An Open-label Phase 2 Trial of Dual TORC1/TORC2 Inhibitor ATG-008 in HBV+ Advanced Hepatocellular Carcinoma (HCC) Subjects Who Have Received at Least One Prior Line of Systemic Therapy (TORCH)
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Sponsor: Antengene Therapeutics Limited

 
 
 
 
 
 
 
 
 
 
 
 
Clinical Trial Protocol 
 
 
 
 
 
English Translated Version 
 
 
 
 
 
Name of Product: 
ATG-008 
Protocol Number: ATG-008-HCC-001 
Protocol Title: 
An Open-label Phase 2 Trial of Dual TORC1/TORC2 
Inhibitor ATG-008 in HBV+ Advanced Hepatocellular 
Carcinoma (HCC) Subjects Who Have Received at Least 
One Prior Line of Systemic Therapy (TORCH) 
Protocol Date: 
30 Aug 2019 (Final) V2.0 
Date of Replaced 
Version 
8 Jan 2018 (Final) V1.0 
IND Number: 
NA 
Sponsor 
Name/Address: 
ANTENGENE THERAPEUTICS LIMITED  
Rock center, 301-307 Lockhart Road 
Hong Kong SAR,  
P. R. China 
CONFIDENTIALITY STATEMENT 
This clinical trial protocol is confidential and the property of Antengene 
Corporation and may not be used, disclosed or published without their consent. 

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MEDICAL / EMERGENCY CONTACT INFORMATION 
 
 
 
 
Medical: 
 
Name:  Stephen Xie 
Title:  Director Research and Development 
Phone: +86 21 3250 1119 
E-mail: stephen.xie@antengene.com 
 
 
 

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ANTENGENE THERAPEUTIC LIMITED SIGNATURE PAGE 
 
 
Signature of Antengene Therapeutic Limited, CEO 
dd/mmm/yyyy 
 Jay Mei 
Printed Name of Antengene Therapeutic Limited 
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
Signature of Site Principal Investigator 
 
dd mmm yyyy 
Printed Name  
Institution Name:  
 
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct remains in compliance with the protocol, informed 
consent, Institutional Review Board (IRB)/Ethics Committee (EC) procedures, 
instructions from Antengene representatives, the Declaration of Helsinki, ICH Good 
Clinical Practices Guidelines, and local regulations governing the conduct of clinical 
studies. 
 
 
 

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PROTOCOL SYNOPSIS 
Study Title 
An Open-label Phase 2 Trial of Dual TORC1/TORC2 Inhibitor ATG-008 in HBV+ Advanced 
Hepatocellular Carcinoma (HCC) Subjects Who Have Received at Least One Prior Line of 
Systemic Therapy (TORCH) 
Indication 
Hepatitis B virus (HBV) positive, unresectable HCC subjects who have received at least one prior 
line of systemic therapy. 
Objectives 
The primary objectives of the trial are:  
 
To evaluate pharmacokinetics (PK), safety, tolerability and overall response rate (ORR) of 
ATG-008 in HBV+ HCC subjects who have received at least one prior line of systemic 
therapy. 
The secondary objectives of the trial are: 
 
To evaluate overall survival (OS) 
 
To evaluate time to progression (TTP) 
 
To evaluate progression-free survival (PFS) 
 
To evaluate disease control rate (DCR) 
 
To evaluate duration of response (DOR) 
 
To evaluate time to response (TTR) 
 
To evaluate survival rate 
Trial Design 
ATG-008-HCC-001 is an Asian multi-regional clinical trial (MRCT) in which ATG-008 will be 
administered orally to hepatitis B positive (HBV+) HCC subjects who have received at least one 
prior line of systemic therapy. It is designed as an open-label phase 2 trial evaluating the 
pharmacokinetics (PK), safety, tolerability and efficacy of oral ATG-008 administered daily until 
the radiologic disease progression (according to RECIST 1.1) or intolerable toxicity.  
Study Population 
Number and Population of Subjects: 
Approximately 30 HBV+, unresectable HCC subjects who have received at least one prior line of 
systemic therapy will be enrolled in this trial, including 6 at the dose of 15mg and 24 at the dose 
of 30mg.  
According to the previous study results, the sponsor plans to continue to enroll approximately 40 
hepatitis B virus (HBV) positive, unresectable HCC subjects who have previously received at 
least one prior line of systemic therapy. Among which, approximately 20 subjects will receive 
oral ATG-008 at an initial dose of 45 mg, once daily (QD) and another approximately 20 subjects 
will receive oral ATG-008 at an initial dose of 20 mg, twice daily (BID). The pharmacokinetic 
(PK) samples will be collected from 10 subjects each in the two dose groups. 
If the overall response rate (ORR) of tumor is greater than 15% in the study dose group (45 
mg/QD or 20 mg/BID), then this study will be expanded to enroll additional approximately 110 
subjects using ORR as the primary study endpoint, to further evaluate the efficacy and safety of 
ATG-008. 

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Inclusion Criteria: 
1. Male or female aged from 18 to 70 years (inclusive) at the time when the ICF is signed. 
2. Confirmed pathologic or radiologic diagnosis of HCC according to the American 
Association for the Study of Liver Disease (AASLD) guidelines. 
3. Unresectable stage B (intermediate) or C (advanced) HCC according to the Barcelona 
Clinic Liver Cancer (BCLC) staging. If stage B, the subject must have progressed after, or 
not be eligible for, surgical or locoregional therapy. 
4.  There is at least one measurable lesion according to RECIST 1.1 criteria. 
5. HBV+ is defined as chronic HBV infection or a history of HBV infection, based on any of 
the following serologic results: HBcAb+, HBsAg+, HBV-DNA+.  
6. Received at least one prior line of systemic therapy (with radiologic disease progression 
during or following sorafenib and/or chemotherapy). Subjects with alternative treatments 
such as regorafenib and/or anti PD-1 antibodies etc. approved by local health authorities are 
allowed to enter study if they meet all other inclusion/exclusion criteria. 
a. Chemotherapy includes FOLFOX (fluorouracil, leucovorin and oxaliplatin) or any 
other platinum-containing regimen. 
b. Chemotherapy ≥ two cycles. 
7. ECOG performance status score of 0 or 1.  
8. Satisfactory serum chemistry results, evidenced by the following: 
a. AST (SGOT) and ALT (SGPT) ≤ 5x upper limit of normal (ULN). 
b. Total bilirubin ≤ 2 × ULN. 
c. Creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min. 
d. Lipase and amylase ≤2 x ULN; 
9. Adequate bone marrow function, evidenced by the following: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109 cells/L. 
b. Platelets ≥ 75 × 109 cells/L. 
c. Hemoglobin ≥ 9 g/dL. 
10. Coagulation function: international normalized ratio (INR) ≤2.0, prothrombin time (PT) 
≤1.5 x ULN; 
11. Child-Pugh A and B7 and hepatic encephalopathy scored as 1 point; 
12. Except hearing loss and alopecia, all toxicities caused by previous anti-tumor therapies must 
recover to ≤ Grade 1 (based on NCI-CTCAE Version 4.03); 
13. Male subjects (including those who have had a vasectomy) must agree to use a condom 
during sexual intercourse with females of child-bearing potential, and shall not conceive a 
child starting from the time of ICF signature, while on study medication, and for 3 months 
after the last dose of study drug. 
14. Female subjects of child-bearing potential must have both of the following: 
a. Agree to the use of two study physician-approved contraceptive methods 
simultaneously, or practice complete abstinence starting at the time of ICF 
signature, while on study medication, and for 28 days following the last dose of 
study drug. 
i. True abstinence: When this is in line with the preferred and usual lifestyle of 

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the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
ii. Acceptable contraceptive methods include: Oral, injectable, or implantable 
hormonal contraceptive; intra-uterine device; barrier contraceptive with 
spermicide; or vasectomized partner, together with at least one barrier method. 
b. Have negative serum pregnancy test result at screening, confirmed by negative 
urine pregnancy test within 72 hours prior to first dose of study drug (if serum test 
occurred > 72 hours from first dose); pregnancy test must have a sensitivity of at 
least 25 mIU/mL. 
Exclusion Criteria: 
The presence of any of the following will exclude a subject from enrollment: 
1. Intolerant to sorafenib/regorafenib, e.g.:  
a. The drug is discontinued due to adverse events; 
b. The related adverse events of Grade ≥2 continued/relapsed after supportive 
treatment and/or dose reduction or dose interruption at least 7 days; 
c. The treatment course is less than 21 days within 28 days before discontinuation; the 
lowest daily dose of sorafenib is 400 mg/day. 
2. Medical history of hepatic encephalopathy; 
3. Central nervous system metastases; 
4. Treatment with molecular targeted therapies such as sorafenib, regorafenib or lenvatinib 
within 4 weeks before screening; 
5. Treatment with locoregional HCC therapy (including but not limited to TACE, RFA), 
systemic chemotherapy, hormonal therapy (e.g., tamoxifen), traditional Chinese medicine 
with anti-tumor effects, or clinical investigational drugs within 4 weeks prior to Screening; 
6. Tested positive for both HBV and hepatitis C virus (HCV). 
a. HCV positive is defined as anti-HCV or HCV-RNA positive 
7. Life expectancy of less than 3 months. 
8. Prior therapy with mTOR (TORC1 and/or TORC2) inhibitors including sirolimus, 
temsirolimus, everolimus, and other investigational or approved mTOR/PI3K/AKT 
inhibitors. 
9. Have received major surgery within 4 weeks before screening or plan to receive major 
surgery during study period; 
10. Receiving active, ongoing treatment with systemic corticosteroids at a prednisone 
equivalent dose of ≥ 10 mg daily or other systemic immune system modulators. The 
exceptional cases of such criterion are listed as follows: 
a. Intranasal, inhaled and topical steroids or local steroid injection (e.g., intra-articular 
injection); 
b. Prednisone not more than 10 mg/day or its equivalent physiological dose of systemic 
corticosteroids; 
c. Steroids as the prophylatic medication of allergic reactions (pretreatment before CT 

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scan); 
11. Imaging test results showing main portal venous tumor thrombus, inferior vena cava tumor 
thrombus, or heart involvement; 
12. Uncontrolled diabetes, defined as HbA1c > 7%. 
13. Prior organ transplant.  
14. Uncontrolled pleural effusion or pericardial effusion (with clinical symptoms, fluctuation of 
effusion or requiring repeated drainage, oral diuretics etc.) at screening; Ascites at 
screening, which can be detected by physical examination, or clinical symptoms caused by 
ascites, or requiring special treatment such as repeated drainage, peritoneal drug perfusion 
etc. (subjects who only have a small amount of ascites which can be detected by imaging 
examination can be enrolled). 
15. Persistent diarrhea or malabsorption ≥ National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE, Version 4.03) grade 2, despite medical 
management, or any significant gastrointestinal disorder that could affect the absorption of 
study drug. 
16. Medical history of active upper gastrointestinal hemorrhage, ulcer or esophageal varices 
associated with hemorrhage or such diseases within 6 months; 
17. Subjects who have medical history of human immunodeficiency virus infection and/or 
acquired immunodeficiency syndrome; 
18. Concurrent active second malignancy for which the subject is receiving therapy, excluding 
non-melanomatous skin cancer, non-progressive prostate cancer treated with hormonal 
therapy, or carcinoma in situ of the cervix. Any cancer curatively treated >5 years prior to 
entry is permitted. 
19. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection 
(e.g., tuberculosis) requiring antibiotic, antifungal, or antiviral therapy (other than 
anti-HBV therapy), acute or chronic pancreatitis or psychiatric illness/social situations that 
would limit compliance with study requirements. 
20. Subjects who have clinically significant cardiovascular diseases such as Grade Ⅱ and 
above cardiac dysfunction (New York Heart Association criteria), ischaemic heart diseases 
(e.g., myocardial infarction or unstable angina pectoris), clinically significant 
supraventricular or ventricular arrhythmia, uncontrolled hypertension (systolic blood 
pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), echocardiography 
showing ejection fraction <50%, QTc interval >450 ms (male), QTc interval >470 ms 
(female); 
21. The subject’s complications or other conditions may affect protocol compliance or make 
the subjects unsuitable to participate in this study at the discretion of the investigator. 
Study Rationale 
➢ Clinical efficacy: compared to the study results of Celgene, the current preliminary 
clinical study data of this study showed that ATG-008 treatments with 15 mg and 30 mg 
were effective, but the expected tumor control rate had not been observed yet. It was 
preliminarily considered that the best dose range of ATG-008 might have not been 
achieved.  
According to the results of study CC-223-ST-001-B which has been completed by Celgene, the 

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ORR of solid tumor HCC cohort was 5.7% (3/53), among which, the best efficacy of 3 subjects (all 
had positive HBV) was PR and 2 of them were treated with 45 mg/QD ATG-008 (the maximum 
tolerated dose [MTD] of ATG-008 monotherapy was 45 mg/day, the intolerable dose was 60 
mg/day). 
As of 18 Jul 2019, the preliminary clinical study data showed that this study enrolled a total of 35 
HCC subjects (all were Asian; among which, 15 subjects were from Chinese mainland, 13 from 
Korea and 7 from Taiwan. 7 subjects received oral ATG-008 at the initial daily dose of 15 mg and 
28 subjects received 30 mg). Among 35 subjects, 1 subject achieved PR, 14 subjects achieved SD, 
19 subjects achieved PD and 1 subject still received the first cycle of treatment and no efficacy 
evaluation has been performed yet. The survivors accounts for approximately 65.7% (23/35). The 
diameter of the targeted lesions of tumors decreased after treatment from baseline in 38.2% (13/34) 
subjects. Currently, subjects who received the longest treatment had completed 11 cycles of 
treatment.  
➢ Clinical safety: the safety profile currently observed in this study was similar to the 
results of foreign studies completed by Celgene and that of mTOR targeted drugs 
The most common related TEAEs in study CC-223-ST-001 completed by Celgene were decreased 
appetite (64.2%), diarrhea (60.4%), fatigue (60.4%), hyperglycemia (60.4%), nausea (50.9%), 
aspartate aminotransferase increased (43.4%), and pruritus (34%). 
No suspected and unexpected serious adverse reactions (SUSAR) were reported in this study. One 
case of DLT was observed in 15 mg dose group and no DLT in 30 mg group. The most frequently 
reported study drug-related TEAEs were skin rash and hyperglycemia (45.7% each), decreased 
appetite and pruritus (31.4% each), diarrhea and stomatitis (28.6% each), weight loss (22.9%), 
fatigue and platelet count decreased (20.0% each), white blood cell count decreased, mouth 
ulceration and proteinuria (17.1% each), nausea, hepatic dysfunction and hand-foot syndrome (14.3% 
each), discomfort and AST elevated (11.4% each).  
As ATG-008 is firstly and orally administered hepatitis B virus (HBV) positive, HCC Asian 
subjects who have previously received at least one prior line of systemic therapy in this study, the 
overall safety profile of ATG-008 is similar to that of foreign clinical studies in Europe and 
America, and no unexpected new safety signal is reported, it is further confirmed that ATG-008 is 
well tolerated and further dose escalation is allowed. 
➢ Clinical PK: the PK profile of this study was similar to the PK profile of foreign patients 
in Europe and America  
The foreign study (Europe and America) CC-223-ST-001-Part A demonstrated that the unchanged 
ATG-008 showed linear relationship within the dose range of 7.5 mg~60 mg, and the exposure 
level of metabolite M1 also presented linear relationship with the dose. 
The preliminary PK results of this study (ATG-008 15 mg and 30 mg) showed that the exposure 
level of active compound and its metabolite presented linear relationship with the dose. Compared 
with PK parameters of foreign studies in Europe and America, the active compound had 
numerically higher Cmax and shorter Tmax. The active compound and its metabolite had similar 
elimination rate (in different dose groups). Analysis of difference in PK parameters in Europe, 
America, and Asia showed that the difference in exposure level mainly caused by Cmax difference, 
which might be related to lighter body weight and smaller volume of distribution of Asian patients. 
According to the currently available data, it was estimated that the exposure level of 20 mg/BID 
might be lower than that of 45 mg/QD, supporting that the administration mode BID could be 
explored in this study. According to the above clinical efficacy, safety and PK study results, the 
sponsor proposed to add 2 dose groups, i.e., 45 mg/QD and 20 mg/BID (approximately 20 subjects 

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each), to further explore and evaluate the PK, safety, tolerability and efficacy of ATG-008 in 
advanced HBV+ HCC subjects. 
Length of Trial 
The first part of this study had enrolled 35 subjects. 
According to the previous study results, the sponsor proposes to continue to enroll approximately 
40 subjects. Approximately 6 months are needed for enrollment period. Completing PK (PK 
samples will be collected from 10 subjects each in the two dose groups), safety and preliminary 
efficacy evaluations is expected to take approximately 6 months. 
The end of Study is defined as either the date of the last visit of the last subject to complete the 
trial, or the date of receipt of the last data point (e.g., date of death) from the last subject that is 
required for primary analysis, whichever is the earlier date. 
Study Treatments 
The starting dose of ATG-008 will be 15 mg daily for 28 days each cycle for the first 6 fully 
evaluable (including PK outcomes) subjects. Providing dose-limiting toxicity (DLT) occur in less 
than 2 of 6 subjects who complete Cycle 1, additional 24 subjects will be enrolled at the starting 
dose of 30 mg daily. Subjects who tolerated the 15-mg dose level, may then dose-escalate to 30 
mg at the Investigator’s discretion until enrollment of 30-mg group starts. 
According to the previous study results, the sponsor plans to continue to enroll approximately 40 
subjects with hepatitis B virus (HBV) positive, unresectable HCC subjects who have previously 
received at least one prior line of systemic therapy. Among which, approximately 20 subjects will 
receive oral ATG-008 at an initial dose of 45 mg/QD and another 20 subjects will receive oral 
ATG-008 at an initial dose of 20 mg/BID. 
If the overall response rate (ORR) of tumor is greater than 15% in the study dose group (45 
mg/QD or 20 mg/BID), then this study will be expanded to enroll additional approximately 110 
subjects using ORR as the primary study endpoint, to further evaluate the efficacy and safety of 
ATG-008. 
The subjects enrolled will be treated with ATG-008 at an initial dose of 45 mg/QD or 20 mg/BID 
in continuous 28-day cycles (except cycle 1) until the appearance of radiologic disease 
progression, toxicity, subject or physician decision or death. At the discretion of the Investigator, 
treatment may continue beyond radiologic progression until clear symptomatic deterioration if no 
other treatment options are available.  
Continuous dose interruption of up to 2 weeks and the total discontinuation time not more than 4 
weeks is allowed in this study. Dose reduction principle: 30 mg/QD can be reduced to 20 mg/QD 
and 15 mg/QD; 45 mg/QD can be reduced to 30 mg, 20 mg, 15 mg/QD; 20 mg/BID can be 
reduced to 15 mg/BID or other doses to mitigate toxicity. If further dose reduction is required, it 
can be implemented according to the considerations of the investigator and discussion between 
the investigator and medical monitors of the sponsor. Dose re-escalation (higher than the initial 
dose is not permitted) will be allowed if the same toxicity does not recur at the reduced dose for 
least one cycle (4 weeks).  
Antiviral therapy is required, and HBV-DNA viral load will be monitored in all subjects with 
chronic HBV infection. Serum AST/ALT is also monitored. 
After cessation of study drug treatment, subsequent anti-cancer therapy and survival status will be 
followed in all subjects until death. 
Overview of Efficacy Assessments 

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Subjects will be evaluated for tumor response and progression according to RECIST 1.1 
guidelines every 8 weeks (± 5 days) until radiologic disease progression, death or withdrawal of 
consent. mRECIST may be also used when the trial is expanded, if necessary. 
All anticancer treatments administered, especially for HCC, following the last dose of study drugs 
will be captured until death or withdrawal of consent. Disease progression and date of progression 
on each subsequent therapy will be documented. Following disease progression, survival will be 
followed every 8 weeks (± 1 week) until death or withdrawal of consent. 
Overview of Safety Assessments 
All subjects will be monitored for adverse events, starting from the time the subject signs the 
informed consent form (ICF) until 28 days after the last dose of study drug. A thorough evaluation 
of medical conditions will be conducted during screening for eligibility. Vital signs, laboratory 
assessments (e.g. serum chemistry, hematology, fasting plasma glucose, glycated hemoglobin 
[HbA1c]), 12-lead electrocardiogram (ECGs), and ECOG performance status will be monitored. 
Contraception must be practised during the trial to avoid pregnancy in trial subjects and their 
partners, and females of child-bearing potential will have regular pregnancy testing. 
Overview of Pharmacokinetic Assessments 
Blood samples will be collected for intensive sampling in all 30 subjects in order to estimate the 
PK of ATG-008 and metabolites in Asian subjects. 
As for the 2 dose groups 45 mg/QD and 20 mg/BID, PK samples of 10 subjects each should be 
collected to further evaluate the PK profile of ATG-008 and its metabolites.  
Overview of Exposure-Response Analyses 
Exposure-response analyses will be performed to evaluate relationships between ATG-008 and/or 
M1 exposure and clinical outcomes of efficacy and safety. 
Statistical Summary 
The primary efficacy endpoint is ORR, and the primary analysis population for both efficacy and 
safety analysis is the Treated population.  
All efficacy and safety results will be tabulated and/or summarized using for the Treated 
population by treatment arm. 

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TABLE OF CONTENTS 
 
 
MEDICAL / EMERGENCY CONTACT INFORMATION.................................................................. 2 
PROTOCOL SYNOPSIS ....................................................................................................................... 5 
TABLE OF CONTENTS ..................................................................................................................... 12 
LIST OF TABLES ............................................................................................................................... 15 
LIST OF FIGURES.............................................................................................................................. 15 
1. INTRODUCTION ........................................................................................................................ 20 
1.1. 
Hepatocellular Carcinoma .............................................................................................. 20 
1.2. 
Mammalian Target of Rapamycin ................................................................................... 22 
1.2.1. 
Hepatocellular Carcinoma and mTOR ..................................................................... 22 
1.3. 
ATG-008.......................................................................................................................... 23 
1.3.1. 
ATG-008 Preclinical Data ........................................................................................ 23 
1.3.2. 
ATG-008 Clinical Data ............................................................................................ 25 
1.4 
Study Rationale ............................................................................................................... 31 
1.4.1 
Rationale for Dose of ATG-008 ............................................................................... 32 
2. STUDY OBJECTIVES ................................................................................................................. 34 
2.1 
Primary Objective ........................................................................................................... 34 
2.2 
Secondary Objectives...................................................................................................... 34 
3. STUDY ENDPOINTS .................................................................................................................. 34 
3.1 
Primary Endpoint ............................................................................................................ 34 
3.2 
Secondary Endpoints ...................................................................................................... 34 
4. OVERALL STUDY DESIGN ...................................................................................................... 34 
4.1 
Study Design ................................................................................................................... 34 
4.2 
Study Design Rationale................................................................................................... 36 
4.3 
Study Duration ................................................................................................................ 37 
4.4 
End of Trial ..................................................................................................................... 38 
5. TABLE OF EVENTS .................................................................................................................... 39 
6. PROCEDURES ............................................................................................................................. 43 
6.1. 
Screening Period ............................................................................................................. 43 
6.2. 
Treatment Period ............................................................................................................. 45 
6.2.1 
End of Treatment...................................................................................................... 46 
6.3. 
Follow-up Period ............................................................................................................ 46 
6.3.1 
28-day Follow-up ..................................................................................................... 46 
6.3.2 
Efficacy Follow-up .................................................................................................. 46 
6.3.3 
Survival Follow-up .................................................................................................. 46 
6.4. 
Response Assessments .................................................................................................... 46 
6.4.1 
Assessment of Radiologic Response According to RECIST 1.1 ............................. 47 
6.5. 
Pharmacokinetics ............................................................................................................ 47 
6.5.1 
Intense Blood Sampling ........................................................................................... 48 
6.5.2 
PK urine collection .................................................................................................. 48 
7. STUDY POPULATION ................................................................................................................ 49 
7.1 
Number of Subjects......................................................................................................... 49 
7.2 
Inclusion Criteria ............................................................................................................ 49 
7.3 
Exclusion Criteria ........................................................................................................... 50 
8. DESCRIPTION OF STUDY TREATMENTS .............................................................................. 52 
8.1 
Description of Investigational Product(s) ....................................................................... 52 
8.2 
Treatment Administration and Schedule ......................................................................... 52 

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8.2.1 
Treatment modification ............................................................................................ 52 
8.2.2 
Overdose .................................................................................................................. 54 
8.3 
Method of Treatment Assignment ................................................................................... 54 
8.4 
Packaging and Labeling .................................................................................................. 54 
8.5 
Investigational Product Accountability and Disposal ..................................................... 54 
8.6 
Investigational Product Compliance ............................................................................... 55 
9. CONCOMITANT MEDICATIONS AND PROCEDURES ......................................................... 55 
9.1 
Recommended Concomitant Medications and Procedures ............................................. 55 
9.2 
Permitted Concomitant Medications and Procedures ..................................................... 55 
9.3 
Prohibited Concomitant Medications and Procedures .................................................... 56 
9.4 
Required Concomitant Medications and Procedures ...................................................... 57 
10. 
STATISTICAL ANALYSES .................................................................................................. 57 
10.1 
Overview ......................................................................................................................... 57 
10.2 
Study Population Definitions .......................................................................................... 58 
10.2.1 Treated Population ................................................................................................... 58 
10.2.2 Per-Protocol Population ........................................................................................... 58 
10.3 
Sample Size and Power Considerations .......................................................................... 58 
10.4 
Background and Demographic Characteristics ............................................................... 58 
10.5 
Subject Disposition ......................................................................................................... 58 
10.6 
Efficacy Analysis ............................................................................................................ 58 
10.6.1 Analysis of the Primary Efficacy Endpoint ............................................................. 59 
10.6.2 Analysis of the Secondary Efficacy Endpoints ........................................................ 59 
10.6.3 Subgroup Analyses................................................................................................... 59 
10.6.4 PK analysis............................................................................................................... 60 
10.6.5 Exploratory Analyses ............................................................................................... 60 
10.7 
Safety Analysis................................................................................................................ 60 
11. 
ADVERSE EVENTS ............................................................................................................. 60 
11.1 
Monitoring, Recording and Reporting of Adverse Events.............................................. 61 
11.2 
Evaluation of Adverse Events ......................................................................................... 61 
11.2.1 Seriousness ............................................................................................................... 61 
11.2.2 Severity/Intensity ..................................................................................................... 62 
11.2.3 Causality .................................................................................................................. 63 
11.2.4 Duration ................................................................................................................... 63 
11.2.5 Action Taken ............................................................................................................ 63 
11.2.6 Outcome ................................................................................................................... 63 
11.3 
Abnormal Laboratory Values .......................................................................................... 63 
11.4 
Pregnancy ........................................................................................................................ 64 
11.4.1 Females of Childbearing Potential ........................................................................... 64 
11.4.2 Male Subjects ........................................................................................................... 64 
11.5 
Reporting of Serious Adverse Events ............................................................................. 64 
11.5.1 Safety Queries .......................................................................................................... 65 
11.6 
Expedited Reporting of Adverse Events ......................................................................... 65 
12. 
DISCONTINUATIONS ......................................................................................................... 66 
12.1 
Discontinuation from Investigational Product ................................................................ 66 
12.2 
Discontinuation from the Trial ........................................................................................ 66 
13. 
EMERGENCY PROCEDURES ............................................................................................ 66 
13.1 
Emergency Contact ......................................................................................................... 67 
14. 
REGULATORY CONSIDERATIONS .................................................................................. 68 
14.1 
Good Clinical Practice .................................................................................................... 68 
14.2 
Investigator Responsibilities ........................................................................................... 68 

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14.3 
Subject Information and Informed Consent .................................................................... 68 
14.4 
Confidentiality ................................................................................................................ 69 
14.5 
Protocol Amendments ..................................................................................................... 69 
14.6 
Institutional Review Board/Independent Ethics Committee Review and Approval ....... 69 
14.7 
Ongoing Information for Institutional Review Board / Ethics Committee ..................... 70 
14.8 
Closure of the Trial ......................................................................................................... 70 
15. 
DATA HANDLING AND RECORDKEEPING .................................................................... 71 
15.1 
Data/Documents .............................................................................................................. 71 
15.2 
Data Management ........................................................................................................... 71 
15.3 
Record Retention ............................................................................................................ 71 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 72 
16.1 
Trial Monitoring and Source Data Verification .............................................................. 72 
16.2 
Audits and Inspections .................................................................................................... 72 
17. 
PUBLICATIONS ................................................................................................................... 74 
18. 
REFERENCES ....................................................................................................................... 75 
19. 
APPENDICES ....................................................................................................................... 79 
19.1 
Appendix A: RECIST 1.1 ............................................................................................... 79 
19.1.1 Definitions................................................................................................................ 79 
19.1.2 Tumor Response Evaluation .................................................................................... 79 
19.2 
Appendix B: Cytochrome P-450 (CYP) interactions...................................................... 82 
19.2.1 CYP3A4 Inhibitors .................................................................................................. 82 
19.2.2 CYP3A4 Inducers: ................................................................................................... 83 
19.3 
Appendix C: Guidance for Managing Hyperglycemia ................................................... 83 
19.4 
Appendix D: Liver Cancer Staging, and Child-Pugh Classification .............................. 84 
19.4.1 Barcelona Clinic Liver Center Staging ....................................................................... 84 
19.4.2 Child-Pugh Classification of Liver Failure .............................................................. 84 
 
 
 
 
 

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LIST OF TABLES 
 
 
 
Table 1: List of Abbreviations .................................................................................................... 16 
Table 2: 
Overall Survival for HCC by Starting Dose and by HBV Status in Phase 2 of 
Study CC-223-ST-001 (Treated Population) ...................................................................... 27 
Table 3: 
Table of Events ....................................................................................................... 39 
Table 4: 
Dose Reduction Recommended Guidelines for Suspected Drug-related 
Toxicity53 
Table 5: 
Time Point Response: Patients With Target (± Non-target) Disease ................. 81 
Table 6: 
Time Point Response: Subjects With Non-target Disease Only ......................... 81 
Table 7: 
Child-Pugh Classification ...................................................................................... 84 
 
 
 
 
 
LIST OF FIGURES 
 
Figure 1: 
Overall Study Design ............................................................................................. 36 
Figure 2: 
Barcelona-Clinic Liver staging classification and treatment schedule .............. 84 
 
 
 
 

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Table 1: List of Abbreviations 
Abbreviation 
Term 
AASLD 
American Association for the Study of Liver Disease 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
Adverse event 
AFP 
Alpha-fetoprotein 
AKT 
Serine/threonine kinase 
ALT (SGPT) 
Alanine amino transferase 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate amino transferase 
ATG-008 
Formerly CC-223, a dual mTOR kinase inhibitor 
BCLC 
Barcelona Clinic liver cancer 
BCRP 
Human breast cancer resistance protein 
BSC 
Best supportive care 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CC-223 
Former (US) code name for ATG-008, a dual mTOR kinase inhibitor 
CK 
Creatinine kinase 
CL/F 
Clearance as a function of bioavailability 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTPM 
Clinical trials planning meeting 
CYP 
Cytochrome P 
DCR 
Disease control rate 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose-limiting toxicity 
DMC 
Data monitoring committee 
EASL 
European Association for the Study of Liver 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGF 
Endothelial growth factor 
EGFR 
Epidermal growth factor 
 

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Abbreviation 
Term 
ERK 
Extracellular signal-regulated kinase 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of treatment 
EU 
European Union 
FACT 
Functional Assessment of Cancer Therapy 
FCBP 
Females of child bearing potential 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
fT4 
Index of free thyroxin 
GCP 
Good clinical practice 
G-CSF 
Granulocyte colony stimulating factor 
GI 
Gastrointestinal 
GM-CSF 
Granulocyte macrophage colony stimulating factor 
HbA1c 
Hemoglobin A1c 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HER3 
Human epidermal growth factor 3 
hERG 
Human ether-à-go-go-related gene 
HNSTD 
Highest nonseverely toxic dose 
HR 
Hazard ratio 
IA 
Interim analysis 
IC50 
50% inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
Ig 
Immunoglobulin 
IGF 
Insulin like growth factor 
INR 
International normalized ratio 
IP 
Investigational product 
IRS1 
Insulin receptor substrate 1 
LDH 
Lactate dehydrogenase 
M1 
Major human metabolite of ATG-008 
MedDRA 
Medical Dictionary for Regulatory Affairs 
 

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Abbreviation 
Term 
mm 
Millimeter 
MRI 
Magnetic resonance imaging 
mRECIST 
Modified Response EvaluationCcriteria in Solid Tumors 
mRNA 
Messenger ribonucleic acid 
MRCT 
Multi-regional clinical trial 
MTD 
Maximum tolerated dose 
mTOR 
Mammalian target of rapamycin 
NCI CTCAE  
National Cancer Institute Common Terminology Criteria for Adverse Events  
NET 
Neuroendocrine tumor 
NSCLC 
Non-small cell lung cancer 
OAT 
Organic anion transporter 
OCT 
Organic cation transporter 
ORR 
Overall response rate 
OS 
Overall survival 
pAKT 
Phosphorylated AKT 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PI 
Principal Investigator 
PI3K 
Phosphoinositide 3-kinase 
PK 
Pharmocokinetic 
PR 
Partial response 
PT 
Prothrombin time 
PTEN 
Phosphatase and tensin homolog 
PTT 
Partial thromboplastin time 
QD 
Once daily 
QLQ 
Quality of life questionnaire 
QTcF 
Fridericia correction 
RBC 
Red blood cell 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors 1.1 
RFA 
Radiofrequency ablation 
RR 
Response rate 

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Abbreviation 
Term 
SAE 
Serious adverse event 
SC 
Steering committee 
SD 
Stable disease 
SOP 
Standard operating procedure(s) 
STD10 
Severely toxic dose in 10% 
SUSAR 
Suspected unexpected serious adverse reaction(s) 
SUV 
Standardized uptake value 
TACE 
Transcatheter arterial chemoembolization 
TEAE 
Treatment emergent adverse event 
TSH 
Thyroid stimulating hormone 
TTP 
Time to progression 
ULN 
Upper limit of normal 
US 
United States of America 
Vd/F 
Volume of distribution as a function of bioavailability 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
 
 
 
 

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1. 
INTRODUCTION 
1.1. 
Hepatocellular Carcinoma 
Hepatocellular carcinoma represents up to 90% of all primary liver cancers in the world (Hashim, 
2016; Torre, 2016). Liver cancer ranks in incidence and mortality among the top 10 cancers 
worldwide. It is the fifth most common cancer in men and the ninth most common cancer in 
women, with 554,000 new cases in men and 228,000 in women worldwide in 2012. It is the second 
most common cause of death from cancer, estimated to be responsible for nearly 745,000 deaths in 
2012 (9.1% of the total cancer mortality) (Ferlay, 2015).  
HCC shows great geographical variation with a high incidence in Asia and Sub-Saharan Africa 
and a rising incidence in the United States of America (US) and Europe (Parkin, 2005; El Serag, 
1999; Zhu, 2016). Hepatitis C virus (HCV) infection is the predominant risk factor for HCC in 
Western countries and Japan, whereas HBV is the predominant risk factor for HCC in Southeast 
Asia and Africa. Chronic HBV infection now accounts for 80% of all newly diagnosed HCC in 
Asia (Zhu, 2016). More than 50% of new cases and deaths occur in China (Parkin, 2005) where it 
is the second most common cancer (Yang, 2005a), and 80-90% of cases are caused by chronic 
infection with hepatitis B (Raza, 2007).  
It is expected that hepatitis B vaccine will eventually reduce the incidence of HCC. Many 
countries now offer hepatitis B vaccination of all newborns. However, three or four decades will 
be needed to assess the real impact of hepatitis B virus control on HCC incidence because 
diagnosis of hepatitis-related HCC occurs at a mean age of 55-60 years (Lau, 2008). 
HCC is diagnosed based on pathology or radiology. Pathological diagnosis is generally based on 
immunostaining for GPC3, HSP70, and glutamine synthetase and/or gene expression profiles 
(GPC3, LYVE1, and survivin) to differentiate high grade dysplastic nodules from early HCC. In 
addition, classic radiologic features have been used in clinical practice to make the diagnosis of 
HCC. Guidelines for HCC diagnosis have been developed by the European Association for the 
Study of Liver (EASL) and European Organization for Research and Treatment of Cancer 
(EORTC) (Llovet, 2012b) and American Association for the study of Liver Disease (AASLD) 
(Bruix, 2010). Specifically, the AASLD guidelines stipulate that HCC can be diagnosed either by 
pathology or radiology meeting the following criteria: 
 Dynamic imaging obtained by 4-phase multidetector CT scan or dynamic contrast- 
enhanced MRI 
 Arterial hypervascularity was present 
 Venous-delayed phase washout was present. 
An expert panel has considered these non-invasive criteria as acceptable to be used as entry 
criteria in clinical trials of HCC (Llovet, 2008b). 
Among several available classification systems for HCC, the Barcelona Clinic Liver Cancer 
(BCLC) classification has emerged as the standard and has been recommended for use in trial 
design and clinical management of HCC (Llovet, 2008a). According to the BCLC staging 
classification and treatment schedule, patients with very early stage HCC (Stage 0) and early stage 
HCC (Stage A) are candidates for radical therapy (resection, liver transplantation, or local ablation 
via percutaneous ethanol injection or radiofrequency ablation). Patients with intermediate stage 
HCC (Stage B) may benefit from transarterial chemoembolization. Patients with advanced stage 
HCC (Stage C) benefit from sorafenib. Patients with end-stage HCC (Stage D) receive 
symptomatic treatment (see Section 19.4.1). 
The prognosis for HCC remains very poor despite advances in diagnostic technology and 

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treatment. Five-year survival rates for advanced stage disease are only 3% to 5% worldwide 
(Parkin, 2005). Potentially curative treatments are applied to only 30% to 40% of patients in 
developed countries (Llovet, 2003). The risk of recurrence is approximately 70% at 5 years after 
resection and prognosis after recurrence is poor (Llovet, 2003). Patients with HCC of Stage B and 
C have a median survival ranging from 10 to 14 months following appropriate treatments. 
To date, sorafenib at a dose of 400 mg twice-daily is the only first-line systemic therapy proven to 
prolong overall survival (OS) in subjects with advanced HCC. One phase 3 trial (SHARP) 
conducted in Europe, North America, South America and Australia showed that sorafenib as 
first-line therapy improved OS compared with placebo (10.7 months versus 7.9 months, Hazard 
Ratio (HR)=0.69, 95%CI, 0.55-0.87; p<0.001) (Llovet, 2008b). A second trial conducted in Asia 
(ORIENTAL) with similar design confirmed the survival benefit of sorafenib although Asian 
subjects had a poorer overall outcome (6.5 months versus 4.2 months, HR=0.68, 95%CI, 
0.50-0.93; p=0.014) (Cheng, 2009). Three recent phase 3 trials of other therapeutic agents 
performed in advanced stage HCC in the first-line setting have failed to demonstrate a survival 
benefit, or even non-inferiority, over single agent sorafenib. These included two single-agent trials 
of the multi-targeted kinase inhibitors, brivanib and linifanib, and a combination trial of erlotinib 
(an epidermal growth factor [EGFR] inhibitor) plus sorafenib (Johnson, 2013; Cainap, 2015; Zhu, 
2015). 
Systemic chemotherapy was usually used as a palliative treatment. However, a phase 3 trial 
(EACH) revealed a possible beneficial role for FOLFOX4 (fluorouracil, leucovorin and 
oxaliplatin) in China and other Asian countries (Qin, 2013). This trial evaluated 371 subjects with 
HCC in China, Taiwan, Korea and Thailand and randomized them (1:1) to either FOLFOX4 or 
doxorubicin. FOLFOX4 showed significant improvement in progression-free survival (PFS) (2.93 
months versus 1.77 months, HR=0.62, 95% CI, 0.49-0.79, p<0.001), RR (67% versus 8.15%, p 
=0.02), DCR (52.17% versus 31.55%, P < 0.0001) than for those treated with doxorubicin. No 
improvement was found in median OS (6.40 months versus 4.97 months, HR=0.80, 95% CI, 
0.63-1.02, P=0.07) but a further follow-up of 7 months showed a beneficial effect of mOS in 
FOLFOX4 group (6.47 months versus 4.90 months, p = 0.04). The oxaliplatin-containing 
FOLFOX4 regimen for treatment of advanced HCC was subsequently approved by the Chinese 
Food and Drug Administration (CFDA) in 2013.   
The pursuit for second-line therapy has not identified any very promising new treatment options 
for HCC. Results of a second-line trial of brivanib versus placebo (randomized 2:1) in 395 
subjects with advanced HCC who progressed on or were intolerant to sorafenib failed to 
demonstrate improvement in OS (9.4 versus 8.2 months, HR 0.89, p = 0.33) (Llovet, 2012a). 
Secondary endpoints showed an improvement with brivanib, including time to progression (TTP) 
(4.2 versus 2.7 months, HR=0.56, p=0.0001), disease control rate (71% versus 49%, p<0.0001) 
and overall tumor response rate (12% versus 2%, p=0.003). T h e  f ailure of this trial was 
attributed at least partially to an imbalance in baseline prognostic factors, including the frequency 
of macrovessel invasion and alpha-fetoprotein (AFP) levels, both of which were higher in the 
brivanib arm. Subjects were stratified by study site, ECOG performance status, sorafenib 
outcome, and vascular invasion/extrahepatic spread. Results demonstrated tumor responses in 3% 
to 4% of subjects with a median time to progression of 3 to 4 months. 
No effective second-line therapy existed for sorafenib failures until the approval of regorafenib by 
the US FDA in 2017 following results of a randomised, double-blind, parallel-group, phase 3 trial 
(RESOURCE) in the second-line setting (Bruix, 2017). The trial enrolled 573 HCC subjects who 
progressed on sorafenib and randomised them (2:1) to either regorafenib (n=379) or placebo 
(n=194). Regorafenib improved median OS (10.6 months versus 7.8 months, HR=0.63, 95% CI, 
0.50-0.79; one-sided p<0.0001), median PFS (3.1 months versus 1.5 months, p<0.0001) and TTP 

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(3.2 months versus 1.5 months, p<0.0001) compared with placebo.  
Even today, treatment options for unresectable stage HCC are severely limited. There remains a 
high unmet medical need for effective therapies in this disease, particularly in Asian HBV+ HCC 
subjects failing at least one prior line of systemic therapy. 
1.2. 
Mammalian Target of Rapamycin 
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase related to the lipid 
kinases of the phosphoinositide 3-kinase (PI3K) family. It functions as a sensor of mitogen, 
energy and nutrient levels and is a central controller of cell growth. mTOR exists in 2 complexes: 
mTORC1, which complexes with raptor and is rapamycin sensitive, and mTORC2, which 
complexes with rictor and is rapamycin insensitive (Kim, 2002; Sarbassov, 2004). mTORC1 
integrates signals from growth factor receptors with cellular nutritional status and controls the 
level of messenger ribonucleic acid (mRNA) translation by modulating the activity of key 
translational components. The functions of mTORC2 are less well understood than those of 
mTORC1 (Feldman, 2009). mTORC2 is thought to modulate growth factor signaling by 
phosphorylating kinases such as AKT (a serine/threonine kinase), which leads to its activation. 
Active AKT promotes cell survival in many ways, including suppressing apoptosis, promoting 
glucose uptake, and modifying cellular metabolism (Gibbons, 2009). The PI3K–AKT pathway is 
inappropriately activated in many cancers and is vital to the growth and survival of cancer cells 
(Engelman, 2009).  Therefore, mTOR inhibitors are being developed as potential therapeutic 
agents for the treatment of various cancers. Rapamycin and its analogues inhibit the mTORC1 
complex alone and stimulate the upstream kinase AKT by inhibiting the negative feedback loop 
between p70S6 kinase and insulin receptor substrate 1 (IRS1). This may explain, at least in part, 
the resistance to rapamycin analogues exhibited by the majority of cancer cell lines and tumors 
(Gibbons, 2009). The inhibition of both mTORC1 and mTORC2 by mTOR kinase inhibitors 
would therefore be expected to inhibit AKT instead of activating it. 
1.2.1. 
Hepatocellular Carcinoma and mTOR 
Activation of several signaling pathways have been implicated in human hepatocarcinogenesis. 
These include pathways involved in cell proliferation (PI3K/mTOR, EGFR, IGF1R, Met), liver 
development and cell differentiation (Wnt and Hedgehog), inflammation and angiogenesis 
(Villanueva, 2008b). 
The PI3K/AKT/mTOR pathway is an important signaling pathway driving cell growth and 
proliferation in HCC. Loss of phosphatase and tensin homolog (PTEN) expression, often due to 
promoter hypermethylation, is a common aberration present in 30% – 50% of HCC and is 
associated with mTOR pathway activation, vascular endothelial growth factor (VEGF) activation 
and a more aggressive phenotype (Yang, 2005b; Mi, 2006; and Hayashi, 2009). 
Analysis of 314 HCC samples for genetic alterations and protein expression levels showed 
activation of insulin-like growth factor (IGF) pathway, overexpression of endothelial growth 
factor (EGF), loss of PTEN, and activation of mTOR signaling in 50% of the samples. Rictor 
copy number gain, also associated with mTOR pathway activation, was observed in 25% of HCC.  
TORC2 pathway activation, associated with increased expression of phosphorylated AKT 
(pAKT), is observed in the majority of HCC and is associated with vascular invasion, high tumor 
stage and grade, and a poor prognosis (Villanueva, 2008a). 
Rapamycin has been shown to inhibit HCC cell-line proliferation in vitro, and tumor growth and 
angiogenesis in vivo (Semela, 2007). Similar results have been observed with the rapamycin 
analogue, everolimus, in xenograft models (Huynh, 2009; Villanueva, 2008a). These studies 
provide a strong rationale for clinical investigation of mTOR pathway inhibitors in subjects with 

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HCC and for compounds with inhibitory activity against both TORC1 and TORC2 complexes. 
Although the mechanisms mediating sorafenib resistance have not been completely characterized, 
preclinical studies suggest that activation of EGFR, STAT3 and PI3K/AKT signaling are 
involved.  Hepatocellular carcinoma cell lines with acquired sorafenib resistance 
exhibit 
increased levels of pAKT and p85 (a PI3K regulatory subunit) and down-regulation of PTEN, 
consistent with activation of the mTOR pathway. Furthermore, treatment of resistant cells with an 
allosteric AKT inhibitor restored sensitivity of resistant cells to sorafenib induced apoptosis 
(Chen, 2012). In a separate study, HCC cells with acquired resistance to sorafenib were shown to 
have aberrant activation of EGFR/human epidermal growth factor 3 (HER3) receptors as well as 
over-expression of several EGFR ligands. These enhanced autocrine/paracrine loops led to the 
constitutive activation of extracellular signal-regulated kinase (ERK) and AKT and conferred 
increased sensitivity to gefitinib (Blivet-Van Eggepoël, 2012). 
These data provide additional support for treatment of HCC following progression on sorafenib 
with mTOR targeted therapies that inhibit both TORC1 and TORC2 complexes, thereby blocking 
pAKT activation. 
1.3. 
ATG-008 
ATG-008 (formerly CC-223, CC0482223) is a potent and selective inhibitor of the mTOR kinase 
in development for the treatment of solid and hematologic malignancies. It is a dual inhibitor of 
both the mTORC1 and mTORC2 complexes, which is hoped may minimize development of 
resistance due to increased phosphorylation of AKT. 
1.3.1. 
ATG-008 Preclinical Data 
ATG-008 was screened against a panel of 138 cancer cell lines (40 hematological, 43 breast, 2 
colorectal, 7 endometrial, 1 glioma, 11 HCC, 1 melanoma, 27 non-small cell lung, 5 ovarian, and 
1 prostate cancer). In the majority of cell lines, ATG-008 treatment resulted in concentration- 
dependent growth inhibitory activity. ATG-008 inhibited the mTOR pathway in multiple cell 
lines, as evidenced by inhibition of both direct (4EBP1 and AKT Ser473) and indirect (S6RP, 
PRAS40, GSK3β) substrates of the 2 complexes mTORC1 and mTORC2 that contain the mTOR 
kinase. 
ATG-008 has demonstrated potent antiproliferative activity in a panel of 11 HCC cell lines in 
vitro, with activity greater than either sorafenib or erlotinib. The two most sensitive cell lines have 
Rictor copy number gain. Synergistic antiproliferative activity with the combination of ATG-008 
and sorafenib was observed across multiple cell lines and a synergistic effect of the combination 
on inhibition of anchorage independent cell growth was observed in HepG2, but not SK-Hep1 
HCC cells. 
Characterization of the in vivo antitumor activity of ATG-008 in xenograft models has focused on 
PC3 human prostate, U87MG glioblastoma and HCT-116 colorectal tumors. ATG-008 
significantly inhibited PC3, U87MG, and HCT-116 tumor growth in a dose- and schedule- 
dependent manner. The minimum dose required to obtain approximately 65% tumor volume 
reduction compared with vehicle control was 5 mg/kg dosed twice daily, 1 mg/kg dosed once 
daily, and 25 mg/kg dosed once daily for PC3, U87MG and HCT-116 tumors, respectively. In 
addition, ATG-008 also caused regression of larger (464 mm3) PC3 tumors. The antitumor effect 
of ATG-008 in PC3 and U87MG tumors was not only due to the inhibition of tumor cell 
proliferation but also due to increased apoptosis and antiangiogenic activity. In PC3, U87MG, and 
HCT-116 tumor-bearing mice treated with ATG-008, significant inhibition of mTOR pathway 
markers S6RP and AKT Ser473 was observed following a single oral dose or multiple doses, 
indicating that the antitumor activity was mediated through the inhibition of both mTORC1 

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(S6RP) 
and 
mTORC2 
(AKT 
Ser473). 
In 
PC3 
tumors, 
the 
pharmacokinetic 
(PK)/pharmacodynamic relationship of compound exposure and biomarker response indicated that 
> 80% inhibition of phosphorylated S6 ribosomal protein (pS6RP) and > 60% inhibition of pAKT 
at serine 473 (pAKT Ser473) were obtained at total drug plasma concentrations greater than 0.2 
M. Maintenance of plasma levels > 0.2 M and this degree of biomarker inhibition through 8 hours 
twice daily confers good antitumor activity in PC3 tumors. The combinatorial effects of ATG-008 
and sorafenib were tested in a human HCC orthotopic xenograft model. Both agents demonstrated 
single agent activity, and a synergistic inhibitory effect on tumor growth. 
CC0483131 (O-desmethyl-ATG-008), the major human metabolite of ATG-008 (M1), has 
antiproliferative activity in vitro, inhibited mTOR pathway biomarkers in vitro and in vivo, and 
exhibited antitumor activity. These data suggest that the presence of the M1 metabolite could 
contribute to the therapeutic activity of ATG-008 in subjects. 
In vitro and in vivo preclinical studies have been conducted to characterize the absorption, 
distribution, metabolism and excretion (ADME) of ATG-008. The results demonstrate that 
ATG-008 has acceptable ADME profiles. In vitro plasma protein binding is moderate (92.4%) for 
CC- 223 and high (98.1%) for the major metabolite M1 (O-desmethyl-ATG-008), and was 
concentration-independent. In a quantitative whole body autoradiography study, drug-derived 
radioactivity was widely distributed in rat tissues after oral administration, and elimination from 
tissues was nearly complete at 168 hours post-dose. The fecal route was the major excretion 
pathway, while biliary excretion and urinary clearance also contributed to the elimination of [14C] 
ATG-008-derived radioactivity in rats and dogs. Formation of M1 (CC0483131) was the major 
metabolic pathway in humans, mediated by cytochrome P450 (CYP)3A4/5, with a minor 
contribution from CYP2C9. Oxidative metabolism of M1 in human liver microsomes was slow, 
mediated by CYP2C8 and CYP3A4/5 and glucuronidation of M1 is a minor pathway mediated by 
UGT1A8. In vitro CYP inhibition studies demonstrate that ATG-008 is a weak inhibitor of 
CYP2C9 and CYP2C19 (50% inhibitory concentration [IC50] ≥ 27.4 μM) and is not expected to 
precipitate clinically relevant drug-drug interactions at projected therapeutic concentrations due to 
the inhibition of the metabolism of co-administered substrates of these enzymes. In human 
hepatocyte cultures, ATG-008 (1 to 10 μM) treatment for two days did not induce the catalytic 
activities or messenger ribonucleic acid (mRNA) levels of CYP1A2 and CYP2B6 to a notable 
extent.  ATG-008 increased CYP3A4 mRNA expression to a variable extent (approximately 1% 
to 64% of the response observed with the positive control rifampicin), but did not induce the 
catalytic activity of CYP3A4/5 to a notable extent. ATG-008 metabolite M1 is a weak inhibitor of 
CYP2C9 and CYP2C19, with estimated IC50 values of 63 μM and 46 μM, respectively. M1 is not 
a time-dependent inhibitor of the CYP enzymes. In human hepatocyte cultures, M1 (5 to 50 μM) 
treatment for two consecutive days did not induce the catalytic activities of CYP1A2, CYP2B6 
and CYP3A4/5 to a notable extent. M1 treatment did not increase the mRNA level of CYP1A2, 
but increased CYP2B6 mRNA expression up to an average of 12.4% of the response observed 
with the positive control phenobarbital, and CYP3A4 mRNA expression up to an average of 
34.8% of the response observed with the positive control rifampicin. ATG-008 is not a substrate 
but is an inhibitor (IC50 = 3.67 μM) of human p-glycoprotein. ATG-008 is a substrate and an 
inhibitor (IC50 = 11.7 μM) of human breast cancer resistance protein (BCRP). At a clinically 
relevant concentration of 1 μM, ATG-008 did not show any notable inhibition of organic anion 
transporter 1 (OAT1), OAT3, OATP1B1, OATP1B3, or organic cation transporter 2 (OCT2) 
transportability in vitro. ATG-008 metabolite M1 is a substrate and a weak inhibitor of P-gp. M1 
is also a substrate and an inhibitor of BCRP. 
ATG-008 was evaluated in a core battery of safety pharmacology studies (neurobehavior, 
respiratory and cardiovascular) as well as the human ether-à-go-go-related gene (hERG) assay 

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and mutagenesis assay. ATG-008 had no effects on central nervous system (CNS) function in rats 
at single doses up to 10 mg/kg. In a rat respiratory study, there were no adverse effects on 
respiration observed in a 28-day repeat-dose study. There was minimal inhibition in the hERG 
assay (IC50 = 112 µM). The M1 metabolite demonstrated minimal inhibition (IC50 > 100 µM) in 
the in vitro hERG assay. In an assessment of cardiovascular function in dogs, a small decrease in 
heart rate and a concomitant prolongation in R Wave to R Wave (RR) interval were observed 
1-hour postdose at 3 mg/kg but were not considered significant. 
ATG-008 was negative in the microbial mutagenesis assays, the in vitro assay for chromosomal 
aberrations in human peripheral blood lymphocytes, and the in vivo rat bone marrow 
micronucleus assay. 
The potential toxicity of ATG-008 has been characterized in pivotal good laboratory practice 
repeat-dose toxicity studies of 28 days in duration with a 28-day recovery period in rats and dogs. 
In the definitive 28-day oral toxicity studies, doses were 0.75, 1.5, 3 and 10 mg/kg/day in dogs 
and 1, 3 and 10 mg/kg/day in rats. A 28-day drug-free recovery period was included at the end of 
the dosing period in each study. The primary target organs of toxicity after 28 days of repeated 
administration in rats and in dogs were similar and included the gastrointestinal tract (acute 
inflammation), bone marrow (hypocellularity) and lymphoid tissues (lymphoid depletion in 
peripheral lymph nodes, thymus, spleen and/or Peyer’s patches). In exploratory studies, 
modulation of insulin and glucose was observed in rats and dogs, consistent with the 
pharmacology of mTOR inhibitors. 
In rats, the severely toxic dose in 10% of animals tested (STD10) was 10 mg/kg/day, and in dogs, 
1.5 mg/kg/day was established as the highest nonseverely toxic dose (HNSTD). Systemic 
exposures in rats at 3 and 10 mg/kg/day (10595 and 45 ng·hr/mL, respectively) are approximately 
9- and 38-fold higher than human exposure at 30 mg/day (1202 ng·hr/mL).  
Exposure in dogs at the HNSTD of 1.5 mg/kg/day is approximately 2-fold greater than human 
exposure at 30 mg/day. The M1 metabolite was observed in the plasma of rats and dogs but at 
levels lower than those that occur in humans (data on file). 
1.3.2. 
ATG-008 Clinical Data 
To date, five clinical studies with ATG-008 have been completed and one other is ongoing. Three 
clinical pharmacology studies (CC-223-CP-001, CC-223-CP-002, and CC-223-CP-003) involved 
50 
healthy 
subjects. 
Study 
CC-223-ST-001 
and 
CC-223-NSCL-001, 
and 
ongoing 
CC-223-DLBCL-001, enrolled 402 subjects with various solid and hematologic malignancies. 
Details were listed below. 
 
CC-223-CP-001 (Formulation study: Tablet vs API in capsule) 
CC-223-CP-002 (ADME and food effect study) 
CC-223-CP-003 (Drug-drug interaction study) 
CC-223-ST-001 (First in human dose escalation and expansion study in multiple tumor types) 
CC-223-NSCL-001 (Combination study in NSCL) 
CC-223-DLBCL-001 (Combination study in DLBCL) 
In Study CC-223-CP-001, 18 healthy adult male subjects were administered a single 20-mg 
ATG-008 capsule, four 5-mg ATG-008 tablets, and a single 20-mg tablet with a 7-day interdose 
washout between each treatment. The 20 mg ATG-008 capsules, 5 mg ATG-008 tablets, and 
20-mg ATG-008 tablets had comparable ATG-008 exposure indicating comparable 
bioavailability. ATG-008 is rapidly absorbed with mean peak concentrations of ATG-008 and 
M1 generally observed within 1 to 3 hours. The mean terminal half-lives for ATG-008 and M1 

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were approximately 6 and 14 hours, respectively. 
Study CC-223-CP-002 was conducted in 18 healthy adult male subjects (6 subjects in Part 1 and 
12 subjects in Part 2). Subjects in Part 1 received a single 20-mg oral dose of ATG-008 capsule 
containing a microtracer of [14C]ATG-008 solution. Subjects in Part 2 received a single oral 
20-mg dose of ATG-008 under fed or fasted conditions. ATG-008 was well absorbed 
systemically, as reflected by unchanged ATG-008, accounting for less than 2% of the 
administered dose recovered in urine and feces combined. ATG-008 represented approximately 
16% of circulating TRA exposure. ATG-008 was extensively metabolized to 7 metabolites 
measured in urine and feces: M1, M2, M4, M7, M8, M11, and M13. Of these 7 metabolites, only 
M1, M2, and M13 were measurable in plasma. M1 was formed via odemethylation and was the 
primary circulating entity in plasma representing approximately 77% of circulating TRA 
exposure. Renal elimination was the primary excretion route for TRA. ATG-008 and M1 
exposure were not markedly changed in healthy adult males administered a single, 20-mg oral 
dose of ATG-008 with or without consuming a high, fat meal. Tmax was delayed 1 and 3 hours 
for ATG-008 and M1, respectively, after ATG-008 was administered with a meal. These 
differences are expected to have minimal clinical impact. 
In Study CC-223-CP-003, 14 healthy adult male subjects received ketoconazole (a strong 
CYP3A4 inhibitor) co-administered with a single 20 mg dose of ATG-008. After 
coadministration with ketoconazole (400 mg), a strong CYP3A4 inhibitor, there were moderate 
increases by approximately 60% and 70% increase in ATG-008 and M1 exposure, respectively, 
following a single 20 mg dose of ATG-008. The moderate increase was much less than the 
pronounced increase (>3-fold) observed in the CYP3A4 inhibition assay in vitro, suggesting a 
compensatory non-CYP3A4 mediated metabolism/elimination pathway, moderated the inhibited 
CYP3A4 activity on overall ATG-008 metabolism and elimination. These findings may be 
extrapolated to coadministration of ATG-008 with other moderate to strong CYP3A4 inhibitors, 
the resultant moderate increase in ATG-008 exposure supports clinical management rather than 
prospective dose adjustment of ATG-008. 
The first-in-human, phase 1/2 dose escalation and expansion clinical study (CC-223-ST-001) to 
assess the safety, tolerability, PK and preliminary efficacy of ATG-008 in subjects with solid 
tumors and hematologic malignancies, was completed in November 2016. During the dose 
escalation phase (phase 1), 28 subjects were treated with continuous once daily (QD) dosing 
across 5 dose levels:  7.5 mg (n=1), 15 mg (n=2), 30 mg (n=9), 45 mg (n=9) and 60 mg (n=7). 
The dose of 45 mg QD was selected for the expansion phase (phase 2) of this study which was 
conducted in 198 subjects across 7 tumor types including HCC, non-small cell lung cancer 
(NSCLC), glioblastoma multiforme (GBM), hormone receptor positive breast cancer (HRPBC), 
neuroendocrine tumor (NET) of non-pancreatic origin, diffuse large B-cell lymphoma (DLBCL) 
and multiple myeloma (MM). CC-223-ST-001 is the sole study evaluating HCC subjects to date. 
Study CC-223-NSCL-001 evaluated the safety, tolerability, and PK of single- and 
multiple-ascending doses of CC-223 combined with either erlotinib or CC-486 (oral azacytidine) 
in subjects with advanced NSCLC and who had failed at least one line of standard therapy. It was 
a phase 1b dose escalation and expansion study evaluating escalating doses of CC-223 in 
combination with 2 doses of erlotinib administered concurrently with CC-223 (Arm A) or 2 doses 
of CC-486 administered either concurrently with CC-223 (Arm B) or sequentially with CC-223 
(Arm C), followed by expansion of one or more combination cohorts at one or more selected 
doses. This study was terminated early, during the dose-finding phase, due to the changing 
landscape in NSCLC treatment and changes in the sponsor’s overall strategy and portfolio 
management. The study was not terminated because of any specific safety concerns. 

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Study CC-122-DLBCL-001 (ongoing) is evaluating CC-223 as part of novel combinations with 
CC-122 and CC-292 administered as doublets, and as triplets in combination with rituximab, in 
subjects with relapsed or refractory DLBCL. As of the 2 May 2016 data cutoff date, a total of 102 
subjects were enrolled into the ongoing dose escalation phase of the study. 
1.3.2.1 CC-223-ST-001 Efficacy in Hepatocellular Carcinoma 
In phase 2 of the CC-223-ST-001 study, 53 subjects with HCC received at least 1 dose of 
ATG-008 (CC-223). Overall, 41 (77.4%) were included in the efficacy-evaluable (EE) population. 
Twelve (22.6%) subjects, including 8 Asian, were considered HBV+ and 41 (77.4%) were 
HBV-.White was the major race (30 of 41). The majority (48 of 53, 90.6%) of subjects with HCC 
had received prior sorafenib treatment, including 100% (8 of 8) of HBV+ Asian subgroup. A total 
of 15% subjects had received chemotherapy including cisplatin, oxaliplatin or doxorubicin; 17% 
had received both sorafenib and chemotherapy. 
The initial ATG-008 starting dose (n=25) was 45 mg/QD but later subjects (n=28) started 
treatment at 30 mg/day because of frequent dose modifications required to mitigate toxicity. For 
the whole population, the median OS (mOS) was 30.0 weeks (95% CI: 20.9, 61.1). The mOS in 
the 30-mg and 45-mg dose groups was 38.9 weeks (95% CI: 19.6, 63.3) and 25.0 weeks (95% CI: 
15.0, not estimable), respectively (Table 2). The difference between the dose groups was not 
statistically significant. The mOS in the HBV+ and HBV- subgroups was 52.4 weeks (95% CI: 
25.6, 89.1) and 22.4 weeks (95% CI: 15.4, 50.1), respectively. OS for HBV+ subjects was more 
favorable than for HBV- subjects, but the difference was not statistically significant (p = 0.1897). 
The objective response rate (ORR) (complete response [CR] + partial response [PR]) was 5.7% 
(95% CI: 1.2%, 15.7%). By HBV status, the ORR was 25.0% (95% CI: 5.5%, 57.2%) for subjects 
who were HBV+ and 0% for those who were HBV-. Overall, no subject had a CR; 3 (5.7%) 
subjects had a best response of PR (all 3 subjects were HBV+, 2 of them were treated with 
45mg/QD); and 26 (49.1%) subjects had a best response of stable disease (SD) (8 [66.7%] HBV+ 
subjects and 18 [43.9%] HBV- subjects). Six (11.3%) subjects had a best overall response of 
progressive disease (PD) (1 [8.3%] HBV+ subject and 5 [12.2%] HBV- subjects).  
The DCR for all subjects was 54.7% (95% CI: 40.4%, 68.4%). By HBV status, the DCR was 
91.7% (95% CI: 61.5%, 99.8%) for subjects who were HBV+ and 43.9% (95% CI: 28.5%, 60.3%) 
for those who were HBV-. 
The rate of target tumor shrinkage (ie, lesions reducing in size relative to screening) for all subjects 
was 45.3% (95% CI: 31.6%, 59.6%). By HBV status, the target tumor shrinkage rate was 66.7% 
(95% CI: 34.9%, 90.1%) for subjects who were HBV+ and 39.0% (95% CI: 24.2%, 55.5%) for 
those who were HBV-. 
Table 2: Overall Survival for HCC by Starting Dose and by HBV Status in Phase 2 of Study 
CC-223-ST-001 (Treated Population) 
 
HCC 
Overall 
(N=53) 
30 mg/day 
(N=28) 
45 mg/day 
(N=25) 
HBV+ 
(N=12) 
HBV- 
(N=41) 
Death, n (%) 
33 (62.3) 
23 (82.1) 
10 (40.0) 
7 (58.3) 
26 (63.4) 
Censored, n (%) 
20 (37.7) 
5 (17.9) 
15 (60.0) 
5 (41.7) 
15 (36.6) 
Median OS 
(weeks) (95% CIa) 
30.0 
(20.9, 61.1) 
38.9 
(19.6, 63.3) 
25.0 
(15.0, NA) 
52.4 
(25.6, 89.1) 
22.4 
(15.4, 50.1) 
CI = confidence interval; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; NA = not applicable; OS = 
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a  Median and the 2-sided 95% CI were based on Kaplan-Meier estimate of OS. 
Five subjects had a > 30% regression of target tumor lesions. Of these, best overall responses by 
RECIST 1.1 were PR (3 subjects), SD (1 subject), and PD (1 subject). The 3 subjects with PR were 
HBV+, the subject with SD was HBV-, and the subject with PD was HBV-. 
Percent change in 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) imaging was 
calculated from screening to the C1D15 assessment as a potential functional imaging biomarker of 
mTOR pathway inhibition in tumor lesions resulting in altered glucose uptake and metabolism. 19 
(35.8%) subjects had ≥ 25% SUV reduction from baseline, 20 (37.7%) had ≥ 15% SUV reduction, 
and 26 (49.1%) subjects had reduction in uptake that was greater than or equal to 0. The difference 
between on treatment and baseline values in SUV uptake was statistically significant (p < 0.0001). 
In addition to these encouraging signals of antitumor activity in HCC, radiologic tumor responses 
were also observed in all other tumor types but especially in subjects with NSCLC and DLBCL 
and with rapid symptom improvement in NET carcinoid subjects. 
In summary, this study demonstrated preliminary evidence of broad antitumor activity of 
ATG-008 across multiple solid and hematologic malignancies, with a particularly encouraging 
signal of activity in subjects with unresectable, sorafenib refractory HCC. 
1.3.2.2 CC-223-ST-001 Safety 
As of 1 Apr 2014, interim unaudited data are available on 226 subjects treated with ATG-008, 
including 28 subjects from phase 1 dose escalation, and 198 subjects from phase 2, most of whom 
started treatment with the MTD of 45 mg QD in continuous cycles of 28 days.   
During the dose escalation phase of the study, dose-limiting toxicity (all grade 3) occurred in 4 
subjects and included hyperglycemia (30 mg), rash (45 mg), fatigue (60 mg), and mucositis (60 
mg). The maximum tolerated dose (MTD) was established to be 45 mg QD.  
Preliminary results from this ongoing study as of the SAE database cut-off date of 1 Apr 2014, 
showed most frequent treatment-emergent SAEs gastrointestinal disorders (18.2%), infections 
(14.1%), general disorders (8.6%), metabolism and nutritional disorders (7.6%), respiratory 
disorders (6.6%), renal disorders (5.6%), and others < 5%. The SAEs assessed as being at least 
possibly related to ATG-008 included blood and lymphatic system disorders (thrombocytopenia), 
gastrointestinal disorders (abdominal pain, ascites, nausea, vomiting, diarrhea), general disorders 
(general physical health deterioration, pyrexia), infections and infestations (sepsis, infection, 
pneumonia), metabolic and nutrition disorders (hyperglycemia, dehydration), renal and urinary 
disorders (acute renal failure), and respiratory disorders (dyspnoea). 
1.3.2.2.1 
CC-223-ST-001 Safety in Hepatocellular Carcinoma 
During the dose escalation phase (phase 1) of the study, dose-limiting toxicity (all grade 3) 
occurred in 4 subjects and included hyperglycemia (30 mg), rash (45 mg), fatigue (60 mg), and 
mucositis (60 mg). The maximum tolerated dose (MTD) was established to be 45 mg QD.  
Safety review of the subjects with HCC indication included data from CC-223-ST-001 study 
(phase 1 and 2). As of the cutoff date of 1 June 2016, 52 (98.1%) out of the 53 subjects enrolled 
and treated in the HCC cohort in phase 2 experienced at least one treatment-emergent adverse 
events (TEAE) considered as related to study drug by the Investigator. 
The most common related TEAEs were decreased appetite (64.2%), diarrhea (60.4%), fatigue 
(60.4%), hyperglycemia (60.4%), nausea (50.9%), aspartate aminotransferase increased (43.4%) 
and pruritus (34%).   
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enrolled in phase 2 reported at least 1 SAE. Eight (15.1%) subjects had at least 1 SAE suspected 
by the Investigator to be related to ATG-008. The only drug-related SAE reported in more than 1 
subject in this cohort was dehydration (in 2 subjects). 
Additional SAEs were reported among HCC subjects after the CC-223-ST-001 CSR clinical cutoff 
date of 01 Apr 2014. As of 01 Jun 2016, 29 (54.7%) subjects reported at least 1 SAE. Eight (15.1%) 
subjects had at least 1 SAE suspected by the Investigator to be related to ATG-008. The only 
drug-related SAE reported in more than 1 subject in this cohort was dehydration (in 2 subjects). 
Which mean no additional SAE relate to ATG-008 were reported after the CSR clinical cutoff date.    
Report of the QTcF intervals and the PK-PD relationships for CC-223 and its metabolites revealed 
that there was no significant effect of CC-223administration on cardiac repolarization or other ECG 
parameters. Additionally, a review of TEAEs in the CC-223-ST-001 study revealed no clinically 
significant SAEs, dose reductions or discontinuations due to QTc interval prolongation. 
As of the CSR clinical cutoff date, eight deaths out of 53 HCC subjects while on study or during the 
study-specified follow-up period were reported, including two deaths due to disease progression, 
two death due to sepsis, and one death due to bacterial sepsis, and one death due to hepatic cancer 
metastatic, one death due to hepatic encephalopathy, and one death due to hemorrhage intracranial; 
none was considered related to study drug. No additional deaths occurred in HCC cohort after the 
CSR clinical cutoff date till 01 Jun 2016.  
To date, the overall safety profile appears consistent with published findings for other agents 
targeting mTOR and related cellular pathways, and is also consistent with preclinical toxicology 
findings for ATG-008. 
1.3.2.3 CC-223-ST-001 Pharmacokinetics 
Preliminary PK results in subjects (n = 27) in CC-223-ST-001 phase 1 indicate that ATG-008 is 
rapidly absorbed with peak ATG-008 plasma levels (Tmax) achieved between 1 and 3 hours after 
single and multiple daily doses of ATG-008. Across the dose range of 30 mg to 60 mg, both the 
maximum observed concentration (Cmax) and AUC appear to increase in a dose-proportional 
manner. The terminal half-life of ATG-008 is approximately 4.86 to 5.64 hours. ATG-008 plasma 
accumulation after multiple dosing was minimal (<25%) after repeated dosing. ATG-008 systemic 
exposure in humans is not markedly different from that observed in animal species administered 
multiple oral doses of ATG-008 at or near the maximum tolerated dose in humans (45 mg QD). 
The major pharmacologically-active metabolite, M1, achieved plasma exposure levels 
approximately 15-fold greater than parent exposure. 
In dose expansion (phase 2) of CC-223-ST-001, ATG-008 and M1 plasma concentrations were 
measured in all subjects administered 30 or 45 mg QD ATG-008. Following single and multiple 
oral doses of ATG-008 at dose levels of 30 mg/day and 45 mg/day, ATG-008 was rapidly absorbed 
with maximum plasma concentrations occurring at a median Tmax of 1.02 to 2.96 hours. Total body 
exposures (AUC∞) after a single oral dose of ATG-008 appeared to increase in a dose-proportional 
manner from 30-mg to 45-mg dose levels. Peak exposures (Cmax) after a single oral dose also 
appeared to increase in a dose-proportional manner from 30-mg to 45-mg dose levels. Maximum 
plasma concentrations of M1 occurred at a median Tmax of 3.08 to 6.13 hours. Total body 
exposures (AUCτ) of M1 after a single oral dose appeared to increase in a dose-proportional 
manner from 30mg to 45-mg dose levels. Peak exposures (Cmax) of M1 after a single oral dose also 
appeared to increase in a dose-proportional manner from 30-mg to 45-mg dose levels. There was no 
apparent difference in ATG-008 or M1 PK when comparing across tumor types in phase 2. 
Additionally, in HCC subjects following single and multiple oral doses of ATG-008 at dose levels 
of 30 mg/day and 45 mg/day, ATG-008 was rapidly absorbed with maximum plasma 

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concentrations occurring at a median Tmax of 1.0 to 3.0 hours. Total body exposures (AUC∞) after a 
single oral dose of ATG-008 in subjects with HCC appeared to increase in a dose-proportional 
manner from 30-mg to 45-mg dose levels. Peak exposures (Cmax) after a single oral dose of 
ATG-008 in subjects with HCC also appeared to increase in a dose-proportional manner from 
30-mg to 45-mg dose levels. Maximum plasma concentrations of metabolite M1 occurred at a 
median Tmax of 5.0 to 14.47 hours. Total body exposures (AUCτ) of M1 in subjects with HCC after 
a single oral dose appeared to increase in a dose-proportional manner from 30-mg to 45-mg dose 
levels. Peak exposures (Cmax) of M1 in subjects with HCC after a single oral dose also appeared to 
increase in a dose-proportional manner from 30-mg to 45-mg dose levels. There was a significant 
accumulation of M1 in subjects with HCC upon multiple doses of ATG-008.  
Nonclinical in vitro pharmacological assessment of M1 indicates that the metabolite is 
approximately 1.5 to 2-fold less potent in inhibiting the mTOR pathway compared to ATG-008. In 
vivo, approximately 5-fold greater exposure of the M1 metabolite is required to achieve similar 
inhibition of the mTOR pathway compared to ATG-008 in the PC3 human prostate xenograft 
model. In vitro metabolism studies indicate that M1 is formed via O-demethlyation. Preliminary PK 
results indicate the terminal half-life of M1 is approximately 2- to 3-fold longer than that of 
ATG-008. Final PK results are pending study completion.  
Pharmacodynamic markers of mTOR kinase inhibition include TORC1 (pS6, p4EBP1) and TORC2 
(pAKT) biomarkers in blood using both stimulated and unstimulated assays in monocytes, B cells 
and T cells. Near maximal inhibition of both TORC1 and TORC2 biomarkers was achieved at peak 
plasma concentrations achieved in the 30 and 45 mg QD dosing cohorts. PK-pharmacodynamic 
modeling of inhibition of tumor biomarkers showed near maximal inhibition (approximately 65% to 
80%) of both TORC1 and TORC2 markers with drug levels above 100 ng/mL and 200 ng/mL for 
pS6 and pAKT, respectively. The additive effect of M1, which has a 2- to 3-fold longer half-life than 
that of ATG-008, may partly explain sustained mTOR inhibition predicted to last 8 to 20 hours. 
Preclinical EC50 concentrations for these biomarkers were 19 and 69 ng/mL ATG-008, respectively. 
TORC1 inhibition, assessed using a p4EBP1 assay, also showed concentration dependency, but to a 
lesser extent than that observed for TORC2 biomarkers. In the expansion phase of the study, TORC1 
and TORC2 biomarker inhibition in blood was comparable across all tumor types. 
1.3.2.4 Preliminary Clinical Results of Study ATG-008-HCC-001 
The preliminary clinical study data up to 24 May 2019 showed that a total of 33 HCC subjects were 
enrolled (7 subjects received oral ATG008 at the initial daily dose of 15 mg and 26 subjects received 
30 mg). Subjects who were treated with ATG-008 were Asian, among which, 13 (39.4%) subjects 
each from China mainland and Korea, 7 (21.2%) subjects from Taiwan. Of 33 subjects, 16 (48.5%) 
out of them achieved SD and 13 (39.4%) achieved PD. Another 4 (12.1%) subjects still received the 
first cycle of treatment and no efficacy evaluation has been performed yet. DCR was 48.5% (16 
subjects, 95%CI: 30.8-66.5); approximately half of the subjects (48.5%) had not reported disease 
progression. The median PFS was 2.0 months (95%CI: 1.9-3.8). The survivors accounted for 
approximately 78.8% (26/33). The median OS had not achieved (95%CI: 4.8-not achieved). The 
3-month survival rate was 96% and 6-month survival rate was 58%. The diameter of the targeted 
lesions of tumors decreased after treatment from baseline in 42.9% (12/28 subjects) subjects. Among 
which, the diameter of tumors decreased >20% from baseline in 4 (14.3%) subjects. 
All subjects completed the first cycle of study treatment. Subjects who received the longest 
treatment completed 9 cycles, with the average treatment cycles of 3.2 (±1.6).  
The most frequently reported study drug-related TEAEs were skin rash (42.4%), hyperglycemia 
(36.4%), decreased appetite, stomatitis and pruritus (30.3% each), diarrhea (24.2%), weight loss 

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(21.2%), fatigue (18.2%), platelet count decreased and white blood cell count decreased (12.1% 
each), and nausea, AST elevated, neutropenia, blood creatinine increased, proteinuria and hepatic 
dysfunction (9.1% each).  
The most frequently reported Grade 3 and above study drug related TEAEs were hyperglycemia 
(24.2%), skin rash (18.2%), pruritus (12.1%), stomatitis (9.1%), and fatigue (6.1%). 
In summary, preclinical evaluation demonstrates that overall, ATG-008 has an acceptable 
benefit-to-risk ratio with signals of antitumor activity observed across several tumor types, including 
encouraging tumor responses in sorafenib-refractory HCC. Data from the first-in-human phase 1/2 
study suggest that the safety profile of ATG-008 is comparable in scope to other mTOR pathway 
inhibitors.  Based on the aggregate safety, PK and pharmacodynamic data available, a ATG-008 
dose regimen of 30 mg QD has been selected.  
According to the previous study results, the sponsor plans to continue to enroll approximately 40 
hepatitis B virus (HBV) positive, unresectable HCC subjects who have previously received at least 
one prior line of systemic therapy. Among which, approximately 20 subjects will receive oral 
ATG-008 at an initial dose of 45 mg/QD and another 20 subjects will receive oral ATG-008 at an 
initial dose of 20 mg/BID. The pharmacokinetic (PK) samples will be collected from 10 subjects 
each in the two dose groups. The monotherapy will be further evaluated in subjects with 
unresectable, sorafenib-refractory HCC. 
The current Investigator’s Brochure contains more detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of ATG-008. 
1.4 
Study Rationale 
There remains a high unmet medical need for effective therapies for subjects with unresectable 
HCC refractory to, or following failure of, at least one prior line of systemic therapy. A strong 
biologic rationale exists for targeting of the mTOR pathway in HCC, in particular inhibition of 
pAKT. ATG-008, an mTOR kinase inhibitor targeting both TORC1 and TORC2 complexes, has 
demonstrated promising preclinical and clinical activity against HCC, especially in HBV+ HCC 
subjects. Furthermore, resistance to sorafenib can be mediated by mTOR pathway activation 
lending further support to the development of ATG-008 in unresectable HCC in the second-line 
setting.  
As described earlier, the greatest incidence and mortality of HBV+ HCC patients are in Asian 
countries (especially in China), and this contrasts sharply with western countries. It is critical to 
have effective treatment for patients failed at least one prior line of systemic therapy in Asian 
subjects. 
➢ Clinical efficacy: compared to the study results of Celgene, the current preliminary 
clinical study data of this study showed that ATG-008 treatments with 15 mg and 
30 mg were effective, but the expected tumor control rate had not been observed yet. It 
was preliminarily considered that the best dose range of ATG-008 might have not been 
achieved. 
According to the results of study CC-223-ST-001-B which has been completed by Celgene, the 
ORR of solid tumor HCC cohort was 5.7% (3/53), among which, the best efficacy of 3 subjects 
(all had positive HBV) was PR and 2 of them were treated with 45 mg/QD ATG-008 (the 
maximum tolerated dose [MTD] of ATG-008 monotherapy was 45 mg/day, the intolerable dose 
was 60 mg/day). 
As of 18 Jul 2019, the preliminary clinical study data showed that this study enrolled a total of 35 
HCC subjects (all were Asian, among which, 15 subjects were from Chinese mainland, 13 from 

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Korea and 7 from Taiwan. 7 subjects received oral ATG-008 at the initial daily dose of 15mg and 
28 subjects received 30mg). Among 35 subjects, 1 subject achieved PR, 14 subjects achieved SD, 
19 subjects achieved PD and 1 subject still received the first cycle of treatment and no efficacy 
evaluation has been performed yet. The survivors accounts for approximately 65.7% (23/35). The 
diameter of the targeted lesions of tumors decreased after treatment from baseline in 38.2% 
(13/34) subjects. Currently, subjects who received the longest treatment had completed 11 cycles 
of treatment. 
➢ Clinical safety: the safety profile currently observed in this study was similar to the 
results of foreign studies completed by Celgene and that of mTOR targeted drugs 
The most common related TEAEs in study CC-223-ST-001 completed by Celgene were decreased 
appetite (64.2%), diarrhea (60.4%), fatigue (60.4%), hyperglycemia (60.4%), nausea (50.9%), 
aspartate aminotransferase increased (43.4%) and pruritus (34%). 
No suspected and unexpected serious adverse reactions (SUSAR) were reported in this study. One 
case of DLT was observed in 15mg dose group and no DLT in 30mg group. The most frequently 
reported study drug-related TEAEs were skin rash and hyperglycemia (45.7% each), decreased 
appetite and pruritus (31.4% each), diarrhea and stomatitis (28.6% each), weight loss (22.9%), 
fatigue and platelet count decreased (20.0% each), white blood cell count decreased, mouth 
ulceration and proteinuria (17.1% each), nausea, hepatic dysfunction and hand-foot syndrome 
(14.3% each), discomfort and AST elevated (11.4% each). 
As ATG-008 is firstly and orally administered hepatitis B virus (HBV) positive, HCC Asian 
subjects who have previously received at least one prior line of systemic therapy in this study, the 
overall safety profile of ATG-008 is similar to that of foreign clinical studies in Europe and 
America, and no unexpected new safety signal is reported, it is further confirmed that ATG-008 is 
well tolerated and further dose escalation is allowed. 
➢ Clinical PK: the PK profile of this study was similar to the PK profile of foreign 
patients in Europe and America 
The foreign study (Europe and America) CC-223-ST-001-Part A demonstrated that the unchanged 
ATG-008 showed linear relationship within the dose range of 7.5 mg~60 mg, and the exposure 
level of metabolite M1 also presented linear relationship with the dose. 
The preliminary PK results of this study (ATG-008 15 mg and 30 mg) showed that the exposure 
level of active compound and its metabolite presented linear relationship with the dose. Compared 
with PK parameters of foreign studies in Europe and America, the active compound had 
numerically higher Cmax and shorter Tmax. The active compound and its metabolite had similar 
elimination rate (in different dose groups). Analysis of difference in PK parameters in Europe, 
America and Asia showed that the difference in exposure level mainly caused by Cmax difference, 
which might be related to lighter body weight and smaller volume of distribution of Asian patients. 
According to the currently available data, it was estimated that the exposure level of 20 mg/BID 
might be lower than that of 45 mg/QD, supporting that the administration mode BID could be 
explored in this study. 
According to the above clinical efficacy, safety and PK study results, the sponsor proposes to add 
2 dose groups, i.e., 45 mg/QD and 20 mg/BID (approximately 20 subjects each), to further explore 
and evaluate the PK, safety, tolerability and efficacy of ATG-008 in advanced HBV+ HCC 
subjects. 
1.4.1 Rationale for Dose of ATG-008 
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required due to mitigate toxicity: The numbers of subjects with dose reductions for subjects 
starting at the 30 mg and 45 mg dose levels were 12/28 (42.9%) and 18/25 (72.0%), respectively; 
median time to first dose reduction due to a TEAE was 43.0 days and 26.5 days, respectively. 
Despite the dose reductions, encouraging signals of activity were observed in the HCC cohort 
including three subjects that met the criteria for radiologic PR (> 30% reduction in target lesions) 
at the first restaging evaluation after 2 cycles of treatment, reduction in SUV uptake by PET, and 
reductions in AFP. All 3 HCC subjects in phase 2 with radiologic PR were HBV+, required dose 
reduction to 30 mg.  
Based on the high frequency of dose reductions, 45 mg daily was not considered to be an 
acceptable dose for further study in unresectable HCC. A dose of 30 mg daily was well tolerated in 
most subjects and resulted in near maximal mTOR biomarker [pAKT, pS6 and phosphorylated 
4E-binding protein 1 (P4EBP1)] inhibition in blood with at least 40% to 70% inhibition of each 
marker. Plasma ATG-008 drug exposures at 30 mg also exceeded levels associated with mTOR 
biomarker inhibition and antitumor activity in preclinical tumor xenograft models. In addition, the 
most durable tumor response was observed in a subject with breast cancer at the 30-mg dose level 
during phase 1 of the study. Antengene believes these data support the selection of 30 mg QD as 
the most appropriate dose of ATG-008 and 15 mg QD and 30 mg QD for PK study in unresectable 
HCC in the study. 
Moreover, the pre-clinical study results (Study AP2908) showed that ATG-008 treatment group 
had dose- and dosing regimen- dependent tumor inhibition: when the drug was administered at 5 
and 10 mg/kg BID, it was demonstrated that significant dose-dependent tumor volume decrease 
was observed under the two dose levels (65% and 80% in 5 and 10 mg/kg, respectively, p<0.001). 
After the last administration, the total plasma AUC10h was 8.6 and 23.7 μM·h in 5 and 10mg/kg 
dose levels, respectively. The 65% tumor volume decrease confirmed that the minimum effective 
dose required to inhibit PC3 tumor growth was 5 mg/kg BID. In PC3 tumors, the PK/PD 
relationship indicated that > 80% inhibition of pS6RP and > 60% inhibition of pAKT Ser473 were 
obtained at total drug plasma concentrations greater than 0.2 μM. Maintenance of plasma levels > 
0.2 μM and this degree of biomarker inhibition degree through BID dosing for 8 hours confers 
good anti-tumor efficacy in PC3 tumors. U87MG human glioblastoma and xenograft models of 
HCT-116 human colorectal tumor also showed that ATG-008 had dose and dosing 
regimen-dependent tumor inhibition.  Moreover, approximately 50% of HCT-116 tumor volume 
decrease was observed at the dose level of 10 mg/kg BID. 
According to the results of study CC-223-ST-001-B which has been completed by Celgene, 
substantial biomarker inhibition of p4E-BP1 (>40% median inhibition at C1D15-1.5 hours) and 
pAKT (>70% median inhibition at C1D15-1.5 hours) had been achieved under MTD of the dose 
of 45 mg/QD. The median inhibition rate of p4E-BP1 and pAKT after the first dosing was slightly 
lower at the lower dose of 30 mg/QD. However, during the later administration period, inhibition 
of two biomarkers had no dose-related difference. 
In addition, according to the results of study CC-223-ST-001-B which has been completed by 
Celgene, the ORR of solid tumor HCC cohort was 5.7% (3/53), among which, the best efficacy of 
3 subjects (all had positive HBV) was PR and 2 of them were treated with 45 mg/QD ATG-008 
(the maximum tolerated dose (MTD) of ATG-008 monotherapy was 45 mg/day, the intolerable 
dose was 60 mg/day). Compared to the study results of Celgene, the current preliminary clinical 
study data of this study showed that ATG-008 treatments with 15 mg and 30 mg were effective, 
but the expected tumor control rate had not been observed yet. It was preliminarily considered that 
the best dose range of ATG-008 might have not been achieved. 
Meanwhile, the PK profile of this study was similar to the PK profile of foreign patients 

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(indicating that PK profile of ATG-008 showed linear relationship). Based on the clinical 
observation results, low dose of ATG-008 can achieve steady state plasma concentration at which 
the drug exert effect, indicating that the administration mode of BID at a low dose may have 
certain advantage on maintaining effective steady state concentration compared to the 
administration mode of QD.  
According to the above bases, this study proposes to add 2 dose groups, i.e., 45 mg/QD and 
20 mg/BID (approximately 20 subjects each), to further explore and evaluate the PK, safety, 
tolerability and efficacy of ATG-008 in advanced HBV+ HCC subjects. 
 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 
To evaluate pharmacokinetics (PK), safety, tolerability and overall response rate (ORR) of 
ATG-008 in HBV+ HCC subjects who have received at least one prior line of systemic 
therapy. 
2.2 
Secondary Objectives 
 
To evaluate overall survival (OS) 
 
To evaluate time to progression (TTP) 
 
To evaluate progression-free survival (PFS) 
 
To evaluate disease control rate (DCR) 
 
To evaluate duration of response (DOR)  
 
To evaluate time to response (TTR) 
 
To evaluate survival rate 
 
3. 
STUDY ENDPOINTS 
3.1 
Primary Endpoint 
 
Cmax, AUC, tmax, T1/2, CL/F and Vd/F of ATG-008 and M1 after single and multiple doses. 
 
The incidence of treatment emergent adverse events (TEAEs), SAEs, laboratory 
abnormalities and other safety parameters 
 
ORR: Percentage of subjects with PR, or CR 
3.2 
Secondary Endpoints 
 
Kaplan-Meier estimate of OS 
 
TTP: the time from the first dose date until disease progression  
 
PFS: the time from the first dose date until disease progression or death from any cause 
 
DCR: the percentage of subjects with CR, or PR or stable disease (SD)  
 
DOR: the time from the criteria are first met for CR/PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented 
 
TTR: the time from the first dose date to the first documentation of response of PR or better.  
 
6, 9 and 12 month of survival rate (percentage of patients alive) 
 
4. 
OVERALL STUDY DESIGN 
4.1 
Study Design 
ATG-008-HCC-001 is a MRCT trial in which ATG-008 will be administered orally in HBV+ 
HCC subjects who have received at least one prior line of systemic therapy in Asian countries. 
The trial is designed as an open-label phase 2 trial to assess PK, safety, tolerability and efficacy of 
oral ATG-008 administered until the appearance of radiologic disease progression (according to 
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data are available.  
According to the previous study results, the sponsor will plan to continue to enroll approximately 
40 hepatitis B virus (HBV) positive, unresectable HCC subjects who have previously received at 
least one prior line of systemic therapy. Among which, approximately 20 subjects will receive 
oral ATG-008 at an initial dose of 45 mg/QD and another 20 subjects will receive oral ATG-008 
at an initial dose of 20mg/BID. The pharmacokinetic (PK) samples will be collected from 10 
subjects each in the two dose groups so as to further evaluate the PK profile of ATG-008 and its 
metabolites. 
If the overall response rate (ORR) of tumor is greater than 15% in the study dose group 
(45 mg/QD or 20 mg/BID), then this study will be expanded to enroll additional approximately 
110 subjects using ORR as the primary study endpoint, to further evaluate the efficacy and safety 
of ATG-008. 
At the discretion of the Investigator, treatment may continue beyond radiologic progression until 
symptomatic deterioration if no other therapeutic options are available. Subjects may also receive 
best supportive care according to local practice. All subjects will continue to be followed after 
treatment discontinuation for radiologic tumor response until disease progression, death or 
withdrawal of consent (as defined in Section 6.4, if applicable) and new anticancer treatments 
until death or withdrawal of consent. Subjects will also be followed for survival until death or 
withdrawal of consent. 
The starting dose of ATG-008 will be 15 mg daily for 28 days each cycle for the first 6 fully 
evaluable (including PK outcomes) subjects. Providing DLTs occur in less than 2 of 6 subjects who 
complete Cycle 1, additional 24 subjects will be enrolled at the starting dose of 30 mg daily. 
Subjects who tolerated the 15-mg dose level for at least 1 cycle may then dose-escalate to 30 mg at 
the Investigator’s discretion. 
DLTs included hyperglycemia, rash, fatigue, and mucositis, any of which ≥ grade 3, based on 
CC-223-ST-001 results. 
The trial will consist of the following periods: 
 Screening (see Section 6.1) 
 Treatment (see Section 6.2) 
 End of treatment (see Section 6.2.1) 
 Follow-up (see Section 6.3) 
 
 

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Figure 1: 
Overall Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: HCC = hepatocellular carcinoma 
1 Evaluations also may stop if the subject withdraws consent, or is lost to follow-up. 
4.2 
Study Design Rationale 
The HCC subject population who received at least one prior line of systemic therapy represents a 
setting of high unmet need for which few effective therapies are currently available. Strong 
biologic rationale exists for targeting both the TORC1 and TORC2 signaling pathways in this 
disease. High basal mTOR pathway activation, including pAKT, is mediated through multiple 
genetic and epigenetic mechanisms and is present in the majority of HCC tumors. Furthermore, 
PI3K/mTOR pathway activation represents a potential mechanism of resistance to sorafenib. 
Encouraging signals of anti-tumor activity with ATG-008, including radiologic tumor regression 
and prolonged SD, have been observed and warrant further investigation of this drug in this 
population. 
The selected ATG-008 dose of 30 mg QD represents a dose with an acceptable safety and activity 
profile and anticipated dose reductions in less than 30% of subjects. While 45 mg QD was 
established as the MTD during the phase 1 dose escalation of the CC-223-ST-001 study, further 
experience with this dose during the expansion phase demonstrated an unacceptably high rate of 
dose reductions due to toxicity. Following dose reduction to 30 mg QD, most subjects were able to 
tolerate this lower dose without further dose modifications. Drug exposures at 30 and 45 mg 
demonstrated near maximal mTOR pathway inhibition in blood of both TORC1 (by pS6) and 
TORC2 (by pAKT) at both dose levels. Clinical antitumor activity was observed at 30 mg QD 
including a durable PR in a subject with breast cancer treated in the 30-mg dose escalation cohort. 
An open-label trial is acceptable and appropriate given limited effective second-line and later 
Phase 2 
Screening: unresectable HBV+ advanced HCC 
subjects who previously received at least one prior 
line of systemic therapy (Day -28 to Day -1) 
ATG-008 15mg/d dose study 
(N=6) 
ATG-008 30mg/d dose study 
(N=24) 
ATG-008 45mg/d dose study 
(N=20) 
ATG-008 20mg/d dose study 
(N=20) 
End of Treatment 
Treat until radiologic results showing disease 
progression, death, subject/investigator’s decision to 
stop or unacceptable toxicity; 
Post-treatment Follow-up 
End of treatment 
Safety evaluation, 28 days after treatment 
Tumor evaluation until radiologic results showing 
disease progression, new anti-cancer therapy, or death1 
Survival follow-up until death 
Post-treatment Follow-up 
End of treatment 
Safety evaluation, 28 days after treatment 
Tumor evaluation until radiologic results showing 
disease progression, new anti-cancer therapy, or death1 
Survival follow-up until death 
End of Treatment 
Treat until radiologic results showing 
disease 
progression, 
death, 
subject/investigator’s decision to stop 
or unacceptable toxicity; 
ATG-008 45 mg/d or 20 mg/Bid dose study 
(N=110) 
Screening: unresectable HBV+ advanced HCC 
subjects who previously received at least one 
prior line of systemic therapy (Day -28 to Day 
-1)
Expansion 
If 
ORR>15%, 
additional 
approximately 
110 subjects will 
be enrolled.

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therapies in unresectable HCC. The high frequency of HCC in the Asia-Pacific region warrants 
inclusion of Asian countries in this MRCT study.  
The starting dose of ATG-008 will be 15 mg daily for 28 days each cycle for the first 6 fully 
evaluable (including PK outcomes) subjects. Providing DLTs occur in less than 2 of 6 subjects who 
complete Cycle 1, additional 24 subjects will be enrolled at the starting dose of 30 mg daily. 
Subjects who tolerated the 15-mg dose level, may then dose-escalate to 30 mg at the Investigator’s 
discretion until enrollment of 30-mg group starts.  
As of 18 Jul 2019, the preliminary clinical study data showed that this study enrolled a total of 35 
HCC subjects (all were Asian, among which, 15 subjects were from Chinese mainland, 13 from 
Korea and 7 from Taiwan). 7 subjects received oral ATG-008 at the initial daily dose of 15 mg and 
28 subjects received 30 mg). Among 35 subjects, 1 subject achieved PR, 14 subjects achieved SD, 
19 subjects achieved PD and 1 subject still received the first cycle of treatment and no efficacy 
evaluation has been performed yet. The survivors accounts for approximately 65.7% (23/35). The 
diameter of the targeted lesions of tumors decreased after treatment from baseline in 38.2% (13/34) 
subjects. Currently, subjects who received the longest treatment had completed 11 cycles of 
treatment. 
No suspected and unexpected serious adverse reactions (SUSAR) were reported in this study. One 
case of DLT was observed in 15 mg dose group and no DLT in 30 mg group. The most frequently 
reported study drug-related TEAEs were skin rash and hyperglycemia (45.7% each), decreased 
appetite and pruritus (31.4% each), diarrhea and stomatitis (28.6% each), weight loss (22.9%), 
fatigue and platelet count decreased (20.0% each),  white blood cell count decreased, mouth 
ulceration and proteinuria (17.1% each), nausea, hepatic dysfunction and hand-foot syndrome 
(14.3% each), discomfort, and AST elevated (11.4% each). 
Consequently, ATG-008 is firstly and orally administered hepatitis B virus (HBV) positive, HCC 
Asian subjects who have previously received at least one prior line of systemic therapy in this 
study, the preliminary efficacy has been observed, the overall safety profile of ATG-008 is similar 
to that of previous foreign clinical studies and similar drugs, and no unexpected new safety signal is 
reported, it is further confirmed that ATG 008 is well tolerated. 
In addition, according to the results of study CC-223-ST-001-B which has been completed by 
Celgene, the ORR of solid tumor HCC cohort was 5.7%, among which, the best efficacy of 3 
subjects (all had positive HBV) was PR and 2 of them were treated with 45 mg ATG-008 daily (the 
maximum tolerated dose (MTD) of ATG-008 monotherapy was 45 mg/day, the intolerable dose 
was 60 mg/day). 
Considering the observed preliminary efficacy and favorable safety and tolerability of ATG-008, 
this study proposes to continue to enroll approximately 40 subjects to receive ATG-008 at an initial 
dose of 45 mg/QD or 20 mg/BID (approximately 20 subjects each) to further evaluate the PK, 
safety, tolerability and efficacy of ATG-008. 
If ORR of tumor is greater than 15% in the study dose group (45 mg/QD or 20 mg/BID), then this 
study will be expanded to enroll additional approximately 110 subjects using ORR as the primary 
study endpoint, to further evaluate the efficacy and safety of ATG-008.  
4.3 
Study Duration 
The screening period will last up to 28 days. Once treatment begins, subjects will remain on 
ATG-008 until radiologic disease progression (according to RECIST 1.1), toxicity, subject or 
physician decision, withdrawal of consent, or death. It is expected that most subjects will receive 
study drug for 1 to 12 months. If treatment is discontinued for reasons other than disease 

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progression or death or withdrawal of consent, subjects will be followed for radiologic progression 
until disease progression. Regardless of treatment status, all subjects will be followed for survival 
until death or study discontinuation. 
According to the previous study results, the sponsor will continue to enroll approximately 
40 subjects. Approximately 6 months are needed for enrollment period. Completing PK (PK 
samples will be collected from 10 subjects each in the two dose groups), safety and preliminary 
efficacy evaluations is expected to take approximately 6 months.  
 
4.4 
End of Trial 
The end of Study is defined as either the date of the last visit of the last subject to complete the 
trial, or the date of receipt of the last data point (e.g., date of death) from the last subject that is 
required for analysis, whichever is the earlier date. 
 

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5. 
TABLE OF EVENTS 
Table 3: Table of Events 
 
 
Screening 
Period 
Treatment Period 
Follow-up Period 
 
Screening 
Cycle 1 
(single 
dosing) 
Cycle 1 
(continuing 
dosing) 
Cycle 2 
Subsequent cycles 
End of Treatment 
 
Study Daya 
-29 to -2b 
-1 
0 
1 
15 
1 
15 
1 
 
Disease 
progression/ 
survival 
Study Entry 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Prior cancer history 
X 
 
 
 
 
 
 
 
 
 
Prior cancer therapies c 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
 
 
 
Prior/ concomitant 
medication evaluation 
X 
 
 
Continuous, until 28 days after treatment discontinuation  
Prior/ concomitant 
procedures evaluation 
X 
 
 
Continuous, until 28 days after treatment discontinuation  
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 

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Table 3: Table of events (continued) 
 
 
Screening 
Period 
Treatment Period 
Follow-up Period 
 
Screening 
Cycle 1 (single 
dosing) 
Cycle 1 
(continuing 
dosing) 
Cycle 2 
Subsequent cycles 
End of 
Treatment 
Study Daya 
-29 to -2b 
-1 
0 
1 
15 
1 
15 
1 
 
Disease 
progression/ 
survival 
Investigational Product 
Administer ATG-008 
 
X 
 
Daily, continuously 
 
 
Safety Assessment 
Adverse event collection 
Continuous starting after informed consent signature, until 28 days after last dose of IP 
Weight 
X 
 
 
X 
 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Hematology laboratory 
X(-7 to -1) 
 
 
 
X 
X 
X 
X 
X 
 
Coagulation function test 
X(-7 to -1) 
 
 
 
 
X 
 
X 
 
 
Fasting chemistry 
laboratory test 
X(-7 to -1) 
 
 
 
X 
X 
X 
X 
X 
 
Special chemistry: 
Amylase, lipase, TSH, fT4 
X(-7 to -1) 
 
 
 
 
X 
 
X 
 
 
 
 
 
 

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Table 3: Table of events (continued) 
 
 
Screening 
Period 
Treatment Period 
Follow-up Period 
 
Screening 
Cycle 1 (single 
dosing) 
Cycle 1 
(continuing 
dosing) 
Cycle 2 
Subsequent 
cycles 
End of 
Treatment 
Study Daya 
-29 to -2b 
-1 
0 
1 
15 
1 
15 
1 
 
Disease 
progression/ 
survival 
HbA1c 
X(-7 to -1) 
 
 
 
 
 
 
Every other cycle 
starting in Cycle 3 
 
 
AFP 
X 
 
 
 
 
X 
 
X 
X 
 
HBV and HCV serologies 
(HBsAg, 
HBeAg, 
HBsAb, 
HBeAb, HBcAb, HCVAb) 
X 
 
 
 
 
 
 
 
 
 
HBV viral loadd 
X 
 
 
 
 
X 
 
X 
 
 
Urine routine 
X(-7 to -1) 
 
 
 
X 
X 
X 
X 
 
 
12-lead electrocardiogram 
(local assessment) 
X 
 
 
 
 
 
 
 
X 
 
Serum β-hCG (in FCBP) 
X 
 
 
As clinically indicated 
 
Urine β-hCG（FCBP） 
Xe (-72 hrs to 0 
hr from dosing)  
 
 
 
X 
 
X 
X 
 
PK samples(blood)f 
 
X 
X 
X 
X 
 
 
 
 
 
PK samples (urine) g 
 
X 
X 
 
 
 
 
 
 
 
 
 
 

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Table 3: Table of events (continued) 
 
 
a  All visits have a ± 3 day window, except Cycle 1 Day 1 (which must occur within 28 days of signing the ICF). 
b Screening assessments must be performed prior to study treatment, however these events may occur on the same calendar day as long as the chronological order is followed. 
c   Prior cancer therapies includes surgery, radiation, systemic, locoregional or any other therapy (e.g. hormonal) for the subject's cancer. 
d  HBV viral load is collected in subsequent cycles only in subjects with chronic HBV infection, positive HBeAg, positive HBcAb or positive viral load at screening. 
e  Urine β-hCG (or local serum) at screening within 72 hours of Cycle 1 Day -1 dose. 
f  PK samples (blood) should be taken at each scheduled day, according to the schedule in Section 6.5.1. 
g  PK samples (urine) should be taken at each scheduled day, according to the schedule in Section 6.5.2. 
 
 
 
Screening 
Period 
Treatment Period 
Follow-up Period 
 
Screening 
Cycle 1 
(single 
dosing) 
Cycle 1 
(continuing dosing) 
Cycle 2 
Subsequent 
cycles 
End of 
Treatment 
Study Daya 
-29 to -2b 
-1 
0 
1 
15 
1 
15 
1 
 
Disease progression/ 
survival 
Efficacy Assessments 
Tumor assessments (CT/MRI, see Section 
6.4) 
X 
 
 
Every 8 weeks (± 5 days) from enrollment (first dose), until radiologic progression 
ECOG performance status 
X 
 
 
X 
 
X 
 
X 
X 
 
Follow-up 
Survival follow-up 
 
 
 
 
 
 
 
 
 
Every 8 weeks (± 1 
week) 
Anticancer therapy after treatment 
discontinuation 
 
 
 
 
 
 
 
 
 
Every 8 weeks (± 1 
week) 

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6. 
PROCEDURES 
6.1. 
Screening Period 
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 28 days of first dosing except as noted below (e.g., 
eligibility laboratory assessments). All screening assessments must be performed prior to 
enrollment (first dose) and subsequently treatment, however these events may occur on the 
same calendar day as long as the chronological order is followed. 
Any questions regarding subject eligibility should be directed to the Antengene Medical 
Monitor or designee. Waivers to the protocol will not be granted during the conduct of this 
trial, under any circumstances. 
Unless otherwise specified, all laboratory analysis will be performed at site. Screening 
eligibility criteria laboratory values must be performed within 7 days of the first dose of study 
drug and demonstrate subject eligibility. Screening assessments may be repeated within the 
screening window if necessary, and the most recently obtained result should be used to 
demonstrate eligibility. Other laboratory evaluations not specifically designated to be 
performed within 7 days of the first dose of study drug can be performed at any time during 
Screening, however for convenience it is recommended they be collected at the same time. 
The screening assessments which are study specific (such as assessment samples need to be 
taken and sent centrally) and are belong to local clinical routine practice, can be accepted if 
they are done before ICF taken. 
Subjects should fast for at least 6 hours prior to those clinical visits which require evaluation 
of PK and fasting chemistry examination. 
The following will be performed at screening and specified in the Table of Events, Table 3: 
• Informed consent. 
• Demographics (age, gender, race, height, weight, region). 
• Prior cancer history (including specific information regarding diagnosis, staging, 
and histology). 
• Prior cancer therapies: Includes surgery, radiation, systemic, locoregional, or any 
other therapy (e.g. hormonal) for the subject’s cancer (reason for discontinuation 
of prior therapies, e.g. disease progression, intolerance or others, should be 
recorded as well). 
• Medical history (includes relevant medical conditions occurring > 28 days before 
screening should also be included). 
• Prior and concomitant medication evaluation (includes those taken ≤ 28 days 
before the screening visit, except those taken for cancer which are recorded as 
part of prior cancer therapy). 
• Prior and concomitant procedures (includes all procedures occurring ≤ 28 days 
before the screening visit). 
• Adverse event evaluation (begins when the subject signs the informed consent 
form [ICF]). 
• Vital signs (including blood pressure, temperature and pulse). 
• Hematology: Complete blood count (CBC) with differential, including red blood 
cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count with 
absolute differentials (neutrophils, lymphocytes, monocytes, eosinophils and 

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basophils), and platelet count; within 7 days of the first dose of study drug. 
• Coagulation panel: Prothrombin time (PT), international normalized ratio (INR), 
partial thromboplastin time (PTT); within 7 days of the first dose of study drug. 
• Fasting chemistry laboratory: Includes sodium, potassium, chloride, calcium, 
magnesium, phosphorus, glucose, blood urea nitrogen (BUN), creatinine, 
albumin, total protein, alkaline phosphatase, bilirubin (total and direct), aspartate 
amino transferase (AST/SGOT), alanine amino transferase (ALT/SGPT), lactate 
dehydrogenase (LDH), uric acid, cholesterol and triglycerides; within 7 days of 
the first dose of study drug. 
• Special chemistry laboratory: Amylase, lipase, thyroid stimulating hormone 
(TSH), free T4 (fT4); within 7 days of the first dose of study drug. 
• Hemoglobin A1c (HbA1c) within 7 days of the first dose of study drug. 
• AFP. 
• Hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies (hepatitis B 
surface antigen [HBsAg], hepatitis B e antigen [HBeAg], hepatitis B surface 
antibody [HBsAb], hepatitis B e antibody [HBeAb], hepatitis B core antibody 
[HBcAb], hepatitis C virus antibody [HCVAb]). 
• HBV viral load. 
• Urine routine within 7 days of the first dose of study drug. 
• 12-lead electrocardiogram (ECG), single local assessment; when an ECG 
time-point coincides with any other assessment, the ECG should always be 
collected first. 
• Pregnancy test (β-hCG) is required for all female subjects of child-bearing 
potential. Serum β-hCG pregnancy test will be performed at screening. A urine 
(or local serum) pregnancy test will be performed to assess subject eligibility 
within 72 hours prior to the first administration of study drug. 
• Response assessment/tumor evaluation (see Section 6.4). Tumor scans (CT/MRI) 
evaluable per RECIST 1.1 performed ≤ 28 days prior to first dose of study drug 
need not be repeated for the purposes of screening. For stratification purposes, 
macroscopic vascular invasion is defined as HCC involvement of branches of 
portal or hepatic veins detected by gross pathological examination or radiological 
imaging; extrahepatic spread is defined as HCC involvement of organs or lymph 
nodes outside liver. 
• ECOG performance status. 
 
 

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6.2. 
Treatment Period 
After signed the ICF within 28 days, the eligible subjects must start treatment as soon as 
possible. For all subsequent visits, an administrative window of ± 3 days is permitted, 
otherwise specified. 
Subjects will receive a single dose of ATG-008 on Day -1, followed by a 48-hour observation 
for PK sample collection.  
• 
Oral daily dosing of 15 mg or 30 mg begin on Day 1 and will continue in 28-day cycles  
• 
It is planned that approximately 20 subjects will receive oral ATG-008 at an initial dose 
of 45 mg/QD and another 20 subjects will receive oral ATG-008 at an initial dose of 
20 mg/BID. The 28 continuous days are regarded as one treatment cycle. The 
pharmacokinetic (PK) samples will be collected from 10 subjects each in the two dose 
groups. 
The subjects will continue to use ATG-008 until radiologic disease progression, intolerable 
toxicities, or withdrawal of consent for further dosing (in which case subjects will continue to 
be followed for further anticancer treatment and survival status unless consent for this has 
been explicitly withdrawn). Subjects will fast ≥ 6 hours before those clinical visits which 
require evaluation of PK and fasting chemistry examination. PK, safety and tolerability for 
the 30-mg dose level will follow the assessment of the 15-mg dose level if DLTs occur in less 
than 2 of 6 subjects at the 15-mg dose level who complete Cycle 1. 
The following evaluations will be performed at the frequency specified in the Table of Events, 
Table 3. The evaluations should be performed prior to dosing on the visit day, unless 
otherwise specified.  
 
Adverse event evaluation (continuously) 
 
Concomitant medications evaluation (including medications for best supportive 
care) 
 
Concomitant procedures evaluation 
 
ECOG performance status 
 
Vital signs, weight 
 
Hematology laboratory 
 
Coagulation panel 
 
Fasting chemistry laboratory 
 
Special chemistry laboratory 
 
HbA1c  
 
Urine routine 
 
AFP 
 
HBV viral load (in subjects with positive HBsAg, HBeAg HBcAb or positive 
viral load at screening). 
 
Urine β-hCG (females of childbearing potential (FCBP) only) 
 
Radiologic response assessment/tumor evaluation and assessment of disease 
progression (see Section 6.4) 

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 
PK sampling (see Section 6.5) 
Detailed evaluations are listed in Table 3. 
6.2.1 End of Treatment 
An end of treatment (EOT) evaluation should be performed for subjects who are withdrawn 
from treatment for any reason as soon as possible after the decision to permanently 
discontinue treatment has been made. 
The following evaluations will be performed as specified in the Table of Events: 
 
Adverse event evaluation 
 
Concomitant medications evaluation 
 
Concomitant procedures evaluation 
 
Vital signs and weight. 
 
Hematology laboratory 
 
Fasting chemistry laboratory 
 
AFP 
 
12-lead ECG, single local assessment 
 
Urine β-hCG (FCBP only) 
For subjects who discontinue study drug for reasons other than radiologic progression (or 
withdrawal of consent for additional follow-up procedures), tumor evaluations will be 
continued at the schedule defined in the Table of Events Table 3, and do not need to be 
performed specifically for the EOT visit. 
6.3. 
Follow-up Period 
6.3.1 28-day Follow-up 
All subjects will be monitored for reporting of new or follow-up of existing AEs for 28 days 
after the last dose of study drug. Any clinically relevant assessments or laboratory 
parameters should have unscheduled assessments conducted until resolution, at the 
discretion of the Investigator. 
6.3.2 Efficacy Follow-up 
All subjects who discontinue treatment for reasons other than disease progression, death or 
withdrawal of consent for post-treatment follow-up procedures will continue to undergo 
response assessments and collection of new anticancer therapies as specified in Section 6.4. 
6.3.3 Survival Follow-up 
After the last dose of study drug, all subjects will be followed every 8 weeks (± 1 week) for 
survival until death or lost to follow-up. Even when subjects withdraw consent for further 
treatment, every effort should be made to obtain post-treatment follow-up information which 
includes new anticancer therapies and survival status. 
Survival follow-up may be conducted by record review and/or telephone contact with the 
subject, family or the subject’s treating physician. 
6.4. 
Response Assessments 
Tumor response assessments should be performed in Screening (up to 28 days before the 
start of study drug) and every 8 weeks (± 5 days) from the first dose date until disease 
progression, death or withdrawal of consent from additional follow-up procedures. Tumor 

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assessments includes imaging (CT or MRI) of the chest, abdomen and pelvis at baseline. 
Subjects with brain lesions will have brain scans at screening and at each tumor 
assessment. After Screening, tumor assessments will be performed on completion of C2, 
C4 and C6 (i.e,, C3, 5 and 7/Day1±7 days) using the same scanning modalities used at 
baseline. Corticosteroids (if used) dosage must be stable ≥ 5 days prior to all scans. EOT 
scan need not be repeated if prior scan was < 28 days.  
If a subject discontinues study drug due to toxicity, subject or physician decision, the 
collection of response assessments should continue at the same schedule. Additionally, if a 
subject continues treatment beyond radiologic disease progression until symptomatic 
deterioration (see Appendix A, Section 19.1.2.4), tumor evaluations should continue until 
study drug is stopped. Evaluation of response should be performed using RECIST 1.1 
guidelines.  
New anticancer therapy includes any systemic medication, locoregional therapy, surgery, 
radiation or any other therapy intended to treat the subject’s cancer. 
6.4.1 Assessment of Radiologic Response According to RECIST 1.1 
Response will be assessed using RECIST 1.1 Appendix. Response assessments (tumor 
evaluations) include computed tomography (CT) scan or magnetic resonance imaging 
(MRI). The regions to be imaged are the chest, abdomen and pelvis, as well as any other 
region clinically indicated for tumor imaging. Subjects with brain metastases will have 
brain scans at Screening and at each tumor reassessment. The same mode of imaging for 
lesion evaluation at screening must be consistently used throughout the study. 
The CT imaging should include contrast unless medically contraindicated. Conventional CT 
should be performed with contiguous cuts of 5 mm or less in slice thickness. Spiral CT should 
be performed by use of a 5 mm contiguous reconstruction algorithm. 
All subjects with evidence of radiologic tumor response (CR or PR) should have the response 
confirmed with repeat assessments at the next scheduled scan, but after no less than 28 days. 
Response assessments must have occurred ≥ 5 weeks from the first dose date to be considered 
as SD for a best response. 
The Investigators will evaluate RECIST 1.1 response after each restaging and overall 
assessment. All related scans will be collected and saved for future independent central 
review.  
If ORR of tumor is greater than 15% in the study dose group (45 mg/QD or 20 mg/BID), 
then this study will be expanded to enroll additional approximately 110 subjects using ORR 
as the primary study endpoint, to further evaluate the efficacy and safety of ATG-008. 
All scans will be collected and then be reviewed centrally for independent analysis of ORR 
and other objective tumor response outcomes. mRECIST will then also be applied in tumor 
assessment, if necessary. 
Additional details and definitions of response according to RECIST 1.1 are found in 
Appendix A in Section 19.1. 
 
6.5. 
Pharmacokinetics 
PK blood samples (2 mL/sample) will be collected from each subject as described in Table 3. 
For all PK draws, the following information will be documented: The dose of study drug 
administered, the actual time of study drug dosing, the actual time of each PK sample 
collection, and the nominal or scheduled time for PK sample collection. The laboratory 
manual includes procedures for collecting, processing, storing, and shipping PK samples.  

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6.5.1 Intense Blood Sampling  
A total of 30 subjects will undergo intense PK sampling; 6 subjects at the 15-mg dose and 24 
subjects at the 30-mg dose level.  
As for the 2 dose groups 45 mg/QD and 20 mg/BID, PK samples of 10 subjects each should 
be collected. 
Blood (2 mL/sample) will be drawn at the following times in Cycle 1.  
Sampling time points for subjects received ATG-008 at the initial doses of 15 mg, 30 mg 
and 45 mg/QD: 
On Day -1: 0hr (< 15min prior to dosing), 0.5hr ± 5 mins, 1hr ± 10mins, 1.5hr ± 10mins, 3hr 
± 10mins, 5hr ± 15mins, 8hr ± 30mins, 24hr ± 60mins and 48hr ± 60mins after the first dose 
of ATG-008  
On Day 15: 0hr (< 15min prior to dosing), 0.5hr ± 5mins, 1hr ± 10mins, 1.5hr ± 10mins, 3hr 
± 10mins, 5hr ± 15mins, 8hr ± 30mins and 24hr ± 60mins after the Day 15 dose.  
Sampling time points for subjects received ATG-008 at the initial dose of 20 mg/BID: 
At Day -1: 0hr (15 minutes before dosing); the first dose of 20 mg: 0.5hr ±5min, 1hr±10min, 
1.5hr±10min, 3hr±10min, 5hr±15min, 8hr±30min and 12hr±30min; second dosing of 20 mg: 
12hr±30min after dose of ATG-008;  
At Day 15: 0hr (15 minutes before dosing); the first dose of 20 mg: 0.5hr ±5min, 1hr±10min, 
1.5hr±10min, 3hr±10min, 5hr±15min, 8hr±30min and 12hr±30min after dose of ATG-008; 
When study drug dosing has been interrupted before the Day 15 assessments, PK sampling 
should be delayed until ATG-008 has been administered continuously for at least 7 days in 
order to more accurately determine steady state kinetics.  
 
After Day 15, if the dose of ATG-008 is reduced and (optional) subject consent is obtained, 
approximately 10 days later blood will be withdrawn for additional PK assessments at the 
following times in order to conduct intrasubject assessment of PK at lower dose levels: 
Predose (< 15mins prior to dosing),  1hr ± 10mins, 1.5hr ± 10mins, 3hr ± 10mins, and 5hr ± 
15mins. 
 
6.5.2 PK urine collection  
Urine sampling time points for subjects received ATG-008 at the initial doses of 15 mg, 
30 mg and 45 mg/QD: 
Total urine collections for PK analysis on Day -1 through Day 0 will be taken over the 
following times: Predose (<30 minutes prior to dosing, to completely empty the bladder), 0-4 
hr and 4-8 hr and 8-24 hr.  
Urine sampling time points for subjects received ATG-008 at the initial dose of 20 
mg/BID: 
At Day -1: 0hr (30 minutes prior to dosing), 0-4 hr, 4-8 hr and 8-12 hr after the first dose of 
ATG-008; 
 
 

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7. 
STUDY POPULATION 
7.1 Number of Subjects 
The 35 HBV+, unresectable HCC subjects who have received at least one prior line of 
systemic therapy have been enrolled in this study. 
According to the previous study results, the sponsor plans to continue to enroll 
approximately 40 subjects to receive ATG-008 at an initial dose of 45mg/QD or 20 mg/BID. 
If ORR of tumor is greater than 15% in the study dose group (45 mg/QD or 20 mg/BID), this 
study will be expanded to enroll additional approximately 110 subjects using ORR as the 
primary study endpoint, to further evaluate the efficacy and safety of ATG-008. 
 
7.2 Inclusion Criteria 
Subjects must meet all the following criteria to be enrolled in the study: 
1. Male or female aged from 18 to 70 years (inclusive) at the time when the ICF is signed. 
2. Confirmed pathologic or radiologic diagnosis of HCC according to the American 
Association for the Study of Liver Disease (AASLD) guidelines. 
3. Unresectable stage B (intermediate) or C (advanced) HCC according to the Barcelona 
Clinic Liver Cancer (BCLC) staging. If stage B, the subject must have progressed after, 
or not be eligible for, surgical or locoregional therapy. 
4. There is at least one measurable lesion according to RECIST 1.1 criteria.  
5. HBV+ is defined as chronic HBV infection or a history of HBV infection, based on 
any of the following serologic results: HBcAb+, HBsAg+, HBV-DNA+. 
6. Received at least one prior line of systemic therapy (with radiologic disease 
progression during or following sorafenib and/or chemotherapy). Subjects with 
alternative treatments such as regorafenib and/or anti PD-1 antibodies etc. approved by 
local health authorities are allowed to enter study if they meet all other 
inclusion/exclusion criteria. 
a. Chemotherapy is defined FOLFOX (fluorouracil, leucovorin and oxaliplatin), or 
any other platinum-containing regimen. 
b. Chemotherapy ≥ two cycles 
7. ECOG performance status score of 0 or 1.  
8. Serum chemistry results, evidenced by the following: 
a. AST (SGOT) and ALT (SGPT) ≤ 5x upper limit of normal range (ULN). 
b. Total bilirubin ≤ 2 x ULN. 
c. Creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min. 
d. Lipase and amylase ≤2 x ULN; 
9. Adequate bone marrow function, evidenced by the following: 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109 cells/L. 
b. Platelets ≥ 75 x 109 cells/L. 

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c. Hemoglobin ≥ 9 g/dL. 
10. Coagulation function: international normalized ratio (INR) ≤2.0, prothrombin time 
(PT) ≤1.5 x ULN; 
11. Child-Pugh A and B7 and hepatic encephalopathy scored as 1 point; 
12. Except hearing loss and alopecia, all toxicities caused by previous anti-tumor therapies 
must recover to ≤ Grade 1 (based on NCI-CTCAE Version 4.03); 
13. Male subjects (including those who have had a vasectomy) must agree to use a condom 
during sexual intercourse with females of child-bearing potential, and shall not 
conceive a child starting from the time of ICF signature, while on study medication, 
and for 3 months after the last dose of study drug. 
14 Female subjects of child-bearing potential must have both of the following: 
a. Agree to the use of two study physician-approved contraceptive methods 
simultaneously or practice complete abstinence starting at the time of ICF 
signature, while on study medication, and for 28 days following the last dose 
of study drug. 
i. True abstinence: When this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
ii. Acceptable contraceptive methods include: Oral, injectable, or 
implantable hormonal contraceptive; intra-uterine device; barrier 
contraceptive with spermicide; or vasectomized partner, together with 
at least one barrier method. 
b. Have negative serum pregnancy test result at Screening confirmed by negative 
urine pregnancy test within 72 hours prior to first dose of study drug (if serum 
test occurred > 72 hours from first dose); pregnancy test must have a 
sensitivity of at least 25 mIU/mL. 
 
7.3 Exclusion Criteria 
The presence of any of the following will exclude a subject from enrollment: 
1. Intolerant to sofafenib/regorafenib, e.g.:  
a. The drug is discontinued due to adverse events; 
b. The related adverse events of Grade ≥2 continued/relapsed after supportive 
treatment and/or dose reduction or dose interruption at least 7 days; 
c. The treatment course is less than 21 days within 28 days before discontinuation; 
the lowest daily dose of sorafenib is 400mg/day. 
2.  Medical history of hepatic encephalopathy; 
3. Central nervous system metastases; 
4. Treatment with molecular targeted therapies such as sorafenib, regorafenib or 
lenvatinib within 4 weeks before screening; 
5. Treatment with locoregional HCC therapy (including but not limited to TACE, RFA), 
systemic chemotherapy, hormonal therapy (e.g., tamoxifen), traditional Chinese 

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medicine with anti-tumor effect, or clinical investigational drugs within 4 weeks prior 
to Screening. 
6. Tested positive for both HBV and hepatitis C virus (HCV). 
a. HCV positive is defined as anti-HCV or HCV-RNA positive 
7. Life expectancy of less than 3 months. 
8. Prior therapy with mTOR (TORC1 and/or TORC2) inhibitors including sirolimus, 
temsirolimus, everolimus and other investigational or approved mTOR/PI3K/AKT 
inhibitors. 
9. Have received major surgery within 4 weeks before screening or plan to receive major 
surgery during study period; 
10. Receiving active, ongoing treatment with systemic corticosteroids at a prednisone 
equivalent dose of ≥ 10 mg daily or other systemic immune system modulators. The 
exceptional cases of such criterion are listed as follows: 
a. Intranasal, inhaled and topical steroids or local steroid injection (e.g., 
intra-articular injection); 
b. Prednisone not more than 10 mg/day or its equivalent physiological dose of 
systemic corticosteroids; 
c. Steroids as the prophylatic medication of allergic reactions (pretreatment before 
CT scan); 
11. Imaging test results showing main portal venous tumor thrombus, inferior vena cava 
tumor thrombus or heart involvement; 
12. Uncontrolled diabetes, defined as HbA1c > 7%. 
13. Prior organ transplant. 
14. Uncontrolled pleural effusion or pericardial effusion (with clinical symptoms, 
fluctuation of effusion or requiring repeated drainage, oral  diuretics etc.) at 
screening; Ascites at screening, which can be detected by physical examination, or 
clinical symptoms caused by ascites, or requiring special treatment such as repeated 
drainage, peritoneal drug perfusion etc. (subjects who only have a small amount of 
ascites which can be detected by imaging examination can be enrolled). 
15. Persistent diarrhea or malabsorption ≥ National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE, Version 4.03) grade 2, despite 
medical management, or any significant gastrointestinal disorder that could affect the 
absorption of study drug. 
16. Medical history of active upper gastrointestinal hemorrhage, ulcer or esophageal 
varices associated with hemorrhage or such diseases within 6 months; 
17. Subjects who have medical history of human immunodeficiency virus infection and/or 
acquired immunodeficiency syndrome; 
18. Concurrent active second malignancy for which the subject is receiving therapy, 
excluding non-melanomatous skin cancer, non-progressive prostate cancer treated 
with hormonal therapy, or carcinoma in situ of the cervix. Any cancer curatively 
treated >5 years prior to entry is permitted. 
19. Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection (e.g., tuberculosis) requiring antibiotic, antifungal, or antiviral therapy (other 
than anti-HBV therapy), acute or chronic pancreatitis or psychiatric illness/social 

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situations that would limit compliance with study requirements. 
20. Subjects who have clinically significant cardiovascular diseases such as Grade Ⅱ and 
above cardiac dysfunction (New York Heart Association criteria), ischaemic heart 
diseases (e.g., myocardial infarction or unstable angina pectoris), clinically significant 
supraventricular or ventricular arrhythmia, uncontrolled hypertension (systolic blood 
pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), echocardiography 
showing ejection fraction <50%, QTc interval >450 ms (male), QTc interval >470 ms 
(female); 
21. The subject’s complications or other conditions may affect protocol compliance or 
make the subjects unsuitable to participate in this study at the discretion of the 
investigator; 
8. 
DESCRIPTION OF STUDY TREATMENTS 
8.1 Description of Investigational Product(s) 
Antengene Corporation will supply ATG-008 in 15 mg, 20 mg, and 30 mg tablets; ATG-008 
tablets are manufactured using conventional solid oral dosage form excipients. 
Study drugs are stored at room temperature at 15-25 Celsius degree. 
8.2 Treatment Administration and Schedule 
The first part of this study will consist of two cohorts. Six subjects will receive a single dose 
of 15 mg ATG-008 on Day -1 and then receive 15 mg ATG-008 daily in 28-day cycles. 
Providing dose-limiting toxicity (DLT) occur in less than 2 of those 6 subjects who complete 
Cycle 1, 24 new subjects will receive a single dose of 30 mg ATG-008 on Day-1 and then 
receive 30 mg ATG-008 daily in 28-day cycles. Subjects who tolerated the 15-mg dose level 
may then dose-escalate to 30 mg at the Investigator’s discretion. 
According to the previous study results, the sponsor will plan to continue to enroll 
approximately 40 hepatitis B virus (HBV) positive, unresectable HCC subjects who have 
received at least one prior line of systemic therapy. Among which, approximately 20 subjects 
will receive oral ATG-008 at an initial dose of 45 mg/QD and another 20 subjects will 
receive oral ATG-008 at an initial dose of 20 mg/BID. The pharmacokinetic (PK) samples 
will be collected from 10 subjects each in the two dose groups. 
Each dose of study drug will be taken at the same time each day, and can be taken with or 
without food. On clinic visit days, study drug will be administered in the clinic after all 
predose tests have been completed. Subjects should come to the clinic after fasting for 6 
hours and food will be taken after all fasting tests have been completed prior to dosing. 
In addition to study drug, all subjects may receive best supportive care (BSC) as determined 
by the Investigator according to local/institutional guidelines. Best supportive care is defined 
as non-specific anti-tumor treatment with the effect to maximize quality of life, including 
antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional 
support and excluding surgery, TACE, RFA, immunotherapy, anticancer hormonal therapy, 
systemic chemotherapy, and radiotherapy (Zafar, 2008). 
Treatment cycles are defined for administrative purposes as 28 days (except cycle 1). 
8.2.1 Treatment modification 
At the discretion of the Investigator and subject, starting with Cycle 3, Day 2, dosing may be 
moved to the end of the day to manage AEs (e.g. gastrointestinal). 
8.2.1.1 Treatment Delay 

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Study drug may be taken up to 12 hours late if dosing has been delayed on a single day; 
otherwise that day’s dose should be omitted and dosing continue on the following day. The 
subject should never take more than the scheduled dose on any single day. 
If study drug is interrupted for more than 21 consecutive days, treatment should be 
permanently discontinued unless agreed in advance with Antengene. 
8.2.1.2 Dose Adjustments 
Dosing may be reduced or interrupted for toxicities according to Table 4. Dose adjustments 
are to be made according to the AE showing the greatest degree of toxicity. Toxicities will be 
graded using the NCI CTCAE v4.03. 
If considered necessary, the dose of ATG-008 should be reduced from 30 mg/d to 20 mg/day, 
as the first dose reduction level. If a second dose reduction is considered necessary, the 
ATG-008 dose should be reduced to 15 mg/day.  
Continuous dose interruption of up to 2 weeks and the total discontinuation time not more 
than 4 weeks is allowed in this study. 
Dose reduction principle for subjects who are enrolled to receive oral ATG-008 at an initial 
dose of 45 mg/QD or 20 mg/BID: 45 mg/QD can be reduced to 30 mg, 20 mg, 15 mg/QD; 20 
mg/BID can be reduced to 15mg/BID or other doses so as to mitigate toxicity. If further dose 
reduction is required, it can be implemented according to the considerations of the 
investigator and discussion between the investigator and medical monitors of the sponsor. 
Dose re-escalation (higher than the initial dose is not permitted) will be allowed if the same 
toxicity does not recur at the reduced dose for least one cycle (4 weeks). 
The dose reduction guidelines listed in Table 4 below are recommended to be used for dose 
modifications. 
Table 4: Dose Reduction Recommended Guidelines for Suspected Drug-related Toxicity 
Adverse Event 
Grade 
Action 
Thrombocytopenia 
3 
If bleeding present, reduce study drug one dose level. 
4 
If present for more than 7 days, hold study drug until ≤ grade 2. 
Then reduce study drug one dose level. 
Neutropenia 
3 
If associated with fever, reduce study drug one dose level. 
4 
If present for more than 7 days or associated with fever, hold study 
drug until ≤ grade 2. Then reduce study drug one dose level. 
Increased bilirubin 
3 
If > 5 x ULN, hold study drug until ≤ grade 2. Then reduce study 
drug one dose level. 
4 
Hold study drug until ≤ grade 2. Then reduce study drug one dose 
level. 
Transaminase increase 
3 
If > 10 x ULN, hold study drug until ≤ grade 2. Then reduce study 
drug one dose level. 
4 
Hold study drug until ≤ grade 2. Then reduce study drug one dose 
level. 
Stomatitis / mucositis / 
vomiting / diarrhea 
3 
If unable to control with optimal medical management within 7 days, 
reduce study drug one dose level. 
4 
Hold study drug until ≤ grade 2. Then reduce study drug one dose 
level. 
Hyperglycemia 
3 or 4 
If unable to control with optimal medical management within 7 days, 
reduce study drug one dose level. Management guidelines provided 
in Appendix C (Section 19.3). 

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Rash 
3 
If fails to respond to optimal medical management within 7 days, 
hold study drug until ≤ grade 2. Then reduce study drug one dose 
level. 
4 
Discontinue study drug. 
Pneumonitis 
1 
Continue study drug and monitor closely. 
2 
Hold study drug until ≤ grade 1. Then maintain or reduce study drug 
one dose level. 
3 or 4 
Discontinue study drug. 
Fatigue 
3 
If fails to respond to optimal medical management within 7 days, 
hold study drug until ≤ grade 2. Then reduce study drug one dose 
l
l
Other 
3 
Reduce study drug one dose level. 
4 
Discontinue study drug. 
 
8.2.2 Overdose 
On a per dose basis, an overdose is defined as any amount over the protocol-specified dose of 
study drug assigned to a given subject, regardless of any associated adverse events or 
sequelae. On a frequency basis, an overdose is defined as anything more frequent than the 
protocol required frequency. 
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form. See 
Section 11.1 for the reporting of adverse events associated with overdose. 
 
8.3 Method of Treatment Assignment 
Subjects who are in the first part of this study and are enrolled into screening period of will 
be assigned with one available subject number The assignment to cohort of 15mg or 30mg 
will be in sequence.  
As for approximately 40 HCC subjects who are planned to be enrolled, subjects will be 
randomly assigned with one available subject number during screening period to receive oral 
ATG-008 at an initial dose of 45 mg/QD or 20 mg/BID. 
8.4 Packaging and Labeling 
ATG-008 are packaged in bottles. The study drug will be labeled per local regulations. 
8.5 Investigational Product Accountability and Disposal 
Antengene (or designee) will review with the Investigator and relevant site personnel the 
process 
for Investigational Product return, disposal, and/or destruction including 
responsibilities for the site vs. Antengene (or designee). 
Investigational product containers that are returned should be retained by the site until a 
representative from Antengene or other Antengene-designated personnel have completed an 
inventory, unless otherwise agreed with Antengene. Completely used containers should be 
destroyed according to local guidelines, and disposition should be recorded on the 
Investigational Drug Accountability Record Form. 
The Investigator, or a designee, shall record the dispensing of study drug to subjects in the 
study drug accountability record. The study drug record will be made available to Antengene, 
or other authorized Antengene-designated monitoring personnel for the purpose of accounting 
for the study drug supply. Inspections of the study drug supply for inventory purposes and 
assurance of proper storage will be conducted as necessary. Any significant discrepancy will 
be recorded and reported to Antengene or a designee and a plan for resolution will be 

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documented. 
Investigational product will not be loaned or dispensed by the Investigator to another 
Investigator or site. Under certain circumstances, and with Antengene permission, cooperative 
groups may manage investigational product between locations within their network as clinical 
trial agreement and local guidelines permit. 
8.6 Investigational Product Compliance 
Accurate recording of all study drug administration will be made in the appropriate section of 
the subject’s case report form (CRF) and source documents. The Investigator or designee is 
responsible for accounting for all study-specific study drug either administered or in their 
custody during the course of the study. 
9. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
9.1 Recommended Concomitant Medications and Procedures 
Antiviral therapy can reduce the risk of developing HCC, decrease the risk of HBV 
reactivation, reduce the recurrence, and improve OS and DFS of HCC patients (Ge, 2015). 
Therefore, antiviral therapy is required for all subjects with chronic HBV infection manifested 
by positive HBcAb IgM or total, positive HBsAg or HBeAg, or positive DNA-HBV viral 
load, or according to local practice. Standard treatment options may include entecavir, 
tenofovir, or telbivudine, recommended by Clinical Practice of Primary Liver Cancer 2017 
(NFHPC, 2017). Lamivudine is not recommended due to higher rates of resistance in subjects 
with active HBV infection (HBsAg+, HBeAg+, viral load positive). Continued antiviral 
therapy is recommended for at least 6 months following completion of study drug treatment, 
or as required by local practice. 
 
9.2 Permitted Concomitant Medications and Procedures 
Over the course of this trial, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease 
progression. In 
general, the use of any concomitant medication/therapies considered 
necessary for the care of the subject is permitted. 
Prophylactic antiemetics are not required.  If nausea and vomiting develop, the subject may 
then receive antiemetics at the discretion of the treating physician. 
Stable, therapeutic doses of anticoagulants are permitted; however subjects on warfarin should 
have PT/INR/PTT monitored as clinically indicated. 
Subjects receiving recombinant erythropoietin or darbepoetin alfa for at least 4 weeks prior to 
starting the study drug may continue their pretreatment doses throughout the trial. 
Parenteral flu vaccination is permitted. 
Anti-diabetic drugs (e.g., biguanides, insulin) are recommended to control drug-induced 
hyperglycemia.  It is recommended that biguanides (e.g., metformin) be held 12 hours prior 
to and 48 hours following intravascular administration of iodinated contrast media because of 
their potential for acute alteration in renal function. 
Treatment-related rash should be treated according to standard medical practice and 
Investigator judgment. Careful descriptions should be documented to help determine the 
nature of the rash later classification of the rash.  Depending on the severity and type of 
rash, specific treatments may need to be administered, and study drug may need to be 
withheld temporarily or permanently (as described in Table 4). Treatments for rash may 
include 
non-occlusive 
moisturizers, 
topical 
or 
systemic 
antihistamines 
(e.g., 

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diphenhydramine), and/or corticosteroids (with appropriate consideration to the risk of 
hyperglycemia). Superinfections should be cultured and appropriate topical or systemic 
antibiotic therapy considered. 
Treatment-related mucositis and mouth ulcers should be treated as early as possible and 
according to standard medical practice and Investigator judgment. This may include 
analgesics, topical preparations (suspensions, pastes), and short courses of systemic steroids 
with temporary dose interruption and/or dose reduction for more severe cases. Alcohol or 
peroxide-containing mouthwashes should be avoided. 
Acute renal insufficiency has been reported with ATG-008 and other agents in this drug class. 
Typically, this has been associated with drug-related gastrointestinal toxicities (anorexia, 
nausea, vomiting, diarrhea, mucositis) leading to dehydration and electrolyte abnormalities.  
Treatment with rehydration, antiemetics, and antidiarrheals is recommended, as medically 
indicated.  Study drug dose adjustments may be used to manage these toxicities. 
Drug-related pancreatitis including asymptomatic amylase and lipase elevations, as well as 
symptomatic pancreatitis, has been reported with ATG-008 as with other drugs in this class.  
Routine amylase and lipase safety lab monitoring is included in the protocol.  It is 
recommended that subjects with symptoms of clinical pancreatitis including abdominal pain, 
nausea and vomiting be managed with bowel rest and pain management as medically 
indicated. study drug dose adjustments may be used to manage these toxicities. 
Drug-related noninfectious pneumonitis, a class effect of drugs targeting the mTOR pathway, 
has been reported with ATG-008. The diagnosis should be considered in subjects presenting 
with non- specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, 
dyspnea, or interstitial pulmonary infiltrates, and in whom infectious, neoplastic and other 
causes are 
excluded by appropriate investigations. Those with radiological features 
suggestive of non- infectious pneumonitis but with minimal symptoms may continue study 
drug without dose alteration. Moderate symptoms may require interrupting therapy, and 
corticosteroids may be indicated. Once symptoms have resolved, study drug may be 
reintroduced at the assigned or a reduced dose level, depending on the subject’s general 
clinical status. For severe symptoms, study drug should be discontinued and corticosteroids 
used until clinical symptoms have resolved. 
Routine infectious disease prophylaxis (other than for HBV infection as described in Section 
9.1) is not recommended. However, antibiotic, antiviral, antipneumocystis, antifungal, or 
other prophylaxis may be implemented during the trial at the discretion of the Investigator. 
Treatment with bisphosphonates (e.g., pamidronate, zolendronate), or other agents (e.g., 
denosumab) to prevent or delay progression of bone metastases is permitted.  Maintenance 
of a stable dosing regimen throughout the study is recommended. 
Subjects may receive physiologic replacement doses of glucocorticoids (up to the equivalent 
of 10 mg daily prednisone) as maintenance therapy for adrenal insufficiency. 
All concomitant treatments (treatment or prevention purpose), including blood and blood 
products, must be reported on the CRF. 
 
9.3 Prohibited Concomitant Medications and Procedures 
Administration of other chemotherapy, immunotherapy, antitumor hormonal therapy, other 
investigational therapy or other anticancer therapy during the treatment period is not allowed. 
Focal palliative radiotherapy or surgical intervention for non-target lesions for treatment of 
cancer-related symptoms is allowed during trial treatment at the discretion of the 
Investigator. TACE is not allowed during clinical trial treatment period. Surgical intervention 

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or radiation of target lesions followed for RECIST 1.1 during this trial will require 
discontinuation of the subject from trial treatment. 
Traditional herbal or Chinese medicine for cancer (e.g., Minor Bupleurum Decoction [xiao 
chai hu tang] and cinobufagin [hua chan su]) is not permitted while on trial treatment and 
should be stopped prior to the first dose date. 
Routine prophylaxis with granulocyte-colony stimulating factor (G-CSF) or granulocyte- 
macrophage colony stimulating factor (GM-CSF) is not allowed.  These should be used with 
therapeutic intent and only when indicated, according to standard medical practice and 
Investigator judgment. 
The administration of α-interferon is prohibited during trial treatment. 
In vitro metabolism studies demonstrated that oxidative metabolism of ATG-008 is primarily 
catalyzed by CYP3A4/5, and to a limited extent CYP2C9.  Hence concomitant potent 
CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir) and inducers (e.g., 
rifampicin, phenobarbital, phenytoin, carbamezepine) are better avoided during treatment 
with study drug when possible. Foods and beverages containing grapefruit may be allowed. 
A list of common medications belonging to these classes is shown in Appendix B, Sections 
19.2.1 and 19.2.2. 
Medications metabolized by CYP3A4/5 and CYP2C9 may be administered in this trial but 
subjects must be monitored for drug interactions and potentiation of toxicity.  All such 
medication must be recorded on CRFs, including dose and dose frequency. 
In vitro studies demonstrate that ATG-008 may be a moderate activator of pregnane X 
receptor and moderate inducer of CYP3A4/5. The in vivo magnitude of the ATG-008 
induction is unknown but it might reduce the clinical effectiveness of oral or injectable 
contraceptives. For this reason double contraceptive methods must be used throughout the 
trial by fertile subjects. 
 
9.4 Required Concomitant Medications and Procedures 
See Section 9.1 for details. In addition, all subjects may receive BSC as clinically indicated. 
10. 
STATISTICAL ANALYSES 
10.1 Overview 
This is an Asian multi-regional clinical trial (MRCT) in which ATG-008 will be 
administered orally to hepatitis B positive (HBV+) HCC subjects who have received at least 
one prior line of systemic therapy.  
According to the previous study results, the sponsor will plan to continue to enroll 
approximately 40 hepatitis B virus (HBV) positive, unresectable HCC subjects who have 
received at least one prior line of systemic therapy. Among which, approximately 20 subjects 
will receive oral ATG-008 at an initial dose of 45 mg/QD and another 20 subjects will 
receive oral ATG-008 at an initial dose of 20 mg/BID. The pharmacokinetic (PK) samples 
will be collected from 10 subjects each in the two dose groups so as to further evaluate the 
PK profile of ATG-008 and its metabolites. 
If ORR of tumor is greater than 15% in the study dose group (45 mg/QD or 20 mg/BID), this 
study will be expanded to enroll additional approximately 110 subjects using ORR as the 
primary study endpoint, to further evaluate the efficacy and safety of ATG-008. 
It is designed as an open-label phase 2 trial evaluating the pharmacokinetics (PK), 
tolerability and efficacy of oral ATG-008 administered daily until the radiologic disease 

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progression (according to RECIST 1.1) or intolerable toxicity. 
The sections below provide an overview of the proposed statistical considerations and 
analyses. The final statistical analysis methods will be documented in detail in the Statistical 
Analysis Plan (SAP). 
10.2 Study Population Definitions 
10.2.1 Treated Population 
The Treated population will consist of all enrolled subjects who received at least one dose of 
study drug. It is equivalent to the Safety population. The Treated population will be used for the 
primary efficacy and safety analyses for this single arm Phase 2 study. Treated population will 
be used (instead of Safety population) for the rest of the protocol. 
10.2.2 Per-Protocol Population 
The per-protocol population consists of all treated subjects who met all eligibility criteria and 
received at least 80% of doses during Cycle 1, and have at least one postbaseline tumor 
assessment. The primary and secondary efficacy endpoints will also be analyzed based on the 
Per-protocol population and considered as supportive for this study. 
10.3 Sample Size and Power Considerations 
For the primary efficacy endpoint, ORR, the sample size is based on one-sample binomial 
test with normal approximation. The null hypothesis to be tested is that the ORR (defined as 
the proportion of subjects with at least a partial response (PR) based on the Treated 
population subjects) is ≤10%; the alternative hypothesis is that the ORR is ≥ 18%. With these 
hypotheses, a sample size of 130 (20+110) subjects in the Treated population would provide 
80% power at a one-sided 0.025 significance level. This criterion requires that the lower limit 
of the 95% confidence interval (CI) for the ORR is greater than 10%. 
10.4 Background and Demographic Characteristics 
Subject age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations.  
Medical history data will be summarized using frequency tabulations by system organ class 
and preferred term. 
Background, demographic characteristics, and medical history will be summarized using both 
Treated and per-protocol populations. 
10.5 Subject Disposition 
Subject disposition (analysis population, entered, discontinued, along with primary reason for 
discontinuation) will be summarized using frequency and percent. A summary of subjects 
enrolled by site will be provided. Protocol deviations will be summarized using frequency 
tabulations. 
Subject disposition and protocol deviations will be summarized using both Treated and 
per-protocol populations. 
10.6 Efficacy Analysis 
All efficacy results will be summarized for the Treated population as the primary analysis. 
The primary and secondary efficacy endpoints will also be analyzed using the per-protocol 
population as supportive analysis. Subgroup and exploratory efficacy analyses will be 
conducted using only the Treated population. 

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10.6.1 Analysis of the Primary Efficacy Endpoint 
Overall response rate (ORR) is the primary efficacy endpoint. A responder is any subject who 
achieves a CR or PR. ORR is defined as the percentage of subjects that achieve a CR or PR.  
ORR will be summarized with 95% confidence interval (CI), and tested using one sample 
binomial test for the Treated population analyzed in a similar way as for DCR. Subgroup 
analysis for ORR will be performed for subgroups specified in Section 10.6.3. 
ORR with 95% confidence intervals will also be provided for the per-protocol population. 
The primary analysis for ORR will be performed at approximately 3 months after the last 
subject is first dosed. All other endpoints will be analyzed at the same time. The analysis will 
be updated at 12 months after the last subject’s first dose date.  
10.6.2 Analysis of the Secondary Efficacy Endpoints 
Overall Survival is defined as the time from the first dose date until death. A subject who has 
not been reported as a death will be censored at the last available date the subject is known to 
be alive, or the clinical cut-off date, whichever is earlier. 
Time to progression (TTP) will be calculated as the time from the first dose date to disease 
progression. Subjects who do not have disease progression will be censored at the date of the 
last tumor assessment that the subject was progression free, or the clinical cutoff date, 
whichever is earlier. 
Progression free survival (PFS) is defined as the time from the first dose date to the date of 
disease progression according to RECIST 1.1 or death (due to any cause) on or prior to the 
clinical cutoff date, whichever occurs earlier. Subjects who do not have disease progression 
or have not died will be censored at the date of the last tumor assessment that the subject was 
progression free on or prior to the clinical cutoff date.  
Disease control rate (DCR) is defined as the percentage of subjects with complete (CR), or 
partial response (PR) or stable disease (SD). 
For responders, time to response (TTR) and response duration will be analyzed. 
TTR is the time from the first dose date to the first documentation of response of PR or 
better. TTR will be summarized for responders using summary statistics.  
Duration of response (DOR) is defined as the time from the time when criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented for responders. DOR will be censored using the same 
censoring rules as used for PFS. 
Survival rate is defined as the Kaplan-Meier estimated proportion of subjects surviving at 6, 
9, 12 months. 
10.6.3 Subgroup Analyses 
The effect of treatment on the efficacy variable ORR, OS, PFS, TTP and DCR will be 
investigated within subgroups defined by the following baseline prognostic variables if the 
study is expanded: 
• Age group (≤ 65, > 65 years); 
• Baseline ECOG Performance Status (0 or 1); 
• Macroscopic vascular invasion (involvement of branches of portal or hepatic 
veins: yes or no); 
• Extrahepatic spread (yes or no); 

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• Median baseline level of albumin (> median or ≤ median); 
• Median baseline level of alkaline phosphatase (> median or ≤ median); 
• Median baseline level of total bilirubin (> median or ≤ median); 
• Prior systemic therapy (First line or more than first-line) 
• Portal vein thrombosis (yes or no); 
• AFP (≤400ug/L or >400ug/L) 
• Liver involvement by HCC (≤50% or >50%) 
• BCLC Stage (B or C);  
The analysis methods described in previous sections will be used for each subgroup 
separately. A forest plot for subgroups will be also provided for the primary efficacy 
endpoint ORR. 
10.6.4 PK analysis 
Intensive PK modeling will be performed for ATG-008 and M1 on the plasma and urine 
concentration data. Descriptive statistics of model fitting and PK parameters will be 
summarized in appropriate tables and figures. 
10.6.5 Exploratory Analyses 
10.6.5.1 
Evaluate Changes in AFP 
An AFP response is defined as normalization or > 50% decline from baseline. The AFP 
response rate is the percentage of subjects with baseline elevation in AFP who meet AFP 
response criteria. The response rate will be summarized descriptively. 
10.6.5.2 
Exposure-Response Analyses 
Exploratory analyses may be conducted to evaluate the relationship between ATG-008 and M1 
exposure and select response variables. Graphical exploration may initially be performed to 
identify significant trends between drug exposure and response. Depending on the findings, 
appropriate modeling and simulation may be conducted to quantify exposure-response 
relationships using pharmacostatistical modeling. 
 
10.7 Safety Analysis 
All safety results will be summarized for the Safety population. 
Safety and tolerability will be monitored through continuous reporting of adverse events and 
serious adverse events, laboratory abnormalities, and incidence of subjects experiencing dose 
modifications, dose interruptions, and/or premature discontinuation of study drug. Data from 
all subjects who receive one or more doses of study drug will be included in the safety 
analyses. Adverse events, physical examination findings (including vital sign measurements), 
clinical laboratory information, ECG interpretations and concomitant medications/procedures 
will be tabulated and summarized by treatment arm. Descriptive statistics will be provided for 
both baseline and change from baseline of ECG values by treatment arm. All toxicities will be 
summarized by severity grade based on the CTCAE, Version 4.03, frequency and relationship 
to treatment. Adverse events will be coded according to the Medical Dictionary for Regulatory 
Affairs (MedDRA). Serious adverse events, AEs of interest, AEs Grade 3 or higher, and AEs 
leading to discontinuation or death will be summarized and listed separately. 
11. 
ADVERSE EVENTS 

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11.1 Monitoring, Recording and Reporting of Adverse Events 
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a trial. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concurrent impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 11.3), regardless of etiology. Any 
worsening (i.e., any clinically significant adverse change in the frequency or intensity of a 
pre-existing condition) should be considered an AE. A diagnosis or syndrome should be 
recorded on the AE page of the CRF rather than the individual signs or symptoms of the 
diagnosis or syndrome. 
Clinically significant signs and symptoms associated with disease progression are expected to 
be reported as AEs; however progression of HCC (PD) that is asymptomatic or solely 
documented radiographically per RECIST 1.1 does not require reporting as an AE. 
An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product should be reported as an AE.  
If an overdose is associated with an AE, the overdose and adverse event should be reported as 
separate terms. See Section 8.2.2 for the definition of overdose. In the event of overdose, the 
subject should be monitored as appropriate and should receive supportive measures as 
necessary. There is no known specific antidote for ATG-008 overdose. Actual treatment 
should depend on the severity of the clinical situation and the judgment and experience of the 
treating physician. 
All subjects will be monitored for AEs during the trial. Assessments may include monitoring 
of any or all of the following parameters: The subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or other 
appropriate tests and procedures. 
All AEs and SAEs will be recorded by the Investigator from the time the subject signs 
informed consent to 28 days after the last dose of study drug. However serious adverse events 
made known to the Investigator at any time thereafter that are suspected of being related to 
study drug will also be reported. AEs and serious adverse events (SAEs) will be recorded on 
the AE page of the CRF and in the subject’s source documents. All SAEs must be reported to 
Antengene Drug Safety or designee within 24 hours of the Investigator’s knowledge of the 
event by facsimile, or other appropriate method, using the SAE Report Form, or approved 
equivalent form. 
 
11.2 Evaluation of Adverse Events 
A qualified Investigator will evaluate all adverse events as to: 
11.2.1 Seriousness 
An SAE is any AE occurring at any dose that: 
• Results in death; 
• Is life-threatening (i.e., in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE); 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay); 
• Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions); 
• Is a congenital anomaly/birth defect; 

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• Constitutes an important medical event. 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should 
be considered serious. 
Events not considered to be SAEs are hospitalizations for: 
• Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
• The administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication of 
such transfusion is a reportable SAE. 
• A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures is a 
reportable SAE. 
• Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
• A procedure that is planned (i.e., planned prior to starting of treatment on trial); must 
be documented in the source document and the CRF. Hospitalization or prolonged 
hospitalization for a complication from such a procedure is a reportable SAE. 
• An elective treatment of a pre-existing condition unrelated to the studied indication. 
• Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above. 
If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report 
Form must be completed. 
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to study drug, action taken regarding study drug, and outcome. 
For death caused by study indication progression of disease (PD) will not be reported as 
SAE. 
11.2.2 Severity/Intensity 
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to 
the current active minor version of CTCAE, Version 4.03; 
Adverse events that are not defined in the CTCAE should be evaluated for severity/intensity 
according to the following scale: 
• Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
• Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required 
• Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible 

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• Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable 
• Grade 5 = Death - the event results in death 
The term “severe” is often used to describe the intensity of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache). This criterion is not the same as 
“serious” which is based on subject/event outcome or action criteria associated with events 
that pose a threat to a subject’s life or functioning. 
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
11.2.3 Causality 
The Investigator must determine the relationship between the administration of study drug and 
the occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
Not suspected: 
A causal relationship of the adverse event to study drug administration 
is unlikely or remote, or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed event. 
Suspected: 
There is a reasonable possibility that the administration of study drug 
caused the adverse event. ‘Reasonable possibility’ means there is evidence to suggest a 
causal relationship between the study drug and the adverse event. 
Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed and provided as additional information becomes 
available. 
If an event is assessed as suspected of being related to a comparator, ancillary or additional 
study drug that has not been manufactured or provided by Antengene, then the name of the 
manufacturer when reporting the event will be provided. 
11.2.4 Duration 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of 
the event. 
11.2.5 Action Taken 
The Investigator will report the action taken with study drug as a result of an AE or SAE, as 
applicable (e.g., discontinuation or reduction of study drug, as appropriate) and report if 
concomitant and/or additional treatments were given for the event. 
11.2.6 Outcome 
The Investigator will report the outcome of the event for both AEs and SAEs. All SAEs that 
have not resolved upon discontinuation of the subject’s participation in the trial must be 
followed until recovered, recovered with sequelae, not recovered or death (due to the SAE). 
11.3 Abnormal Laboratory Values 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• Results in discontinuation from the trial; 
• Requires treatment, modification/interruption of study drug dose, or any other 
therapeutic intervention; or 
• Is judged to be of significant clinical importance. 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 

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need to be documented as a serious adverse event. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the 
diagnosis or syndrome should be recorded on the AE page/screen of the CRF. If the 
abnormality was not a part of a diagnosis or syndrome, then the laboratory abnormality should 
be recorded as the AE. If possible, the laboratory abnormality should be recorded as a medical 
term and not simply as an abnormal laboratory result (e.g., record thrombocytopenia rather 
than decreased platelets). 
11.4 Pregnancy 
All pregnancies or suspected pregnancies occurring in either a female subject or partner of a 
male subject are immediately reportable events.  
11.4.1 Females of Childbearing Potential 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age 
or disease state) of a female subject occurring while the subject is on study drug, or within 28 
days of the subject’s last dose of study drug, are considered immediately reportable events. 
study drug is to be discontinued immediately and the subject instructed to return any unused 
portion of the study drug to the Investigator. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Antengene Drug Safety immediately by facsimile, or other 
appropriate method, using the Pregnancy Initial Report Form, or approved equivalent form. 
The female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation. 
The Investigator will follow the female subject until completion of the pregnancy and must 
notify Antengene Drug Safety immediately about the outcome of the pregnancy (either normal 
or abnormal outcome) using the Pregnancy Follow-up Report Form or approved equivalent 
form. 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE to Antengene Drug Safety by facsimile, or 
other appropriate method, within 24 hours of the Investigator’s knowledge of the event using 
the SAE Report Form, or approved equivalent form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the study drug should also be reported to Antengene Drug 
Safety by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form. 
11.4.2 Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant up to 3 
months after stopping study drug, the male subject taking study drug should notify the 
Investigator, and the pregnant female partner should be advised to call her healthcare provider 
immediately. 
11.5 Reporting of Serious Adverse Events 
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form 
in addition to being recorded on the AE page/screen of the CRF. All SAEs must be reported 
to Antengene Drug Safety designee within 24 hours of the Investigator’s knowledge of the 
event by facsimile, or other appropriate method, using the SAE Report Form, or approved 
equivalent form. This instruction pertains to initial SAE reports as well as any follow-up 
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The Investigator is required to ensure that the data on these forms is accurate and consistent. 
This requirement applies to all SAEs (regardless of relationship to study drug) that occur 
during the trial (from the time the subject signs informed consent to 28 days after the last dose 
of study drug), and those made known to the Investigator at any time thereafter that are 
suspected of being related to study drug.  Serious adverse events occurring prior to treatment 
(after signing the ICF) will be captured. SAEs should be followed to resolution. 
The SAE report should provide a detailed description of the SAE and include a concise 
summary of hospital records and other relevant documents.  If a subject died and an autopsy 
has been performed, copies of the autopsy report and death certificate are to be sent to 
Antengene Drug Safety as soon as these become available. Any follow-up data will be detailed 
in a subsequent SAE Report Form, or approved equivalent form, and sent to Antengene Drug 
Safety. 
Where required by local legislation, the Investigator is responsible for informing the IRB/EC 
of the SAE and providing them with all relevant initial and follow-up information about the 
event. The Investigator must keep copies of all SAE information on file including 
correspondence with Antengene and the IRB/EC. 
11.5.1 Safety Queries 
Queries pertaining to SAEs will be communicated from Antengene Drug Safety to the site via 
facsimile or electronic mail. The response time is expected to be no more than five (5) 
business days. Urgent queries (e.g., missing causality assessment) may be handled by phone. 
11.6 Expedited Reporting of Adverse Events 
For the purpose of regulatory reporting, Antengene Drug Safety will determine the 
expectedness of events suspected of being related to study drug based on the Investigator 
Brochure. 
All SUSARs will be reported in an expedited manner in accordance with 21 CFR 312.32. 
For participating Asian countries, Antengene or an authorized representative will report in an 
expedited manner to Regulatory Authorities and Ethics Committees concerned, SUSARs in 
accordance with Directive 2001/20/EC and the Detailed Guidance on collection, verification 
and presentation of adverse reaction reports arising from clinical trials on investigational 
products for human use (ENTR/CT3) and also in accordance with country-specific 
requirements. 
Adverse events such as disease progression, death related to disease progression (in the absence 
of serious study drug-related events) and serious events due to the relapse of the studied 
indication will not be subject to expedited reporting by Antengene to regulatory authorities. 
Antengene or an authorized representative shall notify the Investigator of the following 
information: 
• Any AE suspected of being related to the use of study drug in this trial or in other 
studies that is both serious and unexpected (i.e., SUSAR); 
• Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects. 
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Antengene and the IRB/EC. (See Section 15.3 for record retention 
information). 

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Antengene Drug Safety Contact Information: 
For Antengene Drug Safety contact information, please refer to the Serious Adverse Event 
Report Form Completion Guidelines or to the Pregnancy Report Form Completion 
Guidelines 
12. 
DISCONTINUATIONS 
12.1 Discontinuation from Investigational Product 
The following events are considered sufficient reasons for discontinuing a subject from the 
study drug: 
• Adverse Event(s) (that are intolerable) 
• Disease progression 
• Symptomatic deterioration (global deterioration of health status) 
• Physician decision 
• Withdrawal by subject (from treatment only) 
• Death 
• Lost to follow up 
• Protocol violation 
• Other (to be specified on CRF) 
The reason for treatment discontinuation should be recorded in the CRF and in the source 
documents.  Subjects will continue to be followed for post-treatment anticancer therapy and 
survival status until death. 
 
12.2 Discontinuation from the Trial 
The following events are considered sufficient reasons for discontinuing a subject from the 
trial: 
• Death 
• Protocol violation 
• Lost to follow-up 
• Withdrawal of consent for post-treatment follow-up 
• Other (to be specified on CRF) 
The reason for trial discontinuation should be recorded in the CRF and in the source 
documents. 
At the time of withdrawal, it should be determined if the subject is withdrawing from 
treatment alone, or from treatment and collection of further data (e.g., survival). 
13. 
EMERGENCY PROCEDURES 

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13.1 Emergency Contact 
In emergency situations, the Investigator should contact the responsible physician at the 
number listed on the Emergency Contact Information page of the protocol (after title page). 
In the unlikely event that the physician cannot be reached, the Emergency Center should be 
contacted at the number listed.  The Emergency Call Center is open 24 hours a day and 7 
days a week. The representatives there are responsible for contacting an alternative on-call 
Antengene/CRO Medical Director, who will then assist the enquirer promptly. 
The back-up 24-hour emergency contact call center should only be used in the event that the 
physician cannot be reached. 
 
 

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14. 
REGULATORY CONSIDERATIONS 
14.1 Good Clinical Practice 
The procedures set out in this trial protocol pertaining to the conduct, evaluation, and 
documentation of this trial are designed to ensure that Antengene, an authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International Conference 
on Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles 
outlined in the Declaration of Helsinki. The trial will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this trial in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities. 
 
14.2 Investigator Responsibilities 
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in the 
local regulations.  Antengene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff. 
The Investigator should ensure that all persons assisting with the trial are adequately informed 
about the protocol, amendments, trial treatments, as well as study-related duties and functions. 
The Investigator should maintain a list of Sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study-related duties. 
The Investigator is responsible for keeping a record of all subjects who sign an ICF and are 
screened for entry into the trial.  Subjects who fail screening must have the reason(s) recorded 
in the subject’s source documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (e.g., 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of CRFs and queries. 
 
14.3 Subject Information and Informed Consent 
The Investigator must obtain informed consent of a legal representative prior to any study-related 
procedures. 
Documentation that IC occurred prior to the study subject’s entry into the trial and of the 
informed consent process should be recorded in the subject’s source documents including the 
date. The original ICF signed and dated by the subject and by the person consenting the subject 
prior to the subject’s entry into the study, must be maintained in the Investigator’s trial files and 
a copy given to the subject.  In addition, if a protocol is amended and it impacts on the content 
of the informed consent, the ICF must be revised. S ubjects participating in the trial when the 
amended protocol is implemented must be re- consented with the revised version of the ICF.  
The revised ICF signed and dated by the subject and by the person consenting the subject must be 
maintained in the Investigator’s trial files and a copy given to the subject. 

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14.4 Confidentiality 
Antengene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Antengene 
requires 
the Investigator to permit Antengene's representatives and, when necessary, 
representatives from regulatory authorities, to review and/or copy any medical records relevant to 
the trial in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in writing 
from the appropriate individual. 
 
14.5 Protocol Amendments 
Any amendment to this protocol must be approved by the Antengene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval. 
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes. 
 
14.6 Institutional Review Board/Independent Ethics Committee Review and 
Approval 
Before the start of the trial, the protocol, ICF, and any other appropriate documents will be 
submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their dates 
of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is sought. 
If applicable, the documents will also be submitted to the authorities in accordance with local legal 
requirements. 
Study drug can only be supplied to an Investigator by Antengene or an authorized representative 
after documentation on all ethical and legal requirements for starting the trial has been received 
by Antengene or an authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number (if 
applicable), study site (or region or area of jurisdiction, as applicable), and any other documents 
reviewed. It must mention the date on which the decision was made and must be officially signed 
by a committee member. Before the first subject is enrolled in the trial, all ethical and legal 
requirements must be met. 
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised. 
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 

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regulatory authorities. 
Any advertisements used to recruit subjects for the trial must be reviewed by Antengene and the 
IRB/EC prior to use. 
14.7 Ongoing Information for Institutional Review Board / Ethics Committee 
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC: 
• Information on serious or unexpected adverse events as soon as possible; 
• Periodic reports on the progress of the trial; 
• Deviations from the protocol or anything that may involve added risk to subjects. 
14.8 Closure of the Trial 
Antengene reserves the right to terminate this trial at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (e.g., IRB/EC, regulatory authorities, etc.). 
In addition, the Investigator or Antengene has the right to discontinue a single site at any time 
during the trial for medical or administrative reasons such as: 
• Unsatisfactory enrollment; 
• GCP noncompliance; 
• Inaccurate or incomplete data collection; 
• Falsification of records; 
• Failure to adhere to the trial protocol. 
 

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15. 
DATA HANDLING AND RECORDKEEPING 
15.1 Data/Documents 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
trial and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: Hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification 
as being accurate copies; microfiche; x-ray film/tumor scans and reports; and records kept at 
the pharmacy, and the laboratories, as well as copies of CRFs or CD-ROM. 
 
15.2 Data Management 
Data will be collected via CRF and entered into the clinical database per Antengene or an 
authorized representative's standard operating procedures (SOPs). These data will be 
electronically verified through use of programmed edit checks specified by the clinical team. 
Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary.  Resolutions to these issues will be reflected in 
the database.  An audit trail within the system will track all changes made to the data. 
 
15.3 Record Retention 
Essential documents must be retained by the Investigator for a minimum of 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 have elapsed since 
the formal discontinuation of clinical development of the ATG-008. The Investigator must 
retain these documents for the time period described above or according to local laws or 
requirements, whichever is longer. Essential documents include, but are not limited to, the 
following: 
• Signed ICF for all subjects; 
• Subject identification code list, screening log (if applicable), and enrollment log; 
• Record of all communications between the Investigator and the IRB/EC; 
• Composition of the IRB/EC; 
• Record of all communications between the Investigator, Antengene, and their 
authorized representative(s); 
• List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in the 
trial, curriculum vitae, and their signatures; 
• Copies of CRFs (if paper) and of documentation of corrections for all subjects; 
• Trial drug accountability records; 
• Record of any body fluids or tissue samples retained; 
• All other source documents (subject records, hospital records, laboratory records, 

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etc.); 
• All other documents as listed in Section 8 of the ICH consolidated guideline on 
GCP (Essential Documents for the Conduct of a Clinical Trial). 
Investigators must notify Antengene if they wish to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified 
period. The Investigator must obtain approval in writing from Antengene prior to destruction 
of any records. If the Investigator is unable to meet this obligation, the Investigator must ask 
Antengene for permission to make alternative arrangements. Details of these arrangements 
should be documented. 
All trial documents should be made available if required by relevant health authorities. 
Investigator/Institution should take measures to prevent accidental or premature destruction of 
these documents.  
16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
All aspects of the trial will be carefully monitored by Antengene or an authorized 
representative for compliance with applicable government regulations with respect to current 
GCP and standard operating procedures. 
16.1 Trial Monitoring and Source Data Verification 
Antengene ensures that appropriate monitoring procedures are performed before, during and 
after the trial. All aspects of the trial are reviewed with the Investigator and the staff at a trial 
initiation visit and/or at an Investigator meeting.  Prior to enrolling subjects into the trial, a 
Antengene representative will review the protocol, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone. During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other trial 
documentation will be inspected/reviewed by the Antengene representative in accordance 
with the Study Monitoring Plan. 
Accuracy will be checked by performing source data verification that is a direct comparison 
of the entries made onto the CRFs against the appropriate source documentation.  Any 
resulting discrepancies will be reviewed with the Investigator and/or his/her staff.  Any 
necessary corrections will be made directly to the CRFs or via queries by the Investigator 
and/or his/her staff. Monitoring procedures require that informed consents, adherence to 
inclusion/exclusion criteria and documentation of SAEs and their proper recording be 
verified.  Additional monitoring activities may be outlined in a study-specific monitoring 
plan. 
16.2 Audits and Inspections 
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Antengene.  Representatives of this unit will conduct audits of clinical 
research activities in accordance with Antengene or its authorized repreentative's SOPs to 
evaluate compliance with Good Clinical Practice guidelines and regulations. 
The Investigator is required to permit direct access to the facilities where the trial took place, 
source documents, CRFs and applicable supporting records of trial subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (e.g., China Food and Drug 
Administration, Taiwan Food and Drug Administration, Korea Food and Drug Administration) 
and company authorized representatives. The Investigator should make every effort to be 
available for the audits and/or inspections. When Investigators are contacted by any 

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regulatory authority regarding an inspection, they should contact Antengene immediately.  

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17. 
PUBLICATIONS 
Antengene will publish the results of this trial in a peer-reviewed medical publication, journal, 
or findings may also be used for teaching purposes. Additionally, this trial and its results may 
be submitted for inclusion in all appropriate health authority trial registries, as well as 
publication on health authority trial registry websites, as required by local health authority 
regulations. Selection of first authorship will be based on several considerations, including, 
but not limited to, trial participation, subject enrollment, contribution to the protocol 
development, and analysis and input into the manuscript, related abstracts, and presentations 
in a trial. 
 
 

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19. 
APPENDICES 
19.1 Appendix A: RECIST 1.1 
The following information is extracted/summarized from Eisenhauer 2009, New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Please refer to 
the primary reference for further information. 
 
19.1.1 Definitions 
At screening, tumor lesions/lymph nodes will be categorized as measurable or non-measurable. 
 
19.1.1.1 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
19.1.1.2 
Non-measurable Disease 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
 
19.1.1.3 
Special Considerations for Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local (radiation) therapy 
should be considered measurable or non-measurable according to Eisenhauer, 2009. 
 
19.1.2 Tumor Response Evaluation 
 
19.1.2.1 
Target Lesions 
When more than one measurable tumor lesion is present at baseline all lesions up to a 
maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. Note that pathological nodes must meet 
the measurable criterion of a short axis of ≥ 15 mm by CT scan and only the short axis of 
these nodes will contribute to the baseline sum. All other pathological nodes (those with short 
axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that have a short 

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axis < 10 mm are considered non-pathological and should not be recorded or followed. At 
baseline, the sum of the target lesions (longest diameter of tumor lesions plus short axis of 
lymph nodes: overall maximum of 5) is to be recorded. 
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately 
measured but are considered to be present, a default value of 5 mm may be used. If lesions are 
too small to measure and indeed are believed to be absent, a default value of 0 mm may be 
used. 
 
19.1.2.2 
Non-target Lesions 
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above 
those listed as target lesions are considered non-target lesions. Measurements are not required 
but these lesions should be noted at baseline and should be followed as “present”, “absent” or 
“unequivocal progression”. 
 
19.1.2.3 
Response Criteria 
Target and non-target lesions are evaluated for response separately, and then the tumor burden 
as a whole is evaluated as the Overall response. 
 
19.1.2.3.1 Target Lesion Response 
Target lesions will be assessed as follows: 
 Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
< 10 mm. 
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
 Progressive Disease (PD): At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: 
the appearance of one or more new lesions is also considered progression.) 
 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of diameters while 
on study. 
 
19.1.2.3.2 Non-target Lesion Response 
Non-target lesions will be assessed as follows: 
 Complete Response (CR): Disappearance of all non-target lesions and 
normalisation of tumor marker level. All lymph nodes must be 
non-pathological in size (< 10 mm short axis). 
 Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 Progressive Disease (PD): Unequivocal progression (see comments below) of 
existing non-target lesions. (Note: the appearance of one or more new lesions 
is also considered progression.) 

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When the patient also has measurable disease: In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy. A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to quality for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare. 
When the patient has only non-measurable disease: This circumstance arises in some 
Phase 3 trials when it is not a criterion of study entry to have measurable disease. The same 
general concepts apply here as noted above, however, in this instance there is no measurable 
disease assessment to factor into the interpretation of an increase in non-measurable disease 
burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are truly non-measurable) a useful test that can be applied when assessing patients 
for unequivocal progression is to consider if the increase in overall disease burden based on 
the change in non-measurable disease is comparable in magnitude to the increase that would 
be required to declare PD for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase 
diameter in a measurable lesion). Examples include an increase in a pleural effusion from 
‘trace’ to ‘large’, an increase in lymphangitic disease from localised to widespread, or may 
be described in protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal 
progression’ is seen, the patient should be considered to have had overall PD at that point. 
While it would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so, therefore the increase must be 
substantial. 
 
19.1.2.3.3 Overall Response 
Overall response should be assessed according to Table 5 for subjects with target lesions, 
and Table 6 for subjects with only non-target lesions. 
Table 5: Time Point Response: Patients With Target (± Non-target) Disease 
Target lesions response 
Non-target lesion response 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/ non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = inevaluable 
 
Table 6: Time Point Response: Subjects With Non-target Disease Only 
 

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Non-target lesions response 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/ non-PD 
No 
a 
Non-CR/ non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE 
=inevaluable 
a  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised. 
 
19.1.2.4 
Symptomatic Deterioration 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective 
progression even after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy. The objective 
response status of such patients is to be determined by evaluation of target and non-target 
disease. 
19.2 Appendix B: Cytochrome P-450 (CYP) interactions 
A sample list of CYP450 inhibitors and inducers are provided.  This list is not intended to 
be exhaustive, and the prescribing information of the concomitant medication should be 
consulted if the status is unclear. Additionally, a website such as www.drug-interaction.com 
could be consulted, if appropriate. 
 
19.2.1 CYP3A4 Inhibitors 
Source: Cytochrome P450 Drug Interaction Table (Flockhart, 2007) 
Amiodarone 
Indinavir 
Aprepitant 
Itraconazole 
Chloramphenicol 
Ketoconazole 
Cimetidine 
Mibefradil 
Ciprofloxacin 
Mifepristone 
Clarithromycin 
Nefazodone 
Delaviridine 
Nelfinavir 
Diethyldithiocarbamate 
Norfloxacin 
Diltiazem 
Ritonavir 
Erythromycin 
Saquinavir 
Fluconazole 
Star fruit 
Fluvoxamine 
Telithromycin 
Gestodene 
Verapamil 

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Grapefruit juice 
Voriconazole 
Imatinib 
19.2.2 CYP3A4 Inducers: 
Source: Cytochrome P450 Drug Interaction Table (Flockhart, 2007). 
(EIAED are marked with asterisks) 
Barbiturates* 
Phenobarbital* 
Carbamazepine* 
Phenytoin* 
Efavirenz 
Pioglitazone 
Glucocorticoids 
Primidone* 
Modafinil 
Rifabutin 
Nevirapine 
Rifampin 
Oxcarbazepine 
St. John's wort 
 
19.3 Appendix C: Guidance for Managing Hyperglycemia 
Hyperglycemia is a potential class effect of drugs inhibiting mTOR signaling pathways 
(Sankhala, 2009). Consequently, this protocol requires close monitoring and early 
intervention for hyperglycemia. 
To detect meaningful incipient hyperglycemia, in Cycle 1 careful review of blood glucose 
results and possible hyperglycemic symptoms are need during the routine weekly clinic visits.  
Subjects must also be instructed how to contact study staff immediately in the event of 
symptoms (eg, polyuria, thirst), in which case prompt assessment in the clinic is necessary.   
In the event of modest or intermittent hyperglycemia, more frequent monitoring may be 
required.  In the event of persistent fasting hyperglycemia (> 126 mg/dL), or at any time 
considered appropriate by the Investigator, it is recommended that oral hypoglycemic therapy 
be initiated.  Metformin hydrochloride 464 mg PO nocte is an appropriate starting therapy.  
It is recommended that dosage be increased by 464 mg every 3 days (or slower in the event of 
gastrointestinal or other intolerance) to a maximum of 2000 mg. Glucophage, and other 
biguanide therapy, should be temporarily suspended when planned radiological tumor 
assessments (e.g., CT scan) involve iodinated contrast (see Section 6.4.1).  Subjects should 
be instructed on how to recognize hypo- and hyperglycemia. Treatment interruptions of > 3 
weeks will necessitate removal of the subject from this study. 
Goldberg, 2004; Goldberg, 2005; and Turina, 2006 are suggested resources for hyperglycemia 
management. 

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19.4 Appendix D: Liver Cancer Staging, and Child-Pugh Classification 
19.4.1 Barcelona Clinic Liver Center Staging 
Figure 2: 
Barcelona-Clinic Liver staging classification and treatment schedule 
 
BCLC = Barcelona-Clinic Liver staging classification and treatment schedule. 
Note: From Pons, 2005 adapted from Llovet., 2003. 
19.4.2 Child-Pugh Classification of Liver Failure 
Subjects with Child-Pugh A and B7 and hepatic encephalopathy scored as 1 point meet this 
individual inclusion criterion for the study.  
Table 7: Child-Pugh Classification 
1 point 
2 points 
3 points 
Bilirubin (mg/dL) 
< 2 
2-3 
> 3 
Albumin (g/L) 
> 3.5 
2.8-3.5 
< 2.8 
Prothrombin time prolonged in seconds (INR) 1-4 (< 1.7) 
4-6 (1.7-2.3) 
> 6 (> 2.3) 
Ascites 
None 
Slight 
Moderate 
Hepatic encephalopathy 
None 
Grade 1-2 
Grade 3-4 
Child A: 5-6 points; Child B; 7-9 points; Child C: ≥ 10 points 
Source: Pugh, 1973