A Phase 2 Study to Assess the Safety and Efficacy of HBI-8000 in Combination With Pembrolizumab for Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer
Sponsor: HUYABIO International, LLC.



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STATEMENT OF COMPLIANCE 
 
The study will be conducted in compliance with this clinical study protocol, Good Clinical 
Practice (GCP) as outlined by International Council for Harmonisation (ICH) E6 (R2), and all 
applicable local regulations including US Code of Federal Regulations [CFR] Title 21 and with 
the ethical principles laid down in the Declaration of Helsinki. Enrollment at the clinical study 
site may not begin prior to receiving Institutional Review Board (IRB) approval of this protocol, 
the Investigator’s Brochure (IB), and all patient facing materials (e.g., all advertising materials or 
materials given to the subject during the study).  
Any amendments to the protocol and changes to the consent document must also be approved by 
the IRB before implementation of that amendment. 
The Principal Investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the Sponsor and documented approval from the 
IRB of record, unless such a change is necessary to eliminate an immediate hazard to the study 
subjects. 
 

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INVESTIGATOR AGREEMENT 
PROTOCOL TITLE: 
A Phase 2 Study to Assess the Safety and Efficacy of 
HBI-8000 in Combination with Pembrolizumab for Advanced 
or Metastatic Non-Small Cell Lung Cancer (NSCLC) 
PROTOCOL NO: 
HBI-8000-305 
 
I have read this protocol and agree to conduct this study in accordance with ethical principles as 
outlined in the International Council for Harmonisation (ICH) guidelines on Good Clinical 
Practice, and the US Code of Federal Regulations (CFR Title 21), any applicable laws and 
requirements and any additional conditions mandated by the US Food and Drug Administration 
and/or Institutional Review Board (IRB). 
I acknowledge that I am responsible for the overall study conduct and I agree to personally 
conduct or supervise the described clinical study. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of HUYABIO International, LLC. 
 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, 
title, and the name of the center in which the study will be conducted. Return the signed copy to 
Sponsor/Contract Research Organization (CRO).  
 
I have read this protocol in its entirety and agree to conduct the study accordingly:  
 
Signature of Investigator: 
________________________________ Date:  _______________ 
 
 
           (DDMMMYYYY) 
 
Printed Name: 
_________________________________  
 
Investigator Title: 
_________________________________  
 
Name/Address of Study Site: _________________________________  
 
 
_________________________________  
 
 
_________________________________ 
 

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STUDY SYNOPSIS 
Name of Sponsor/ 
Company: 
HUYABIO International, LLC 
Name of Finished 
Product: 
HBI-8000 (tucidinostat) 
Name of Active 
Ingredient: 
N-(2-amino-4-fluorophenyl)-4-{[(2E)-3-(pyridin-3-yl)prop-2-enamido]methyl} 
benzamide 
Title of Study: 
A Phase 2 Study to Assess the Safety and Efficacy of HBI-8000 in Combination with 
Pembrolizumab for Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) 
Protocol No: 
HBI-8000-305 
Lead Investigator: 
Lyudmila Bazhenova, MD 
Indication 
Advanced or Metastatic NSCLC 
Study Population 
Subjects ≥18 years of age with advanced or metastatic NSCLC who have not received 
immune checkpoint inhibitor for their disease but have programmed death ligand 1 
(PD-L1) expression Tumor Proportion Score (TPS): ≥1%. 
Study center(s): 
Multicenter study (US): 6-10 
Study duration: 
Approximately 38 months (including follow-up) 
The study will include a screening period (up to 28 days), up to 24 months of treatment of 
HBI-8000 with pembrolizumab, up to 1 month post-treatment follow-up for safety, and up 
to 12 months after the last dose of HBI-8000 for survival follow-up by telephone 
calls/e-mails. 
Phase 
2 
Study Treatment 
HBI-8000 tablets 30 mg/dose, orally twice a week  
An HBI-8000 treatment cycle consists of twice a week dosing over 21 consecutive days. 
Pembrolizumab will be administered at 400 mg every 6 weeks or 200 mg every 3 weeks 
according to Prescribing Information and institutional practice. 
Treatment will continue until disease progression or unacceptable toxicity occurs. Should 
toxicity be deemed not related to pembrolizumab but HBI-8000, subject may continue to 
receive pembrolizumab under standard of care. Should toxicities be deemed related to 
pembrolizumab, the subject may continue receiving HBI-8000 at the discretion of 
Investigator. 
Objectives: 
Primary: 
•
To evaluate the efficacy of HBI-8000 in combination with a standard dose and
regimen of pembrolizumab as a first line checkpoint inhibitor therapy for
advanced or metastatic NSCLC, as measured by Objective Response Rate (ORR)
according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria
version 1.1 [Eisenhauer 2009].
Secondary: 
•
To evaluate the safety and tolerability of HBI-8000 in combination with a
standard dose and regimen of pembrolizumab
•
To explore the additional efficacy parameters for HBI-8000 in combination with
a standard dose and regimen of pembrolizumab as measured by Disease Control
Rate (DCR), Duration of Response (DoR), and Progression-Free Survival (PFS)

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Study design 
This is a multicenter, open label, Phase 2 study of HBI-8000 in combination with a U.S. 
Food and Drug Administration (FDA) approved dose of pembrolizumab as a first line 
checkpoint inhibitor therapy for advanced or metastatic NSCLC where subjects must have 
programmed death ligand 1 (PD-L1) expression Tumor Proportion Score (TPS) ≥1%. 
Planned number of 
subjects: 
20 to 24 subjects are planned for the study. 
Diagnosis and 
main criteria for 
inclusion: 
Inclusion Criteria 
Subjects may be entered in the study only if they meet all the following criteria: 
1.
Adults at least 18 years of age.
2.
Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
3.
Histopathologically confirmed diagnosis of NSCLC PD-L1 expression TPS ≥1% as
determined by an FDA-approved test.
4.
Have at least one measurable target lesion as defined by RECIST v.1.1.
5.
Have not received immune checkpoint inhibitor therapy or more than one regimen of
chemotherapy for advanced or metastatic disease. Subjects who have previously
received immune checkpoint inhibitor therapy in the adjuvant or neoadjuvant setting
may be allowed if disease progression occurred >6 months after the last dose and no
clinically significant immune related toxicities leading to treatment discontinuation
were observed.
6.
Prior adjuvant or neoadjuvant systemic therapy with chemotherapy, EGFR or ALK
mutation directed therapy must have been completed >4 weeks before Cycle 1 Day 1
(C1D1) dosing and recovered from all treatment related toxicity.
7.
Any prior palliative radiotherapy or minor surgery must be completed at least
2 weeks and 1 week respectively before C1D1 dosing and recovered from all
treatment related toxicities.
8.
Adequate major organ functions at baseline as evidenced by laboratory findings
within 14 days prior to C1D1 study drug administration as defined below:
a.
White blood cells (WBC) ≥3000/μL, neutrophils ≥1500/μL, platelets
≥100×103/μL, hemoglobin ≥9.0 g/dL, independent of transfusion.
b.
Serum creatinine ≤1.5 mg/dL, normal electrolytes, phosphorus, and calcium.
c.
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
≤3 × upper limit of normal (ULN), alkaline phosphatase ≤2.5 × ULN unless
bone metastases present, bilirubin ≤1.5 × ULN (unless known Gilbert’s
disease where it must be ≤3 × ULN) and serum albumin ≥3.0 g/dL.
d.
Thyroid stimulating hormone (TSH) within normal limits.
9.
Life expectancy ≥12 weeks.
10. A negative serum pregnancy test at baseline for women of childbearing potential
(WOCBP).
11. Women of childbearing potential. (WOCBP), non-surgically sterile or premenopausal
female capable of becoming pregnant and men (due to potential risk of drug exposure
through the ejaculate) must agree to use an acceptable method of contraception while
enrolled on this study, and for a period of 5 months following the last dose of
treatment. Acceptable methods of birth control in this trial include 2 highly effective
methods of birth control (as determined by the Investigator; one of the methods must
be a barrier technique) or abstinence.
12. Have the ability to understand and the willingness to sign a written informed consent
document.
Exclusion Criteria 
Subjects who fulfill any of the following criteria at screening will not be eligible for 
admission into the study: 
1.
History of Grade ≥3 hypersensitivity reactions to monoclonal antibodies.

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2.
History of a cardiovascular illness including: QT interval corrected by heart rate
using Fridericia’s correction formula (QTcF) >450 ms in male or >470 ms in female,
congenital long QT syndrome, congestive heart failure (New York Heart Association
Grade III or IV) (Appendix 2); unstable angina or myocardial infarction within the
previous 6 months; or symptomatic cardiac arrhythmia despite medical management.
3.
Uncontrolled hypertension, systolic blood pressure (SBP) >160 mmHg or diastolic
blood pressure (DBP) >100 mmHg.
4.
Central nervous system metastasis or leptomeningeal disease except when treatment
for brain metastasis is completed >14 days prior to C1D1 and stable for ≥4 weeks on
<10 mg daily prednisone or equivalent.
5.
History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled
peptic ulcer disease or bowel resection that affects absorption of orally administered
drugs.
6.
Recurrent pleural effusion requiring repetitive palliative thoracentesis within
3 months prior to study entry, except for subjects with a pleurex port.
7.
Active, known, or suspected autoimmune disease, or history of immune-mediated
toxicity leading to treatment discontinuation, except for type I diabetes mellitus,
hypothyroidism only requiring hormone replacement or skin disorders (such as
vitiligo, psoriasis, or alopecia) not requiring systemic therapy.
8.
Active pneumonitis, history of non-infectious pneumonitis that required treatment
with steroids, or history of interstitial lung disease.
9.
Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
10. Known history of testing positive for human immunodeficiency virus (HIV), known
acquired immunodeficiency syndrome (AIDS).
11. Active hepatitis B (hepatitis B surface antigen [HBVsAg] positive), or hepatitis C
(HCV antibody test or serum hepatitis C ribonucleic acid [RNA] positive).
12. Received approved live vaccines within 30 days of planned C1D1. Inactivated viral
vaccines or vaccines based on subviral component are allowed; however intranasal
influenza vaccines (e.g., Flu-Mist) are not allowed. COVID-19 vaccination should be
administered >7 days before C1D1.
13. Any condition requiring chronic systemic treatment with either corticosteroids
(>10 mg daily prednisone equivalents) or other immunosuppressive medications, or
steroids use within 14 days of study drug administration. Inhaled or topical steroids
are permitted.
14. Use of other investigational agent (drug not marketed for any indication) within 28
days or at least 5 half-lives (whichever is shorter) before study drug administration.
15. Pregnant or breast-feeding women.
16. Second malignancy unless in remission for 2 years; subjects with non-melanomatous
skin cancer, carcinoma in situ of the cervix treated with curative intent, or curatively
treated prostate cancer with prostate-specific antigen (PSA) <2.0 ng/mL can be
included.
17. Underlying medical conditions that, in the Investigator’s opinion, will make the
administration of study drug hazardous or obscure the interpretation of toxicity
determination or adverse events.
18. Unwilling or unable to comply with procedures required in this protocol.
Criteria for evaluation: 
Safety Endpoints:  
Adverse events (AEs) reported by the subjects or observed during physical examination, vital signs 
assessment, electrocardiograms (ECGs) will be recorded by severity according to NCI CTCAE v5.0 and 
association with HBI-8000 and pembrolizumab will be assessed. Laboratory test results will be recorded 
and assessed against normal ranges. ECOG performance status will be monitored. 
Efficacy Endpoints: 
Target lesion(s) and non-target lesion(s) will be assessed by imaging studies at screening (baseline 
assessment), in the last week of Cycle 2 including C3D1, and then every 6 weeks (±3 days) thereafter. 
Tumor assessments will follow guidelines specified in RECIST criteria v1.1. 

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•
ORR (complete response [CR]+partial response [PR])
•
DCR (CR+PR+Stable disease [SD])
•
DoR (Duration of response)
•
PFS (Progression-Free Survival)
After the discontinuation of HBI-8000 treatment, subjects without disease progression will be followed 
for progression with imaging of measurable disease every 12 (±1) weeks until progression, initiation of 
another anti-cancer treatment, or referral to hospice whichever occurs first. Survival follow-up will be 
performed every 12 (±1) weeks by telephone contact or e-mail for up to 12 months after the last dose of 
HBI-8000. 
Statistical methods: 
General: 
Statistical analyses will be performed using SAS® v9.4 or higher (SAS Institute, Cary NC, US). Statistical 
analyses of safety, tolerability and efficacy endpoints will be primarily descriptive in nature. Continuous 
variables will be summarized using descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum). Categorical variables will be summarized with the number and percentage (n, %) of subjects within 
each category. Time to event variables (i.e., PFS, DoR) will be analyzed using the Kaplan-Meier method. Where 
confidence limits are appropriate, the confidence level will be 95% (two sided), unless otherwise stated. 
All subjects in the safety population (who received any amount of HBI-8000) will be included in the final 
summaries and listings of the safety data. 
Sample Size Estimation: 
Approximately 20 to 24 subjects are planned to be enrolled to characterize safety and allow for preliminary 
evaluation of efficacy endpoints in the specific patient population of interest. 
Interim Analysis: 
There will be no interim analysis for this Phase 2 study. 

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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................. 2 
SPONSOR’S APPROVAL ......................................................................................................... 3 
INVESTIGATOR AGREEMENT ............................................................................................... 4 
STUDY SYNOPSIS.................................................................................................................... 5 
Schedule of Events (Dosing and Assessments) ..................................................................... 9 
LIST OF ABBREVIATIONS.................................................................................................... 15 
1 
BACKGROUND ............................................................................................................... 19 
1.1 
Introduction .............................................................................................................. 19 
1.1.1 Non-Small Cell Lung Cancer (NSCLC) ......................................................... 19 
1.1.2 Rationale for HBI-8000 and immune checkpoint combination ....................... 21 
1.1.3 HBI-8000 (tucidinostat) ................................................................................. 22 
1.1.3.1 HBI-8000 (tucidinostat) and Preclinical Pharmacology .................... 23 
1.1.3.2 Clinical Studies ............................................................................... 24 
1.1.3.3 HBI-8000 Safety Profile .................................................................. 25 
1.1.3.4 Overall Safety Risk Assessment ...................................................... 26 
1.1.3.5 Overall Risk/Benefit Assessment ..................................................... 26 
1.1.4 Rationale for Statistical Design ...................................................................... 26 
1.1.5 HBI-8000 Dose Selection and Justification for Combination with 
Pembrolizumab ............................................................................................. 26 
2 
OBJECTIVES .................................................................................................................... 27 
2.1 
Primary Objectives.................................................................................................... 27 
2.2 
Secondary Objectives ................................................................................................ 27 
2.3 
Criteria for Evaluation .............................................................................................. 27 
2.3.1 Safety Endpoints ........................................................................................... 27 
2.3.2 Efficacy Endpoints ........................................................................................ 28 
3 
STUDY DESIGN ............................................................................................................... 28 
3.1 
Overall Design .......................................................................................................... 28 
3.1.1 Expected Duration of Subject Participation.................................................... 29 
3.1.2 Tumor Status and Survival Follow-Up ........................................................... 29 
3.1.3 Study Population ........................................................................................... 29 
3.2 
Justification for Dose ................................................................................................ 29 
3.3 
End of Treatment Definition ..................................................................................... 29 
3.4 
End of Study Definition ............................................................................................ 30 
4 
STUDY POPULATION ..................................................................................................... 30 
4.1 
Inclusion Criteria ...................................................................................................... 30 
4.2 
Exclusion Criteria ..................................................................................................... 31 
4.3 
Subject Registration .................................................................................................. 32 
4.3.1 Subject Registration ...................................................................................... 32 
4.3.2 Blinding ........................................................................................................ 32 

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4.4 
Withdrawal Criteria .................................................................................................. 32 
4.4.1 Subject Withdrawal from the Study ............................................................... 32 
4.4.2 Lost to Follow-up .......................................................................................... 33 
4.5 
Discontinuation of Investigational Product and Participant Withdrawal ..................... 33 
5 
STUDY TREATMENT ..................................................................................................... 34 
5.1 
Investigational Product(s) Administered .................................................................... 34 
5.1.1 HBI-8000 Information ................................................................................... 34 
5.1.2 Pembrolizumab Information .......................................................................... 34 
5.2 
Clinical Supplies Storage and Accountability ............................................................ 34 
5.2.1 Clinical Materials .......................................................................................... 34 
5.2.2 Investigational Product Storage ..................................................................... 35 
5.2.3 Investigational Product Accountability .......................................................... 35 
5.3 
Investigational Product Compliance .......................................................................... 35 
5.4 
Concomitant Therapy ................................................................................................ 36 
5.4.1 Prohibited Medications and Therapy ............................................................. 36 
5.4.2 Supportive Care and Other Medications ........................................................ 36 
5.4.3 Restricted Medications .................................................................................. 37 
5.5 
Food Effects.............................................................................................................. 37 
5.6 
Dose Modification .................................................................................................... 37 
5.6.1 HBI-8000 Administration .............................................................................. 37 
5.6.1.1 HBI-8000 Dose Reduction ............................................................... 37 
5.6.1.2 HBI-8000 Dose Delay Independent of Pembrolizumab 
Administration . ............................................................................... 39 
5.6.2 Pembrolizumab Administration ..................................................................... 39 
6 
STUDY ASSESSMENTS AND PROCEDURES ............................................................... 40 
6.1 
Study Visits and List of Procedures ........................................................................... 40 
6.1.1 Screening Assessments (within 28 days prior to start of treatment) ................ 40 
6.1.2 Baseline Assessments (within 14 days prior to start of treatment) .................. 41 
6.1.3 Treatment Phase Assessments ....................................................................... 41 
6.1.4 End of Treatment (EoT) Safety Visit Assessments ......................................... 41 
6.1.5 Tumor Status and Survival Follow-up ........................................................... 42 
6.2 
Study Procedures Details .......................................................................................... 42 
6.2.1 Efficacy Assessments .................................................................................... 42 
6.2.1.1 Tumor Response Criteria ................................................................. 42 
6.2.2 Safety Assessments ....................................................................................... 43 
6.2.2.1 Vital Signs, ECG, Physical Examinations, and ECOG Assessments. 44 
6.2.2.2 Clinical Laboratory Assessments ..................................................... 44 
6.2.2.3 PD-L1 Testing ................................................................................. 45 
6.2.2.4 Adverse Events ................................................................................ 45 
6.3 
Safety Monitoring Plan ............................................................................................. 50 
7 
STATISTICAL CONSIDERATIONS ................................................................................ 51 
7.1 
Sample Size Determination ....................................................................................... 51 
7.2 
Populations for Analyses ........................................................................................... 51 
7.3 
Subject Disposition ................................................................................................... 52 

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7.4 
Pretreatment Characteristics ...................................................................................... 52 
7.4.1 Medical History ............................................................................................. 52 
7.4.2 Exposure to Study Medications ..................................................................... 52 
7.5 
Statistical Analyses ................................................................................................... 52 
7.5.1 Efficacy Analyses .......................................................................................... 52 
7.5.2 Safety Analyses ............................................................................................. 53 
7.5.2.1 Adverse Events ................................................................................ 53 
7.5.2.2 Laboratory Tests .............................................................................. 54 
7.5.2.3 Vital Signs and Physical Examination .............................................. 54 
7.5.2.4 Concomitant Medications ................................................................ 54 
7.5.3 Interim Analyses ........................................................................................... 54 
7.5.4 Guidance to Address a Pandemic or Other Global Health Emergencies and 
Potential Impact on the Clinical Study ........................................................... 54 
8 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......... 56 
8.1 
Data Collection and Management.............................................................................. 56 
8.1.1 Electronic Case Report Forms ....................................................................... 56 
8.1.2 Source Documentation .................................................................................. 56 
8.1.3 Data Management/Coding ............................................................................. 56 
8.2 
Quality Control and Quality Assurance ..................................................................... 57 
8.2.1 Monitoring .................................................................................................... 57 
8.2.2 Retention of Patient Records and Study Files................................................. 57 
8.2.3 Quality Assurance Audit................................................................................ 58 
8.2.4 Site Audits..................................................................................................... 58 
8.3 
Ethics ........................................................................................................................ 58 
8.3.1 Ethical Conduct of the Study ......................................................................... 58 
8.3.2 Institutional Review Board or Independent Ethics Committee ....................... 58 
8.3.3 Subject Information and Informed Consent.................................................... 59 
8.3.4 Confidentiality .............................................................................................. 59 
8.3.5 Subject Data Protection ................................................................................. 59 
8.3.6 Protocol Amendments ................................................................................... 59 
8.3.7 Study Closure ................................................................................................ 60 
8.3.7.1 Study Discontinuation ..................................................................... 60 
8.3.7.2 Site Discontinuation ........................................................................ 60 
8.4 
Study Administration ................................................................................................ 61 
8.4.1 Data Handling and Record Keeping ............................................................... 61 
8.4.2 Direct Access to Source Data/Documents ...................................................... 61 
8.4.3 Investigator Obligations ................................................................................ 61 
8.4.4 Financial Disclosure ...................................................................................... 61 
8.4.5 Protocol Signatures........................................................................................ 61 
8.4.6 Publication Policy ......................................................................................... 62 
9 
REFERENCES .................................................................................................................. 63 
APPENDIX 1. 
PERFORMANCE SCALES – ECOG AND LANKSY .................................. 65 
APPENDIX 2. 
NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION ........................................................................................................... 66 

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APPENDIX 3. 
STRONG CYP3A4 INDUCERS AND INHIBITORS ................................... 67 
APPENDIX 4. 
RECIST V1.1 AND IRRECIST ................................................................... 68 
 
LIST OF TABLES 
Table 1: 
Schedule of Dosing and Assessments........................................................................ 9 
Table 2: 
Clinical Studies Conducted with HBI-8000............................................................. 24 
Table 3: 
Investigational Products .......................................................................................... 34 
Table 4: 
Probability of Detecting AEs that Occur at Various Frequencies ............................. 51 
 
LIST OF FIGURES 
Figure 1: 
Structural Formula for HBI-8000 (tucidinostat) ...................................................... 23 
Figure 2: 
RENCA Renal Adenocarcinoma Cell Line Treated with HBI-8000 and 
Anti-PD1 ................................................................................................................ 24 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical classification system 
ATL 
Adult T-cell leukemia/lymphoma 
AUC 
Area under the curve 
BIW 
Twice a week 
BRAF 
B-Raf proto-oncogene, serine/threonine kinase gene 
BUN 
Blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus disease 2019 
CPI 
Checkpoint inhibitor 
CR 
Complete response 
CRO 
Contract research organization 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T lymphocyte 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DCR 
Disease control rate 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 

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Abbreviation 
Definition 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EoT 
End-of-treatment 
ESF 
Eligibility Screening Form 
FAS 
Full analysis set 
FDA 
Food and Drug Administration (US) 
GCP 
Good clinical practice 
G-CSF 
Granulocyte-colony stimulating factor 
HBVsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDAC 
Histone deacetylase 
HDACi 
Histone deacetylase inhibitor 
HDPE 
High-density polyethylene 
HEENT 
Head, eye, ear, nose, and throat 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
HUYABIO 
HUYABIO International LLC 
IC50 
50% inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
INR 
International normalized ratio 
IP 
Investigational Product 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
IV 
Intravenous 
LAR 
Legally authorized representative 
LDH 
Lactate dehydrogenase 

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Abbreviation 
Definition 
MDSC 
Myeloid-derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NK 
Natural killer 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression-Free Survival 
PPS 
Per-Protocol Set 
PR 
Partial response 
PSA 
Prostate specific antigen 
PSRMC 
Product Safety and Risk Management Committee 
PT 
Prothrombin time 
PTCL 
Peripheral T-cell lymphoma 
Q2W 
Every two weeks 
QTc 
QT interval corrected by heart rate 
QTcF 
QT interval corrected by heart rate using Fridericia’s correction formula 
RBC 
Red blood cell 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RENCA 
Renal adenocarcinoma 
RNA 
Ribonucleic acid 
ROS 
c-ros oncogene 
RP2D 
Recommended Phase 2 dose 

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Abbreviation 
Definition 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Stable disease 
SOP 
Standard operating procedure 
STD 
Sum of target lesion(s) diameter(s) 
SUSAR 
Suspected unexpected serious adverse drug reaction 
T4 
Thyroxine 
TEAE 
Treatment-emergent adverse event 
TIW 
Three times a week 
TReg 
Regulatory T-cell 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States (of America) 
USP 
United States Pharmacopeia 
USPI 
US package insert 
WBC 
White blood cell 
WHO 
World Health Organization 
WHO DDE 
World Health Organization drug dictionary enhanced 
 

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1 
BACKGROUND 
1.1 
Introduction 
HBI-8000 (chidamide, tucidinostat) is an orally bioavailable inhibitor, selective for 
cancer-associated histone deacetylase (HDAC) isoenzymes 1, 2, 3, and 10. By affecting the 
acetylation of histones and non-histones in cancerous and immune cells, it regulates the gene 
expression epigenetically without changing the DNA sequence and modulates immune functions 
and malignant phenotypes. Selective HDAC inhibitors (HDACi) such as HBI-8000 have been 
shown to alter the expression of genes which are aberrant, silenced or overexpressed in cancer 
cells. HUYABIO International, LLC (HUYABIO) is developing HBI-8000 as a monotherapy for 
the treatment of hematological malignancies and in combinations for the treatment of solid tumors 
such as melanoma, breast, kidney, and lung cancers. Combination regimens of HDACi with other 
cancer drugs have shown synergistic effects both in pre-clinical and clinical studies. At the same 
time, these combinations have enhanced the efficacy, reduced the toxicity and tumor resistance to 
therapy [Hontecillas-Prieto 2020]. 
Programmed cell death protein (PD-1) and its ligands (PD-1/PD-L1 axis) play a fundamental 
role in the evasion of tumor cells from antitumor immunity. The safety and efficacy of HBI-8000 
in combination with nivolumab, an inhibitor to PD-1/PD-L1 axis, has been evaluated in a Phase 
1b/2 study (HBI-8000-302) in patients with advanced melanoma, renal cell carcinoma (RCC) 
and non-small cell lung cancer (NSCLC). Interim results from the Phase 1b part of the study 
established that HBI-8000, 30 mg twice weekly in combination with the standard dose of 
nivolumab was well tolerated. The tolerability was further confirmed in the expanded cohorts in 
Phase 2. Efficacy signals were also observed throughout this study, including patients with 
NSCLC regardless of their prior exposure to immune checkpoint inhibitor(s).  
The hypothesis is that HBI-8000, combined with approved immune checkpoint inhibitors can 
improve the antitumor immune response in cancer patients, possibly by enhancing tumor 
immunogenicity and inflammatory response in tumor microenvironment. In the present study, the 
safety and efficacy of HBI-8000 in combination with KEYTRUDA® (pembrolizumab) in 
advanced and metastatic NSCLC will be explored. Efficacy will be assessed based on objective 
response rate (ORR), progression-free survival (PFS), and duration of response (DoR). 
1.1.1 
Non-Small Cell Lung Cancer (NSCLC) 
Immune checkpoint therapy in Non-Small Cell Lung Cancer (NSCLC)  
According to American Cancer Society Facts and Figures 2021, there will be approximately 
235,760 new cases of lung cancer, resulting in 131,880 deaths in the United States (US) [SEER 
2021]. Despite reductions in the incidence of lung cancer over the past 20 years, lung cancer 
remains the 2nd most common cancer (12.4%) in both men and women in the US, and the leading 
cause of cancer death (21.7%). Despite progress in treatment, the relative survival rate of lung 
cancer was 21.7% from 2011-2017 [SEER 2021]. 
Historically, platinum containing chemotherapy has been the mainstay of systemic therapy for 
NSCLC.  With the discovery of tyrosine kinase inhibitors targeting specific aberrant gene 
expressions in NSCLC, such as epidermal growth factor receptor (EGFR), the anaplastic 
lymphoma kinase (ALK) and the c-ros oncogene (ROS) receptor tyrosine kinase, small molecule 

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non-cytotoxic therapies targeting these genes (erlotinib, gefitinib, and afatinib and osimertinib in 
EGFR mutations and crizotinib, ceritinib, alectinib and brigatinib in ALK and ROS mutated 
NSCLC) were integrated into NSCLC management more recently. 
The activities of immune checkpoint inhibitors in NSCLC were observed in clinical studies of 
pembrolizumab and nivolumab.  
Nivolumab, a human immunoglobulin G4 (IgG4) anti-PD-1, was the first drug approved as 
second line therapy for advanced NSCLC in 2015. The results from CheckMate 017 study 
showed nivolumab significantly improved OS, PFS and ORR over the standard therapy of 
docetaxel in NSCLC with squamous histology and the clinical benefits were independent of 
PD-L1 expression [Brahmer 2015]. The safety profiles were acceptable with 7% 
treatment-related AEs of Grade 3 or 4 in nivolumab group of 7% as compared with 55% of those 
in the docetaxel group. The clinical benefit of nivolumab in non-squamous NSCLC, was 
evaluated in CheckMate 057 study. Although in this study, nivolumab did not extend PFS, it 
improved OS and ORR regardless of the level of PD-L1 tumor membrane expression levels. 
Grade 3 to 5 treatment-related adverse events were reported in 10% of nivolumab and 54% of 
docetaxel-treated patients [Borghaei 2015]. Results of both studies were updated subsequently 
[Horn 2017]. The 2-year OS rate was 23% in nivolumab group comparing to 8% docetaxel group 
in squamous and 29% versus 16% in non-squamous NSCLC. The relative reductions in the risk 
of death with nivolumab versus docetaxel remained similar to those reported in the primary 
analyses. Durable responses were observed with nivolumab; 10 (37%) of 27 confirmed 
responders with squamous NSCLC and 19 (34%) of 56 with nonsquamous NSCLC had ongoing 
responses after 2 years’ minimum follow-up. No patient in either docetaxel group had an 
ongoing response. In the pooled analysis, the relative reduction in the risk of death with 
nivolumab versus docetaxel was 28% (hazard ratio (HR), 0.72; 95% CI, 0.62 to 0.84), and rates 
of treatment-related adverse events were lower with nivolumab than with docetaxel (any grade, 
68% v 88%; grade 3 to 4, 10% v 55%). Both studies demonstrated clinical benefit of nivolumab 
across tumor histology and all levels of PD-L1 expression.  
Pembrolizumab is a humanized IgG4 anti-PD-1. Various dosing regimens of pembrolizumab 
were evaluated in the Phase 1b study KEYNOTE 001 in 101 patients with treatment-naïve 
NSCLC. The most common treatment related AEs were fatigue (27.7%), followed by pruritus 
(14.9%), hypothyroidism (13.9%), rash (13.9%), arthralgia (11.9%), and nausea (11.9%).  
However, Grade 3/4 treatment-related AEs occurred in 12% subjects [Hui 2017]. The 
immune-mediated AEs, regardless of attribution to treatment as reported by investigators, were 
observed in 22% of patients, with hypothyroidism being most common in 15% of patients. All 
were of grade 1 or 2 severity, except for 1 case each of grade 3 pneumonitis, hypophysitis, 
colitis, and dermatitis, manageable with steroids and supportive care. There were no 
treatment-related deaths. Efficacy was apparent in all treatment regiments and was more 
prominent in tumors with higher PD-L1 expression. 
KEYNOTE 010, a phase 2/3 study, further evaluated the efficacy and safety of pembrolizumab 
at 2 and 10 mg/kg given every 3 weeks (Q3W) in previously treated NSCLC. This study 
demonstrated superior overall survival (OS) over standard-of-care docetaxel treatment in patients 
with previously treated, PD-L1-positive NSCLC [Herbst 2016]. Improvement of PFS and ORR 
over docetaxel were also evident in all patients with positive PD-L1 expression status assessed 
by an immunohistochemical assay reported as tumor proportion score (TPS) ≥1% of either 

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archival or newly biopsied tumor specimens [Herbst 2019]. (The overall safety profile of this 
combination was well tolerated, consistent with findings from KEYNOTE 001 study. Similarly, 
in the KEYNOTE-042 study, patients with NSCLC (squamous and non-squamous) had better 
outcomes when treated with pembrolizumab alone than chemotherapy (paclitaxel/carboplatin or 
pemetrexed/carboplatin). Survival in the pembrolizumab arm was superior at all levels of PD-L1 
expression. Higher PD-L1 expression resulted in greater improvement. For patients with tumor 
TPS ≥50%, median OS was 20.0 months (95% CI 15·4–24·9) for the pembrolizumab group vs. 
12.2 months (10·4–14·2) for the chemotherapy group (HR=0.69; 95% CI: 0.56, 0.85; p=0.0003); 
for TPS of >20%, median OS was 17.7 (15·3–22·1) for the pembrolizumab group vs. 13 months 
(11·6–15·3) for chemotherapy group (HR=0.77; 95% CI: 0.64, 0.92; p=0.0020); and for TPS  
>1%, median OS was 16.7 months (13·9–19·7) for the pembrolizumab group vs. 12.1 months 
(11·3–13·3) for chemotherapy group  (HR=0.81; 95% CI: 0.71, 0.93; p=0.0018). 
Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated 
patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led 
to death in 13 (2%) and 14 (2%) patients, respectively [Mok 2019].   
Pembrolizumab was also evaluated in combination with chemotherapy. In the first-line setting of 
advanced NSCLC, results from KEYNOTE-189 study showed superiority of 
pembrolizumab/chemotherapy over chemotherapy alone in PFS and ORR in all PD-L1 
expressing disease. The estimated rate of overall survival at 12 months was 69.2% (95% CI, 64.1 
to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the 
placebo combination group (HR for death, 0.49; 95% CI, 0.38 to 0.64; P <0.001). Median 
progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the 
pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the 
placebo-combination group (HR for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P 
<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the 
pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.  
The improvement of PFS was more prominent among patients whose tumors had TPS ≥50% 
(HR=0.42) than TPS 1% - 49% (HR=0.55) Incidence of grade 3-5 adverse events was similar in 
the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups [Gandhi 
2018; Gadgeel 2020]. 
Thus, pembrolizumab became the first FDA approved checkpoint inhibitor for first-line 
treatment of patients with metastatic NSCLC whose tumors express PD-L1 as determined by an 
FDA-approved test, with expansion of indication for second-line treatment of lung cancer to 
include all patients with PD-L1 expressing NSCLC. This approval was based on results of two 
randomized, open-label, active-controlled trials that demonstrated statistically significant 
improvements in PFS and OS for patients randomized to pembrolizumab compared with 
chemotherapy. Shortly after, pembrolizumab was approved for first-line treatment of patients 
with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation 
or metastatic NSCLC based on KEYNOTE-042. 
1.1.2 
Rationale for HBI-8000 and immune checkpoint combination   
Inhibition of different subtypes of HDAC could have distinct effects on regulatory T cell (TREG) 
activity [Wang 2009; Beier 2012; Pili 2012; Shen 2012]. Furthermore, a recent publication 
demonstrated the newly discovered role of HDAC2 in the nuclear translocation of PD-L1 that 
regulates the immune-response gene expression [Gao 2020]. This observation is consistent with 

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the notion that inhibition of HDAC2-dependent acetylation of intracellular transport system 
could enhance the therapeutic effect of immune checkpoint inhibitors commonly used in clinics.  
Recent reports suggest that HDACi has a significant effect on the expression of immune 
checkpoint co-inhibitory and co-stimulatory molecules. Additionally, HDACi may affect 
immunogenicity, antigen-presenting cells and T cell priming, regulatory T cells, myeloid-derived 
suppressor cells (MDSCs), and effector cell functions. For example, HDAC inhibition has been 
shown to upregulate PD-1 ligand in melanoma and thereby augmenting immunotherapy with 
PD-1 blockade [Woods 2015]. Class I HDAC inhibitors upregulate the expression of PD-L1 and 
to a lesser extent PD-L2 in human and murine melanoma cell lines and in tumor tissue from 
cancer patients. The upregulation of PD-ligands was durable and lasted beyond 96 hours. These 
results suggest that combination of Class I HDAC inhibitors, such as HBI-8000, may have 
additive or synergistic activity in combination with PD-1 blockade antibodies.  
The direct evidence supporting the synergy of HBI-8000 with immune checkpoint inhibitors was 
observed in animal models. Gene expression analysis of the treated MC38 tumors revealed 
significant changes in mRNA expression of immune checkpoints, with enhanced dendritic cell 
and antigen-presenting cell functions, and modulation of MHC class I and II molecules. These 
findings suggest that HBI-8000 mediates epigenetic modifications in the tumor 
microenvironment, leading to improved efficacy of immune checkpoint inhibitors, and provide 
strong rationale for combination therapies with immune checkpoint inhibitors and HBI-8000 in 
the clinical setting.  
1.1.3 
HBI-8000 (tucidinostat) 
HBI-8000 (tucidinostat, chidamide), N-(2-amino-4-fluorophenyl)-4-{[(2E)-3-(pyridine-3-
yl)prop-2-enamido]methyl} benzamide, is a member of the benzamide class of HDACi designed 
to bind and prevent access to the catalytic pocket primarily of Class I HDACs [Pan 2014]. 
HUYABIO initiated clinical development of this compound in 2012 in the United States (US) 
and 2014 in Japan. The Ministry of Health, Labor and Welfare (MHLW) in Japan approved 
tucidinostat 10 mg tablet for treatment of relapsed or refractory adult T-cell leukemia/lymphoma 
(ATLL) in June 2021 and a new drug application for relapsed and refractory peripheral T-cell 
lymphoma (PTCL) is under regulatory review. Worldwide, in addition to the Phase 1b/2 study 
(HBI-8000-302), a phase 3 study (HBI-8000-303) in metastatic melanoma has been initiated to 
evaluate the efficacy of HBI-8000 in combination with nivolumab. In China, this compound 
(tucidinostat) was developed by Shenzhen Chipscreen Biosciences Co., Ltd. (Chipscreen). It was 
approved by China Food and Drug Administration (CFDA) in December 2014 for the treatment 
of relapsed or refractory PTCL, and for hormone receptor-positive advanced breast cancer in 
combination with aromatase inhibitor in Nov 2019. As of December 2020, approximately 26,000 
cancer patients were treated with this drug in China under the brand name of Epidaza®. 
HBI-8000 is an orally bioavailable, low-nanomolar inhibitor of cancer-associated HDAC 
enzymes with favorable pharmacology and tolerability profiles relative to existing benzamide 
and non-benzamide HDAC inhibitors. Please refer to the Investigator’s Brochure for further 
information on HBI-8000. 
The structural formula for HBI-8000 is shown in Figure 1. 

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Study ID 
HBI-8000 
Dose 
Disease 
N 
Phase 
(Status) 
Treatment 
Countries 
HBI-8000-
101 
5-60 mg
TIW
Advanced 
Solid Tumors 
25 
Phase 1 
(Completed) 
Monotherapy US 
HBI-8000-
201 
30 or 40 
mg BIW 
Non-
Hodgkin’s 
Lymphoma 
14 
Phase 1 
(Completed) 
Monotherapy Japan 
HBI-8000-
304 
20 mg 
single 
dose 
Normal 
volunteers 
16 
Phase 1 
(Completed) 
Food 
effect/drug-
drug 
interaction 
US 
Abbreviations: ATL = adult T-cell leukemia/lymphoma; BIW = twice weekly; NSCLC = non-small cell lung 
cancer; PTCL = peripheral T-cell lymphoma; RCC = renal cell carcinoma; US = United States. 
1.1.3.3 
HBI-8000 Safety Profile 
As a monotherapy, the main safety findings for HBI-8000 are myelosuppression 
(thrombocytopenia, neutropenia, leukopenia, and anemia) observed in heavily pre-treated 
relapsed and refractory T-cell lymphoma patients. Additional toxicities included gastrointestinal 
symptoms, fatigue and asymptomatic laboratory abnormalities. Toxicities were generally mild 
and manageable with supportive care, dose reductions, interruption, or delays. 
In clinical studies, treatment with HBI-8000 has been associated with exposure-related 
myelosuppression, categorized as important identified risk and includes thrombocytopenia, 
anemia, and neutropenia or lymphopenia. These myelosuppression related toxicities were more 
severe in patients with relapsed and refractory hematological malignancies than in patients with 
solid tumors. In general, the hematologic AEs are manageable with supportive care such as 
hematological growth factor administration, dosing interruption and dose reduction. Other 
important identified risks are pneumonitis, interstitial lung disease, and interstitial pneumonia. 
In the HBI-8000-302 study, the safety of HBI-8000 administered in combination with standard 
dose immune checkpoint inhibitor (CPI), nivolumab, has been evaluated in 89 patients total 
including 49 with melanoma, 29 with NSCLC and 11 with renal cell carcinoma. The most 
common AEs of all grades associated with HBI-8000 were fatigue (59.6%), thrombocytopenia 
(49.4%), nausea (48.3%), diarrhea (47.2%), anemia (42.7%), dyspnea (37.1%), peripheral edema 
(33.7%), anorexia (32.6%), neutropenia (31.5%) and leukopenia (31.6%). The most reported 
Grade 3 or higher adverse events were lymphopenia, neutropenia, hypophosphatemia, fatigue, 
anemia and diarrhea.  Only 3 subjects had transaminase elevation were reported as Grade 3. The 
safety profiles so far have been consistent with those observed in HBI-8000 monotherapy, 
although the hematological toxicities were less severe and less frequent, as expected with solid 
tumor patient population. There has been no evidence of increased risk for immune-related 
toxicity over those expected with nivolumab treatment alone. 
Arrhythmia including QTc prolongation may occur and are categorized as important potential 
risk. However, recently, a QT interval corrected by heart rate (QTc) HBI-8000-302 

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QTc-sub-study with time-matched PK was completed to evaluate the potential for QTc 
prolongation. There was no evidence of QTc prolongation when HBI-8000 was administered in a 
dose range of 20 to 40 mg BIW. Other important potential risks that may occur are electrolyte 
abnormality (hyponatremia and hypokalemia) and hypersensitivity. 
1.1.3.4 
Overall Safety Risk Assessment 
In clinical studies, treatment with HBI-8000 has been associated with exposure-related 
myelosuppression, including thrombocytopenia, anemia, and neutropenia or leukopenia. These 
myelosuppression related toxicities were more severe (grade 3 or 4) in patients with relapsed and 
refractory hematological malignancies who have been treated with high dose cytotoxic 
chemotherapy, than in patients with solid tumors. In general, the hematologic AEs are 
manageable with supportive care such as hematological growth factor administration, dosing 
interruption and dose reduction.  
When HBI-8000 was administered concurrently with CPI (nivolumab) in patients with solid 
tumor, the combination was well tolerated, with toxicity profiles consistent with either agent 
alone, without apparent exacerbation of known toxicities or new toxicity, manageable with 
standard supportive therapy established for either agent.  
1.1.3.5 
Overall Risk/Benefit Assessment 
In general, HBI-8000 in combination with immune CPI, nivolumab. is well tolerated by cancer 
patients. Evidence of enhanced efficacy was observed, compared to CPI single agent, with 
durability of response, Therefore, the potential clinical benefit appears to outweigh the potential 
risks from combining HBI-8000 with the standard of care of pembrolizumab. 
1.1.4 
Rationale for Statistical Design 
This open label Phase 2 study is designed to characterize safety and allow for preliminary 
evaluation of efficacy endpoints in the specific patient population of interest.  With a sample size 
of 20 to 24 subjects the probability that an adverse event with at least a 10% incidence will be 
detected in at least one subject is high (87.8% to 92.0%) (Table 4).  Obtaining this information 
will help in planning for future immuno-oncology studies. 
1.1.5 
HBI-8000 Dose Selection and Justification for Combination with 
Pembrolizumab 
The safety of HBI-8000 in combination with immune checkpoint inhibitor has been evaluated 
with the standard dose of nivolumab.  In study HBI-8000-302 (Phase 1b), patients received 
HBI-8000 tablets, 20, 30, or 40 mg BIW, with the standard IV dose of nivolumab at 240 mg 
every two weeks (Q2W) until maximum tolerated dose (MTD) was achieved and the frequency 
and severity of toxicities of this combination were evaluated.  
A total of 15 patients evaluable for dose-limiting toxicity (DLT) were enrolled. At 40 mg BIW, 
DLTs were observed: Grade 3 headache in one melanoma patient and Grade 3 fatigue in one 
RCC patient. Following the 3 + 3 design, an additional 3 patients were evaluated at the 30-mg 
dose level, in whom no DLT was observed. The recommended phase 2 dose (RP2D) selected for 
cohort expansion portion of this study was 30 mg BIW.   

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Overall, in Study HBI-8000-302 the safety of HBI-8000 administered in combination with 
standard dose immune CPI, nivolumab, has been evaluated in over 89 patients with melanoma, 
NSCLC and renal cell carcinoma. The most common AEs of all grades associated with 
HBI-8000 were fatigue, thrombocytopenia, anemia, diarrhea, nausea and anorexia.  However, 
only neutropenia, thrombocytopenia, hypophosphatemia, fatigue, and less frequently, nausea, 
anorexia, diarrhea, and transaminase elevation were reported as Grade 3, lymphopenia was 
reported as Grade 4.  Thus, the collective data investigating dose and schedule of HBI-8000 as 
related to safety, QTc prolongation, tolerability, PK, and related efficacy have established the 30 
mg twice weekly to be appropriate when used in combination with nivolumab, and likely other 
immune checkpoint inhibitors, at approved dosing and regimen. (See Investigator’s Brochure for 
more information.) 
This phase 2 study will evaluate HBI-8000 30 mg administered twice weekly in pembrolizumab 
combination, with appropriate dose modification guidelines. 
2 
OBJECTIVES 
2.1 
Primary Objectives 
The primary objective of the study is: 
•
To evaluate the efficacy of HBI-8000 in combination with a standard dose and
regimen of pembrolizumab as a first line checkpoint inhibitor therapy for advanced or
metastatic NSCLC, as measured by Objective Response Rate (ORR) according to
RECIST criteria version 1.1 [Eisenhauer 2009].
2.2 
Secondary Objectives 
The secondary objectives of the study are: 
•
To evaluate the safety and tolerability of HBI-8000 in combination with a standard
dose and regimen of pembrolizumab
•
To explore the additional efficacy parameters for HBI-8000 in combination with a
standard dose and regimen of pembrolizumab as measured by Disease Control Rate
(DCR), Duration of Response (DoR), and Progression-Free Survival (PFS)
2.3 
Criteria for Evaluation 
2.3.1 
Safety Endpoints 
Adverse events reported by the subjects or observed during physical examination, vital signs 
assessment, electrocardiograms (ECGs) will be recorded by severity according to National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0, and 
association with HBI-8000 and pembrolizumab will be assessed. Laboratory test results will be 
recorded and assessed against normal ranges. ECOG performance scores, as applicable, will be 
monitored. 

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2.3.2 
Efficacy Endpoints 
Target lesion(s) and non-target lesion(s) will be assessed by imaging studies at screening 
(baseline assessment), in the last week of Cycle 2 including C3D1, and then every 6 weeks 
(±3 days) thereafter. Tumor assessments will follow guidelines specified in RECIST criteria 
v1.1. 
•
ORR (complete response [CR]+partial response [PR])
•
DCR (CR+PR+Stable disease [SD])
•
DoR
•
PFS
After the discontinuation of HBI-8000 treatment, subjects without disease progression will be 
followed for progression with imaging of measurable disease every 12 (±1) weeks until 
progression, initiation of another anti-cancer treatment, or referral to hospice whichever occurs 
first. Survival follow-up will be performed every 12 (±1) weeks by telephone contact or e-mail 
for up to 12 months after the last dose of HBI-8000. 
3 
STUDY DESIGN 
3.1 
Overall Design 
This is a multicenter, open label, non-randomized, Phase 2 study of HBI-8000 in combination 
with a Food and Drug Administration (FDA) approved dose of pembrolizumab as the first 
checkpoint inhibitor therapy for advanced or metastatic NSCLC where subjects have 
programmed death ligand 1 (PD-L1) expression Tumor Proportion Score (TPS) ≥1%. Prior to 
enrollment, the PD-L1 expression status must be available. Historical data may be used to assess 
for eligibility. If historical data is not available, tumor tissue will be analyzed locally by an 
FDA-approved test to yield PD-L1 status prior to enrollment. 
The dose of HBI-8000 is 30 mg twice weekly. Pembrolizumab is administered according to 
prescribing information. 
The study will include a screening period of up to 28 days before the first dose of HBI-8000. 
Study Treatment may be with or without pembrolizumab. HBI-8000 and pembrolizumab will 
continue up to 24 months. HBI-8000 will continue until disease progression, unacceptable 
toxicity related to HBI-8000 ensues or withdrawal of informed consent to receive HBI-8000.  
The Treatment Phase allows for up to 24 months of treatment (cycles are 21 days), providing the 
subject does not experience disease progression or unacceptable toxicity. An End of Treatment 
safety visit will be performed 30 (±3) days after last dosing of HBI-8000. If HBI-8000 is 
discontinued due to unacceptable toxicities related to HBI-8000, pembrolizumab may continue 
as single agent under standard of care. Subjects will be followed for up to 12 months after the 
last dose of HBI-8000 for disease status, including initiating a new cancer treatment and 
experiencing disease progression, death, or becoming lost to follow-up or consent withdrawal.  

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3.1.1 
Expected Duration of Subject Participation 
Subject participation duration from screening through end of treatment visit is approximately up 
to 38 months, including:  
Screening period: 
Up to 28 days 
Treatment period: 
Until radiographic disease progression per RECIST v1.1 
(assessed by the Investigator), unacceptable toxicity, or 
other reasons for discontinuation with a maximum 
treatment duration of 24 months, unless there is an 
agreement between the Sponsor and the Investigator to 
allow HBI-8000 beyond 24 months.  
Short-term Follow up/ 
End of treatment (EoT) period 
Up to 30 days (±3 days) after the last dose HBI-8000. This 
will be defined as EoT. 
Long-term Follow-up period: 
Every 12 weeks (3 months) up to a maximum of 12 months 
after the last dose of HBI-8000.  
3.1.2 
Tumor Status and Survival Follow-Up 
Subjects without disease progression who completed up to 24 months of treatment or 
discontinued from HBI-8000 due to reasons other than PD are followed with imaging studies 
every 12 (±1) weeks until progression is documented, another anti-cancer treatment is initiated, 
or referral to hospice, whichever occurs first.   
All subjects will be contacted approximately every 12 (±1) weeks by telephone contact or e-mail 
for survival follow-up for up to 12 months after the last dose of HBI-8000. 
3.1.3 
Study Population 
Approximately 20-24 subjects with advanced or metastatic non-small cell lung cancer will be 
enrolled at approximately 6-10 investigational sites in the United States. Subjects that have 
signed an informed consent but did not receive HBI-8000 may be considered for this study 
provided they are re-consented and undergo screening procedures specified in the protocol. 
Under no circumstances will subjects who enroll in this study and have completed treatment as 
specified, be permitted to enroll for a second time. 
3.2 
Justification for Dose 
The Sponsor plans to evaluate HBI-8000 at 30 mg orally twice a week (BIW) in combination 
with pembrolizumab administered intravenously at 400 mg every 6 weeks or 200 mg every 3 
weeks in the present study (HBI-8000-305). This dosing regimen was selected based on clinical 
observations related to safety, tolerability, PK, and efficacy from previously conducted Phase 
1b/2 study (HBI-8000-302). 
3.3 
End of Treatment Definition 
The end of treatment is defined as the date of the last dose of HBI-8000 taken by the subject. 

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3.4 
End of Study Definition 
The study completes when all subjects have experienced progressive disease or 12 months after 
the last dose of HBI-8000 administration, whichever comes first. All subjects will be followed 
until death, lost to follow-up, withdrawn consent from study participation entirely, or study 
terminated by Sponsor. 
4 
STUDY POPULATION 
4.1 
Inclusion Criteria 
Subjects may be entered in the study only if they meet all of the following criteria: 
1. Adults at least 18 years of age.
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
3. Histopathologically confirmed diagnosis of NSCLC PD-L1 expression TPS ≥1% as
determined by an FDA-approved test.
4. Have at least one measurable target lesion as defined by RECIST v.1.1.
5. Have not received immune checkpoint inhibitor therapy or more than one regimen of
chemotherapy for advanced or metastatic disease. Subjects who have previously received
immune checkpoint inhibitor therapy in the adjuvant or neoadjuvant setting may be
allowed if disease progression occurred >6 months after the last dose and no clinically
significant immune related toxicities leading to treatment discontinuation were observed.
6. Prior adjuvant or neoadjuvant systemic therapy with chemotherapy, EGFR or ALK
mutation directed therapy must have been completed >4 weeks before Cycle 1 Day 1
(C1D1) dosing and recovered from all treatment related toxicity.
7. Any prior palliative radiotherapy or minor surgery must be completed at least 2 weeks
and 1 week respectively before C1D1 dosing and recovered from all treatment related
toxicities.
8. Adequate major organ functions at baseline as evidenced by laboratory findings within
14 days prior to C1D1 study drug administration as defined below:
a.
White blood cells (WBC) ≥3000/μL, neutrophils ≥1500/μL, platelets ≥100×103/μL,
hemoglobin ≥9.0 g/dL, independent of transfusion.
b. Serum creatinine ≤1.5 mg/dL, normal electrolytes, phosphorus, and calcium,
c.
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper
limit of normal (ULN), alkaline phosphatase ≤2.5 × ULN unless bone metastases
present, bilirubin ≤1.5 × ULN (unless known Gilbert’s disease where it must be
≤3 × ULN) and serum albumin ≥3.0 g/dL.
d. Thyroid stimulating hormone (TSH) within normal limits.
9. Life expectancy ≥12 weeks.
10. A negative serum pregnancy test at baseline for women of childbearing potential
(WOCBP).

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11. Females of childbearing potential (non-surgically sterile or premenopausal female
capable of becoming pregnant) and all males (due to potential risk of drug exposure
through the ejaculate) must agree to use an acceptable method of contraception while
enrolled on this study and for 5 months after the last dose of study drug. Acceptable
methods of birth control in this trial include 2 highly effective methods of birth control
(as determined by the Investigator; one of the methods must be a barrier technique) or
abstinence.
12. Have the ability to understand and the willingness to sign a written informed consent
document.
4.2 
Exclusion Criteria 
Subjects who fulfill any of the following criteria at screening will not be eligible for admission 
into the study: 
1. History of Grade ≥3 or above hypersensitivity reactions to monoclonal antibodies.
2. History of a cardiovascular illness including: QT interval corrected by heart rate using
Fridericia’s correction formula (QTcF) >450 ms in male or >470 ms in female,
congenital long QT syndrome, congestive heart failure (New York Heart Association
Grade III or IV) (Appendix 2); unstable angina or myocardial infarction within the
previous 6 months; or symptomatic cardiac arrhythmia despite medical management.
3. Uncontrolled hypertension, systolic blood pressure (SBP) >160 mmHg or diastolic blood
pressure (DBP) >100 mmHg.
4. Central nervous system metastasis or leptomeningeal disease except when treatment of
brain metastasis is completed >14 days prior to C1D1 and stable for ≥4 weeks on <10 mg
daily prednisone or equivalent.
5. History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled peptic
ulcer disease or bowel resection that affects absorption of orally administered drugs.
6. Recurrent pleural effusion requiring repetitive palliative thoracentesis within 3 months
prior to study entry, except for subjects with a pleurex port.
7. Active, known, or suspected autoimmune disease, or history of immune-mediated
toxicity leading to treatment discontinuation, except for type I diabetes mellitus,
hypothyroidism only requiring hormone replacement or skin disorders (such as vitiligo,
psoriasis, or alopecia) not requiring systemic therapy.
8. Active pneumonitis, history of non-infectious pneumonitis that required treatment with
steroids, or history of interstitial lung disease.
9. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
10. Known history of testing positive for human immunodeficiency virus (HIV), known
acquired immunodeficiency syndrome (AIDS).
11. Active hepatitis B (serum hepatitis B surface antigen [HBVsAg] positive), or hepatitis C
(HCV antibody test or serum hepatitis C ribonucleic acid [RNA] positive).
12. Received approved live vaccines within 30 days of planned C1D1. Inactivated viral
vaccines or vaccines based on subviral component are allowed; however intranasal
influenza vaccines (e.g. Flu-Mist) are not allowed. COVID-19 vaccination should be
administered >7 days before C1D1.

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13. Any condition requiring chronic systemic treatment with either corticosteroids (>10 mg
daily prednisone equivalents) or other immunosuppressive medications, or steroids use
within 14 days of study drug administration. Inhaled or topical steroids are permitted.
14. Use of other investigational agent (drug not marketed for any indication) within 28 days
or at least 5 half-lives (whichever is shorter) before study drug administration.
15. Pregnant or breast-feeding women.
16. Second malignancy unless in remission for 2 years; subjects with non-melanomatous skin
cancer, carcinoma in situ of the cervix treated with curative intent, or curatively treated
prostate cancer with prostate-specific antigen (PSA) <2.0 ng/mL can be included.
17. Underlying medical conditions that, in the Investigator’s opinion, will make the
administration of study drug hazardous or obscure the interpretation of toxicity
determination or adverse events.
18. Unwilling or unable to comply with procedures required in this protocol.
4.3 
Subject Registration 
4.3.1 
Subject Registration 
Based on medical history, potentially eligible subjects will be identified. After obtaining 
informed consent, the screening procedures will be performed. Once a subject’s eligibility has 
been confirmed, a 4-digit subject number will be assigned. The first 2 digits are the site number 
(provided by the Sponsor or CRO to investigational sites). The following 2 digits are a sequential 
number within an investigational site. An Eligibility Screening Form (ESF) provided by the 
Sponsor or CRO documenting the Investigator’s assessment of each screened subject with regard 
to the protocol’s inclusion and exclusion criteria is to be completed, submitted for review and 
approval by the Sponsor or Sponsor representative and kept at the investigational site   
4.3.2 
Blinding 
This is an open-label study; no blinding procedures will be performed. 
4.4 
Withdrawal Criteria 
4.4.1 
Subject Withdrawal from the Study 
Subjects may withdraw from the study at any time for any reason. The Investigator should try to 
ascertain the reason for withdrawal as completely as possible. The Investigator may also decide 
to discontinue a subject from the study. HBI-8000 may be discontinued, and the subject 
withdrawn from the study under the following circumstances: 
•
Unacceptable toxicity (AE)
•
Progression of the disease under study
•
Decision by the Investigator or subject to permanently discontinue HBI-8000
•
Intercurrent illness that would, in the judgment of the Investigator, affect clinical
assessments, patient safety, or follow-up to a significant degree
•
Significant protocol deviations that jeopardize the usefulness of the data

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•
Subject noncompliance, examples include omitting >1/3 of protocol specified dose
over 6 consecutive weeks, not adhering scheduled safety assessments, etc.
•
Subject is beginning another anti-cancer treatment
•
Subject becomes pregnant
•
Subject request to withdraw informed consent
•
Death
All subjects who withdraw from HBI-8000 must complete an EoT safety follow-up visit, to be 
performed 30 (± 3) days after the last dose of HBI-8000, or before initiation of new cancer 
treatment, whichever is earlier. After HBI-8000 is discontinued, the subjects should be followed 
for disease progression (if not already recorded) and survival. Only subjects who have withdrawn 
from study participation entirely, including the period after HBI-8000 is discontinued, will not be 
followed. In other words, a subject may withdraw consent for treatment but still allow follow-up, 
in which case he/she should be followed for safety, survival, and disease status. 
4.4.2 
Lost to Follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. Lost to follow-up is defined by the inability to reach the subject after a minimum of three 
documented phone calls, faxes, or emails as well as lack of response by subject to one registered 
mail letter. All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use permissible local methods to obtain the date 
and cause of death. 
4.5 
Discontinuation of Investigational Product and Participant Withdrawal 
Subjects discontinued from HBI-8000 for toxicity in the absence of disease progression may 
continue to receive pembrolizumab under standard of care and be followed for disease response 
as long as consent to study participation remains effective. Similarly, if pembrolizumab 
administration is discontinued due to unacceptable toxicities (other than immune-mediated 
reactions) associated with pembrolizumab, the subject may continue to receive HBI-8000, at the 
Investigator’s discretion in consultation with Sponsor Medical Monitor and be followed for 
disease response as long as consent to study participation remains effective. When both 
HBI-8000 and pembrolizumab have been discontinued and disease has not progressed, the 
subject will continue to be followed for disease status in the Follow-up Phase until evidence of 
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5.2.2 
Investigational Product Storage 
HBI-8000 Investigational Product: The storage and distribution condition is 15° to 30° Celsius 
(59°F to 86° Fahrenheit).  
HBI-8000 must be stored out of the reach of children and in original container with tightly closed 
cap to protect from moisture. 
Pembrolizumab: Must be stored under refrigeration at 2 to 8°Celsius (36 to 46°Fahrenheit), 
protected from light by storing it in the original package until time of use. It must not be frozen 
or shaken. 
Pembrolizumab does not contain a preservative. Diluted pembrolizumab from the 100 mg/4 mL 
vial should be stored either: 
•
At room temperature for no more than 6 hours from the time of dilution. This includes
room temperature storage of the diluted solution, and the duration of infusion.
•
Or, under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 96 hours from the
time of dilution. If refrigerated, allow the diluted solution to come to room temperature
prior to administration. Do not shake.
Discard diluted pembrolizumab after 6 hours at room temperature or after 96 hours under 
refrigeration. 
Do not freeze. 
5.2.3 
Investigational Product Accountability 
The Investigator, or his/her designee, must maintain a complete and accurate record of the 
receipt and distribution of all study medication using the Drug Accountability Form provided by 
the CRO, or local site equivalent. 
All study medication must be accounted for at the termination of the study, and a written 
explanation provided for any discrepancies. The study monitor will conduct a final drug 
reconciliation for all subjects. All records of HBI-8000 administration, accountability records, 
and disposition records will be examined and reconciled by the study monitor. All unused, 
partially used, and expired study medication and packaging materials are to be inventoried and 
returned to depot or destroyed as per the sites’ Standard Operating Procedure (SOP). The timing 
of the returns will be coordinated with the study monitor. The Investigator is not permitted to 
destroy unused clinical drug supplies or packaging materials unless authorized by HUYABIO or 
Sponsor representative. 
5.3 
Investigational Product Compliance 
The prescribed dosage, timing, and mode of administration may not be changed. Any departures 
from the intended regimen must be recorded in the eCRFs. Treatment compliance will be 
monitored by drug accountability as well as the subject’s medical record and eCRF. 
Study subjects will be provided with a drug diary to record times of administration, AEs, and 
missed doses. Study subjects will be instructed to bring the drug diary and study drug bottles 
(including empty bottles) to each study visit for reconciliation. 

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At each visit, prior to dispensing HBI-8000, previously dispensed HBI-8000 will be reviewed by 
the Investigator or designee and compliance assessed. Subjects exhibiting poor compliance as 
assessed by tablet counts should be counseled on the importance of good compliance to the study 
dosing regimen. 
5.4 
Concomitant Therapy 
All concomitant medications, defined as medications other than study medications, which are 
taken at baseline and throughout HBI-8000 treatment phase by the study subjects must be 
recorded on the eCRF. 
Palliative radiation therapy (limited-field) is permitted only for pain control to sites of bone 
disease present at baseline. The Sponsor Medical Monitor must be consulted prior to initiating 
any radiotherapy. 
5.4.1 
Prohibited Medications and Therapy 
Concomitant administration of the following types of drugs and procedures is not allowed: 
•
Recently completed drug-drug interaction study showed a mild (approximately 40%)
increase of AUC of HBI-8000 when itraconazole, a strong CYP3A4, was
administered concurrently.  The use of potent CYP3A4 inducers or inhibitors
(Appendix 3 ) should be avoided.
•
Live vaccines within 30 days prior to the first dose of trial treatment and while
participating in the trial.  Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu (that
contain a live virus), H1N1 flu, rabies, BCG, and typhoid vaccine.
•
Surgery for tumor control or symptoms management is not permitted during the
study.
•
Concomitant administration of anti-tumor treatment other than the Study Treatment,
or procedures that could interfere with the evaluation of safety or anti-tumor effect of
Study Treatment, is prohibited during the study.
5.4.2 
Supportive Care and Other Medications
Systemic use of corticosteroids at doses ≤10 mg/day of prednisolone, or converted equivalent 
dose, is permitted during the study. Brief use of higher dose of prednisone or its equivalent is 
also permitted to manage immune related toxicities as indicated. Supportive care to mitigate 
toxicities such as anti-emetics for nausea, and granulocyte-colony stimulating factor (G-CSF) for 
neutropenia are also allowed. 
Palliative and supportive care is permitted during the course of the trial for underlying medical 
conditions and management of symptoms.  
Palliative radiation therapy (limited field) is permitted only for pain control if considered 
medically necessary by the treating physician as long as the lesion is NOT a RECIST 1.1 defined 
target lesion and is NOT administered for tumor control. Study treatment should be held during 
the course of palliative radiotherapy and should be resumed no earlier than the next scheduled 
administration of study treatment. The specifics of the radiation treatment, including the location, 

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will be recorded. The Sponsor Medical Monitor must be consulted prior to initiating any 
radiation therapy. 
In order to provide optimal patient care, and to account for individual medical conditions, the 
Investigator may apply discretion to prescribe supportive care (e.g., acetaminophen, 
diphenhydramine, antimicrobials) according to local institutional guidelines. After the first cycle, 
pre-medication for anticipated adverse events may also be provided, according to local 
institutional guidelines. 
Subjects must be instructed to first consult with their study doctor before taking any additional 
medications (including over-the-counter or prescription medications and supplements including 
those prescribed/recommended by other physicians/dentists) during the study. 
5.4.3 
Restricted Medications 
•
Antiarrhythmic drugs such as amiodarone, disopyramide, procainamide, etc., and
other drugs known to prolong the QT interval such as clarithromycin, moxifloxacin,
bepridil, etc., may increase QT interval prolongation, and their coadministration
should therefore be avoided.  If such a drug is going to be co-administered, the
patient’s condition should be monitored closely.
•
Bisphosphonates and/or RANKL inhibitor therapies used to prevent bone resorption,
cannot be initiated after informed consent has been signed. These therapies may be
continued IF treatment with an agent from one of these two classes was initiated
PRIOR to signing informed consent.
•
COVID-19 vaccination should be administered >7 days before Cycle 1 Day 1.
5.5 
Food Effects 
The study evaluating the effect of food on oral bioavailability of HBI-8000 has shown 
comparable drug exposure of HBI-8000 tablets when taken under fasting or fed conditions. In 
this study, HBI-8000 should be taken approximately 30 minutes after a meal. 
Due to potential food-drug interactions, grapefruit, grapefruit juice, Seville oranges, and any 
products that contain Seville oranges or grapefruit should be avoided within 7 days prior to 
C1D1 through 7 days after the last dose of HBI-8000.  
5.6 
Dose Modification 
5.6.1 
HBI-8000 Administration 
Subjects will take 30 mg of Study Treatment orally approximately 30 minutes after a meal, 
beginning on Day 1 and continue every 3 to 4 days on the BIW schedule without interruption 
(e.g., Monday and Thursday, or Monday and Friday repeating every week).  
5.6.1.1 
HBI-8000 Dose Reduction 
Once HBI-8000 dose is reduced, it will not be increased. This dose reduction guideline applies to 
the entire study duration. 

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If a subject experiences any of the toxicities described below, the dose of HBI-8000 will be 
reduced. One dose reduction (30 mg to 20 mg) is allowed for non-hematological toxicities, and 
two dose reductions (30 mg to 20 mg and 20 mg to 10 mg) are allowed for hematological 
toxicities. Dose reduction for other toxicities not described below may be possible after approval 
from the sponsor. 
A.
Hepatic Non-Hematologic Toxicity
•
Isolated Grade 4 AST/ALT
•
Isolated Grade 3 AST/ALT that fails to return to Grade 1 or less within 5 days
•
Isolated total bilirubin ≥Grade 3
•
AST or ALT >3 × ULN AND concurrent total bilirubin >2 × ULN
B.
Non-Hepatic Non-Hematological Toxicity
Any Grade 3 or greater non-hepatic non-hematologic toxicity except for the following:
•
Grade 3 electrolyte abnormalities that are not complicated by associated clinical
adverse experiences, last less than 48 hours and either resolve spontaneously or
respond to conventional medical intervention.
•
Grade 3 nausea or vomiting that lasts less than 48 hours, and either resolves
spontaneously or responds to conventional medical intervention.
•
Isolated Grade 3 elevation of amylase or lipase not associated with clinical or
radiographic evidence of pancreatitis.
•
Isolated Grade 3 fever that lasts ≤3 days and is not associated with hemodynamic
compromise (i.e., hypotension, clinical or laboratory evidence of impaired end-organ
perfusion).
C.
Immune-related AEs (irAE)
•
Any Grade 2 or greater eye pain or reduction in visual acuity that does not respond to
topical therapy and does not improve to Grade 1 severity within 2 weeks of the
initiation of topical therapy or any Grade 2 or greater eye pain or reduction in visual
acuity that requires systemic treatment.
•
Any other Grade 3 or greater irAE
If pembrolizumab is withheld or permanently discontinued due to an
immune-mediated reaction, HBI-8000 should be withheld or permanently
discontinued, respectively.
D.
Hematologic Toxicity
•
Grade 4 neutropenia ≥7 days in duration
•
Grade 4 thrombocytopenia, or any Grade 3 thrombocytopenia associated with
clinically significant bleeding

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•
Grade ≥3 febrile neutropenia
•
Grade ≥3 hemolysis
HBI-8000 treatment will resume at a reduced dose only after toxicity has returned to Grade ≤1 
within 14 days from the occurrence of the toxicity. For neutropenia, the use of G-CSF should be 
considered. If the same toxicity recurs despite allowed dose reduction(s), HBI-8000 will be 
discontinued. If toxicity is not related to pembrolizumab, at Investigator’s discretion a subject 
may continue to receive pembrolizumab while remaining in study Follow-Up.  
5.6.1.2 
HBI-8000 Dose Delay Independent of Pembrolizumab Administration  
At the Investigator’s discretion, the dose of HBI-8000 may also be delayed for up to 14 days 
from the scheduled time of dosing, for any toxicity possibly or probably related to HBI-8000 that 
does not meet toxicity criteria described in Section 5.6.1.1. In the event of Grade 3 
uncomplicated thrombocytopenia or neutropenia HBI-8000 dosing should be held until recovery 
to Grade ≤1 before resuming again. Supportive care with hematological growth factors may be 
prescribed at the discretion of the Investigator. 
Dosing may be interrupted to assess or treat intercurrent illnesses. The Sponsor’s representative 
should be notified of any treatment interruption. In the event of interruption of >14 days, 
resumption of dosing should be discussed with Sponsor to assess potential benefit for 
continuation of HBI-8000.  
5.6.2 
Pembrolizumab Administration 
Pembrolizumab will be administered by intravenous infusion in accordance with KEYTRUDA® 
Prescribing Information (Package Insert and institutional practice either as 200 mg on Day 1 of 
every cycle or 400 mg on Day 1 of every other cycle (Cycle 1, 3, 5, etc.).  If administration of 
HBI-8000 is delayed or interrupted due to an AE not attributed to pembrolizumab, administration 
of pembrolizumab will not be affected. 
To manage infusion reactions, pembrolizumab will be administered only at sites that are fully 
equipped to handle infusion reactions, and with study personnel that are properly trained. 
5.6.2.1.1 Pembrolizumab Dose Modifications 
Dose modifications for pembrolizumab should be followed according to the most recent 
approved label for KEYTRUDA®; therefore, withhold or permanently discontinue 
pembrolizumab for adverse events as outlined in the KEYTRUDA US package insert (USPI) as 
per its use in non-small cell lung cancer. 
In the event that pembrolizumab is discontinued (for reasons other than immune-mediated 
reactions), HBI-8000 may be continued until one of the conditions for HBI-8000 discontinuation 
is met at the Investigator’s discretion in consultation with Sponsor Medical Monitor. 
5.6.2.1.2 Pembrolizumab Dose Delay Independent of HBI-8000 Administration 
Investigators should withhold a dose as described in the KEYTRUDA USPI (Recommended 
treatment modifications) until it is reduced to a Grade 1 or resolved. Once resolved, the dose may 
be reinstated. For subjects who were treated with steroids for irAE, steroids need to be tapered to 

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a dose 10 mg or less of prednisone or equivalent over at least 1 month before resuming 
pembrolizumab. The administration of HBI-8000 may continue as scheduled during 
pembrolizumab dosing interruption.  
5.6.2.1.3 Infusion-Related Reactions 
Pembrolizumab can cause severe infusion-related reactions. For severe and life-threatening 
infusion reactions, pembrolizumab should be discontinued; for mild or moderate infusion 
reactions the infusion should be interrupted, or the rate of infusion slowed. Immediate access to 
an Intensive Care Unit or equivalent environment and resuscitation equipment and appropriate 
medical therapy (including epinephrine, corticosteroids, IV antihistamines, bronchodilators, and 
oxygen) must be available to treat infusion-related reactions.  
All Grade 3 or 4 infusion reactions should be reported within 24 hours to HUYABIO Medical 
Monitor and reported as a serious adverse event (SAE) if criteria are met. Infusion reactions 
should be graded according to NCI-CTCAE guidelines. 
5.6.2.1.4 Severe Hypersensitivity Reactions 
If a hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical care. Subjects should be instructed to report any delayed reactions to the Investigator 
immediately based on the appropriate complete guideline for emergency treatment of 
anaphylactic reactions. 
Corticosteroids can be administered intravenously. The subject should be placed on a monitor 
immediately and the Intensive Care Unit must be alerted for possible transfer if needed. 
Investigators should withhold a dose as described in the KEYTRUDA® USPI (Dose 
Modifications). 
6 
STUDY ASSESSMENTS AND PROCEDURES 
The procedures and assessments to be performed during each period of the study are outlined in 
the Schedule of Dosing and Assessments (Table 1) and described in the following section. 
6.1 
Study Visits and List of Procedures 
6.1.1 
Screening Assessments (within 28 days prior to start of treatment) 
Written informed consent for participation in the study must be obtained before performing any 
study-specific screening tests or evaluations. Informed Consent Forms (ICFs) for all subjects 
screened will be maintained at the study site. 
Screening assessments will be performed within 28 days prior to Day 1. Results of standard of 
care tests or examinations performed prior to obtaining informed consent and within 28 days prior 
to Day 1 may be used (and do not need to be repeated during screening unless they do not meet 
the criteria defined in the protocol). 
The following will be collected or performed between Day -28 and Day -1: 
•
Written informed consent

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•
Inclusion/exclusion criteria review for confirmation of eligibility
•
Medical history, concomitant medications, baseline signs and symptoms,
demographics, and height
•
HBsAg and anti-HCV serology tests
•
Cancer diagnosis history including histological diagnosis, PD-L1 expression, known
mutation status for B-Raf proto-oncogene serine/threonine kinase gene (BRAF) V600,
EGFR, and ALK and treatment history
•
Brain magnetic resonance imaging (MRI) if clinically indicated, and radiographic
tumor assessment. If a subject has metal implants, a computerized tomography (CT)
scan should be used instead of an MRI.
6.1.2 
Baseline Assessments (within 14 days prior to start of treatment)
Baseline assessments may be completed within 14 days before C1D1. If there is any history or 
findings suggestive of significant heart disease, a cardiology consultation should be obtained. 
Women of childbearing potential must have a negative serum pregnancy test at baseline within 14 
days of start of treatment per the Schedule of Dosing and Assessments (Table 1). 
Baseline assessments include a complete physical examination, vital signs, ECOG performance 
status, weight, concomitant medications, laboratory tests (hematology, chemistry, coagulation and 
urinalysis), serum pregnancy test (if applicable), and ECG.  
All screening and baseline assessments must be completed and reviewed to confirm that subjects 
meet all eligibility criteria. Subject registration and ESF approval will be obtained in accordance 
with Section 4.3. 
6.1.3 
Treatment Phase Assessments 
Cycle 1 Day 1: physical exam, vital signs, ECOG performance status, weight, concomitant 
medications, and laboratory assessments will be performed according to the Schedule of Dosing 
and Assessments (Table 1).  
All visits and assessments from Cycle 2, Day 1 onwards may be performed ±3 days from the date 
of the projected visit date. First assessment of tumor response will be scheduled on C3D1 and 
every 6 weeks (±3 days) thereafter, or sooner if a subject develops clinical signs and symptoms of 
disease progression, until disease progression or end of study treatment. 
6.1.4 
End of Treatment (EoT) Safety Visit Assessments 
The EoT safety follow-up visit will be conducted 30 (±3) days following the last dose of HBI-8000, 
or before the initiation of new cancer treatment, whichever is earlier. Assessments will include a 
physical examination, vital signs, ECOG performance status, weight, concomitant medications, 
laboratory tests (hematology, chemistry, coagulation and urinalysis), serum pregnancy test (if 
applicable), ECG, and assessment of any ongoing adverse events. 
Subjects with HBI-8000-related AEs of Grade ≥2 observed at the EoT visit should be followed-up 
and assessed monthly until the AEs have resolved to Grade ≤1 or are determined to be chronic or 
subject receives other anti-cancer therapy. 

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Any pregnancies while on this study or within 28 days of the last dose of HBI-8000 will be 
followed up, with female subject’s permission, until the birth of the baby (Refer to 
Section 6.2.2.4.8). 
6.1.5 
Tumor Status and Survival Follow-up 
After the discontinuation of treatment (HBI-8000), subjects without disease progression will be 
followed for tumor status with imaging studies of target lesions every 12 (±1) weeks until 
progression, initiation of another anti-cancer treatment, or referral to hospice. Subjects will be 
contacted every 12 weeks (±1) weeks for survival follow-up, until death or end of the study.  
6.2 
Study Procedures Details 
6.2.1 
Efficacy Assessments 
The following evaluations will be performed throughout the course of the study: 
•
Tumor response assessments by physical examination and tumor imaging by CT or
magnetic resonance imaging (MRI) according to RECIST v1.1:  CT scans are the
required modality for measurable disease unless a subject has a clinical condition, e.g.
severe contrast allergy, when CT without contrast may be used per institution
guidelines. The same scanning modality and the same technique must be used to
measure each identified and reported lesion at baseline and throughout the study for a
given subject.
•
Brain magnetic resonance imaging (MRI) if clinically indicated, and radiographic
tumor assessment. If a subject has metal implants, a computerized tomography (CT)
scan should be used instead of an MRI.
6.2.1.1 
Tumor Response Criteria 
All measurable disease (target lesions and non-target lesions) must be documented at screening 
and reassessed at each subsequent tumor evaluation. Reassessment will be done by imaging studies 
according to RECIST Guidelines version 1.1 (Appendix 4), along with physical examinations and 
other methods as needed. At the Investigator’s discretion, CT scans may be repeated at any time 
if PD is suspected.  
Tumor response will be evaluated by the Investigator using the RECIST 1.1 criteria [Eisenhauer 
2009] (Appendix 4) and recorded in the appropriate eCRFs. Tumor response will also be assessed 
centrally. 
Taking into consideration possible pseudo progression, the subject may continue study treatment 
until the next imaging evaluation to assess tumor response according to irRECIST critieria. The 
same scanning modality should be used at baseline and throughout treatment for each subject.  
Subjects with isolated CNS progression, but responsive/stable extracranial disease, may remain on 
the study protocol after consultation with Sponsor Medical Monitor. 

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6.2.1.1.1 Immune-related RECIST (irRECIST) 
Immunotherapeutic agents may produce anti-tumor effects by potentiating endogenous 
cancer-specific immune responses. The response patterns seen with such an approach may extend 
beyond the typical time course of responses seen with cytotoxic agents and can manifest a clinical 
response after an initial increase in tumor burden or even the appearance of new lesions. 
Conventional RECIST 1.1 may thus not provide a complete response assessment of 
immunotherapeutic agents. To account for the unique tumor response characteristics seen with 
treatment with immunotherapy, irRECIST 1.1 has been adapted from conventional RECIST 
[Nishino 2013] (Appendix 4). 
Assessment of potential tumor progression is the responsibility of the Investigator. The 
Investigator will determine the date of progression and report it in the appropriate eCRF. 
6.2.1.1.2 Survival Follow-up 
Post-treatment tumor status in subjects whose disease has not progressed, and survival follow-up 
will be conducted until study completion. Subjects for whom disease progression has not been 
observed will have assessments of tumor status every 12 weeks (±1 week) until a date of disease 
progression is obtained, initiation of another anti-cancer treatment, or referral to hospice. Survival 
will be followed approximately every 12 (±1) weeks by telephone contact or e-mail for up to 12 
months after the last dose of HBI-8000. 
6.2.2 
Safety Assessments 
The following safety evaluations will be performed at screening and various time points 
throughout the course of the study (treatment phase, post-treatment, etc., refer to Table 1): 
•
Medical history
•
Physical examinations
•
Evaluation of adverse events (AEs)
•
ECOG performance status
•
Vital signs
•
Electrocardiogram (ECG)
•
Clinical Safety Laboratory tests: complete blood count (CBC) and serum chemistry,
Thyroid function (Baseline, Day 1 of each Cycle throughout study and EoT Safety
Follow-Up Visit) , hepatitis B and C panel (Screening), urinalysis (Baseline and EoT
Safety Follow-up Visit), serum pregnancy test (at Baseline and during study when
clinically indicated, if applicable)
•
Coagulation tests to include PT/INR, aPTT (at Baseline, at EoT Safety Follow-Up
Visit, and during the study when clinically indicated)
Treatment-emergent adverse events reported by the subjects or observed during physical 
examination, vital sign assessment, ECGs and/or review of laboratory test results will be 
assessed according to NCI CTCAE v.5.0 (CTCAE home page: 
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with HBI-8000 and pembrolizumab. Results of clinical laboratory tests, vital signs, physical 
findings, ECGs and ECOG performance status will be monitored and recorded. 
6.2.2.1 
Vital Signs, ECG, Physical Examinations, and ECOG Assessments 
Vital sign measurements will include temperature, heart rate, systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) in a supine position. Vital sign measurements should be performed 
prior to the ECG and after the subject has been supine for at least 5 minutes.  
Physical examinations will include the evaluation of head, eye, ear, nose, and throat (HEENT), 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological 
systems. Changes from baseline abnormalities should be recorded at each subsequent physical 
examination. New or worsened abnormalities should be recorded as adverse events if appropriate.  
ECOG Performance Status will be used to assess subjects’ performance status. Refer to 
Appendix 1. for definitions of ECOG performance score. 
6.2.2.2 
Clinical Laboratory Assessments 
Hematology testing will include the following parameters: hemoglobin, hematocrit, red blood cell 
(RBC) count, WBC count with differential, and platelet count.  
Coagulation will include the following parameters: prothrombin time (PT), activated partial 
thromboplastin time (aPTT), and International Normalized Ratio (INR). 
Serum chemistry testing will include the following parameters: blood urea nitrogen (BUN), 
creatinine, AST, ALT, lactate dehydrogenase (LDH), total bilirubin (including direct fraction if 
total bilirubin is abnormal), lipase, amylase, thyroid stimulating hormone (TSH), free thyroxine 
(T4) (direct), total protein, albumin, uric acid, alkaline phosphatase, sodium, potassium, calcium, 
magnesium, phosphorus and glucose. 
Urinalysis will be performed using a dipstick method followed by microscopic examination in the 
event of abnormal dipstick results. 
Pregnancy test: All women of childbearing potential (including those who have had a tubal 
ligation) will have a serum pregnancy test at baseline and at the EoT Safety Follow-up visit.  
Adverse Events and Serious Adverse Events: All abnormal laboratory results must be reviewed by 
the Investigator and evaluated. All clinically significant results will be documented as adverse 
events. Clinically significant is defined as an abnormal laboratory value that meets the following 
criteria:  
• Requires additional tests, medication and/or interventions to follow or treat the event 
• Results in subject discontinuation 
• Results in an SAE 
• Manifests clinically  
• Changes the treatment regimen of the subject 
• New onset of any ≥grade 3 event (regardless of relationship to study drug or outcome of 
the event) 

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and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical or surgical) to prevent one of the other serious outcomes listed in the definition 
of an SAE. Examples of such events include, but are not limited to, intensive treatment 
in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization.  
It is common that several other AEs are observed when the SAE qualifying event occurs. Not all 
observed AEs are SAEs. Efforts must be made to identify the chief event(s) leading to the SAE 
qualifying event, e.g., hospitalization. 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
drug is an SAE. 
Any component of a study endpoint that is considered related to study therapy (e.g., death is an 
endpoint) if death occurred due to anaphylaxis, anaphylaxis must be reported. 
Although pregnancy and overdose are not always serious by regulatory definition, these events 
must be reported on a Pregnancy Surveillance form and an AE/SAE form respectively in the eCRF 
within 24 hours of Investigator awareness of the overdose, regardless of association with an AE.  
Pregnancies of study subject or partner of study subject receiving Study Treatment currently or 
within 28 days of last dose, regardless of outcome. 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same Investigator term(s) initially reported, change in event terms 
should be accompanied by proper documentation of the rationale for the event term change.). 
Multiple signs, symptoms and manifestation of disease entity should be subsumed under umbrella 
diagnosis rather than reporting the signs and the symptoms of the diagnosis.  
If an ongoing SAE changes in its intensity or relationship to Study Treatment or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the Sponsor (or 
designee) using the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization 
NOTE: The following hospitalizations are not considered SAEs in sponsored clinical studies: 
• A <24-hour visit to the emergency room or other hospital department, that does not 
result in admission (unless considered to be an important medical event or an event that 
is life threatening) 
• Elective surgery planned prior to signing ICF 
• Admissions as per protocol for a planned medical/surgical procedure 
• Routine health assessment requiring admission for pretreatment assessment/trending of 
health status (e.g., routine colonoscopy) 
• Medical/surgical admission for a purpose other than remedying ill state of health and 
was planned prior to entry into the study. Appropriate documentation is required in all 
these cases. 

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• Admission for a life circumstance that has no bearing on health status and requires no 
medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative) 
• Admission for progressive disease (PD) 
6.2.2.4.2 Intensity of Adverse Events 
The intensity of adverse events will be graded according to the NCI-CTCAE scale: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL). Instrumental ADL 
refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
• Grade 3: Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. Self-care ADL refers to bathing, dressing and undressing, feeding 
oneself, using the toilet, taking medications, and not being bedridden. 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
• Grade 5: Death (at least possibly) related to the AE. 
6.2.2.4.3 Causal Relationship Assessment 
The relationship of an AE to the HBI-8000 and pembrolizumab is to be graded by the Investigator 
as follows: 
Definite: 
• Distinct temporal relationship with the Study Treatment 
• Stops/improves when the Study Treatment has been stopped 
• Can reasonably be explained by known characteristics of the Study Treatment 
Probable: 
• Reasonable temporal sequence from the Study Treatment administration 
• Stops/improves when the Study Treatment has been stopped 
• Event cannot easily be explained by subject’s clinical state or other factors 
Possible: 
• Reasonable temporal relationship with the Study Treatment 
• Event could have been produced by the subject’s clinical state or other factors 
Unlikely: 
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•
Subject’s clinical state is likely to have an association with the effect
Unrelated: 
•
Definitely not associated with the Study Treatment administered
Events that are assessed as “definite”, “probable” and “possible” in relation to HBI-8000 or 
pembrolizumab are regarded as AEs that cannot be denied a causal relationship to the Study 
Treatment and will be handled as “related to HBI-8000 or pembrolizumab” respectively for 
reporting purposes. Events that are assessed as “unlikely” or “unrelated” to HBI-8000 or 
pembrolizumab will be handled as “not related to HBI-8000 or pembrolizumab” respectively for 
reporting purposes. 
6.2.2.4.4 Reporting of Adverse Events 
All treatment-emergent adverse events (TEAEs) reported by the subjects, observed during physical 
examination, vital sign assessment, ECGs and/or review of laboratory test results will be assessed 
according to NCI CTCAE v.5.0 (CTCAE home page: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
and recorded by severity grades and association with HBI-8000 and pembrolizumab in the eCRF. 
The reporting of TEAEs should begin at initiation of Study Treatment. Baseline signs and 
symptoms should also be collected from screening to establish a baseline status for the subjects 
and will be documented as part of the subject’s medical history. The Investigator should complete 
all the details requested including dates of onset, severity, action taken, outcome, relationship to 
HBI-8000 or pembrolizumab. Each event should be recorded separately. 
Disease progression, signs, symptoms and manifestations of disease progression should not be 
recorded as an AE. Diagnostic and therapeutic noninvasive and invasive procedures, such as 
surgery, will not be reported as an AE, but the procedure and/or therapeutic treatment should be 
recorded on the appropriate eCRF. The medical condition for which the procedure was performed 
must also be reported. 
6.2.2.4.5 Time Period and Frequency for Collecting and Reporting of Serious Adverse 
Events and Pregnancy Information 
Following the subject’s written consent to participate in the study, all SAEs whether related or not 
related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. An SAE report should be completed for any event where doubt 
exists regarding its seriousness. 
If the Investigator believes that an SAE is not related to study drug but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
All SAEs must be reported to the Sponsor (or designee) within 24 hours of awareness of the event. 
All available SAE data, irrespective of the extent of available AE information, must also be 
recorded in the eCRF within 24 hours of Investigator awareness of the event. In case the eCRF 
cannot be used by the Investigator to generate the SAE/Pregnancy form, a paper SAE/Pregnancy 
form will be used and submitted to the Sponsor (or designee). Once the eCRF limitation is 

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resolved, the Investigator must, as soon as possible, enter all the information from the paper report 
into the eCRF. 
This timeframe also applies to additional new information (i.e., follow-up) on previously 
forwarded SAE reports. For all SAEs, the Investigator is obligated to pursue and provide 
information to the Sponsor (or designee). In addition, an Investigator may be requested by the 
Sponsor (or designee) to obtain specific additional follow-up information in an expedited fashion. 
In general, this will include a description of the AE in sufficient detail to allow for a complete 
medical assessment of the case and independent determination of possible causality. Information 
on other possible causes of the event, such as concomitant medications and illnesses must be 
provided. In the case of death, a summary of available autopsy findings must be submitted as soon 
as possible to the Sponsor (or designee). All SAEs requiring expedited regulatory reporting will 
be evaluated, summarized, and reported to Investigators.  
Investigators will be notified by the Sponsor (or designee) of all SAEs that require prompt 
submission to their IRB or IEC. Investigators should provide written documentation of IRB/IEC 
notification for each report to the Sponsor (or designee). The Sponsor (or designee) will ensure 
that all SAEs are reported to the appropriate regulatory authorities. 
6.2.2.4.6 Follow-Up of Adverse Events 
Subjects should be asked to specifically describe any signs, symptoms, or AEs (regardless of 
relationship to Study Treatment) they may notice prior to the start of the study or thereafter. At a 
minimum, subjects should be asked to report any changes at each visit to the study center. 
Conditions that the subject experienced prior to informed consent should be recorded in the 
medical history section of the eCRF.  
AEs, Grade 2 and above, considered to be at least possibly related to the Study Treatment must be 
followed up after the EoT assessment until the events have resolved, returned to the baseline level, 
are judged by the Investigator to be stable, or no longer require follow up provided the subject is 
withdrawn from the study due to initiation of new therapy or consent withdrawal for further 
follow-up. AEs that are assessed by the Investigator as unrelated to Study Treatment will be 
followed only to the EoT visit. The outcome of any AEs which do not resolve will be recorded as 
“ongoing” on the eCRF. 
Serious adverse events (SAE) and adverse events of speciaal interest (AESI), namely 
immune-related toxicities, will be collected for up to 90 days following cessation of treatment or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever 
is earlier. 
6.2.2.4.7 Clinical Laboratory Evaluations 
Clinical laboratory tests will be reviewed for results of potential clinical significance at all time 
points throughout the study. The Investigator will evaluate any change in laboratory values. If the 
Investigator determines a laboratory abnormality to be clinically significant, it is considered a 
laboratory AE; however, if the abnormal laboratory value is consistent with a current diagnosis, it 
may be documented accordingly. 
Abnormal laboratory test values that are not considered clinically significant by the Investigator 
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abnormal laboratory test results that require Study Treatment modification or other treatment or 
considered clinically significant by the Investigator are to be recorded in the AE section of the 
eCRF in addition to the laboratory section. Abnormal laboratory results that meet the definition of 
an SAE should also be reported on an AE/SAE form. Relationship (i.e., reasonable causal 
relationship) to HBI-8000 or pembrolizumab and the countermeasures taken will be noted on the 
eCRF. 
6.2.2.4.8 Pregnancy 
If a pregnancy is reported during active treatment of HBI-8000 until EoT, the Investigator must 
inform the Sponsor within 24 hours of learning of the pregnancy. Protocol-required procedures for 
study discontinuation and follow-up must be performed on the subject unless contraindicated by 
pregnancy. Other appropriate pregnancy follow-up procedures should be considered if indicated.  
6.2.2.4.9 Overdose 
Overdose is defined as administration to the subject of a dose of test article that exceeds by more 
than 50 mg/dose or 100 mg/week for HBI-8000, and any dose above the approved 400 mg every 
6 weeks or 200 mg every 3 weeks for pembrolizumab. In the case that the overdose did not result 
in an AE, the Investigator should report this as “overdose, no AE” on the AE/SAE form and specify 
the intended amount, as well as the actual amount, of drug administered. 
All occurrences of overdose must be reported as an AE. 
6.2.2.4.10 Deaths 
All adverse events leading to death that occur during the protocol-specified adverse event reporting 
period, regardless of relationship to Study Treatment, must be recorded on the Adverse Event 
eCRF and immediately reported to the Sponsor (or designee). 
6.2.2.4.11 Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
or any other potential safety assessment required or not required by protocol should also be 
recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
6.3 
Safety Monitoring Plan 
Safety oversight is provided by the Sponsor’s internal, Product Safety and Risk Management 
Committee (PSRMC) that will monitor the study safety data on a periodic basis (frequency of the 
meeting established by the committee) throughout the study, including review of AEs, adverse 
events of special interest (AESI) and SAEs. 
All enrolled subjects will be evaluated clinically and with clinical laboratory tests during their 
participation in this study per Schedule of Dosing and Assessments (Table 1) and as clinically 
indicated. 
Safety evaluations will consist of medical interviews, recording of AEs, physical examinations, 
and laboratory measurements (hematology, chemistry, virology, and urinalysis).  
Subjects will be evaluated for AEs (all grades according to the NCI CTCAE version 5.0), SAEs, 
and any AEs requiring IP interruption or permanent discontinuation. Subjects who, at time of 

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Full Analysis Set (FAS): Full analysis set for efficacy consists of all subjects meeting eligibility 
criteria who receive at least one dose of HBI-8000 in combination with standard of care 
pembrolizumab, have at least one post-baseline assessment of efficacy, with or without imaging 
study. 
Per-Protocol Set (PPS): Per-protocol set for efficacy consists of subjects meeting all eligibility 
criteria, having received at least 9 doses (75% of 2 cycles) of HBI-8000, with at least 1 imaging 
study to evaluate disease status after completing 6 weeks (2 cycles) of treatment. 
Efficacy endpoints will be analyzed in both FAS and PPS.  
7.3 
Subject Disposition 
The disposition of subjects will be tabulated for all enrolled subjects. Subjects who discontinue 
treatment or discontinued from the study will also be summarized and further broken down by 
reason for discontinuation. 
7.4 
Pretreatment Characteristics 
Demographic and baseline characteristics will be summarized with descriptive statistics. 
7.4.1 
Medical History 
Medical histories will be coded using MedDRA (Medical Dictionary for Regulatory Activities) 
version 22.0 or current classification system and summarized by system organ class (SOC) and 
preferred term (PT) for the subjects in the safety set. For each SOC and PT, subjects with 
multiple events will be counted only once. 
7.4.2 
Exposure to Study Medications 
Exposure parameters to HBI-8000 and pembrolizumab will include: 
• Duration of treatment of HBI-8000. 
• Number of pembrolizumab administrations and dose per administration. 
• Cumulative doses of HBI-8000 and pembrolizumab administered.  
• Compliance to HBI-8000 administration 
• Relative dose intensity (RDI) of HBI-8000 administered. 
A detailed description of calculations of each of the above parameters will be provided in the 
SAP. 
7.5 
Statistical Analyses 
7.5.1 
Efficacy Analyses 
Efficacy analyses will be performed on FAS and PPS.  ORR will be estimated based on the 
proportion of subjects whose best overall response is CR or PR. Disease response will be 
assessed using RECIST v1.1 as the primary methodology and iRECIST will be used to exclude 
pseudo-progression when suspected. The estimate of the ORR will be accompanied by a 2-sided 

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95% exact binomial confidence interval (CI). DCR (CR+PR+SD) will be analyzed similarly. 
DOR and PFS will be summarized descriptively using Kaplan-Meier methods. The final SAP 
will provide more details on these analyses. 
The efficacy endpoints are the following: 
• Objective Response Rate (ORR), defined as the percent of subjects with CR or PR 
according to RECIST 1.1 and irRECIST criteria, relative to the efficacy population.  
Subjects who do not have an on-study assessment due to safety issues will be included as 
non-responders. 
• Disease Control Rate (DCR), defined as the percent of subjects with CR, PR or SD 
according to RECIST 1.1 and iRECIST criteria, relative to the efficacy population.   
• Duration of Response (DoR), defined as the time from documentation of tumor 
response to disease progression.  
• Progression-Free Survival (PFS), defined as the time from the start of treatment (Day 1 
Cycle 1) until objective tumor progression or death. 
The EoT Safety Follow-up visit is scheduled 30 ± 3 days after the last dosing of the HBI-8000 or 
before the initiation of new cancer treatment, whichever is earlier. 
Response rate endpoints (ORR, DCR) will be summarized by number and percentage of subjects 
meeting the definition of ORR and DCR along with the corresponding exact 95% CI based on 
binomial distribution. 
Time-to-event endpoints (DoR, and PFS) will be summarized by Kaplan-Meier methods 
(median, 95% CI, number of events, number censored, and Kaplan-Meier figures). 
7.5.2 
Safety Analyses 
The assessment of safety will include general safety information such as adverse events, vital 
signs, laboratory tests (hematology, biochemistry, coagulation, urinalysis), concomitant 
medications, and 12-lead ECGs. 
All safety analyses will be conducted using the Safety Population. Descriptive statistics will be 
used to summarize safety data. 
7.5.2.1 
Adverse Events 
Adverse events will be coded using the MedDRA classification system version 24.0 or higher. The 
severity of the events will be graded by the Investigator according to the NCI CTCAE version 5.0 
or higher. 
All adverse events (AEs) will be summarized, and emphasis will be placed on treatment-emergent 
adverse events (TEAEs). An AE will be considered treatment-emergent if it occurs or worsens in 
severity from pre-treatment state on or after the first dose date of any study treatment through 30 
days after the last dose of any study treatment. All AEs will be listed. 
An overall summary of AE will be provided by the frequency and percentage of subjects 
experiencing an AEs by MedDRA systems organ class (SOC) and preferred term (PT). TEAEs 
will be summarized by the frequency and percentage of subjects experiencing TEAEs SOC and 

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PT, and by worst NCI CTCAE severity grade. Summaries will also be provided for treatment 
related TEAEs, namely, those judged by the Investigator to be at least possibly related to study 
drug treatment.  
Adverse events resulting in discontinuation from treatment or withdrawal from the study, Grade 3 
or higher, serious adverse events, and deaths on-study will be tabulated. 
All AEs noted during the study will be listed per subject, detailing reported term, system organ 
class, preferred term, start date, stop date, severity, relationship to each Treatment, TEAE flag, and 
outcome. 
7.5.2.2 
Laboratory Tests 
Laboratory data will be summarized for the observed values at each scheduled assessment, 
together with the corresponding changes from baseline (the value obtained prior to dosing on Day 
1 of Cycle 1) using descriptive statistics.  
For those analytes that are gradable with CTCAE version 5.0 severity criteria, will be summarized 
by shift tables showing shifts from Baseline grade (i.e., grade prior to dosing on Day 1 of Cycle 1) 
and maximum severity grade on treatment.  
Laboratory values outside the normal range will be flagged in the data listings. 
7.5.2.3 
Vital Signs and Physical Examination 
Vital signs data will be summarized by the observed valued at each scheduled assessment, together 
with the corresponding changes from baseline using descriptive statistics. 
Physical examination findings will be presented in data listings. 
7.5.2.4 
Concomitant Medications 
All documented and reported concomitant medications will be coded using the World Health 
Organization Drug Dictionary Enhanced (WHO DDE) version March 2021 or higher and 
classified by the Anatomical Therapeutic Chemical (ATC) classification system and preferred drug 
name (often the generic drug name).  
7.5.3 
Interim Analyses 
No interim analyses are planned for this study. 
 
7.5.4 
Guidance to Address a Pandemic or Other Global Health Emergencies and 
Potential Impact on the Clinical Study 
In the occurrence of a global health emergency affecting the conduct of the ongoing study, such 
as the coronavirus disease 2019 (COVID-19) pandemic, study conduct may be adjusted due to 
subjects being in self-isolation/quarantine, limited access to public places (including hospitals) 
due to the risk of spreading infections, and health care professionals being committed to critical 
tasks. 

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Adjustments to this protocol may be made as described below, in line with global regulatory 
authorities guidance in order to ensure the safety of study subjects, maintain compliance with 
GCP, and minimize the risks to study integrity during the COVID-19 pandemic [FDA 
September 2020]. Other countries may issue their own guidance requiring country specific 
recommendations to be followed. 
Informed Consent 
If written consent by the study subject is not possible (for example because of physical isolation 
due to COVID-19 or other global health emergencies), consent could be given orally by the 
study subject and documented according to current regulatory guidance and IRB requirements. 
Study subjects or the subject’s legally authorized representative (LAR) and the 
Investigator/designee (person obtaining consent) could sign and date separate ICFs. 
In case a written informed consent cannot be obtained at the clinical site, electronic informed 
consent can be obtained remotely. Alternatively, the consent form may be sent to the 
subject/LAR by facsimile, or e‑mail, and the consent interview may then be conducted by 
telephone/telemedicine when the subject or subject’s legally authorized representative can read 
the consent form during the discussion. If facsimile or email is not possible, the subject or 
subject’s legally authorized representative will be requested to sign and date a blank piece of 
paper with a written statement affirming that subject agrees to participate in the study and 
documented according to the current regulatory guidance and IRB approval. 
If re-consent is necessary for the implementation of new urgent changes in study conduct 
(mainly expected for reasons related to global health emergencies or important safety issues for 
other studies), alternative ways of obtaining consent may include contacting the study subject via 
phone or video-calls and obtaining oral consents, to be documented in the study subjects’ 
medical records, supplemented with e-mail confirmation. 
The informed consent procedure is to remain compliant with the study protocol as well as local 
regulatory requirements. All relevant records should be archived in the Investigator's site master 
file. A correctly signed and dated ICF should be obtained from the study subjects later, as soon 
as possible. 
Study Visits and Procedures 
COVID-19 screening procedures that may be mandated by the health care system in which a 
clinical study is being conducted do not need to be reported as an amendment to the protocol 
even if done during clinical study visits. The Investigator in consultation with the Sponsor will 
decide if it is in the best interest of COVID‑positive subjects to remain in the study. 
In the case of missed visits due to global health emergencies (or other health pandemic) related 
reasons: 
The site should make every effort to contact the study subject to confirm and document the 
reason for the missed visit, and at a minimum evaluate AEs/SAEs, and concomitant medications 
in order to assess subject safety. 

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8 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
8.1 
Data Collection and Management 
8.1.1 
Electronic Case Report Forms 
Electronic Data Capture (EDC) will be used for this study, meaning that all eCRF data will be 
entered in electronic forms at the study center. Data collection will be completed by authorized 
study center staff designated by the Investigator. Appropriate training and security measures will 
be completed with the Investigator and all authorized study center staff prior to the study being 
initiated and any data being entered into the system for any study subjects. 
All data must be entered in English. The eCRFs should always reflect the latest observations on 
the subjects participating in the study. Therefore, the eCRFs are to be completed as soon as possible 
during or after the subject’s visit. To avoid inter-observer variability, every effort should be made 
to ensure that the same individual who made the initial baseline determinations completes all 
efficacy and safety evaluations. The Investigator must verify that all data entries in the eCRFs are 
accurate and correct. If some assessments are not done, or if certain information is not available or 
not applicable or unknown, the Investigator should indicate this in the eCRF. The Investigator will 
be required to electronically sign off on the clinical data.  
8.1.2 
Source Documentation 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used by 
the Investigator or hospital that relate to the subject’s medical history, that verify the existence of 
the subject, the inclusion and exclusion criteria and all records covering the subject’s participation 
in the study. They include laboratory notes, electrocardiogram (ECG) results, memoranda, 
pharmacy dispensing records, subject files, etc. 
The Investigator is responsible for maintaining source documents containing data that is 
attributable, legible, contemporaneous, original, accurate, complete, consistent, enduring, and 
available. Changes to source data should be traceable, should not obscure the original entry, and 
should be explained if necessary (e.g., via an audit trail). Source documents are to be made 
available for inspection by the study monitor at each monitoring visit. The Investigator must 
submit a completed eCRF for each subject who is enrolled, regardless of duration. All supportive 
documentation submitted with the eCRF, such as laboratory or hospital records, should be clearly 
identified with the study and subject number. Any personal information, including subject name, 
should be removed or redacted (deidentified) to preserve individual confidentiality. 
8.1.3 
Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of the 
Data Management and Biostatistics departments of the Sponsor and CRO, where applicable.  
Adverse events and medical history will be coded using the most current version of MedDRA. 
Concomitant medications will be coded using WHO Drug Dictionary Enhanced (WHO DDE).  

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8.2 
Quality Control and Quality Assurance 
According to the Guidelines of Good Clinical Practice (GCP) (CPMP/ICH/135/95), the Sponsor 
is responsible for implementing and maintaining quality assurance and quality control systems 
with written SOPs.  
Quality control will be applied to each stage of data handling.  
The following steps will be taken to ensure the accuracy, consistency, completeness, reliability, 
and integrity of the data: 
• Investigator meeting(s) 
• Site initiation visit 
• Early center visits post-enrollment 
• Routine center monitoring 
• Ongoing center communication and training 
• Data management quality control checks 
• Continuous data acquisition and cleaning 
• Internal review of data 
• Quality control check of the final clinical study report 
• Investigator verification by electronically signing the eCRF 
• In addition, the Sponsor or Sponsor representative(s) may conduct periodic audits of 
the study processes, including, but not limited to study center, vendors, clinical 
database, and final clinical study report. 
8.2.1 
Monitoring 
Investigator site monitoring visits will be conducted according to all applicable regulatory 
requirements and standards. Regular monitoring visits will be made to each center while subjects 
are enrolled in the study. The monitor will complete written reports to the Sponsor’s representative 
for each contact with the Investigator/site, regardless of whether it is by phone or in person. 
8.2.2 
Retention of Patient Records and Study Files 
Records and documents pertaining to the conduct of this study and the distribution of 
investigational materials, including Investigational file, eCRFs, ICFs, laboratory test results, and 
medication inventory records, must be retained by the Investigator for at least 15 years after 
completion or discontinuation of the study, or for the length of time required by relevant national 
or local health authorities, whichever is longer. After that period of time, the documents may be 
destroyed, subject to local regulations. However non-records may be disposed of without the 
written approval of the Sponsor. Written notification should be provided to the Sponsor prior to 
transferring any records to another party or moving them to another location. 

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8.2.3 
Quality Assurance Audit 
Study centers, the study database and study documentation may be subject to Quality Assurance 
audit during the course of the study by the Sponsor or CRO on behalf of Sponsor. In addition, 
inspections may be conducted by regulatory bodies at their discretion. In the event of a Quality 
Assurance audit, the auditor(s) will be allowed access to study treatment records at the study 
center(s) to verify that dispensing has been done accurately. 
8.2.4 
Site Audits 
The Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspection(s) by providing direct access to all study 
records. In the event of an audit, the Investigator agrees to allow the Sponsor, Sponsor 
representatives, or the regulatory agencies access to all study records. 
The Investigator should promptly notify the Sponsor or Sponsor representative of any 
inspection/audits scheduled by any regulatory authorities and promptly forward copies of any 
finding/audit reports received to the Sponsor or Sponsor representative. 
8.3 
Ethics 
8.3.1 
Ethical Conduct of the Study 
This study will be conducted, and the informed consent will be obtained according to the ethical 
principles stated in the Declaration of Helsinki, the applicable guidelines for GCP 
(CPMP/ICH/135/95), or the applicable drug and data protection laws and regulations of the 
countries where the study will be conducted. 
GCP is an international ethical and scientific quality standard for designing, conducting, recording 
and reporting studies that involve the participation of human subjects. The study will be conducted 
in compliance with GCP and the applicable national regulations so as to assure that the rights, 
safety and well-being of the participating study subjects are protected consistent with the ethical 
principles that have their origin in the Declaration of Helsinki. 
8.3.2 
Institutional Review Board or Independent Ethics Committee 
An IRB or IEC must review and approve the final protocol, including the final version of the ICF 
and any other written information and/or materials to be provided to the subjects. The Investigator 
will provide the Sponsor’s representative with documentation of IRB/IEC approval of the protocol 
and informed consent before the study may begin at the study center(s). The Investigator should 
submit the written approval to Sponsor or representative before enrollment of any subject into the 
study.  
The Sponsor or representative reviews and approves any modification(s) to the ICF that are needed 
to meet local requirements. 
The Investigator supplies documentation of required IRB/IEC’s annual renewal of the protocol, 
and any approvals of revisions to the informed consent document or amendments to the protocol 
to the Sponsor’s representative. 

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The Investigator promptly reports to the IRB/IEC, any new information that may adversely affect 
the safety of subjects or the conduct of the study. Similarly, the Investigator will submit written 
summaries of the study status to the IRB/IEC annually, or more frequently if requested by the 
IRB/IEC. Upon completion of the study, the Investigator will provide the ethics committee with a 
brief report of the outcome of the study, if required. 
The Sponsor or Sponsor representative will provide Regulatory Authorities, Ethics Committees 
and Investigators with safety updates/reports according to local requirements, including Suspected 
Unexpected Serious Adverse Drug Reactions (SUSAR), where relevant. 
Each Investigator is responsible for providing the IRB/IEC with safety reports of any serious and 
unexpected adverse drug reactions from the study and any other study conducted with the Study 
Treatment. The Sponsor or Sponsor representative will provide this information to the Investigator 
so that he/she can meet these reporting requirements. 
8.3.3 
Subject Information and Informed Consent 
The Investigator is responsible for ensuring that informed consent is obtained from each subject, 
or their legally authorized representative (LAR) only after the subject/LAR has been given ample 
time and opportunity to inquire about details of the trial and to make a decision regarding 
participation in the trial. In addition, the Investigator is responsible for ensuring that all questions 
about the trial have been answered to the satisfaction of the subject or the subject’s LAR. The 
Investigator/designee provides each subject/LAR with a copy of the signed and dated ICF. The 
Investigator (or designee) is responsible for obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures, including the 
administration of any Study Treatment.  
8.3.4 
Confidentiality 
The Sponsor maintains confidentiality standards by coding each subject enrolled in the study 
through assignment of a unique subject identification number. Subject names are not included in 
data sets that are transmitted to any Sponsor location. 
Subject medical information obtained by this study is confidential and may only be disclosed to 
third parties as permitted by the ICF (or separate authorization for use and disclosure of personal 
health information) signed by the subject, unless permitted or required by law. Medical 
information may be given to a subject’s personal physician or other appropriate medical personnel 
responsible for the subject’s welfare, for treatment purposes. 
8.3.5 
Subject Data Protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
8.3.6 
Protocol Amendments 
Any amendments to the protocol will be require IRB approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to study 
subjects.  

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8.3.7 
Study Closure 
The Sponsor has the right to close this study at any time. In addition, the Sponsor, Sponsor 
representative and or the Investigator have the right to close the study at a particular site(s) at any 
time. Where possible, the agreement to close the study and/or to close a site(s) should be reached 
after mutual consultation. The IRB/IEC must be informed, if required by legislation. 
Should the study be closed prematurely, all unused HBI-8000 will be reconciled with dispensing 
records, documented, and returned to the Sponsor. Alternatively, if directed by the Sponsor, 
unused HBI-8000 (tablets) may be destroyed at the study center after completion of drug 
accountability by the site monitor. 
The Sponsor will notify the Investigators if the study is placed on hold, or if the Sponsor decides 
to discontinue the study or development program. 
8.3.7.1 
Study Discontinuation 
The clinical trial may be terminated early if the extent (incidence and/or severity) of emerging 
effects/clinical endpoints is such that the risk/benefit ratio to the trial population as a whole is 
unacceptable. In addition, further recruitment in the trial or at (a) particular trial site(s) may be 
stopped due to insufficient compliance with the protocol, GCP and/or other applicable regulatory 
requirements, procedure-related problems or the number of discontinuations for administrative 
reasons is too high. 
Reasons for terminating the study may include, but are not limited to, the following: 
• The incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to study subjects  
• Unsatisfactory subject enrollment. 
The Sponsor will notify the Investigator if the study is placed on hold, or if the Sponsor decides to 
discontinue the study or development program. 
8.3.7.2 
Site Discontinuation 
The Sponsor has the right to replace a site at any time.  
Reasons for replacing a site may include, but are not limited to, the following: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Non-compliance with ICH guidelines for GCP. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will promptly 
notify that trial site’s IRB. 

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8.4 
Study Administration 
8.4.1 
Data Handling and Record Keeping 
It is the Investigator’s responsibility to maintain adequate and accurate source documents and trial 
records, including essential study documents (protocol and protocol amendments, completed 
eCRFs, signed ICFs, relevant correspondence, and all other supporting documentation). The study 
site should plan on retaining such documents for approximately 15 years after study completion. 
Subject identification codes will be retained for this same period of time. These documents may 
be transferred to another responsible party, acceptable to Sponsor, who agrees to abide by the 
retention policies. Written notification of transfer must be submitted to Sponsor. The Investigator 
must contact Sponsor prior to disposing of any study records.  
No records can be disposed of without the written approval of the Sponsor. 
8.4.2 
Direct Access to Source Data/Documents 
The Investigator will prepare and maintain adequate and accurate source documents to record all 
observations and other pertinent data for each subject enrolled into the study.  
The Investigator will allow the Sponsor, Sponsor representatives (e.g., CRO), and authorized 
regulatory authorities to have direct access to all documents pertaining to the study, including 
individual subject medical records, as appropriate. 
8.4.3 
Investigator Obligations 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline for 
GCP (GCP, 1997); the US CFR Title 21 parts 50, 56, and 312; and the ethical principles that have 
their origin in the Declaration of Helsinki. The Investigator agrees to conduct the clinical study in 
compliance with this protocol after the approval of the protocol by the IRB/IEC in compliance 
with local regulatory requirements. The Investigator and the Sponsor will sign the protocol to 
confirm this agreement. 
8.4.4 
Financial Disclosure 
Investigators will provide the Sponsor with sufficient, accurate financial information in accordance 
with local regulations to allow the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate health authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and for one year after 
completion of the study. 
8.4.5 
Protocol Signatures 
Each Investigator is responsible for signing the Investigator Agreement following careful review 
of the protocol. A copy of the signed page is sent to the Sponsor (or designee). By signing the 
protocol, the Investigator confirms in writing that he/she has read, understands and will strictly 
adhere to the study protocol and will conduct the study in accordance with ICH Tripartite 
Guidelines for GCP and applicable regulatory requirements. The study cannot start at any center 
where the Investigator has not signed the protocol. 

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8.4.6 
Publication Policy 
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
make the results of the study publicly available. The publication policy with respect to the 
Investigator and study center will be set forth in the Clinical Trial Agreement. Publication may 
include any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  
Authorship credit should be based on 1) substantial contributions to conception and design, or 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it 
critically for important intellectual content; and 3) final approval of the version to be published. 
Authors must meet conditions 1, 2 and 3. Significant contributions to trial execution may also be 
taken into account to determine authorship, provided that contributions have also been made to all 
three of the preceding authorship criteria. Although publication planning may begin before 
conducting the trial, final decisions on authorship and the order of authors’ names will be made 
based on participation and actual contributions to the trial and writing, as discussed above.  
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential will be deleted prior to submission. 

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9. 
REFERENCES 
Barrero MJ. Epigenetic Strategies to Boost Cancer Immunotherapies. Int J Mol Sci 2017; 18(6). 
Beier UH, Wang L, Han R, Akimova T, Liu Y and Hancock WW. Histone deacetylases 6 and 9 
and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific 
mechanisms. Sci Signal 2012; 5(229): ra45. 
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus 
Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015; 
373(17): 1627-1639. 
Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab 
versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J 
Med 2015; 373(2): 123-135. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009; 45(2): 228-247. 
FDA. Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency – Guidance for Industry, Investigators and Institutional Review Boards. 
Rockville, MD; Food and Drug Administration; September 2020. 
Gadgeel S, Rodriguez-Abreu D, Speranza G, Esteban E, Felip E, Domine M, et al. Updated 
Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum 
for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin 
Oncol 2020; 38(14): 1505-1517. 
Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. 
Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J 
Med 2018; 378(22): 2078-2092. 
Gao Y, Nihira NT, Bu X, Chu C, Zhang J, Kolodziejczyk A, et al. Acetylation-dependent 
regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 
immunotherapy. Nat Cell Biol 2020; 22(9): 1064-1075. 
Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus 
docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer 
(KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387(10027): 1540-1550. 
Herbst RS, Baas P, Perez-Gracia JL, Felip E, Kim DW, Han JY, et al. Use of archival versus 
newly collected tumor samples for assessing PD-L1 expression and overall survival: an 
updated analysis of KEYNOTE-010 trial. Ann Oncol 2019; 30(2): 281-289. 
Hontecillas-Prieto L, Flores-Campos R, Silver A, de Álava E, Hajji N and García-Domínguez 
DJ. Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for 
Clinical Trials. Frontiers in Genetics 2020; 11(1113). 
Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, et al. Nivolumab Versus 
Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: 
Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 
017 and CheckMate 057). J Clin Oncol 2017; 35(35): 3924-3933. 
Hui R, Garon EB, Goldman JW, Leighl NB, Hellmann MD, Patnaik A, et al. Pembrolizumab as 
first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a 
phase 1 trial. Ann Oncol 2017; 28(4): 874-881. 
Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Pembrolizumab versus 
chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic 

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APPENDIX 1. PERFORMANCE SCALES – ECOG AND LANKSY 
ECOG 
Grade  
ECOG Status  
0  
Fully active, able to carry on all pre-disease performance without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work  
2  
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours  
3  
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours  
4  
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair  
5  
Dead  
Source: [Oken 1982] 
 

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APPENDIX 2. NEW YORK HEART ASSOCIATION (NYHA) 
FUNCTIONAL CLASSIFICATION 
Class I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation (feeling heart beats), or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes 
fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency 
at rest. If any physical activity is undertaken, discomfort is increased. 
Source: https://www.havhrt.com/heartfailureclassification 

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APPENDIX 3. STRONG CYP3A4 INDUCERS AND INHIBITORS 
CYP3A4 inducers or inhibitors may affect HBI-8000 exposures since HBI-800 is metabolized by 
CYP3A4. CYP3A4 inducers may potentially decrease the efficacy of HBI-8000, and CYP3A4 
inhibitors may potentially increase the systemic exposure and toxicity of HBI-8000. For this 
reason, in HBI-8000-305, the following drugs will be used with extreme caution as concomitant 
medications, at Investigator discretion. 
CYP3A4 INDUCERS 
CYP3A4 INHIBITORS 
Carbamazepine 
Amiodarone 
Ketoconazole 
Dexamethasone 
Anastrozole 
Metronidazole 
Ethosuximide 
Azithromzcin 
Mibefradil 
Glucocorticoids 
Cannabinoids 
Miconazole 
Griseofulvin 
Cimetidine 
Nefazodone 
Nafcillin 
Clarithromycin 
Nelfinavir 
Nelfinavir 
Clotrimazole 
Nevirapine 
Nevirapine 
Cyclosporine 
Norfloxacin 
Oxcarbazepine 
Danazol 
Norfluoxetine 
Phenobarbital 
Delavirdine 
Omeprazole 
Phenylbutazone 
Dexamethasone 
Oxiconazole 
Phenytoin 
Diethyldithiocarbamate 
Paroxetine 
Primidone 
Diltiazem 
Propoxyphene 
Progesterone 
Dirithyromycin 
Quinidine 
Rifabutin 
Disulfiram 
Quinine 
Rifampin 
Entacapone 
Quinupristine and 
dalfopristin 
Rofecoxib 
Erythromycin 
Ranitidine 
St John’s wort 
Ethinyl estradiol 
Ritonavir 
Sulfadimidine 
Fluconazole 
Saquinavir 
Sulfinpyrazone 
Fluoxetine 
Sertindole 
Troglitazone 
Fluvoxamine 
Sertraline 
 
Gestodene 
Troglitazone 
 
Grapefruit juice 
Troleandomycin 
 
Indinavir 
Valproic acid 
 
Isoniazid 
 

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APPENDIX 4. RECIST V1.1 AND irRECIST 
 
Lesion Requirements and Response Criteria 
Lesion Measurement 
Unidimensional 
Baseline Lesion Size a 
≥10 mm  
Malignant lymph nodes b 
For the lymph node (s) to be considered pathologically 
enlarged and measurable, a lymph node must be ≥15 mm 
when assessed by CT scan 
Baseline Lesion Number 
5 lesions total, 2 per organ 
Appearance of New Lesions 
Always represents PD 
Response 
CR: disappearance of all lesions 
PR: ≥30% decrease from baseline STD 
SD: when neither PR nor PD can be established 
PD: ≥20% increase in nadir of STD (minimum 5 mm) 
Confirmation after first 
assessment 
Yes, if response is primary endpoint 
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; RECIST = Response 
Evaluation Criteria in Solid Tumors; SD = stable disease; STD = sum of target lesion(s) diameter(s). 
a CT: 10 mm (when slice thickness is ≤5 mm); or 2× slice thickness (when slice thickness is >5 mm),  
Clinical: 10 mm (must be measurable with calipers) 
b Lymph node: ≥15 mm short axis for target, ≥10 to <15 mm for non-target, <10 mm is non-pathological 
 
Assessment of Overall Response 
Target 
Lesions 
Non-Target Lesions 
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 
Not Evaluable (NE) 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Source: Eisenhauer 2009 

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irRECIST Summary of measurement and response assessment approaches for 
bidimensional and unidimensional assessment based on irRC 
Source: Nishino 2013