent or a current history of 
renal dysfunction, and in case the lesions of the subject are evaluable by non-contrast  
enhanced CT, plain CT is permitted. 
If evaluation by other imaging is needed according to the type of lesion, additional imaging 
will be permitted (e.g., MRI). 
 
 
 
 
 
 
 
 


 
 
9.4.2.1.2 
Definition of lesion which can be used for efficacy assessment (evaluable 
lesion) 
Nodal lesion with the size over 1.5 cm by greatest  dimension  (hereinafter, long dimension)  
on sectional image (e.g.., enlarged lymph node) at screening and extranodal lesion which can 
be followed by imaging are defined as evaluable  lesion. 
9.4.2.1.3 
Definition of lesion which cannot be used for efficacy assessment (non- 
evaluable lesion) 
Non-evaluable lesion is defined as nodal lesion with the size equal to or less than 1.5 cm by 
long dimension on sectional image of CT at screening and extranodal lesion that cannot be 
followed by imaging. 
9.4.2.1.4 
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: 
• The size by Long dimension over 1.5 cm on sectional image of  CT 
• Definitely measurable by 2 orthogonal dimensions (long dimension and its orthogonal 
dimension) on sectional image of CT 
9.4.2.1.5 
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 size over 1.5 cm by long  dimension  on  
sectional image of CT, but not definitely measurable by 2  dimensions  (long  
dimension and its orthogonal dimension) 
• Extranodal lesion: All lesions that can be followed by imaging, but do not meet the 
definition of measurable lesion 
9.4.2.1.6 
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 
should be selected 
• Lesions are selected up to 6 in descending order by long dimension size on sectional 
image of CT. If measurable lesions are less than 6, all  measurable  lesions  are  
selected 
The lengths of long dimension (cm) and short dimension (cm) which is orthogonal to long 
dimension are measured, and their product (2-dimension product: cm2) will be calculated. 
 


 
 
The sum of all 2-dimension products (cm2) will be calculated and defined as the sum of 2-
dimension products at screening. 
2-dimension product of each target lesion (cm2) = long dimension (cm) × short dimension  
(cm) which is orthogonal to long dimension 
The sum of 2-dimension products at screening = 2-dimension product (target lesion 1) + 2-
dimension product (target lesion 6) 
9.4.2.1.7 
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 non-
target lesions. If any tumor lesions are found through gastrointestinal endoscopy, the  lesion is 
to be evaluated as extranodal non-target  lesion. 
 
9.4.2.2 
Evaluation of Skin lesion 
In case tumor lesion on skin  exists,  the lesion is considered as a skin  lesion which can be  
used for efficacy evaluation be evaluated. 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 evaluated according to Severity-Weighted Assessment Tool (Stevens et    
al 2002): Revised Edition (mSWAT). 
9.4.2.2.1 
Evaluation by Modified Severity-Weighted Assessment Tool  (mSWAT) 
A total of body surface area (%BSA) of each part is defined in Table 7 and Figure 4 (e.g.,  
head 7, neck 2, 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) 
 
 
 
 
 
 
 


 
 
 
Table 7: BSA in Body Region 
 
Part 
%BSA 
Patch 
%BSA 
Plaque 
%BSA 
Tumor mass or 
ulcer 
%BSA 
Normal 
Total 
%BSA of 
each part 
Head 
7 
Neck 
2 
Anterior truck 
13 
Posterior truck 
13 
Breech 
5 
Genital area 
1 
Brachial region 
8 
Antebrachial region 
6 
Both hand region 
5 
Femoral region 
19 
Reg region 
14 
Both foot region 
7 
%TBSA of each 
lesion 
100 
Patch: plain erythema 
Plaque: raised lesion 
Tumor mass: nodosity lesion with swell over 1 cm 
Ulcer: lesion with a deficit of skin surface, such as deficit of total epidermis or a part of upper area of hypodermis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Figure 4:  %BSA of each part of human  body 
 
9.4.2.3 
Evaluation of peripheral blood lesion 
Peripheral blood lesion which can be used for efficacy assessment is defined as the findings 
of abnormal lymphocyte which meet following criteria, by hematological  test: 
• 
The rate of abnormal lymphocyte to WBC is equal to or more than 5% and the 
absolute count of abnormal lymphocyte is equal to or more than  1000/mm3. 
9.4.2.4 
Presence or absence of hepatic enlargement and  splenomegaly 
Presence or absence of hepatic enlargement and splenomegaly which are considered to be 
caused by infiltration of lymphocyte is assessed by  CT. 
9.4.2.5 
Evaluation of infiltration to  bone-marrow 
Infiltration to bone-marrow will be evaluated by bone-marrow aspiration or biopsy and 
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. 
 
 


 
 
9.4.3 
Post-dose Evaluation 
9.4.3.1 
Evaluation of nodal and extranodal  lesion 
Computed tomographgy imaging will be performed by the same method as  screening. 
9.4.3.1.1 
Evaluation of target lesion 
Efficacy for target lesion will be assessed by calculating reduction rate (A) and growth  rate 
(B) of the sum of 2-dimension products according to the following  formula: 
 
 
 
(A)＝ 
  (C) at screening - (C) at evaluation 
 
(C) at screening 
 
× 100 
 
 
 
(B)＝ 
(C) at evaluation - minimum (C) 
*1 
 
minimum (C) *1 
 
× 100 
*1: minimum (C) value obtained during the study including the  screening 
 
 
(C) = sum of 2-dimension products 
Criteria for assessment of anti-tumor effect on target lesion are as  follows: 
CR: Absence of enlarged lymph node, AND disappearance of all extranodal  lesions. 
CRu: Reduction rate of the sum of 2-dimension products of ≥75%, but presence of  residual 
lesion 
PR: Reduction rate of the sum of 2-dimension products of ≥50% and <75% 
SD: Effect not reached PR, but not PD 
PD: Growth rate of the sum of 2-dimension products of  ≥50% 
9.4.3.1.2 
Evaluation of nodal non-target lesion 
Criteria for assessment of tumor shrinkage effect on nodal non-target lesion are as  follows: 
Normal: Absence of enlarged lymph node (long dimension over 1.5 cm) in any lymph node 
area. 
Non-growth: Presence of enlarged lymph node, but absence of enlarged lymph node which 
showed apparent growth*2 in comparison with minimum value on and after  screening 
 
 
 


 
 
Growth: Presence of enlarged lymph node which showed apparent growth*2 in comparison 
with minimum value on and after screening 
Non-evaluable: Presence of lymph node area which cannot be  evaluated 
*2 Apparent growth is, only as a guide, the growth of long dimension ≥50%, but  measurement 
on image is not necessary. 
9.4.3.1.3 
Evaluation of extranodal non-target lesion 
Criteria for assessment of tumor shrinkage effect on extranodal target lesion are as follows.   
If gastrointestinal lesion is found at screening, endoscopy will be performed. Confirming by 
biopsy is recommended when a subject is assessed as  “disappearance”. 
Disappearance: All extranodal non-target lesion disappear on image. OR, extranodal non- 
target lesion has been absent since the start of study drug  administration. 
Non-growth: Presence of at least 1 extranodal non-target lesion, but absence of extranodal 
non-target lesion which showed apparent growth*3 in comparison with minimum value after 
screening 
Growth: Presence of extranodal non-target lesion which showed apparent growth*3 in 
comparison with minimum value after  screening 
Non-evaluable: Presence of non-evaluable extranodal non-target  lesion 
*3 Apparent growth is, only as a guide, the growth of long dimension ≥50%, but measurement 
on image is not necessary. 
 
9.4.3.2 
Evaluation of skin lesion by mSWAT 
Criteria for assessment for tumor shrinkage effect on skin lesion by mSWAT are as 
following: 
CR: Absence of skin lesion*4 
PR: Reduction in mSWAT score of ≥50% from screening, but presence of residual skin 
lesion 
SD: Effect not reached PR, but not PD 
PD: ≥25% increase in skin disease from baseline or New tumor mass*5 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. 
*4 In case distinguish between residual lesion and normal skin tissue is difficult, CR is 
determined after confirming disappearance of skin lesion by  biopsy. 
*5 tumor mass : at least 1 cm diameter solid or nodular lesion with evidence of depth and/or 
vertical growth 
 
 


 
 
9.4.3.3 
Evaluation of peripheral blood lesion (Abnormal  lymphocyte) 
Evaluation of peripheral blood lesion will be performed by using the values obtained at the 
screening and Day 1 of subsequent cycles. Criteria for assessment of hematological efficacy 
by evaluation of peripheral abnormal lymphocyte are as  following: 
CR: The rate of abnormal lymphocyte versus WBC <5%, AND absolute count of 
lymphocyte*6 <4000 /mm3. 
PR: Reduction in absolute count of peripheral abnormal lymphocyte ≥50% in   comparison 
with the count at screening 
SD: Effect not reached PR, but not PD 
PD: Absolute count of abnormal lymphocyte* ≥4000 /mm3, AND increase in absolute   count 
of abnormal lymphocyte ≥50% in comparison with the minimum value after  screening. 
*6 Total count of normal lymphocyte and abnormal  lymphocyte 
9.4.3.4 
Evaluation of hepatic enlargement and  splenomegaly 
Criteria for efficacy on tumor shrinkage of hepatic enlargement and splenomegaly which are 
considered to be caused by lymphocyte infiltration are as  follows: 
Disappearance: Both of hepatic enlargement and splenomegaly are disappeared (shrank on 
image and impalpable), OR absence of enlargement since  screening 
Non-exacerbation: Residual hepatic enlargement or splenomegaly, but no apparent 
exacerbation 
Exacerbation: Apparent exacerbation of any of hepatic enlargement or splenomegaly in 
comparison with the minimum status after  screening 
Non-evaluable:  Any of hepatic enlargement or splenomegaly is not  evaluable 
9.4.3.5 
Evaluation of bone-marrow infiltration 
Evaluation of bone-marrow infiltration by bone-marrow aspiration or biopsy after the start of 
study drug administration will be performed only in case the possibility of CR in overall 
response based on other endpoints occurred in subjects who were evaluated as “positive”  
when undetermined” at screening.  The same category used for evaluation at screening will  
be used for assessment (see Section 9.4.2.5). 
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. 
 
 
 


 
 
9.4.3.6 
Presence or absence of new lesion 
Presence or absence of new lesion which do not exist at screening will be  assessed. 
Table 8:  Response Criteria for Adult T-Cell Leukemia-Lymphoma (Tsukasaki  2009) 
 
Response 
Definition 
Lymph 
Nodes 
Extranodal 
Masses 
Spleen, 
Liver 
Skin 
Peripheral 
Blood 
Bone 
Marrow 
Complete 
remission* 
Disappearance of all 
disease 
Normal 
Normal 
Normal Normal Normal† 
Normal 
Uncertified 
complete 
remission* 
Stable residual mass in 
bulky lesion 
≥75% 
decrease‡ 
≥75% 
decrease‡ 
Normal Normal Normal† 
Normal 
Partial 
remission* 
Regression of disease 
≥50% 
decrease‡ 
≥50% 
decrease‡ 
No 
increase 
≥50% 
decrease 
≥50% 
decrease 
Irrelevant 
Stable disease* 
Failure to attain 
complete/partial 
remission and no 
progressive disease 
No 
change 
in size 
No change 
in size 
No 
change 
in size 
No 
change 
in size 
No change No change 
Relapsed disease 
or progressive 
disease 
New or increased 
lesions 
New or 
≥50% 
increase§ 
New or 
≥50% 
increase§ 
New or 
≥50% 
increase 
≥50% 
increase 
New or 
≥50% 
increase‖ 
Reappearance 
Not assessable 
• 
† Provided that <5% of flower cells remained, complete remission was judged to have been attained if 
the absolute lymphocyte count, including flower cells, was <4 × 109/L. 
• 
‡ Calculated by the sum of the products of the greatest diameters of measurable disease. 
• 
§ Defined by ≥50% increase from nadir in the sum of the products of measurable disease. 
• 
‖ Defined by ≥50% increase from nadir in the count of flower cells and an absolute lymphocyte count, 
including flower cells, of >4 × 109/L. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
9.5 
Appendix E: 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. 
 
Table 9:  Drugs Known To Produce Significant QT  Prolongation 
 
List of Drugs Produce 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 
 


 
 
 
List of Drugs Produce QT Prolongation 
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 
Table 10:  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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
9.6 
Appendix F:  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 Adult T-Cell 
Lymphoma (ATL) 
PROTOCOL NO: 
HBI-8000-210 
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 unpublished 
information contained herein will be published or disclosed without prior written approval 
from HUYA Bioscience International. 
 
 
 
 
I have read this protocol in its entirety and agree to conduct the study  accordingly: 
 
 
Signature of Investigator: 
   
                                                           
Printed Name: 
  
  
Investigator Title: 
  
 
Date:    
 
 
 
Name/Address of Site: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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