Conditions: Thymic Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
This study will assess the safety and efficacy of the study drug KN046 in patients with advanced thymic carcinoma who progressed after prior treatment with immune checkpoint inhibitor therapy.

Detailed description:
Patients will receive KN046 intravenously at 5 mg/kg every 2 weeks until progression or excessive toxicity for up to to two years, with the goal of this trial to contribute to the development of active and well tolerated treatments for patients who have progressed on prior treatment therapies.

Recently, molecules that combine PD-1 and CTLA-4 have been developed for patients with lung cancer, with the hope that targeted therapy will be more effective than standard of care therapies. KN046 is believed to be less toxic than other targeted therapies with an assumption that the whole molecule can actively target tumor tissue for a much higher affinity of the anti-PD-L1 portion and a weaker affinity for anti-CTLA-4, leading to less autoimmune disorders and toxicities for patients than seen with other targeted therapies.

Arms:
arm 1: KN046 will be given intravenously every 2 weeks.

Interventions: intervention 1: KN046
Intervention descriptions: intervention 1: KN046 will be given intravenously at 5 mg/kg every 2 weeks. A cycle is defined as 2 treatments (28 days). Treatment will be given until progression, excessive toxicity, or up to two years.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
NCT04925947 


Protocol # 20-08022493 
Version Date  07/20/2022 
 
Page i of 81 
 
Phase II study of KN046 in patients with thymic carcinoma who failed immune checkpoint 
inhibitors 
 
IRB Protocol #: 20-08022493 
IND/IDE #: 155516 
Version Date: 07/20/2022 
Funding Source(s): Jiangsu Pharmaceutical  
 
 
 
 
Principal Investigator: 
 
Barbara Ma, MD 
520 E 70 St, Starr Pavilion 341 
New York, NY 10021 
 
 
Tel: 646-962-2357 
 
 
Fax: 646-962-0115 
 
 
Email: btm9003@nyp.org  
 
 
 
 
 
Statistician: 
 
 
Karla V Ballman, PhD 
 
Weill Cornell Medicine Graduate School 
 
1300 York Ave. Box 65 
 
Tel: (212) 746-6565 
 
Fax: (212) 746-5981 
 
Email: kab2053@med.cornell.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating Sites:  Weill Cornell Medical Center  


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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................... VI 
CONFIDENTIALITY STATEMENT ............................................................................................ VII 
LIST OF ABBREVIATIONS ..................................................................................................... VIII 
1. PROTOCOL SUMMARY ....................................................................................................... 9 
1.1 
Schema .................................................................................................................... 10 
1.2 
Study Objectives ...................................................................................................... 11 
1.2.1  
Primary Objectives ............................................................................................ 11 
- 
To evaluate the anti-tumor activity of KN046 in subjects with thymic carcinoma as 
measured by overall response rate .................................................................................... 11 
1.2.2  
Secondary Objectives ........................................................................................ 11 
1.2.3  
Exploratory Objectives ...................................................................................... 11 
2. BACKGROUND ................................................................................................................. 11 
2.1 
Thymic carcinomas .................................................................................................. 11 
2.2 
KN046 ...................................................................................................................... 13 
2.3 
Rationale ................................................................................................................. 13 
2.3.1. Rationale for study population ................................................................................. 13 
2.3.2. Rationale for KN046 ................................................................................................. 14 
2.3.2.1 Phase I data from trial KN046-AUS-001 ................................................................... 14 
2.3.2.1.1 Safety results of KN046-AUS-001 ......................................................................... 15 
2.3.2.1.2 Efficacy results of KN046-AUS-001 ....................................................................... 21 
2.3.1.1.3 Pharmacokinetic results of KN046-AUS-001 ......................................................... 21 
2.3.2.2. Phase I data from trial KN046-CHN-001 .................................................................. 22 
2.3.2.2.1. Safety results of Phase I KN046-CHN-001 ............................................................ 23 
2.4 
 Risk/Benefit Assessment ......................................................................................... 29 
2.4.1 
Known Potential Risks ....................................................................................... 30 
2.4.2 
Known Potential Benefits .................................................................................. 32 
2.4.3 
Assessment of Potential Risks and Benefits ....................................................... 32 
2.5 
Correlative Studies Background ................................................................................ 32 
3. STUDY DESIGN ................................................................................................................. 33 
3.1 
Overall Design .......................................................................................................... 33 
3.2 
Scientific Rationale for Study Design ........................................................................ 34 
3.3 
Justification for Dose ............................................................................................... 34 
3.4 
End of Study Definition ............................................................................................ 36 
4. SUBJECT SELECTION ......................................................................................................... 37 
4.1 
Study Population ..................................................................................................... 37 
4.2 
Inclusion Criteria ...................................................................................................... 37 


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4.3 
Exclusion Criteria ..................................................................................................... 38 
4.4 
Lifestyle Considerations ........................................................................................... 40 
4.5 
Screen Failures ......................................................................................................... 40 
4.6 Strategies for Recruitment and Retention ..................................................................... 40 
5. REGISTRATION PROCEDURES ........................................................................................... 41 
5.1 
Subject Registration ................................................................................................. 41 
6. STUDY PROCEDURES ........................................................................................................ 41 
6.1 
Schedule of Assessments ......................................................................................... 41 
6.1.1 
Screening Visit (28 days before start of treatment) ............................................ 45 
6.1.2 
Treatment Phase ............................................................................................... 46 
6.1.2.1 
Day 1 of each Cycle (unless otherwise noted in the SOA) ................................ 47 
6.1.2.2 
Day 15 of each Cycle ...................................................................................... 47 
6.1.3 
End of Treatment .............................................................................................. 47 
6.1.4  
Safety Follow Up Phase ..................................................................................... 48 
6.1.5  
Survival Follow Up Phase................................................................................... 48 
7. STUDY INTERVENTION ..................................................................................................... 48 
7.1 
Study Intervention/Device Description ..................................................................... 48 
7.2 
Dilution and Dosing .................................................................................................. 49 
7.3 
Dose modifications .................................................................................................. 49 
7.4. 
Concurrent medications and therapies ..................................................................... 51 
7.4.1 
Permitted medications and procedures ............................................................. 51 
7.4.2 
Prohibited medications and procedures ............................................................ 52 
7.5. 
Special precautions .................................................................................................. 52 
7.5.1 
Infusion-related reactions and hypersensitivity reactions .................................. 52 
7.6 
Packaging and labeling of the investigational medicinal product ............................... 54 
7.7 
Preparation, handling and storage of the investigational medicinal product ............. 54 
7.8 
Investigational medicinal product accountability ...................................................... 55 
7.9 
Assessment of investigational medicinal product compliance ................................... 56 
7.10  Duration of Follow Up ............................................................................................... 56 
7.11. Measures to Minimize Bias: Randomization and Blinding ........................................... 56 
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...................................................................................... 56 
8.1 
Criteria for subject withdrawal ................................................................................. 56 
8.2 
Lost to Follow Up ..................................................................................................... 57 
9. CORRELATIVE/SPECIAL STUDIES ....................................................................................... 57 
9.1. LABORATORY CORRELATIVE STUDIES ............................................................................ 58 
9.1.1 LABORATORY CORRELATIVE STUDY ............................................................................. 58 


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9.1.1.1 COLLECTION OF SPECIMEN(S) ................................................................................... 58 
9.1.1.2 HANDLING OF SPECIMEN(S) ..................................................................................... 58 
WHOLE BLOOD SAMPLES WILL BE STORED IN -80 C WITHIN 16 HOURS TO PRESERVE NUCLEIC 
ACID QUALITY. FORMALIN-FIXED PARAFFIN-EMBEDDED (FFPE) UNSTAINED SECTIONS WILL BE 
STORED IN +4 C AND FFPE BLOCKS WILL BE STORED AT ROOM TEMPERATURE. .................... 58 
9.2. SPECIAL STUDIES ........................................................................................................... 58 
9.2.1 SPECIAL CORRELATIVE STUDIES ................................................................................... 58 
9.2.1.1 ASSESSMENT ............................................................................................................ 59 
9.2.1.2 METHOD OF ASSESSMENT ........................................................................................ 59 
9.2.1.3 TIMING OF ASSESSMENT .......................................................................................... 59 
10.  MEASUREMENT OF EFFECT ............................................................................................ 59 
10.1 Response Criteria ....................................................................................................... 59 
10.2 Duration of response .................................................................................................. 60 
10.3 Progression-Free Survival ........................................................................................... 60 
10.4 Other Response Parameters ....................................................................................... 60 
11. DATA REPORTING / REGULATORY CONSIDERATIONS ...................................................... 60 
11.1 Data Collection ........................................................................................................... 60 
11.1.1 REDCap ................................................................................................................ 60 
11.2 Regulatory Considerations .......................................................................................... 60 
11.2.1 Institutional Review Board/Ethics Committee Approval ....................................... 60 
11.2.2 Ethical Conduct of the Study ................................................................................ 61 
11.2.3 Informed Consent ................................................................................................ 61 
11.2.4 Compliance with Trial Registration and Results Posting Requirements ................. 61 
11.2.5 Record Retention ................................................................................................. 62 
12.1 Study Design/Endpoints ............................................................................................. 62 
12.2 Sample Size/Accrual Rate ........................................................................................... 62 
12.3 Stratification Factors .................................................................................................. 63 
12.4 Analysis of Endpoints ................................................................................................. 63 
12.4.1 Analysis of Primary Endpoints ........................................................................... 63 
12.4.2 Analysis of Secondary Endpoints ....................................................................... 63 
12.4.3. Exploratory Endpoints......................................................................................... 63 
12.5 Interim Analysis ......................................................................................................... 64 
12.6 Reporting and Exclusions ............................................................................................ 64 
12.6.1 Evaluation of Toxicity ........................................................................................ 64 
12.6.2 Evaluation of Response ..................................................................................... 64 


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13. ADVERSE EVENT REPORTING REQUIREMENTS ................................................................ 64 
13.1 Adverse Event Definition ............................................................................................ 64 
13.1.1 Investigational Agent or Device Risks (Expected Adverse Events) .......................... 64 
13.1.2 Adverse Event Characteristics and Related Attributions ..................................... 65 
13.1.3 Recording of Adverse Events ............................................................................. 65 
13.1.4 Reporting of AE to WCM IRB ............................................................................. 65 
13.1.6 Events of Special Interest .................................................................................. 65 
13.1.7 Reporting of Pregnancy ..................................................................................... 65 
13.2 Definition of SAE ........................................................................................................ 66 
13.2.1 Reporting of SAE to IRB ..................................................................................... 66 
13.2.2 Reporting of SAE to FDA .................................................................................... 66 
13.2.3 Reporting of SAE to Jiansu ................................................................................. 66 
13.3 AE/SAE Follow Up ...................................................................................................... 67 
14. DATA AND SAFETY MONITORING PLAN (DSMP) ............................................................. 67 
15. REFERENCES ................................................................................................................... 68 
16. APPENDIX A: GUIDELINES ON THE MANAGEMENT OF IMMUNE RELATED ADVERSE EVENTS
 
70 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Statement of Compliance 
 
 
 
(1) The trial will be carried out in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 


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Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional 
review boards. The contents of this document shall not be disclosed to others without written 
authorization from WCM. 
 
 
 
 


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List of Abbreviations 
 
All abbreviations used throughout the protocol must be defined. Add additional abbreviations specific to 
protocol.  
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTSC 
Clinical Translational Science Center  
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HUD 
Humanitarian Use Device  
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
UIRTSO 
Unanticipated Problem Involving Risks to Subjects or Others 
WCM 
Weill Cornell Medicine 


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1. Protocol Summary 
 
Full Title: 
Phase II study of KN046 in patients with thymic carcinoma who failed 
immune checkpoint inhibitors 
    
Short Title:  
 
 
 
KN046 in thymic cancer with prior IO  
Clinical Phase:  
 
 
II 
Principal Investigator:  
 
Giuseppe Giaccone, MD PhD 
Study Description:  
 
This study will assess the safety and efficacy of KN046 in patients with 
advanced thymic carcinoma who progressed after prior treatment with 
immune checkpoint inhibitors 
Sample Size: 
 
N= 29 
Enrollment: 
 
This study will enroll 29 patients   
Study Population: 
 
These are patients with advanced thymic carcinoma who have had 
progression after treatment with chemotherapy and an immune 
checkpoint inhibitor. They have no prior or current history of 
autoimmune disorders. 
Enrollment Period: 
 
24 months  
Study Design: 
 
Open-label, single arm, single center non-randomized Phase II study to 
investigate the efficacy and safety of KN046 in patients with advanced 
thymic carcinoma who have progressed on prior immune checkpoint 
inhibitor therapy. Subjects will be treated with KN046 5 mg/kg q2wk 
Description of Sites/  
Facilities Enrolling 
Participants: 
 
Weill Cornell Medicine/New York Presbyterian Hospital  
Study Duration: 
 
7/2024 
Participant Duration: 
 
24 months 
Study Agent/Device Name  
KN046 
Intervention Description: 
KN046 will be given intravenously at 5 mg/kg every 2 weeks. A cycle is 
defined as 2 treatments (28 days). Treatment will be until progression or 
excessive toxicity for up to 2 years. 
Primary Objective: 
 
To evaluate the anti-tumor activity of KN046 in subjects with thymic 
carcinoma as measured by overall response rate  
Secondary Objectives:  
To assess the safety and tolerability of KN046 
Exploratory Objectives: 
To explore the association of biomarkers (including, but not limited to, 
PD-L1 expression, tumor immune microenvironment determined by 
multiplex IHC, tumor mutational burden (TMB), T-cell inflamed gene 
expression profile (GEP)) and clinical efficacy parameters  
 
To characterize the safety laboratory results (AChR autoantibody and 
CPK) and the occurrence of adverse events of interest 
Endpoints: 
 
Response rate, progression-free survival, overall survival 
 


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1.1 Schema 
 
 
 
 


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1.2 Study Objectives 
 
 
1.2.1  Primary Objectives  
- 
 To evaluate the anti-tumor activity of KN046 in subjects with thymic carcinoma as measured 
by overall response rate 
 
1.2.2  Secondary Objectives  
- 
To assess the safety and tolerability of KN046 in thymic carcinoma 
1.2.3  Exploratory Objectives 
- 
To explore the association of biomarkers (including, but not limited to, PD-L1 expression, 
tumor immune microenvironment determined by multiplex IHC, tumor mutational 
burden (TMB), T-cell inflamed gene expression profile (GEP)) and clinical efficacy 
parameters  
- 
To characterize the safety laboratory results (AChR and MusK autoantibody and CPK) and 
the occurrence of adverse events of interest 
 
2. Background 
 
2.1 Thymic carcinomas 
 
Thymic epithelial tumors (TETs) are rare tumors of the thymic gland. Surveillance, Epidemiology, and 
End Results (SEER) and the EURopean CAncer REgistry (EUROCARE-5) data suggests that 1.5 
malignant thymic tumors occur for every 1,000,000 person-years, with approximately 400-600 new 
cases each year in the United States. Thymic malignancies are generally divided into thymomas 
(WHOA A-B) and thymic carcinomas (WHO C) (for review, see (1, 2)). Amongst these subtypes, thymic 
carcinomas are the most aggressive histological type of TETs, are rare, and are associated with a 
particularly poor prognosis. Thymic carcinoma accounts for approximately 10-15% of all TETs. Survival 
depends on stage at presentation and completeness of resection. They are often not operable with 
development of distant metastases. In addition, thymic carcinomas are also more resistant to 
chemotherapy than thymomas. Subsequently, patients with thymic carcinomas have inferior survival 
with a 5-year survival rate of about 40%.  
 
An interesting phenomenon that differs between thymomas and thymic carcinomas is that 
autoimmune syndromes are almost exclusively seen in thymomas but are only infrequently seen in 
thymic carcinomas (3-6). Myasthenia gravis is most commonly seen (30-40%) in thymomas. The 
majority of patients with thymomas had at least one autoantibody present even if not associated to 
any autoimmune syndrome whereas, in contrast, only 1 of 4 patients with thymic carcinomas had 
autoantibodies detectable in the blood (7). In patients treated with cixutumumab (anti-IGF1R), 9 of 
37 patients with thymoma developed an autoimmune syndrome while there were none in 12 patients 
with thymic carcinomas (4). Furthermore, patients with autoimmune syndromes had worse survival 
(4). Patient selection based on histology is important.   
 
 


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Standard of care systemic therapy for patients with advanced thymic epithelial tumors is 
chemotherapy. The classic regimens used include PAC (cisplatin, doxorubicin, cyclophosphamide) and 
carboplatin/paclitaxel (8-10). However, chemotherapy induces responses in <50% of patients with 
thymic carcinomas. 
 
The Principal Investigator has conducted several phase II studies in patients with TETS over the years 
and more recently with the use of targeted agents (4, 9, 11-13). Amongst the treatment options listed 
in the NCCN guidelines after chemotherapy has failed, immune checkpoint inhibitor pembrolizumab 
and anti-angiogenesis agent sunitinib are particularly promising, with response rates in the range of 
20-25% in patients (12, 13). Another angiogenesis inhibitor, lenvatinib, has also demonstrated 
marked efficacy in a phase II study performed in Japan (14). Durable responses from pembrolizumab 
has been demonstrated in his previous study (3.2 years median; Giaccone G et al. WCLC 2019)(12).  
 
Thymic carcinomas are the most frequently mutated tumors among TETs. There have been p53 
mutations found in 26% of 47 cases analyzed using next generation sequencing (15). Frequency of 
somatic mutations however is very low in TETs in general. A high tumor mutational burden (TMB) 
may also make tumors more sensitive to immune checkpoint blockade (16, 17). Tumor cell PD-L1 
expression and TMB are established biomarkers of response to immune checkpoint inhibitors. PD-L1 
activates the inhibitor signaling pathway on anti-tumor T cells by binding to PD-1, and its expression 
level influences the activity of anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors. TMB reflects 
the number of non-synonymous single nucleotide variants in a tumor, which affects the odds of 
generating antigens that can trigger an antitumor immune response. Higher TMB is associated with 
improved survival in patients receiving immunotherapy independent of cancer type (18). Robust anti-
tumor immune response requires pre-existing presence of tumor-infiltrating lymphocytes (TILs). 
Therefore, the density of TILs also correlates with patients’ response to immunotherapy (19). PD-L1 is 
commonly expressed in TETs, with 36-100% of tumor cells in thymic carcinoma expressing PD-L1 (20, 
21). These results provide a rationale for using PD-1/PD-L1 inhibitors to treat TETs. 
 
Pembrolizumab in pretreated patients with thymic carcinomas resulted in an overall response rate of 
22.5%, with median PFS of 4.2 months, and a marked correlation between high PD-L1 expression and 
better response (12). Nevertheless, pembrolizumab has been associated with a significant increase in 
immune-related adverse events (irAEs) in 15% (6 of 40) of patients with thymic carcinoma, even after 
selection for no prior history of an autoimmune disorder (12). Similar response rates (19.2%) and 
similar incidence of irAEs (15.4%) were observed in a Korean Phase II trial that also used 
pembrolizumab in 33 patients with TETs, of which 26 had thymic carcinomas (22). Other immune 
checkpoint inhibitors that have been tested in thymic carcinomas include immune checkpoint PD-L1 
inhibitor avelumab (23) and another PD-1 inhibitor nivolumab (24). High PD-L1 expression appears to 
be associated with a greater likelihood of response and a subset of patients achieve durable                                 
responses. Although the responses obtained in my phase II study with pembrolizumab were durable, 
no patient appeared to be cured, as all patients who responded eventually progressed.  
 
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies are active in melanoma, and have 
some more limited activity also in lung cancer. In melanoma, combinations of CTLA-4 and PD-1 
inhibitors have produced better results than either drug alone, albeit at the cost of more toxicity [3]. 
However, they cause occurrence of autoimmune disorders in a significant number of patients, higher 
than with programmed death receptor (PD-1) or programmed death ligand 1 (PD-L1) inhibitors. 
 


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There is an urgent need to develop active and well tolerated treatments for patients with advanced 
thymic carcinoma who have progressed on prior treatment regimens. Combination studies with 
alternative agents are warranted, with careful patient selection based on tumor biomarkers (e.g. PD-
L1 expression in the tumor) or risk of autoimmune disorders in order to minimize toxicity.   
 
2.2 KN046 
Recently molecules that combine PD-1 and CTLA-4 moieties have been developed. KN046 is a novel 
bispecific antibody that can simultaneously bind to both PD-L1 and CTLA-4. KN046 is a dual blocker of 
both PD-L1 pathway and CTLA-4 pathway with a mechanism of action (MOA) that is the same as the 
combination therapy with anti-PD-L1 and anti-CTLA-4 agent. It blocks both the PD-1/PD-L1 interaction 
and CTLA-4 interaction with the costimulatory molecules CD80/CD86, to promote T cell activation. 
KN046 is genetically engineered and recombinantly expressed in CHO cells. KN046 has a wild type 
IgG1 Fc portion that maintains Fc-mediated effector functions, antibody-dependent cell-mediated 
cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).  
 
KN046 is believed to be less toxic with an assumption that the whole molecule can actively target 
tumor tissue via a much higher affinity of the anti-PD-L1 portion and a weaker affinity for anti-CTLA4. 
From phase I studies of this molecule, the incidence of irAEs does not appear to be similar to CTLA-4 
antibodies, but more similar to PD1 antibodies. Thus, KN046 is believed to have strong potency to 
activate the immune system and with lower toxicity, which may provide a strategic advantage over 
the combination of two single agents.  
 
2.3 Rationale 
Thymic carcinoma is sensitive to pembrolizumab, however pembrolizumab is not curative and most 
patients recur. A multicenter study of KN046 is planned by the company in patients with advanced 
thymic carcinoma who have not received immune checkpoint inhibitors. This study will provide safety 
and activity data in that population. The present study will test KN046 in patients with advanced 
thymic carcinoma who failed treatment with immune checkpoint inhibitors. 
2.3.1. Rationale for study population 
This study will recruit subjects who have histologically proven thymic carcinoma.  
The subjects should have inoperable or metastatic disease and have failed at least one prior line of 
systemic therapy including prior immune checkpoint inhibitor immunotherapy. Platinum-based 
chemotherapy, especially cisplatin-based chemotherapy is the preferred first line treatment yielding 
reasonably high response rates. For patients who have failed first line platinum-based chemotherapy, 
there is no standard of care and often anti-angiogenesis agents or immune checkpoint inhibitors are 
used as alternative treatment options. After progression on immune checkpoint inhibitor therapy, 
there is no standard of care and patients need promising candidates for investigational therapies. 
This study will exclude subjects who have history of tumor associated autoimmune diseases with the 
exception of hypothyroidism stable on hormone replacement or Sjogren’s syndrome. In early clinical 
studies from immune checkpoint inhibitors, high rate of immune-related adverse events, mainly 
Myasthenia gravis and myositis, have been observed mainly in thymoma patients. In Phase I KN046-
AUS-001 study, 4 subjects with thymic epithelial tumors were enrolled. Out of 4 patients with TETs, 3 
experienced a major response. However, one patient with thymoma with previous diagnosis of ocular 
myasthenia gravis, developed severe myasthenia symptoms that required hospitalization. This 


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indicates a safety profile from KN046 that is in line with other I-O. Therefore, subjects with thymomas 
will be excluded. Also, subjects with history or baseline positive antiacetylcholine receptor (AChR) 
autoantibody and anti-MuSK autoantibody will be excluded.  
2.3.2. Rationale for KN046 
KN046 is currently being investigated in the following clinical trials:  
• 
Trial KN046-AUS-001 is “a first-in-human, open-label, multicenter, dose-escalation phase I study to 
evaluate safety, tolerability, pharmacokinetics, and immunogenicity of KN046 in subjects with 
advanced solid tumors”. This trial is mainly enrolling subjects from Australia.  
• 
Trial 
KN046-CHN-001 
is 
“A 
phase 
Ia/Ib 
study 
to 
evaluate 
safety, 
tolerability, 
pharmacokinetics/pharmacodynamics and anti-tumor activity of KN046 in subjects with advanced 
solid tumors and hematology malignancies”. This trial is enrolling subjects from mainland China.  
• 
Trial KN046-201 is “A phase II study to evaluate the efficacy, safety and tolerability of KN046 in 
subjects with advanced unresectable or metastatic non-small cell lung cancer who fail platinum-
based chemotherapy”.  
• 
Trial KN046-202 is “A phase II study to evaluate the efficacy, safety and tolerability of KN046 in 
combination with standard-of-care chemotherapy as the first line treatment for subjects with 
advanced unresectable or metastatic non-small cell lung cancer”.  
• 
Trial KN046-203 is “A phase II study to evaluate the efficacy, safety and tolerability of KN046 as a 
monotherapy or in combination with standard-of-care chemotherapy for the treatment of subjects 
with advanced unresectable or metastatic triple-negative breast cancer”.  
• 
Trial KN046-204 is “A phase II study to evaluate the efficacy, safety and tolerability of KN046 as a 
monotherapy as a late line treatment for subjects with locally advanced unresectable or metastatic 
esophageal squamous cell carcinoma”.  
2.3.2.1 Phase I data from trial KN046-AUS-001  
 
A Phase I, open-label, multiple-ascending dose-escalation and expansion Trial KN046-AUS-001 is 
currently ongoing to evaluate the maximum tolerated dose (MTD), recommended phase 2 doses 
(RP2Ds), biological effective dose (BED), the safety, tolerability and pharmacokinetics (PK) of 
intravenously administered KN046 in subjects with metastatic or locally advanced solid tumors.  
 
Trial KN046-AUS-001 consists of a dose escalation phase (3+3 design) followed by an expansion phase. 
The dose escalation phase was designed to provide safety and tolerability, as well as PK data for KN046 
at sequential doses ranging from 0.3 to 10.0 mg/kg in subjects with advanced malignancies, for which 
there are no established standard treatments. As of 20-Jan-2020, enrollment has been completed and 
54 subjects have been treated with KN046.  
 
The dose escalation (3 + 3 design) phase included a total of 13 subjects and was performed at the 
following dose levels: 
• Dose level 1: 0.3 mg/kg (Cohort 1), 1 subject treated 
• Dose level 2: 1.0 mg/kg (Cohort 2), 3 subjects treated 
• Dose level 3: 3.0 mg/kg (Cohort 3), 3 subjects treated 


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• Dose level 4: 5.0 mg/kg (Cohort 4), 6 subjects treated 
• Dose level 5: 10.0 mg/kg (Cohort 5), 3 subjects treated  
 
The 3 + 3 dose escalation algorithm to determine the MTD/RP2Ds/BED is complete and doses of 3.0 
and 5.0 mg/kg once every 2 weeks was determined for the tumor treatment expansion cohorts on the 
basis of safety, PK, preliminary efficacy and ex vivo pharmacodynamics observations.  
 
As of 20-Jan-2020, the dose expansion phase included a total of 14 subjects at 3.0 mg/kg dose level 
and 24 subjects at 5.0 mg/kg dose level.   
• Expansion cohort 1: 3 mg/kg, 14 subjects treated  
• Expansion cohort 2: 5 mg/kg, 24 subjects treated  
 
2.3.2.1.1 Safety results of KN046-AUS-001 
As of January 20, 2020, a total of 54 subjects were included in the safety data analysis, including 16 and 
37 subjects enrolled in the dose escalation and dose expansion, respectively. Median duration of 
therapy was 11 weeks (range: 2 to 67). In total 13.0% patients discontinued KN046 treatment due to 
adverse events.  
 
Four DLT events were observed in three subjects, including (i) one subject with grade 3 treatment-
related hepatic function abnormalities without bilirubin increase from the 5.0 mg/kg Q2W cohort; and 
(ii) one subject with grade 3 pruritic erythematous rash, and one subject with grade 3 aspartate 
aminotransferase increase accompanied by grade 3 arthritis from the 10.0 mg/kg Q2W cohort. The 
relevant subjects recovered within three weeks. Maximum tolerated dose (MTD) has been declared at 
5 mg/kg Q2W. 
 
As of the Data Cut-off Date, 41 (75.9%) out of the 54 subjects had experienced treatment-related 
adverse events (TRAE) of all grades, and 20 (37.0%) subjects had experienced treatment-related 
adverse events at grade 3 or higher levels. 14 (25.9%) subjects had experienced treatment-related SAEs 
and 26 (48.1%) subjects had experienced irAEs, 13 (24.1%) of which were grade 3 or higher levels. The 
most frequent TRAEs included arthralgia (16.7%), fatigue (14.8%), infusion-related reaction (14.8%), 
diarrhea (11.1%) and pruritus (11.1%). Skin and subcutaneous tissue disorders and musculoskeletal and 
connective tissue disorders were the most frequent irAEs. The TRAE and irAEs were not found to occur 
in a dose-dependent manner up to 5 mg/kg Q2W, and neither the number nor severity of TRAE or irAEs 
was exacerbated due to dose escalation at the RP2D or lower levels.  
 
4 subjects with thymic neoplasms were enrolled in KN046-AUS-001. 2 out 4 patients are still under 
treatment (340+ and 240+ days). 1 patient (BOR SD) had spinal injury and off treatment due to this 
treatment unrelated AE. The patient had been on treatment for 146 days before KN046 withdrawal. 
One patient had baseline ocular MG as paraneoplastic disease to underlying advanced thymoma and 
enrolled (the patient did not undergo thymectomy).  After 8 KN046 doses (Q2W), the patient 
developed ocular symptoms and then generalized symptoms requiring intensive care. The investigator 
considered this SAE as disease related due to rapid elevation of anti-acetylcholine receptor levels 
indicating antibody mediated rather T cell mediated which was thought to be unusual as a checkpoint 
inhibitor related toxicity. Imaging at that time showed slow and steady increase (having 13% increase 
in target lesion from baseline) and lack of other organ specific immune related adverse events. The 


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patient was withdrawn from KN046 treatment and developed partial response thereafter. This SAE was 
completely recovered.  
 
 


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Table 2-1 
Subject disposition for Trial KN046-AUS-001 (Safety Population)  
 
0.3 mg/kg 
Q2W 
(N = 1) 
1.0 mg/kg 
Q2W 
(N = 3) 
3.0 mg/kg 
Q2W 
(N = 17) 
5.0 mg/kg 
Q2W 
(N = 30) 
10.0 mg/kg 
Q2W 
(N = 3) 
Total 
(N = 54) 
Subjects enrolled 
 1 (100%)  3 (100%) 17 (100%) 30 (100%)  3 (100%) 54 (100%) 
Subjects dosed 
 1 (100%)  3 (100%) 17 (100%) 30 (100%)  3 (100%) 54 (100%) 
  
Treatment ongoing at data cut-off 
 0 
 0 
 1 (5.9%)  7 (23.3%) 
 0 
 8 (14.8%) 
Treatment termination 
 1 (100%)  3 (100%) 15 (88.2%) 22 (73.3%)  3 (100%) 44 (81.5%) 
Confirmed disease progression 
 1 (100%)  2 (66.7%) 10 (58.8%) 12 (40.0%)  1 (33.3%) 26 (48.1%) 
Intercurrent illness that prevents further administration of 
treatment 
 0 
 0 
 0 
 1 (3.3%) 
 0 
 1 (1.9%) 
Unacceptable adverse experiences 
 0 
 1 (33.3%) 
 0 
 5 (16.7%)  1 (33.3%)  7 (13.0%) 
Subject withdraws consent 
 0 
 0 
 1 (5.9%)  1 (3.3%)  1 (33.3%)  3 (5.6%) 
If in the opinion of the Investigator, a change or discontinuation 
of therapy would be in the best interest of the subject 
 0 
 0 
 3 (17.6%)  2 (6.7%) 
 0 
 5 (9.3%) 
Death 
 0 
 0 
 1 (5.9%) 
 0 
 0 
 1 (1.9%) 
Other 
 0 
 0 
 0 
 1 (3.3%) 
 0 
 1 (1.9%) 
Note: 1. Percentages are based on the number of subjects of each dose level in the evaluable analysis set. 
Program: t_tte.sas  
Executed: 20FEB2020 23:24 
 


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Table 2-2 
Safety summary for Trial KN046-CHN-001 (Safety Population) 
0.3 mg/kg Q2W 
(N = 1) 
1.0 mg/kg Q2W 
(N = 3) 
3.0 mg/kg Q2W 
(N = 17) 
5.0 mg/kg Q2W 
(N = 30) 
10 mg/kg Q2W 
(N = 3) 
Total 
(N = 54) 
Number of TEAE 
  5 
 35 
153 
271 
 34 
498 
Subjects with at least 1 TEAE 
  1 (100%) 
  3 (100%) 
 17 (100%) 
 28 (93.3%) 
  3 (100%) 
 52 (96.3%) 
 Related to KN046 
  1 (100%) 
  2 (66.7%) 
 13 (76.5%) 
 22 (73.3%) 
  3 (100%) 
 41 (75.9%) 
Subjects with at least 1 CTCAE Grade ≥3 TEAE 
  0 
  2 (66.7%) 
 11 (64.7%) 
 19 (63.3%) 
  3 (100%) 
 35 (64.8%) 
 Related to KN046 
  0 
  2 (66.7%) 
  4 (23.5%) 
 11 (36.7%) 
  3 (100%) 
 20 (37.0%) 
Subjects with at least 1 DLT Event 
  0 
  0 
  0 
  1 (3.3%) 
  2 (66.7%) 
  3 (5.6%) 
Subjects with at least 1 irAE 
  0 
  2 (66.7%) 
  9 (52.9%) 
 12 (40.0%) 
  3 (100%) 
 26 (48.1%) 
Subjects with at least 1 CTCAE Grade ≥3 irAE 
  0 
  1 (33.3%) 
  3 (17.6%) 
  6 (20.0%) 
  3 (100%) 
 13 (24.1%) 
Subjects with at least 1 Infusion Reaction 
  0 
  1 (33.3%) 
  3 (17.6%) 
  4 (13.3%) 
  0 
  8 (14.8%) 
Subjects with at least 1 CTCAE Grade ≥3 Infusion Reaction 
  0 
  0 
  0 
  0 
  0 
  0 
Subjects with at least 1 Treatment-emergent SAE 
  0 
  1 (33.3%) 
  9 (52.9%) 
 14 (46.7%) 
  2 (66.7%) 
 26 (48.1%) 
 Related to KN046 
  0 
  1 (33.3%) 
  4 (23.5%) 
  7 (23.3%) 
  2 (66.7%) 
 14 (25.9%) 
Subjects with at least 1 CTCAE Grade ≥3 Treatment-
emergent SAE 
  0 
  1 (33.3%) 
  7 (41.2%) 
 12 (40.0%) 
  1 (33.3%) 
 21 (38.9%) 
 Related to KN046 
  0 
  0 
  3 (17.6%) 
  6 (20.0%) 
  1 (33.3%) 
 10 (18.5%) 
Subjects with at least 1 TEAE Leading to Drug Withdrawn 
  0 
  1 (33.3%) 
  1 (5.9%) 
  7 (23.3%) 
  1 (33.3%) 
 10 (18.5%) 
 Related to KN046 
  0 
  1 (33.3%) 
  1 (5.9%) 
  4 (13.3%) 
  1 (33.3%) 
  7 (13.0%) 
Subjects with TEAE Leading to Death 
  0 
  0 
  0 
  2 (6.7%) 
  0 
  2 (3.7%) 
 Related to KN046 
  0 
  0 
  0 
  0 
  0 
  0 
Note: 1. Percentages are based on the number of subjects of each dose level in the safety analysis set.；2. MedDRA 22.0；3. CTCAE 4.03 
Program: t_ae_pt.sas  
Executed: 20FEB2020 23:21
 
 


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Table 2-3 
Treatment related TEAEs (TRAEs) for Trial KN046-AUS-001 (Safety Population) 
0.3 mg/kg Q2W 
(N = 1) 
1.0 mg/kg Q2W 
(N = 3) 
3.0 mg/kg Q2W 
(N = 17) 
5.0 mg/kg Q2W 
(N = 30) 
10.0 mg/kg Q2W 
(N = 3) 
Total 
(N = 54) 
Preferred Term 
All grades Grade≥3 All grades Grade≥3 All grades Grade≥3 All grades Grade≥3 All grades Grade≥3 All grades Grade≥3 
Subjects with at least 1 
KN046 related TEAE 
 1 (100%) 
 0 
 2 (66.7%)  2 (66.7%) 13 (76.5%)  4 (23.5%) 22 (73.3%) 11 (36.7%)  3 (100%)  3 (100%) 41 (75.9%) 20 (37.0%) 
  
Arthralgia 
 0 
 0 
 1 (33.3%) 
 0 
 4 (23.5%) 
 0 
 4 (13.3%)  1 (3.3%) 
 0 
 0 
 9 (16.7%)  1 (1.9%) 
Fatigue 
 0 
 0 
 0 
 0 
 0 
 0 
 7 (23.3%) 
 0 
 1 (33.3%)  1 (33.3%)  8 (14.8%)  1 (1.9%) 
Infusion related reaction 
 0 
 0 
 0 
 0 
 4 (23.5%) 
 0 
 4 (13.3%)  1 (3.3%) 
 0 
 0 
 8 (14.8%)  1 (1.9%) 
Diarrhea 
 0 
 0 
 0 
 0 
 2 (11.8%) 
 0 
 2 (6.7%) 
 0 
 2 (66.7%) 
 0 
 6 (11.1%) 
 0 
Pruritus 
 0 
 0 
 0 
 0 
 3 (17.6%)  1 (5.9%)  3 (10.0%) 
 0 
 0 
 0 
 6 (11.1%)  1 (1.9%) 
Alanine 
aminotransferase 
increased 
 0 
 0 
 0 
 0 
 1 (5.9%) 
 0 
 1 (3.3%)  1 (3.3%)  2 (66.7%) 
 0 
 4 (7.4%)  1 (1.9%) 
Flushing 
 0 
 0 
 0 
 0 
 1 (5.9%) 
 0 
 3 (10.0%)  1 (3.3%) 
 0 
 0 
 4 (7.4%)  1 (1.9%) 
Nausea 
 0 
 0 
 1 (33.3%) 
 0 
 1 (5.9%) 
 0 
 1 (3.3%)  1 (3.3%)  1 (33.3%) 
 0 
 4 (7.4%)  1 (1.9%) 
Pyrexia 
 0 
 0 
 1 (33.3%) 
 0 
 0 
 0 
 2 (6.7%) 
 0 
 1 (33.3%) 
 0 
 4 (7.4%) 
 0 
Aspartate 
aminotransferase 
increased 
 0 
 0 
 0 
 0 
 0 
 0 
 1 (3.3%) 
 0 
 2 (66.7%)  1 (33.3%)  3 (5.6%)  1 (1.9%) 
Hyperthyroidism 
 0 
 0 
 1 (33.3%) 
 0 
 1 (5.9%) 
 0 
 1 (3.3%) 
 0 
 0 
 0 
 3 (5.6%) 
 0 
Myalgia 
 0 
 0 
 0 
 0 
 1 (5.9%) 
 0 
 2 (6.7%) 
 0 
 0 
 0 
 3 (5.6%) 
 0 
Rash 
 0 
 0 
 0 
 0 
 0 
 0 
 3 (10.0%) 
 0 
 0 
 0 
 3 (5.6%) 
 0 
Transaminases 
increased 
 0 
 0 
 0 
 0 
 1 (5.9%) 
 0 
 2 (6.7%) 
 0 
 0 
 0 
 3 (5.6%) 
 0 
Abdominal pain 
 0 
 0 
 0 
 0 
 0 
 0 
 1 (3.3%) 
 0 
 1 (33.3%) 
 0 
 2 (3.7%) 
 0 
  
Note: 1. Percentages are based on the number of subjects of each dose level in the safety analysis set.；2. MedDRA 22.0；3. CTCAE 4.03 
Program: t_ae_pt.sas  
Executed: 20FEB2020 23:21
 


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Table 2-4 
Immune-related AEs for Trial KN046-AUS-001 (Safety Population) 
0.3 mg/kg Q2W 
(N = 1) 
1.0 mg/kg Q2W 
(N = 3) 
3.0 mg/kg Q2W 
(N = 17) 
5.0 mg/kg Q2W 
(N = 30) 
10.0 mg/kg Q2W 
(N = 3) 
Total 
(N = 54) 
Preferred Term 
All grades Grade≥3 All grades Grade≥3 All grades Grade≥3 All grades Grade≥3 All grades Grade≥3 All grades Grade≥3 
Subjects with at least 1 
irAE 
 0 
 0 
 2 (66.7%)  1 (33.3%)  9 (52.9%)  3 (17.6%) 12 (40.0%)  6 (20.0%)  3 (100%)  3 (100%) 26 (48.1%) 13 (24.1%) 
  
Arthralgia 
 0 
 0 
 1 (33.3%) 
 0 
 2 (11.8%) 
 0 
 2 (6.7%)  1 (3.3%) 
 0 
 0 
 5 (9.3%)  1 (1.9%) 
Infusion related reaction 
 0 
 0 
 0 
 0 
 3 (17.6%) 
 0 
 2 (6.7%) 
 0 
 0 
 0 
 5 (9.3%) 
 0 
Pruritus 
 0 
 0 
 0 
 0 
 3 (17.6%) 
 0 
 1 (3.3%) 
 0 
 0 
 0 
 4 (7.4%) 
 0 
Transaminases 
increased 
 0 
 0 
 0 
 0 
 1 (5.9%) 
 0 
 3 (10.0%) 
 0 
 0 
 0 
 4 (7.4%) 
 0 
Alanine 
aminotransferase 
increased 
 0 
 0 
 0 
 0 
 0 
 0 
 1 (3.3%)  1 (3.3%)  1 (33.3%) 
 0 
 2 (3.7%)  1 (1.9%) 
Aspartate 
aminotransferase 
increased 
 0 
 0 
 0 
 0 
 0 
 0 
 1 (3.3%) 
 0 
 1 (33.3%) 
 0 
 2 (3.7%) 
 0 
Autoimmune arthritis 
 0 
 0 
 0 
 0 
 1 (5.9%)  1 (5.9%)  1 (3.3%) 
 0 
 0 
 0 
 2 (3.7%)  1 (1.9%) 
Autoimmune myositis 
 0 
 0 
 0 
 0 
 0 
 0 
 2 (6.7%)  2 (6.7%) 
 0 
 0 
 2 (3.7%)  2 (3.7%) 
Diarrhea 
 0 
 0 
 0 
 0 
 2 (11.8%) 
 0 
 0 
 0 
 0 
 0 
 2 (3.7%) 
 0 
Hepatic function 
abnormal 
 0 
 0 
 1 (33.3%)  1 (33.3%) 
 0 
 0 
 1 (3.3%)  1 (3.3%) 
 0 
 0 
 2 (3.7%)  2 (3.7%) 
Hepatitis 
 0 
 0 
 0 
 0 
 1 (5.9%) 
 0 
 1 (3.3%) 
 0 
 0 
 0 
 2 (3.7%) 
 0 
Hyperthyroidism 
 0 
 0 
 1 (33.3%) 
 0 
 1 (5.9%) 
 0 
 0 
 0 
 0 
 0 
 2 (3.7%) 
 0 
Myalgia 
 0 
 0 
 0 
 0 
 1 (5.9%) 
 0 
 1 (3.3%) 
 0 
 0 
 0 
 2 (3.7%) 
 0 
Myositis 
 0 
 0 
 0 
 0 
 0 
 0 
 1 (3.3%) 
 0 
 1 (33.3%) 
 0 
 2 (3.7%) 
 0 
  
Note: 1. Percentages are based on the number of subjects of each dose level in the safety analysis set.；2. MedDRA 22.0；3. CTCAE 4.03 
Program: t_ae_pt.sas  
Executed: 20FEB2020 23:21
 


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2.3.2.1.2 Efficacy results of KN046-AUS-001 
All subjects enrolled in this study had previously failed standard-of-care treatments. As of the Data Cut-
off Date, there were 35 evaluable subjects. The efficacy results showed that among the 35 evaluable 
subjects, the ORR (defined as the proportion of subjects with a BOR of confirmed or unconfirmed CR 
or PR), was 16.7% (95% CI 7.0, 31.4). At recommended Phase 2 dose levels (3 mg/kg Q2W and 5 mg/kg 
Q2W), the ORR was 15.4% (95% CI: 1.9, 45.4) and 20.8% (95% CI: 7.1, 42.2), respectively. 
 
4 subjects with thymic neoplasms were enrolled in KN046-AUS-001 (stage IV thymoma 2; thymic 
carcinoma 2). 3 subjects obtained complete response (n = 1) or partial response (n = 2). 1 thymoma 
patient obtained stable disease. KN046 showed preliminary efficacy in this study population.  
Table 2-5 
Efficacy Summary for Trial KN046-AUS-001 (Efficacy Population)  
0.3 mg/kg 
Q2W 
(N = 1) 
1.0 mg/kg 
Q2W 
(N = 3) 
3.0 mg/kg 
Q2W 
(N = 13) 
5.0 mg/kg 
Q2W 
(N = 24) 
10.0 mg/kg 
Q2W 
(N = 1) 
Total 
(N = 42) 
Best Overall Response 
 
 
 
 
 
 
 Complete Response (CR) 
 0 
 0 
 1 (7.7%) 
 0 
 0 
 1 (2.4%) 
 Partial Response (PR) 
 0 
 0 
 0 
 2 (8.3%) 
 0 
 2 (4.8%) 
 Unconfirmed Complete Response 
(uCR) 
 0 
 0 
 0 
 0 
 0 
 0 
 Unconfirmed Partial Response (uPR) 
 0 
 0 
 1 (7.7%) 
 3 (12.5%) 
 0 
 4 (9.5%) 
 Stable Disease (SD) 
 0 
 1 (33.3%) 
 2 (15.4%) 
12 (50.0%) 
 0 
15 (35.7%) 
 Progressive Disease (PD) 
 1 (100%) 
 2 (66.7%) 
 9 (69.2%) 
 7 (29.2%) 
 1 (100%) 
20 (47.6%) 
  
Objective Response Rate (ORR) 
 0 
 0 
 2 (15.4%) 
 5 (20.8%) 
 0 
 7 (16.7%) 
 95% CI 
0.0%, 97.5% 0.0%, 70.8% 1.9%, 45.4% 7.1%, 42.2% 
0.0%, 97.5% 7.0%, 31.4% 
Disease Control Rate (DCR) 
 0 
 1 (33.3%) 
 4 (30.8%) 
17 (70.8%) 
 0 
22 (52.4%) 
 95% CI 
0.0%, 97.5% 0.8%, 90.6% 9.1%, 61.4% 48.9%, 87.4% 0.0%, 97.5% 
36.4%, 
68.0% 
Note: 1. Percentages are based on the number of subjects of each dose level in the evaluable analysis set. 
     2. ORR=CR+PR+uCR+uPR. 
     3. DCR=CR+PR+uCR+uPR+SD. 
Program: t_rs.sas  
Executed: 20FEB2020 23:23  
 
2.3.1.1.3 Pharmacokinetic results of KN046-AUS-001 
Trial KN046-AUS-001 was performed in Australia and enrolled mainly Caucasian patients. The table below 
displays the main PK parameters that were evaluated after the first dose in Trial KN046-AUS-001. After a 
single dose, the terminal half-life does not appear to be dose-dependent and ranges from 100.8 to 181.8 
hours across dose ranges of 3.0 to 10 mg/kg. Formal dose proportionality has not been performed. From 
exploratory analysis, it appears that both Cmax and AUCinf increase with increasing dose across the dose 
range of 0.3 to 10.0 mg/kg. 
Table 2-6 
Summary of Pharmacokinetic Parameters on Cycle 1 Day 1 (KN046-AUS-001) 
 
0.3 mg/kg Q2W 1.0 mg/kg Q2W 3.0 mg/kg Q2W 5.0 mg/kg Q2W 10.0 mg/kg Q2W 
PK parameters 
(N=1) 
(N=3) 
(N=17) 
(N=16) 
(N=2) 
AUCinf (ng*h/mL) 
 
 
 
 
 
    Mean (SD) 
505552 
2463669 
(712624.2) 
8520038.8 
(2472946.6) 
13675607 
(3908026.9) 
17917942 
(3326685.7) 
    Median 
505552 
2540594 
7956885 
13712441 
17917942 
    Geometric Mean 
505552 
2390699.1 
8198420.7 
13141043 
17762861 


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0.3 mg/kg Q2W 1.0 mg/kg Q2W 3.0 mg/kg Q2W 5.0 mg/kg Q2W 10.0 mg/kg Q2W 
PK parameters 
(N=1) 
(N=3) 
(N=17) 
(N=16) 
(N=2) 
Cmax (ng/mL) 
 
 
 
 
 
    Mean (SD) 
6446 
25586.7 
(10153.2) 
96308.8 
(96041.7) 
119118.7 
(41359.7) 
148228 (48202.1) 
    Median 
6446 
25292 
71716 
105547 
148228 
    Geometric Mean 
6446 
24183.6 
79423.8 
113315.1 
144256.1 
Terminal T1/2 (h) 
 
 
 
 
 
    Mean (SD) 
59 
100.8 (19.9) 
165.5 (45.1) 
181.8 (52.5) 
170.5 (0.7) 
    Median 
59 
98 
164 
183.5 
170.5 
    Geometric Mean 
59 
99.5 
159.1 
172.7 
170.5 
CL (mL/h) 
 
 
 
 
 
    Mean (SD) 
35.6 
30.0 (1.7) 
28.6 (7.2) 
26.3 (6.2) 
31.0 (5.4) 
    Median 
35.6 
30.3 
27.7 
25.9 
31.0 
    Geometric Mean 
35.6 
29.9 
27.8 
25.6 
30.7 
 
 
 
 
 
 
2.3.2.2. Phase I data from trial KN046-CHN-001  
KN046-CHN-001 is a Phase Ia/Ib, open-label, multiple-ascending dose-escalation and expansion trial 
currently ongoing to evaluate the MTD, RP2Ds, the safety, tolerability, PK, pharmacodynamics (PD) and 
immunogenicity of KN046 in subjects with metastatic or locally advanced solid tumors. Trial KN046-
CHN-001 plans to recruit over 300 subjects.  
Trial KN046-CHN-001 consists of a dose escalation and expansion phase (mTPI-2 design) (25) followed by 
a cohort expansion phase in multiple solid tumor indications. The dose escalation and expansion phase 
was designed to provide safety and tolerability, as well as PK and PD data for KN046 at sequential doses 
ranging from 1.0 to 5.0 mg/kg in subjects with advanced malignancies, for which there are no 
established standard treatments.  
As of January 20, 2020, the dose escalation and dose expansion phase (Phase Ia) included a total of 88 
subjects and was performed at the following dose levels:  
 
Dose level 1: 1.0 mg/kg Q2W (Cohort 1), 1 subject treated 
 
Dose level 2: 3.0 mg/kg Q2W (Cohort 2), 30 subjects treated;  
 
Dose level 3: 5.0 mg/kg Q2W (Cohort 3), 45 subjects treated; 30 subjects planned  
 
Dose level 4: 5.0 mg/kg Q3W (Cohort 4a), 6 subjects treated  
 
Dose level 4: 300 mg Q3W (Cohort 4b), 6 subjects treated  
In the cohort expansion phase (Phase Ib and Ic), a total of 4 cohorts are planned to assess the efficacy, 
safety and predictive biomarker of KN046 in the following tumor types:  
 
≥Second line treatment of unresectable/metastatic melanoma 


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 
≥Third line treatment of unresectable/metastatic NPC  
 
Second line treatment of unresectable/metastatic UC 
 
Second line treatment of ED-SCLC  
Importantly, availability of tumor tissue is required to participate in the dose and cohort expansion 
phases of this trial. The objectives of these treatment expansion cohorts are to:  
 
Establish the clinical activity of KN046 as a monotherapy in each indication.  
 
Confirm the safety profile observed during the dose escalation phase. 
 
Explore the potential correlation between biomarker (TMB, GEP, and a pattern of expression of 
PD-L1 at the surface of the tumor cells or at the surface of infiltrating immune cells) and clinical activity 
for the purpose of developing a companion diagnostic specific to each of these tumors.  
In order to detect signals of clinical activity and to provide additional safety, PK, PD, and biomarker 
information, and to guide further clinical evaluation of KN046, further expansion in biomarker enriched 
population in Trial KN046-CHN-001 are planned as follows: 
 
Biomarker positive (DDR, TMB) UC  
 
Biomarker positive (TMB, TMB/GEP) ED-SCLC  
Primary objective for escalation cohort is to assess the DLTs of KN046 in Chinese subjects and expansion 
cohorts is to assess the best overall response (BOR) and duration of response (DOR) according to RECIST 
1.1 per IRC assessment.  
Recommended phase 2 doses (RP2Ds) have been determined as 3 and 5 mg/kg Q2W. As of January 20, 
2020, a total of 88 subjects had received KN046 either in the dose escalation or in the dose expansion 
phase (1, 30, 45, 6 and 6 subjects received 1.0 mg/kg Q2W, 3.0 mg/kg Q2W, 5.0 mg/kg Q2W, 5.0 mg/kg 
Q3W and 300 mg, respectively). 
 
2.3.2.2.1. Safety results of Phase I KN046-CHN-001 
As of January 20, 2020, 88 subjects enrolled in the dose escalation study, including 13 and 65 subjects 
enrolled in Phase Ia dose escalation and dose expansion stages, respectively. 88 subjects were included 
in the safety data analysis. Median duration of therapy was 12 weeks (range: 2 to 54). The median 
relative dose intensity of KN046 was 100% (range: 99.5% to 100%). In total 5.7% patients discontinued 
KN046 treatment due to adverse event. The results have exhibited favorable safety profile of our KN046 
and the safety results showed no significant differences from the KN046-AUS-001 trial. 
No subjects experienced DLTs during dose escalation phase. MTD was not reached at 5.0 mg/kg. 5.0 
mg/kg Q2W was determined to be the RP2D. 
As of January 20,2020, 74 (84.1%) out of the 88 subjects had experienced treatment-related adverse 
events of all grades and nine (10.2%) subjects had experienced treatment- related adverse events at 
grade 3 or higher levels. The most frequently observed TRAEs was rash reported in 30 subjects (34.1%), 
followed by pruritus in 28 subjects (31.8%), alanine aminotransferase increased (ALT) in 17 subjects 


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(19.3%), fatigue in 15 subjects (17.0%), infusion related reaction in 15 subjects (17.0%), aspartate 
aminotransferase (AST) increased in 12 subjects (13.6%), pyrexia in 11 subjects (12.5%) and arthralgia 
in 9 subjects (102%). 9 of the 88 subjects (10.2%) experienced at least one ≥Grade 3 TRAEs. These 
included event terms of infusion related reaction (4 subjects; 4.5%), AST increased (3 subjects; 3.4%), 
rash (2 subjects; 2.3%), ALT increased (1 subject; 1.1%), anemia (1 subject; 1.1%), hyponatremia (1 
subject; 1.1%) and transaminase increase (1 subject; 1.1%). No Grade 5 TRAEs were observed. Four 
(4.5%) subjects experienced treatment-related SAE. The event terms of the treatment-related serious 
TEAEs included infusion related reaction (2 subjects; 2.3%), ALT increased (1 subject; 1.1%), AST 
increased (1 subject; 1.1%), pneumonitis (1 subject; 1.1%), rash (1 subject; 1.1%) and transaminases 
increased (1 subject; 1.1%). 40 (45.5%) subjects had experienced irAEs, Four (4.5%) were grade 3. The 
event terms of these irAEs include rash (2 subjects; 2.3%), ALT increased (1 subject; 1.1%), AST 
increased (1 subject; 1.1%), pneumonitis (1 subject; 1.1%) and transaminase increased (1 subject; 
1.1%). None irAE led to death. Similar to the results of the KN046-AUS-001 trial, neither the treatment-
related TEAEs nor the irAEs in the dose escalation study of the KN046-CHN-001 trial were found to 
occur in a dose-dependent manner. 
Overall, the TEAE profile was similar across different dose cohorts and the incidences of TEAEs by TEAE 
category did not increase with increasing dose. 
 


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Table 2-7 
Subject disposition for Trial KN046-CHN-001 (Safety Population) 
Subject disposition 
1.0 mg/kg Q2W 
(n = 1) 
3.0 mg/kg Q2W 
(n = 30) 
5.0 mg/kg Q2W 
(n = 45) 
5.0 mg/kg Q3W 
(n = 6) 
300 mg 
(n = 6) 
Total 
(N = 88) 
Subjects remaining on treatment (%) 
0  
8 (26.7%) 
22 (48.9%) 
2 (33.3%) 
1 (16.7%) 
33 (37.5%) 
Discontinued, n (%) 
1 (100%) 
22 (73.3%) 
23 (51.1%) 
4 (66.7%) 
5 (83.3%) 
55 (62.5% 
      Disease progression  
1 (100%) 
17 (56.7%) 
14 (31.1%) 
2 (33.3%) 
2 (33.3%) 
36 (40.9%) 
      Adverse events  
0 
2 (6.7%) 
3 (6.7%) 
0 
0 
5 (5.7%) 
      Death 
0 
0 
0 
1 (16.7%) 1 
2 (33.3%) 2 
3 (3.4%) 
      Lost to follow-up  
0 
1 (3.3%) 
1 (2.2%) 
0 
0 
2 (2.3%) 
      Other reasons 3 
0 
2 (6.7%) 
5 (11.1%) 
1 (16.7%) 
1 (16.7%) 
9 (10.2%) 
1 Death from disease progression 
2 One subject died from Acute Respiratory Distress Syndrome; For another subjects, the investigator was not be able to determine the reason for the death 
3 Other reasons including eight patients discontinued due to clinical deterioration, one patent discontinued due to investigator determined no longer clinical 
benefit. 
Source: Table 1 Dated 20200213 
 
Table 2-8 
Safety summary for Trial KN046-CHN-001 (Safety Population) 
  
1.0 mg/kg Q2W 
3.0 mg/kg Q2W 
5.0 mg/kg Q2W 
5.0 mg/kg Q3W 
300 mg Q3W 
Total 
 CTCAE version 5.0 
(N = 1) 
(N = 30) 
(N = 45) 
(N = 6) 
(N = 6) 
(N = 88) 
Subjects with at least 1 TEAE 
1 (100%) 
30 (100%) 
44 (97.8%) 
6 (100%) 
6 (100%) 
87 (98.9%) 
       Related to KN046 
1 (100%) 
27 (90.0%) 
36 (80.0%) 
6 (100%) 
4 (66.7%) 
74 (84.1%) 
Subjects with at least 1 CTCAE Grade ≥ 3 TEAE 
1 (100%) 
14 (46.7%) 
9 (20.0%) 
2 (33.3%) 
4 (66.7%) 
30 (34.1%) 
       Related to KN046 
0 
6 (20.0%) 
2 (4.4%) 
1 (16.7%) 
0 
9 (10.2%) 
Subjects with at least 1 IRR 
0 
7 (23.3%) 
6 (13.3%) 
2 (33.3%) 
0 
15 (17.0%) 
Subjects with at least 1 irAE 
0 
20 (66.7%) 
15 (33.3%) 
5 (83.3%) 
0 
40 (45.5%) 
Subjects with at least 1 CTCAE Grade ≥ 3 irAE 
0 
4 (13.3%) 
0 
0 
0 
4 (4.5%) 
Subjects with at least 1 SAE during treatment 2 
1 (100%) 
9 (30.0%) 
4 (8.9%) 
1 (16.7%) 
4 (66.7%) 
19 (21.6%) 
       Related to KN046 3 
0 
4 (13.3%) 
0 
0 
0 
4 (4.5%) 
Subjects with at least 1 TEAE Leading to Drug Withdrawn 
0 
2 (6.7%) 
5 (11.1%) 
1 (16.7%) 
2 (33.3%) 
10 (11.4%) 
      Related to KN046 
0 
2 (6.7%) 
3 (6.7%) 
0 
0 
5 (5.7%) 


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1.0 mg/kg Q2W 
3.0 mg/kg Q2W 
5.0 mg/kg Q2W 
5.0 mg/kg Q3W 
300 mg Q3W 
Total 
 CTCAE version 5.0 
(N = 1) 
(N = 30) 
(N = 45) 
(N = 6) 
(N = 6) 
(N = 88) 
Subjects with at least 1 TEAE Leading to Death 
1 (100%) 
0 
1 (2.2%) 
0 
3 (50.0%) 
5 (5.7%) 
      Related to KN046 
0 
0 
0 
0 
0 
0 
TEAE = treatment emergent adverse event; CTCAE = common terminology criteria for adverse event; IRR = infusion related adverse event; irAE = immune-related adverse event; SAE 
= serious adverse event.  
1 19 subjects experienced 24 SAEs, including Death (2, 2.3%), Infection (2, 2.3%), Infusion related reaction (2, 2.3%), Pneumonitis (2, 2.3%), Acute respiratory distress syndrome (1, 
1.1%), Alanine aminotransferase increased (1, 1.1%), Aspartate aminotransferase increased (1, 1.1%), Bone pain (1, 1.1%), Brain edema (1, 1.1%), Cardiac arrest (1, 1.1%), 
Dysphagia (1, 1.1%), Hemoptysis (1, 1.1%), Hemorrhoidal hemorrhage (1, 1.1%), Hepatic failure (1, 1.1%), Hyponatremia (1, 1.1%), Pleural effusion (1, 1.1%), Pyrexia (1, 1.1%), Rash 
(1, 1.1%), Tachypnoea (1, 1.1%) and Transaminases increased (1, 1.1%). 
2 
Four 
subjects 
experienced 
seven 
treatment-related 
SAEs, 
including 
Infusion related reaction 
(2, 
2.3%), 
Alanine aminotransferase increased 
(1, 
1.1%), 
Aspartate aminotransferase increased (1, 1.1%), Pneumonitis (1, 1.1%), Rash (1, 1.1%) and Transaminases increased (1, 1.1%). 
Source: Table 5.1 Dated 20200213 
Table 2-9 
Treatment related TEAEs (TRAEs) for Trial KN046-CHN-001 (all grades with a frequency ≥10%, or any ≥grade 3) (Safety Population) 
  
1.0 mg/kg Q2W 
3.0 mg/kg Q2W 
5.0 mg/kg Q2W 
5.0 mg/kg Q3W 
300 mg Q3W 
Total 
Preferred Term 
Grade ≥ 3 
(N = 1) 
Total 
(N = 1) 
Grade ≥ 3 
(N = 30) 
Total 
(N = 30) 
Grade ≥ 3 
(N = 45) 
Total 
(N = 45) 
Grade ≥ 3 
(N = 6) 
Total 
(N = 6) 
Grade ≥ 3 
(N = 6) 
Total 
(N = 6) 
Grade ≥ 3 
(N = 88) 
Total 
(N = 88) 
Subjects with at least 1 KN046 related TEAE 
0 
1 (100%) 
6 (20.0%) 
27 (90.0%) 
2 (4.4%) 
36 (80.0%) 
1 (16.7%) 
6 (100%) 
0 
4 (66.7%) 
9 (10.2%) 
74 (84.1%) 
  
  
  
  
  
  
  
  
  
  
  
  
  
Rash 
0 
0 
2 (6.7%) 
14 (46.7%) 
0 
13 (28.9%) 
0 
3 (50.0%) 
0 
0 
2 (2.3%) 
30 (34.1%) 
Pruritus 
0 
0 
0 
10 (33.3%) 
0 
14 (31.1%) 
0 
3 (50.0%) 
0 
1 (16.7%) 
0 
28 (31.8%) 
Alanine aminotransferase increased 
0 
0 
1 (3.3%) 
9 (30.0%) 
0 
6 (13.3%) 
0 
1 (16.7%) 
0 
1 (16.7%) 
1 (1.1%) 
17 (19.3%) 
Fatigue 
0 
0 
0 
8 (26.7%) 
0 
4 (8.9%) 
0 
3 (50.0%) 
0 
0 
0 
15 (17.0%) 
Infusion related reaction 
0 
0 
3 (10.0%) 
7 (23.3%) 
1 (2.2%) 
6 (13.3%) 
0 
2 (33.3%) 
0 
0 
4 (4.5%) 
15 (17.0%) 
Aspartate aminotransferase increased 
0 
0 
1 (3.3%) 
6 (20.0%) 
1 (2.2%) 
3 (6.7%) 
1 (16.7%) 
2 (33.3%) 
0 
1 (16.7%) 
3 (3.4%) 
12 (13.6%) 
Pyrexia 
0 
0 
0 
4 (13.3%) 
0 
7 (15.6%) 
0 
0 
0 
0 
0 
11 (12.5%) 
Arthralgia 
0 
0 
0 
5 (16.7%) 
0 
4 (8.9%) 
0 
0 
0 
0 
0 
9 (10.2%) 
Anemia 
0 
0 
1 (3.3%) 
2 (6.7%) 
0 
0 
0 
0 
0 
0 
1 (1.1%) 
2 (2.3%) 
Hyponatremia 
0 
0 
1 (3.3%) 
2 (6.7%) 
0 
0 
0 
0 
0 
0 
1 (1.1%) 
2 (2.3%) 
Transaminases increased 
0 
0 
1 (3.3%) 
1 (3.3%) 
0 
0 
0 
0 
0 
0 
1 (1.1%) 
1 (1.1%) 
Source: Table 5.5 Dated 20200213 
 


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Table 2-10 
Immune-related AEs for Trial KN046-CHN-001 (Safety Population) 
  
1.0 mg/kg Q2W 
3.0 mg/kg Q2W 
5.0 mg/kg Q2W 
5.0 mg/kg Q3W 
300 mg Q3W 
Total 
Preferred Term 
Grade ≥ 3 
(N = 1) 
Total 
(N = 1) 
Grade ≥ 3 
(N = 30) 
Total 
(N = 30) 
Grade ≥ 3 
(N = 45) 
Total 
(N = 45) 
Grade ≥ 3 
(N = 6) 
Total 
(N = 6) 
Grade ≥ 3 
(N = 6) 
Total 
(N = 6) 
Grade ≥ 3 
(N = 88) 
(N = 88) 
Subjects with at least 1 immune related AE 
0 
0 
4 (13.3%) 
20 (66.7%) 
0 
15 (33.3%) 
0 
5 (83.3%) 
0 
0 
4 (4.5%) 
40 (45.5%) 
  
  
  
  
  
  
  
  
  
  
  
  
  
Rash 
0 
0 
2 (6.7%) 
12 (40.0%) 
0 
10 (22.2%) 
0 
3 (50.0%) 
0 
0 
2 (2.3%) 
25 (28.4%) 
Pruritus 
0 
0 
0 
9 (30.0%) 
0 
11 (24.4%) 
0 
3 (50.0%) 
0 
0 
0 
23 (26.1%) 
Arthralgia 
0 
0 
0 
3 (10.0%) 
0 
2 (4.4%) 
0 
0 
0 
0 
0 
5 (5.7%) 
Fatigue 
0 
0 
0 
3 (10.0%) 
0 
0 
0 
2 (33.3%) 
0 
0 
0 
5 (5.7%) 
Alanine aminotransferase increased 
0 
0 
1 (3.3%) 
2 (6.7%) 
0 
0 
0 
0 
0 
0 
1 (1.1%) 
2 (2.3%) 
Aspartate aminotransferase increased 
0 
0 
1 (3.3%) 
2 (6.7%) 
0 
0 
0 
0 
0 
0 
1 (1.1%) 
2 (2.3%) 
Pneumonitis 
0 
0 
1 (3.3%) 
2 (6.7%) 
0 
0 
0 
0 
0 
0 
1 (1.1%) 
2 (2.3%) 
Transaminases increased 
0 
0 
1 (3.3%) 
1 (3.3%) 
0 
0 
0 
0 
0 
0 
1 (1.1%) 
1 (1.1%) 
 
Source: Table 5.11 Dated 20200213 
 


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2.3.2.2.2 Efficacy results of Phase I KN046-CHN-001 
In general, the subjects enrolled in the KN046-CHN-001 trial had previously failed standard-of-
care treatments, including subjects who failed prior immune checkpoint inhibitors. As of January 
20, 2020, there were 75 evaluable subjects. The efficacy analysis showed that, among the 75 
evaluable subjects, nine had confirmed PRs and 27 had SD. 29 of the evaluable subjects remained 
on the study treatment as of 20-Jan-2020. ORR is 12.0% (95% CI: 5.6, 21.6) in the overall 
population and 12.5% (95% CI: 2.5, 31.2) in subjects who have failed prior immune checkpoint 
inhibitors.  
 
As of January 20, 2020, median progression free survival (PFS) was 2.66 (95% CI: 1.3, 5.5) months. 
Median overall survival (OS) was not reached. PFS rates for 3, 6 and 9 Months were 40.5 (95% CI: 
28.2,52.4), 32.1 (95% CI: 19.8,45.1) and 27.5 (95% CI: 14.9,41.8), respectively. OS rates for 6 and 
9 months were 74.3 (95% CI: 61.4,83.5) and 65.2 (95% CI: 47.4,78.2), respectively. 
 
 
In subjects with prior immune checkpoint inhibitor treatments, median progression free survival 
was 2.69 (95% CI: 1.3,5.5) months. Median overall survival was not reached. PFS rates for 3 and 6 
Months were 41.0% (95% CI: 18.5, 62.5) and 21.9% (95% CI: 4.6, 47.3). OS rates for 6 and 9 months 
were 88% (95% CI: 57.2, 97.1) and 58.7% (95% CI: 8.3, 89.2), respectively. 
Table 2-2 
Efficacy Summary for Trial KN046-CHN-001 (Efficacy Population)  
 
1.0 mg/kg 
3.0 mg/kg 
5.0 mg/kg 
5.0 mg/kg 
300 mg 
  
 
Q2W 
(N = 1) 
Q2W 
(N = 29) 
Q2W 
(N = 36) 
Q3W 
(N = 6) 
Q3W 
(N = 3) 
Total 
(N = 75) 
Best overall response  
 
 
 
 
 
 
  Complete response (CR)  
0 
0 
0 
0 
0 
0 
  Partial response (PR) 
0 
7 (24.1%) 
1 (2.8%) 
0 
0 
8 (10.7%) 
  Unconfirmed CR (uCR) 
0 
0 
0 
0 
0 
0 
  Unconfirmed PR (uPR) 
0 
0 
1 (2.8%) 
0 
0 
1 (1.3%) 
  Stable disease (SD) 
0 
6 (20.7%) 
15 (41.7%) 
4 (66.7%) 
2 (66.7%) 
27 (36.0%) 
  Progressive disease (PD) 
1 (100%) 
14 (48.3%) 
19 (52.8%) 
2 (33.3%) 
1 (33.3%) 
37 (49.3%) 
  Not evaluable (NE) 
0 
2 (6.9%) 
0 
0 
0 
2 (2.7%) 
  
  
  
  
  
  
  
Objective response (ORR) 
0 
7 (24.1%) 
2 (5.6%) 
0 
0 
9 (12.0%) 
  95% CI  
 
10.298, 43.5 
0.680, 18.66 
 
 
5.637, 21.56 
Note: ORR=CR+PR+uCR+uPR; DCR=CR+PR+uCR+uPR+SD≥37 days 
 
Table 2-3 
Efficacy Summary for Trial KN046-CHN-001 in Subjects Who Failed Prior Immune 
Checkpoint Inhibitor (Efficacy Population)  
 
3.0 mg/kg 
5.0 mg/kg 
5.0 mg/kg 
300 mg 
  
 
Q2W 
(N = 3) 
Q2W 
(N = 17) 
Q3W 
(N = 4) 
Q3W 
(N = 1) 
Total 
(N = 25) 
Best overall response  
0 
0 
0 
0 
0 
  Complete response (CR)  
0 
0 
0 
0 
0 
  Partial response (PR) 
1 (33.3%) 
1 (5.9%) 
0 
0 
2 (8.0%) 
  Unconfirmed CR (uCR) 
0 
0 
0 
0 
0 
  Unconfirmed PR (uPR) 
0 
1 (5.9%) 
0 
0 
1 (4.0%) 
  Stable disease (SD) 
1 (33.3%) 
6 (35.3%) 
3 (75.0%) 
0 
10 (40.0%) 
  Progressive disease (PD) 
1 (33.3%) 
9 (52.9%) 
1 (25.0%) 
1 (100%) 
12 (48.0%) 
  Not evaluable (NE) 
2 (6.9%) 
0 
0 
0 
0 


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3.0 mg/kg 
5.0 mg/kg 
5.0 mg/kg 
300 mg 
  
 
Q2W 
(N = 3) 
Q2W 
(N = 17) 
Q3W 
(N = 4) 
Q3W 
(N = 1) 
Total 
(N = 25) 
  
0 
0 
0 
0 
0 
Objective response (ORR) 
1 (33.3%) 
2 (11.8%) 
0 
0 
3 (12.0%) 
  95% CI  
0.840, 90.570 
1.458, 36.441 
0 
0 
2.547, 31.219 
Note: ORR=CR+PR+uCR+uPR; DCR=CR+PR+uCR+uPR+SD≥37 days 
2.3.1.2.3 Pharmacokinetic results of KN046-CHN-001 
Trial KN046-CHN-001 was performed in China and enrolled all Chinese subjects. The below table 
displays the main PK parameters that were evaluated after the first dose in Trial KN046-CHN-001. 
The preliminary concentrations obtained over time and the clearance during the first dosing 
interval were similar in Chinese and Caucasian patients. After single dose, both Cmax and AUCinf 
increase with increasing dose across the dose range of 1.0 to 5.0 mg/kg drug exposure. Terminal 
half-life does not appear to be dose-dependent and ranges from 137 to 157.4 hours across dose 
range of 1.0 to 5 mg/kg. 
Table 2-13 
Summary of Pharmacokinetic Parameters on Cycle 1 Day 1 (KN046-CHN-001) 
 
1.0 mg/kg Q2W 3.0 mg/kg Q2W 5.0 mg/kg Q2W 5.0 mg/kg Q3W 
300 mg Q3W 
PK parameters 
(N=1) 
(N=31) 
(N=18) 
(N=5) 
(N=5) 
AUCinf (ng*h/mL) 
 
 
 
 
 
    Mean (SD) 
1994829 
7165351.4 
(2866653) 
11603361 
(3370238) 
11526905 
(3835867.7) 
9247562 
(2197379.8) 
    Median 
1994829 
6711248 
11093661 
10746387 
8502697 
    Geometric Mean 
1994829 
6739073.5 
11173134 
11013834 
9052837.2 
Cmax (ng/mL) 
 
 
 
 
 
    Mean (SD) 
21935 
66129.2 
(12840.6) 
95843.4 
(16776.7) 
89608.6 
(17786.3) 
96594.2 (19378.1) 
    Median 
21935 
65613 
95070 
91703 
88301 
    Geometric Mean 
21935 
64916.7 
94434.4 
88093.5 
95082.8 
Terminal T1/2 (h) 
 
 
 
 
 
    Mean (SD) 
111 
144.4 (70.2) 
157.4 (58.5) 
137 (91.0) 
141.6 (60.9) 
    Median 
111 
138 
160.5 
173 
132 
    Geometric Mean 
111 
126.4 
143.5 
106.3 
131.8 
CL (mL/h) 
 
 
 
 
 
    Mean (SD) 
27.4 
28.0 (9.4) 
28.4 (9.3) 
24.8 (5.2) 
33.8 (7.2) 
    Median 
27.4 
23.8 
25.45 
26.8 
35.3 
    Geometric Mean 
27.4 
26.6 
27.1 
24.3 
33.2 
 
 
 
 
 
 
 
2.4  Risk/Benefit Assessment  
The risk-benefit relationship has been carefully considered in the planning of the trial. Based on the 
clinical data available to date, the conduct of the trial is considered justifiable using the dose 
established in Trials KN046-AUS-001 and KN046-CHN-001.  


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2.4.1 
Known Potential Risks 
 
The important identified and potential risks with KN046 have been determined based on 
observations in preclinical toxicity or clinical studies; risks reported with other immune 
checkpoint inhibitors (anti-PD-1 and anti-PD-L1) and CTLA-4 antibodies; as well as risks 
generally associated with monoclonal antibodies (mAbs).  
Important identified risks:  
• 
Immune-related adverse events (excluding hypersensitivity reaction);  
• 
Infusion related reactions;  
• 
Systemic hypersensitivity reactions.  
Important potential risks:  
• 
Immunogenicity (anti-KN046 antibody formation);  
• 
Embryo fetal toxicity 
2.4.1.1 Immune-related adverse events 
Investigators should be extremely vigilant and be ready to intervene early in the 
management of irAEs, as the onset of symptoms of irAEs from KN046 treatment (eg, 
hepatitis) may be subtle. Immune-related AEs have been reported with KN046 and with 
other anti-PD-1, anti-PD-L1 and anti-CTLA4 antibodies; these are considered consistent 
with the mechanism of action of immune checkpoint inhibitors.  
An immune-related AE can occur shortly after the first dose or several months after the 
last dose of treatment. All AEs of unknown etiology associated with drug exposure 
should be evaluated for a possible immune etiology. Efforts should be made to rule out 
autoimmunity, infection, neoplastic, metabolic disorder, toxin or other etiologic causes 
prior to classifying an AE as an irAE.  
Management guidelines to irAE are provided. Exclusion criteria E09, E10 and E11 will be 
applied to exclude susceptible subjects. During the study, routine hematologic, 
chemistry (including creatine phosphokinase) and immune safety assays (including AChR 
autoantibody and anti-MuSK autoantibody if clinically indicated) are performed at 
baseline, during the treatment phase and 30- and 90-day safety follow-up. Vital signs 
and physical examinations are closely monitored according to the study protocol.  
From Phase I data of KN046-AUS-001, the most frequent treatment-related adverse 
events included arthralgia (16.7%), fatigue (14.8%), infusion-related reaction (14.8%), 
diarrhea (11.1%) and pruritus (11.1%). Skin and subcutaneous tissue disorders and 
musculoskeletal and connective tissue disorders were the most frequent irAEs. The 
TRAE and irAEs were not found to occur in a dose-dependent manner up to 5 mg/kg 


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Q2W, and neither the number nor severity of TRAE or irAEs was exacerbated due to 
dose escalation at the RP2D or lower levels.  
In Phase I data of KN046-CHN-001, the most frequently observed TRAEs was rash 
reported in 30 subjects (34.1%), followed by pruritus in 28 subjects (31.8%), alanine 
aminotransferase increased (ALT) in 17 subjects (19.3%), fatigue in 15 subjects (17.0%), 
infusion related reaction in 15 subjects (17.0%), aspartate aminotransferase (AST) 
increased in 12 subjects (13.6%), pyrexia in 11 subjects (12.5%) and arthralgia in 9 
subjects (102%). 9 of the 88 subjects (10.2%) experienced at least one ≥Grade 3 TRAEs. 
Similar to the results of the KN046-AUS-001 trial, neither the treatment-related adverse 
events nor the irAEs in the dose escalation study of the KN046-CHN-001 trial were found 
to occur in a dose-dependent manner. 
Management of irAEs include withholding KN046 until resolution of toxicity to Grade 1 
or less. If toxicity is Grade 3 or more, steroids may be used. Further details for 
management can be found in Section Appendix A. 
2.4.1.2. Infusion-related reaction and systemic hypersensitivity reaction 
There is no general consensus on the definition of infusion-related reaction. Though 
technically infusion reactions might be due to hypersensitivity or immune-related 
reaction, the mechanism of action that leads to such reactions is often not known. For 
the purpose of this protocol, it is reaction suspected to be related to the infusion of 
drug, but not classified as immune-related reaction or systemic reaction.  
Infusion-related reactions and systemic hypersensitivity reactions are known to occur 
with protein therapeutic infusions and have been observed in KN046 clinical studies. 
Acute infusion reactions are defined as any AEs that occur during the infusion or within 
2 hours after the infusion is completed. Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. As with other protein therapeutics, hypersensitivity reactions 
usually develop immediately or within a few hours of infusion. However, it might occur 
weeks later as in serum sickness, a type III hypersensitivity, resulting from high titer of 
anti-drug antibody. The time of onset of serum sickness is typically 1~2 weeks after 
commencement of antibody infusion.  
Suggested management guidelines to infusion related reactions and hypersensitivity 
reactions are provided in Section 7.5.1 and Appendix A.  Exclusion criterion E15 will be 
applied to exclude susceptible subjects.  
During KN046 treatment, emergency equipment and medication for the treatment of 
these potential adverse events must be available for immediate use. After completion of 
KN046 infusion, subjects should be observed for at least 2 hours before being 
discharged. Grade 2 or greater infusion-related reactions are considered AE of interest 
and must be reported within 24 hours of identification by the investigator.  
2.4.1.3. Other potential risks 


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KN046 has wide type Fc and maintains antibody-dependent cell-mediated cytotoxicity 
(ADCC) effect. There is a potential risk of tumor lysis syndrome. Monitoring includes 
chemistry and hematology assessments.  
In addition, women with childbearing potential should apply highly effective method of 
contraception (with a failure rate of less than 1.0% per year) from first study treatment 
to 24 weeks after completion of the trial treatment. Investigator must notify the 
Sponsor / designee in an expedited manner of any pregnancy using the Pregnancy 
Report Form which should be transmitted according to the same process for SAE 
reporting. 
 
2.4.2 
Known Potential Benefits  
 
KN046 is a bispecific antibody immune checkpoint inhibitor simultaneously targeting 
two clinically validated immune checkpoints, PD-L1 and CTLA-4, representing a next 
generation immune-oncology blockbuster drug. In Phase I clinical trials in Australia and 
China, among all subjects receiving KN046 at 5 mg/kg Q2W (RP2D), the DCR was 77.8% 
and 69.2% respectively and 10 (55.6%) and 4 (30.8%) subjects had target lesion 
shrinkage, respectively. These subjects have generally failed at least first-line standard 
of care. The results from the Phase I clinical trials have shown a favorable safety profile, 
and early efficacy signals in solid tumors such as nasopharyngeal carcinoma, especially 
in subjects with high PD-L1 expression.  
 
2.4.3 
Assessment of Potential Risks and Benefits 
 
Given the promising antitumor effects of dual blockades from PD-1/PD-L1 and CTLA4 
and comprehensive risk management measures applied, the current trial is justified and 
the benefit of treatment with KN046 in the targeted trial population is considered 
outweigh the potential risk. This clinical trial will be conducted in compliance with the 
clinical trial protocol, international conference on harmonization (ICH), good clinical 
practice (GCP), and the applicable regulatory requirements.  
2.5 Correlative Studies Background 
 
Correlative studies analyzing blood, archival tumor, and new tumor biopsies (in patients who 
develop irAEs) will help identify biomarkers to prognosticate response, toxicity, and correlate 
outcomes. To validate toxicity markers, we will obtain baseline neutrophil-to-lymphocyte ratio 
(NLR), absolute lymphocyte count (ALC), inflammatory cytokines (IL-6, IL-10, IFN-γ, TNFα, etc), 
and Myasthenia gravis autoantibodies. ALC >2000 (26) and NLR <3 (27) correlate with increased 
risk of irAEs. Inflammatory cytokines help calculate CYTOX score, which predicts early risk of 
severe irAEs in melanoma patients (28). ctDNA will assessed at baseline, best response and 
progression. For archival tumors, GEP, RNAseq and WES results will be correlated with clinical 
outcome and treatment response. We will perform immunohistochemistry for T cells (CD3, CD4, 
CD8, FoxP3), DC (CD11c), macrophages (CD68), and PD-L1 expression. When feasible, fresh 
tissue will be used to establish organoids and patient-derived xenograft models for drug testing. 
TCR sequencing will be performed on tumor, serial blood samples and non-lesional/lesional 
tissue biopsies in patients who develop irAEs. 


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Archival tissue or a new biopsy will be used to perform immunohistochemistry for PD-L1 
staining.  PD-L1 expression and response to treatment will be correlated.  
 
Whenever feasible fresh tissue will be obtained to establish new organoids or cell lines. Cells will 
be characterized with several immunohistochemistry markers and a genetic level. 
 
Tumor tissues (either fresh and paraffin embedded) will be submitted to Next-Generation 
sequencing for a selected number of genes. Correlation between number and type of mutations 
and response to treatment will be studied. Results obtained in new biopsies will be compared to 
those obtained before systemic treatment, since potentially this could increase or change the 
mutational spectrum of the tumor. 
 
In patients where a new biopsy will be available, PD-L1 expression will be performed and 
compared to the archival material, since potentially exposure to systemic treatment might 
change the expression of this immune checkpoint. 
o Correlation between PD-L1 expression in thymic carcinomas and response to KN046 therapy 
o Correlation between the type/number of genetic mutations of thymic carcinomas and PD-L1 
expression as well as response to KN046 
o The impact of genetic heterogeneity of thymic carcinomas on the response to KN046. 
 
3. Study Design 
 
3.1 Overall Design 
 
This is a Phase II, open-label, single-center, single arm study in subjects with advanced thymic 
carcinoma after failure of platinum-based combination chemotherapy. Subjects should have 
documented progressive disease after a platinum-based combination chemotherapy and an 
immune checkpoint inhibitor (PD-1 or PD-L1 antibodies). Subjects will be treated with KN046 at 5 
mg/kg Q2W.  
 
For individual subjects, the study begins with a screening period to assess eligibility up to and 
including 28 days prior to the first dose of KN046.  
 
The treatment period begins on Day 1 of Cycle 1. All subjects will be treated with KN046 at 5 mg/kg 
Q2W intravenously until progressive disease according to RECIST 1.1, unacceptable toxicity, 
completion of 2 years of KN046 treatment, start of a new anti-cancer therapy, death, lost follow-up 
or withdrawal of informed consent, whichever comes first. After completion of 2 years of KN046 
treatment, if investigator considers that subject continuing KN046 treatment will obtain clinical 
benefit, KN046 will be administered on a compassionate basis under the treating physician’s 
responsibility. Treatment of KN046 beyond initial investigator evaluated progression (either clinical 
or imaging progression per RECIST 1.1 criteria) is allowed if the subject has an investigator assessed 
clinically stable status and is tolerating the treatment that meets the “Criteria for Continuation of 
Treatment Beyond Progression”. Rechallenge with KN046 will be allowed if a patient responded and 
stopped the treatment for reasons other than progression while on treatment or toxicity. 


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Tumor evaluation will be performed at baseline, every 8 weeks in the first 12 months and every 12 
weeks thereafter. Tumor evaluation will continue until confirmed progressive disease per RECIST 
1.1, starting new anti-cancer therapy, withdrawal of informed consent, or subject’s death, 
whichever comes first. Once objective response is observed, response should be confirmed by a 
second scan at approximately 8 weeks apart (no earlier than 4 weeks and no later than 8 weeks).  
 
Clinical and laboratory assessments will be performed as described in Section 6.  
 
After the last dose of KN046, subject will be asked to have an end-of-treatment (EOT) visit, a 30-day 
safety follow up visit, a 90-day safety follow up visit and overall survival follow up. EOT visit must be 
performed as soon as possible and within 14 days of last dose of KN046. Subjects who do not have 
progressive disease after EOT visit will continue tumor assessment until progressive disease, start of 
a new anti-cancer therapy, subject withdrawal of informed consent or death, whichever comes first. 
Subjects will be contacted every 12 weeks to obtain information pertaining to survival status until 
death, lost to follow-up, withdrawal of consent to survival follow-up or the end of study. 
 
3.2 Scientific Rationale for Study Design 
 
This is an open-label, single arm, single center non-randomized Phase II study to investigate the 
efficacy and safety of KN046 in patients with advanced thymic carcinoma who have progressed on 
prior immune checkpoint inhibitor therapy.  
 
3.3 Justification for Dose  
 
Target engagement pharmacodynamics (PD) of KN046 were assayed using the interleukin-2 (IL-2) 
stimulation ratio in peripheral blood samples drawn from cancer patients at baseline, pre-dose and 
24, 168 and 336 hours post-dose of Cycle 1 Day 1, pre-dose of Cycle 3 Day 1 and 30-day safety 
follow-up (Trial KN046-CHN-001). No IL-2 release from lymphocytes with activated PD-1 pathway. 
Staphylococcal Enterotoxin B causes release, further enhanced by KN046 effect on PD-1/PD-L1.  
 
Pharmacodynamic response was best described by an Imax inhibition model with an IC50 of 138 ng/mL 
and maximum inhibition of 1 (fixed). IC95 for target engagement is estimated at 2629 ng/mL.  
 
Population PK model was built based on available human PK data. Simulation was performed. 5 mg/kg 
every 2 weeks was needed to reach 85% probability of 95% target engagement. 
 
No apparent relationship between dose and safety parameters in terms of TRAE and irAE has been 
observed between 3 and 5 mg/kg dose levels. MTD has been declared at 5 mg/kg Q2W for 
monotherapy.  
 
An exploratory analysis has been performed to investigate the relationship between PK parameters 
(Cmin1 and Cavg,ss) to tumor shrinkage (ORR and sum of longitudinal diameter (SLD)) based on efficacy 
data from Phase I trials (KN046-AUS-001, KN046-CHN-001). Weak correlation has been observed in 
terms of Cavg,ss (calculated by AUCinf/tau) and SLD. Preliminary analysis indicated that higher exposure 
may be associated with better anti-tumor activity.  


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Figure 3-1 
Simulation of KN046 Q2W and Q3W schedules  
KN046 Q2W schedule 
 
 
 
KN046 Q3W schedule 
 
• Percentage of subjects attaining 95% target engagement 
  
Cycle 1 Dose Cmin 
Cycle 6 Dose Cmin 
Regimen 
 Target   
(2629 ng/mL)  
 Target   
(2629 ng/mL)  
3 mg/kg Q2W 
73.5 
76.0 
5 mg/kg Q2W 
85.1 
86.2 
7.5 mg/kg Q2W 
88.7 
89.0 
5 mg/kg Q3W 
62.3 
63.5 
300 mg Q3W 
58.6 
60.2 
Figure 3-2 
Exploratory exposure-efficacy analysis including subjects with prior immune checkpoint 
inhibitor treatment  
Caverage,ss vs target lesion shrinkage 
 
Cmin1 vs target lesion shrinkage 


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3.4 End of Study Definition 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Assessments 
(SoA), Section 6.1. The end of the study is defined as completion of the last visit or procedure shown 
in the SoA in the trial globally. Subjects continuing to derive benefit from trial treatment at the end 
of the study in the opinion of the investigator will be able to continue receiving trial treatment on a 
separate protocol. The Sponsor may terminate the study early.  
 
3.4.1. Premature Termination of the Trial 
The whole study may be discontinued prematurely in the event of any of the following:  
• 
New information leading to unfavorable risk-benefit judgement of the study drug;  
• 
Sponsor’s decision that continuation of the study is not justifiable for medical or ethical 
reasons;  
• 
Poor enrollment of subjects making completion of the study within an acceptable time 
frame unlikely;  
• 
Discontinuation of development of the Sponsor’s study drug or discontinuation of the 
development of the defined indication.  
0
10000
20000
30000
40000
50000
60000
Cavg,ss (ng/mL)
-110
-60
-10
40
90
Target Lesion Shrinkage (%)
3000
8000
13000
18000
Cmin1 (ng/mL)
-110
-60
-10
40
90
Target Lesion Shrinkage (%)
0
10000
20000
30000
40000
50000
60000
Cavg,ss (ng/mL)
-110
-60
-10
40
90
Target Lesion Shrinkage (%)
3000
8000
13000
18000
Cmin1 (ng/mL)
-110
-60
-10
40
90
Target Lesion Shrinkage (%)


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The study can be terminated at any time for any reasons by Alphamab Oncology. Should premature 
termination of the study or the cohort of certain subtype occur, the subject should be seen as soon 
as possible and the same assessments as required for a prematurely withdrawn subject should be 
performed as described in Section Error! Reference source not found.. The investigator may be 
informed of additional procedures to be followed for the purpose of the protection of the subject’s 
interest.  
 
Health authorities and independent ethnic committee (IECs)/institutional review boards (IRBs) will 
be informed about the discontinuation of the study in accordance with applicable regulations.  
The study may also be terminated or suspended upon request of the health authorities.  
 
4. Subject Selection 
 
4.1 Study Population 
 
 
Subjects with a diagnosis of advanced thymic carcinoma who meet the inclusion and exclusion 
criteria will be eligible for participation in this study.   
 
4.2 Inclusion Criteria 
 
1. Signed informed consent form; 
2. Male or female, 18 years of age or older; willing and able to complete all required 
procedures of study;  
3. Pathologically confirmed diagnosis of thymic carcinoma; a tumor sample is required for 
confirmation of pathological diagnosis and further studies on the tumor tissue (see 
correlative science Section 9) 
4. Inoperable or metastatic disease;  
5. Progressive disease documented in the last 6 months 
6. Has failed platinum-based chemotherapy, with progression either during or after treatment  
7. Had failed at least one regimen of systemic therapy containing immune checkpoint blockade 
therapy targeting PD-1, PD-L1, or CTLA-4 for locally advanced unresectable or metastatic 
disease. Subjects should have documented progressive disease while or after an immune 
checkpoint therapy. If subjects discontinued therapy due to reasons other than progressive 
disease, subjects should have completed at least 2 cycles of immune checkpoint therapy  
8. Baseline measurable disease according to RECIST 1.1. Target lesions situated in a previously 
irradiated area are considered measurable if progression has been demonstrated in such 
lesions; 
9. ECOG performance status of 0 or 1; 
10. Adequate organ function assessed within 7 days prior to first trial treatment:  
o Hematological function  
i. ANC≥1.5 x 109/L;  
ii. Hemoglobin≥9 g/dL; 
iii. Platelets≥100 x 109/L;  


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o Renal function 
i. Calculated creatinine clearance≥60 mL/min (Cockcroft-Gault method);  
o Hepatic function 
i. Total bilirubin≤1.5 x ULN (or 2.5 x ULN for documented Gilberts’ syndrome); 
ii. ALT/AST≤3.0 x ULN (or 5.0 x ULN for documented liver metastasis);  
o INR or aPTT ≤1.5 x ULN;  
11. Have a life expectancy of at least 3 months;  
12. If female of childbearing potential, have a negative serum pregnancy test within 7 days prior 
to first trial treatment;  
13. If female of childbearing potential or a male subject with a partner with childbearing 
potential, be willing to use a highly effective method of contraception (with a failure rate of 
less than 1.0% per year) from first study treatment to 24 weeks after completion of the trial 
treatment. 
 
4.3 Exclusion Criteria  
1. Thymomas, thymolipoma, germ cell tumors, teratomas, seminomas;  
2. Leptomeningeal metastasis or untreated active CNS metastasis or leptomeningeal 
metastasis. Subjects with CNS metastasis may be eligible provided they are treated and 
clinically stable for at least 4 weeks and have no evidence of new or enlarging brain 
metastases and also are off steroids 7 days prior to first trial treatment;  
3. Is currently participating and receiving an investigational drug or has participated in a study 
of an investigational drug within 4 weeks or within 5 times of half-life (no less than 2 weeks), 
whichever is shorter, prior to the first dose of trial treatment; 
4. Major surgery for any reason, except diagnostic biopsy, within 4 weeks of the first 
administration of trial treatment and/or if the subject has not fully recovered from the 
surgery within 4 weeks of the first administration of trial treatment; 
5. Radiation within 4 weeks prior to the first administration of trial treatment; palliative 
radiation will be allowed if more than 2 weeks before start of KN046 treatment 
6. Subjects receiving immunosuppressive agents (such as systemic steroids); topical use of 
steroids and steroid inhalers are allowed. Replacement therapy because of adrenal 
insufficiency is also allowed 
7. Vaccination within 28 days of the first administration of trial treatment, except for 
administration of inactivated vaccines (e.g., inactivated influenza vaccines);   
8. Has interstitial lung disease, or a history of pneumonitis that required oral or intravenous 
glucocorticoids to assist with management; 
9. History or current active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent, including but not limited to: 
o Myasthenia gravis (MG), Good syndromes, ISAACS syndromes, polymyositis, 
myocarditis, neuromuscular syndrome (myotonic dystrophy myositis, Eaton-
Lambert syndrome), blood disorders (red cell aplasia, hypogammaglobulinemia, T-


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cell deficiency syndrome, erythrocytosis, pancytopenia, megakaryocytopenia, T-cell 
lymphocytosis, pernicious anemia), systemic lupus erythematosus, sarcoidosis, 
scleroderma, Crohn’s disease, inflammatory bowel disease, Wegener syndrome 
(granulomatosis with polyangitis, Grave’s disease, rheumatoid arthritis, 
hypophysitis, uveitis), autoimmune hepatitis, systemic sclerosis (for example 
scleroderma), Hashimoto thyroiditis (with the exception as stated below), 
hyperparathyroidism, stiff-person syndrome, Addison disease, panhypopituitarism, 
autoimmune vasculitis, autoimmune neuropathy (Guillain-Barre syndrome) etc. 
NOTE: Subjects with Type I diabetes, vitiligo, psoriasis, hypo- or hyperthyroid 
disease, Sjögren syndrome not requiring immunosuppressive treatment are eligible. 
Subjects requiring hormone replacement with corticosteroids are eligible if the 
steroids are administered only for the purpose of hormonal replacement and at 
doses ≤10 mg or equivalent prednisone per day. Administration of steroids for other 
conditions through a route known to result in a minimal systemic exposure (topical, 
intranasal, intra-ocular, or inhalation) are acceptable; 
10. Previous malignant disease other than the target malignancy to be investigated in this study 
with the exception of adequately treated non-melanomatous cancers of the skin, in situ 
carcinoma of the prostate/cervical/breast cancer, or other malignancy treated at least 5 
years previously with surgery and/or curative radiotherapy, and there is no evidence of 
recurrence since that time; 
11. History of uncontrolled intercurrent illness including but not limited to: 
o Active HBV or HCV infection;  
o If HBsAg and HCV antibody positive, HBV DNA and HCV RNA assay should be 
performed. Subjects may be eligible if HBV DNA ≤ 500 UI/ml (or 2000 copies/ml) or 
HCV RNA negative. 
o Known HIV infection or known history of acquired immune deficiency syndrome 
(AIDS);  
o Active tuberculosis infection; 
o Active infection within 2 weeks prior to the first dose of trial treatment that require 
the use of systemic antibiotics; 
o Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHg); 
o Clinically significant (that is, active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months 
prior to enrolment), unstable angina pectoris, congestive heart failure (New York 
Heart Association Classification Class II-IV) or serious cardiac arrhythmia requiring 
medication (including corrected QT interval prolongation of > 470 msec calculated 
according to Fridericia and/or pacemaker or prior diagnosis of congenital long QT 
syndrome; 
12. Persisting toxicity related to prior therapy (including any prior investigational therapy) of 
CTCAE ≥ grade 2 (NCI-CTCAE v5.0) or related toxicity not recovery to baseline, with the 
exception of alopecia of any grade;  


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13. Prior allo-HSCT or solid organ transplant; 
14. Known severe hypersensitivity reactions to antibody drug (≥ grade 3 NCI-CTCAE v5.0), any 
history of anaphylaxis, uncontrolled asthma (that is, 3 or more features of partially 
controlled asthma), or any history of severe drug hypersensitivity (for example immune 
mediated liver toxicity, immune mediated thrombocytopenia or anemia); 
15. Is pregnant or breastfeeding; 
16. Other medical conditions that at the discretion of investigator interfere with the 
requirements of the trial in terms of safety or efficacy evaluation, or treatment compliance. 
These include but are not limited to psychiatric or substance abuse disorder, moderate to 
large pleural fluid/cardiac effusion/ascites, or recurrent/refractory pleural fluid/cardiac 
effusion/ascites. 
17. Subjects with history or baseline positive antiacetylcholine receptor (AChR) autoantibody 
and anti-MuSK autoantibody 
18. Subjects who developed grade 3 or above immune related AE which could not be managed 
by steroid or immune suppressant will be excluded 
 
4.4 Lifestyle Considerations 
 
Not applicable  
 
4.5 Screen Failures  
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, and 
any serious adverse event (SAE). 
 
Individuals may be rescreened if they meet the eligibility criteria for participation in this trial after 
they had failed screening before. Rescreened participants should be assigned the same participant 
number as for the initial screening. 
 
4.6 Strategies for Recruitment and Retention 
 
 
Subjects will be identified and approached by treating medical oncologists or radiation oncologists in 
the outpatient clinic. The trial may also be discussed with patients who are admitted to the hospital. 
 
The trial will be listed on the Joint Clinical Trials Office (JCTO) public website and will also be 
discussed at local professional meetings such as the NY Lung Cancer Learning Center conferences, in 
order to help generate referrals. 
 


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Subjects will not be compensated for taking part in this trial. 
 
  
 
 
5. Registration Procedures 
 
5.1 Subject Registration  
 
Subjects will be registered within the WRG-CT as per the standard operating procedure for 
Subject Registration.  
 
 
 
 
6. Study Procedures 
 
6.1 Schedule of Assessments 
A complete Schedule of Assessments is provided in Error! Reference source not found.. Prior to 
performing any trial assessments not part of the subject’s routine medical care, the investigator 
will ensure that the subject or the subject’s legal representative has provided written informed 
consent.  
 


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Table 4. Schedule of Assessments  
Assessment 
Screenin
g 
Treatment Period 
End 
of 
Treatme
nt (EOT) 
30-day 
Safety 
Follow-
up 
90-day 
Safety 
Follow-
up 
Survival 
Follow-
up  
Visit 
Screening C1D1 
C1D15 C2D1 
C2D15 C3D1 
C3D15 
C4D1 
C4D15 
CXD1 
and 
D15 
EOT 
30-day 
FU 
90-day 
FU 
Every 
12 
weeks  
Day (d) 
(-28~-1) 1(±3d) 
1(±3d) 1(±3d) 1(±3d) 1(±3d) 
1(±3d) 
1(±3d) 
1(±3d) 
1(±3d) 
(within 7 days 
after 
determination 
of treatment 
discontinuatio
n) 
30 days after 
last dose of 
trial 
treatment 
(±7 d) 
90 days after 
last dose of 
trial 
treatment 
(±14 d) 
Every 12 
weeks after 
last dose of 
trial 
treatment 
(±14 d) 
General procedure   
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography and 
history of alcohol 
and tobacco use 2  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oncology history 4  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
concomitant 
medications and 
procedures 5 
X 
X 
X 
X 
(X) 
(X) 
New anti-cancer 
therapy 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Overall survival  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical 
examination and 
test  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE 6 
X 
X 
X 
X 
X 
X 
Full physical 
examination 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height (in cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight (to the 
nearest 0.1 kilogram 
[kg]) 14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 9, 14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 10 
X 
Clinically indicated 
X 
 
 
 
ECOG performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cardiac 
Ultrasonography 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Local laboratory 
test / evaluation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Immunoglobulin  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Hematology test 
(including 
reticulocyte) 11, 14 
X 8 
(X) 
X 
X 
X 
X 
X 
X 
X 
X  
X 
(X) 15 
(X) 15 
 
Coagulation test 
(aPTT, PT, INR)  
X 8 
Clinically indicated 
 
 
 
 
Serum chemistry 12, 
14 
X 8 
(X) 
X 
X 
X 
X 
X 
X 
X 
X  
X 
(X) 15 
(X) 15 
 
Urinalysis 13 
X 8 
Clinically indicated 
X 
(X) 15 
(X) 15 
 
Serum beta-HCG (if 
applicable) 16 
(X) 8 
 
 
 
 
 
 
 
 
 
(X) 
 
 
 
T3, FT3, FT4 and 
TSH 
X 
(X) 
 
 
 
X 
 
 
 
X23, 24 
 
 
 
 
Troponin 
X 
X 
 
X 
 
X 
 
X 
 
X23 
 
 
 
 
Urine beta-HCG (if 
applicable)16 
 
(every 12 weeks; or as clinically indicated) 
 
 
 
 
FSH (if applicable)22  X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV, HCV, HIV 17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANA, ENA25 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP, IL-6 
X 
As clinically indicated (IRR, suspected cytokine release syndrome 
or serum sickness)  
 
 
 
 
Anti-AChR 
autoantibody 
X 
 
 
 
 
 
Anti-MuSK 
autoantibody  
X 
 
 
 
 
 
Lymphocytic 
analysis (B cell 
count) 
X 
 
 
 
 
 
Correlative studies 
 
 
 
 
 
 
Multiplex 
cytokine/chemokine 
assay for calculation 
of CYTOX score 
 (as defined by 
Section 9.1.1) 
X 
As clinically indicated (IRR, suspected cytokine release syndrome 
or serum sickness) 
 
 
 
 
ctDNA26 
X 
To occur at time of best response and at tumor progression 
 
 
 
 
Tumor tissue18 
X 
On-treatment tissue-targeted biopsy if tissue-specific irAE occurs  
 
 
 
TCR sequencing 
X 
On blood and tissue if tissue-specific irAE occurs 
 
 
 
 
Peripheral blood for 
WES  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor evaluation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CT C/A/P19 
X 
To occur every 2 cycles for the first year, then every 4 cycles for 
the second year 
(X) 
(X) 
(X) 
(X) 
PET/CT19 
X 
To occur at best response, and as clinically indicated 
 
 
 
 
Brain CT/MRI 20 
X 
(clinically indicated) 
 
 
 
 
RECIST 1.1 
X 
Every 8 weeks 
 
 
 
 
Investigational drug   
 
 
 
 
 
 
 
 
 
 
 
 
 
KN046 
administration 21 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) Does not need to be repeated if done within 7 days of C1D1 
1 Informed consent should be obtained before any trial related procedure and treatment;  
2 Demographic data include date of birth, sex, race and ethnicity; 
3 Medical history includes past and concurrent nonmalignant diseases and treatment, past and concurrent 
malignant diseases and treatment;  
4 Oncology history includes detailed history of the target indication of this study including histopathological 
diagnosis, grading and staging in accordance to Masaoka staging; all therapy used for prior treatment of the 
tumor (including surgery, radiotherapy, chemotherapy, and immunotherapy); any other conditions that were 
treated with chemotherapy, radiation therapy, or immunotherapy; current cancer signs and symptoms, and AEs 
effects from current and/or previous anticancer treatments; and current cancer disease status; 
5 All medications (including herbal medications) taken and procedures performed within 28 days prior to first trial 
treatment should be recorded; radiation therapy should be recorded; 
6 All AEs will be collected from time of signature of inform consent through 30 days following the last dose of study 
drug or the date of subject initiates new anticancer therapy, whichever is earlier. All SAE and treatment related 
adverse event will be collected from the time of informed consent through 90 days following the last dose of 
study drug. However, if an investigator learns of any SAE, after 90-day safety follow-up period, and she/he 
considers there is a reasonable possibility that the event is related to the study drug, the investigator should 
report to sponsor. All AEs and SAEs should be proactively followed up for each patient, adverse events should 
be followed to resolution or stabilization at a level acceptable to the investigator. 
7 Full physical examination includes an examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and a basic nervous system evaluation; 
8 Examination or test results should be obtained within 7 days prior to first trial treatment;  
9 Vital signs include temperature, respiration rate, pulse rate and blood pressure;  
10 12-lead ECG will be performed in the supine position after the subject has been breathing quietly for 5 minutes; 
The ECG results will be used to evaluate heart rate, atrial-ventricular conduction, QR and QT intervals, and 
possible arrhythmias. Interpretation of the ECG trace must be made by a qualified physician and documented 
on the ECG eCRF. Each ECG trace should be labeled with the Study Number, Subject Identifier Number, and date, 
and kept in the source documents at the site; 
11 Hematology test includes absolute lymphocyte count, absolute neutrophil count, hematocrit, hemoglobin, 
platelet count, red blood cells, white blood cells and differential count, red blood cell morphology, reticulocytes, 
mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration; 
12 Serum chemistry test includes albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate 
aminotransferase, gamma-glutamyl transferase, blood urea nitrogen/total urea, calcium, chloride, creatine 
kinase, creatinine, glucose, lactate dehydrogenase, lipase, phosphorus/phosphates, magnesium, potassium, 
sodium, troponin, total bilirubin, total protein; 


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13 Urinalysis includes bilirubin, blood, glucose, ketones, pH, protein, specific gravity, and color and appearance. If 
urinalysis is positive for protein, segments and 24-hour urine protein exam should be performed;   
14 Examination or test results should be obtained before each trial treatment; 
15 Only be performed when clinically significant abnormal findings are found at EOT visit; 
16 For women of child bearing potential, a serum pregnant test should be performed within 7 days prior to the first 
dose of trial treatment. Subsequently, urine beta-HCG test will be monitored every 12 weeks or as clinically 
indicated. Female subjects who are not considered to be of childbearing potential (for example, age-related 
natural [spontaneous] amenorrhea ≥ 12 consecutive months and increased FSH > 40 mIU/mL), or who are 
surgically sterile or are sexually inactive, are exempt from pregnancy testing; 
17 HBV, HCV and HIV tests include HBsAg, HCV and anti-HIV1/2. If HBsAg is positive, HBsAb, HBeAb, HBeAg, HBcAb 
and HBV DNA should be measured to exclude active HBV infection as clinically indicated; HCV RNA should be 
tested to exclude active HCV infection If anti-HCV is positive; 
18 A tumor biopsy should be collected at Screening unless tissue (blocks or slides) from an archival specimen (biopsy 
or surgery) is available. 10 slides required. On-treatment biopsies would be obtained at time of irAE 
development if it occurs 
19 Tumor assessment will be performed using PET/CT at baseline, at time of best response, and when clinically 
indicated. CT scans of chest, abdomen and pelvis (Chest CT and MRI of Abdomen and Pelvis also acceptable) are 
also required at baseline, every 2 cycles (8 weeks) for the first year, then every 4 cycles (16 weeks) for the second 
year. Screening tumor assessment should be performed within 28 days of first trial treatment in order to 
document baseline status of tumor disease using RECIST 1.1 target and non-target lesions. During treatment 
period, the tumor assessment visit time window is ±7 days. CT or MRI scan (if MRI is used, CT of chest is 
mandatory) should always be used in the same modality as the screening period. If a tumor response is 
documented during the study, confirmation of the response should be performed according to RECIST 1.1, 
preferably at the regularly scheduled 8-week assessment interval, but no sooner than 4 weeks and no later than 
8 weeks after the initial documentation of CR or PR. Confirmation of PR/CR can be done at an assessment later 
than the next assessment after the initial documentation of PR/CR. If disease progression is documented, 
confirmation of PD is required, preferably at 8-week assessment interval (but no sooner than 4 weeks and no 
later than 8 weeks). Tumor assessment will continue until confirmed disease progression per RECIST 1.1, start 
of new anti-cancer therapy, or withdrawal of informed consent, whichever comes first. If treatment 
discontinuation is due to reasons other than RECIST 1.1 defined progressive disease, tumor assessment should 
continue until RECIST 1.1 defined progressive disease, start of new anti-cancer therapy, or withdrawal of 
informed consent, whichever comes first;  
20 Brain CT/MRI scan (either, with contrast preferred) is required at screening if not performed within the previous 
42 days prior to first trial treatment. During treatment period, brain CT/MRI scan should be done if clinically 
indicated by development of new specific symptoms;  
21 Each KN046 will be administered intravenously over at least 90 minutes (90-120 minutes). After the completion 
of KN046 infusion, subject should be observed at site for at least 2 hours.  
22 If necessary to confirm postmenopausal status 
23 Day 1 of each cycle only 
24 To occur on Day 1 of odd Cycles only 
25 If ANA or ENA positive, rheumatologic workup indicated. 
26 Will only repeat ctDNA if genetic alteration detected at baseline. 
 
6.1.1 
Screening Visit (28 days before start of treatment)   
 
During the Screening period and before any trial-related investigations and assessments are 
started, subjects will be asked to sign the informed consent form (ICF). The Screening 
procedures and Baseline assessments will be completed within 28 days of signing the ICF before 
first trial treatment.  


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The subjects’ information that will be documented during Screening includes the demographic 
information (date of birth, sex, race and ethnicity) and the complete medical history (oncology 
history, previous and ongoing medications, prior surgery, radiation and medication therapies, 
and baseline medical condition etc). The AE reporting period for safety surveillance and a 
concomitant medication recording period begins when the subject first signs an informed 
consent.  
 
During Screening, subjects will undergo a complete physical examination, vital signs, recording 
height and body weight, 12-lead ECG, and a determination of the ECOG performance status.  
 
During Screening, pathology reports will be reviewed to confirm diagnosis.  
 
The Screening laboratory examination includes hematology, coagulation, serum chemistry, anti-
AChR autoantibody, anti-MuSK autoantibody, immunoglobulin, urinalysis, troponin, B cell 
count, neutrophil count, lymphocyte count, Cardiac ultrasonography, total T3, free T3, free T4 
and TSH will also be assessed at Screening for all subjects. Viral tests for HBV, HCV and HIV 
should be performed at Screening. 
 
During Screening, a serum beta-human chorionic gonadotropin pregnancy test will be 
performed for females of childbearing potential. Females who are postmenopausal or who have 
undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If 
necessary to confirm postmenopausal status, FSH will be drawn at Screening.  
 
During Screening, the tumor evaluation will be performed using CT scan or MRI or any other 
established methods. A brain CT/MRI scan is required at Screening if not performed within 42 
days prior to first trial treatment.  
 
Failure to establish subject eligibility due to laboratory parameters is allowed to be re-tested 
following consultation with the Medical Monitor.  
 
 
 
 
 
6.1.2 
Treatment Phase 
The Treatment period begins on Cycle 1 Day 1 with the first administration of KN046 and will 
continue until 2 years have passed or until confirmed disease progression per RECIST 1.1, 
significant clinical deterioration (clinical progression), unacceptable toxicity, or any criterion for 
withdrawal from the investigational medicinal product. A subject may remain on KN046 beyond 
disease progression per RECIST 1.1 if their ECOG performance status remains stable, no new 
symptoms or worsening of existing symptoms and if in the opinion of the investigator the 
subject will benefit from continued treatment. For subjects that continue KN046 treatment 
beyond progression, treatment should be stopped immediately if the subject no longer tolerates 
KN046 or if therapeutic failure occurs.  
 
Subjects will be asked to visit the study site every 2 weeks during the Treatment Period. A time 
window of up to 3 days before or after the scheduled visit day (+/-3 days) will be permitted for 
all study procedures except for body weight, which should be measured on the day prior to, or 
the day of, administration of KN046. In addition, the tumor evaluation has a tumor assessment 


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window of up to 7 days before or after the scheduled visit day (+/- 7 days) throughout the 
Treatment phase. 
 
 
6.1.2.1 Day 1 of each Cycle (unless otherwise noted in the SOA) 
 
• 
Concomitant medications and procedures  
• 
Adverse Event Assessment 
• 
Full physical exam  
• 
Body Weight 
• 
Tumor Imaging (if applicable) 
• 
Vital Signs 
• 
12-lead ECG (if clinically indicated) 
• 
ECOG Performance Status 
• 
CBC, metabolic panel, CPK, troponin 
• 
Coagulation tests (if clinically indicated) 
• 
Urinalysis (as defined in SOA) 
• 
T3, FT3, FT4, TSH (as defined in SOA) 
• 
CRP, IL-6 (as clinically indicated) 
• 
Anti-AChR Autoantibody, Anti-MuSK autoantibody (as clinically indicated) 
• 
For C2D1 and C3D1 only: Cardiac Ultrasonography 
• 
Tumor Imaging (to occur every 8 weeks) 
• 
Brain CT/MRI (as clinically indicated) 
 
 
 
 
6.1.2.2 Day 15 of each Cycle 
 
• 
Concomitant medications and procedures  
• 
Adverse Event Assessment 
• 
Full physical exam  
• 
Body Weight 
• 
Tumor Imaging (if applicable) 
• 
Vital Signs 
• 
ECOG Performance Status 
• 
CBC, metabolic panel, CPK, troponin 
• 
Coagulation tests (if clinically indicated) 
• 
Urinalysis (as defined in SOA) 
• 
T3, FT3, FT4, TSH (as defined in SOA) 
• 
CRP, IL-6 (as clinically indicated) 
• 
Brain CT/MRI (as clinically indicated) 
• 
For C2D15 only: Cardiac Ultrasonography 
 
6.1.3 
End of Treatment 
• 
Concomitant medications and procedures  
• 
Adverse Event Assessment 
• 
Physical exam  
• 
Body Weight 
• 
Vital Signs 


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• 
12-lead ECG  
• 
ECOG Performance Status 
• 
CBC, metabolic panel 
• 
Urinalysis (as defined in SOA) 
• 
T3, FT3, FT4, TSH (as defined in SOA) 
• 
Tumor Imaging 
 
 
 
 
6.1.4  Safety Follow Up Phase  
 
• 
Concomitant medications and procedures  
• 
New anti-cancer therapy Assessment 
• 
Adverse Event assessment  
• 
Full physical exam  
• 
Body Weight 
• 
Vital Signs 
• 
ECOG Performance Status 
• 
CBC, metabolic panel 
• 
Coagulation tests (if clinically indicated) 
• 
Urinalysis (as defined in SOA) 
• 
T3, FT3, FT4, TSH (as defined in SOA) 
• 
Tumor Imaging (to occur every 8 weeks) 
 
6.1.5  Survival Follow Up Phase  
 
• 
Concomitant medications and procedures  
• 
New anti-cancer therapy Assessment 
• 
Adverse Event assessment  
• 
Full physical exam  
• 
Body Weight 
• 
Vital Signs 
• 
ECOG Performance Status 
• 
CBC, metabolic panel 
• 
Coagulation tests (if clinically indicated) 
• 
Urinalysis (as defined in SOA) 
• 
T3, FT3, FT4, TSH (as defined in SOA) 
• 
Tumor Imaging (to occur every 8 weeks) 
 
 
7. Study Intervention 
 
7.1 Study Intervention/Device Description   
 
KN046 is the investigational medicinal product of this study.  
 


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KN046 is a sterile, clear and colorless to light yellow solution intended for IV administration. It is 
presented as a 40 mg/1.6 mL/vial in a single use glass vial closed with a rubber stopper and sealed 
with an aluminum polypropylene flip-off seal. 
 
7.2 Dilution and Dosing 
 
Subjects in this trial will receive IV infusion of KN046 over at least 90 minutes (90~120 minutes) once 
every 2 weeks.  
 
The volume of KN046 solution will be calculated based on the body weight of the subject 
determined the day prior to, or on the day of each drug administration. For a 70 kg subject who is 
enrolled and planned to receive 5 mg/kg treatment, the dose of KN046 is 350 mg, and the volume of 
solution is 350 mg/40 mg x 1.6 mL = 14 mL. The dilution needs to be done aseptically by transferring 
14 mL of 40 mg/ 1.6 mL KN046 from 9 vials into 186 mL of sterile 5% dextrose in water to have a 
final concentration of KN046 for infusion at 1~5 mg/mL. The diluted KN046 solution should be mixed 
gently and thoroughly before application by intravenous infusion, with an adequate normal saline 
flush at the end of the infusion.  
 
Visual inspection of the diluted solution and the vials for particulate matter and discoloration prior 
to infusion will be conducted. The infusion duration should be no less than 90 minutes. KN046 
should be administered under the supervision of physician or other study personnel experienced in 
the use of IV agents. Do not administer study drug as an IV push or bolus injection.  
 
For the detailed process of the dilution and infusion, please refer to the Pharmacy Manual.  
 
Every subject will receive KN046 at protocol scheduled dose and regimen until confirmed disease 
progression per RECIST 1.1 criteria, significant clinical deterioration (clinical progression), 
unacceptable toxicity, start of new anti-cancer therapy, withdrawal of informed consent, or until 
protocol-defined criteria for withdrawal from KN046 or the study are met. Dose modifications of 
KN046 is discussed in Section 7.3.  
 
After initial determination of disease progression per RECIST 1.1, if patient is clinically stable, a 
subsequent assessment should be performed preferably 4~8 weeks (but not later) after initial 
documentation of progressive disease (PD) to determine whether there has been a decrease in the 
tumor size, or continued PD (Confirmed Progression).  
 
The decision to continue treatment beyond progression should be discussed with the Principal 
Investigator and Treating physician and documented in the study records.  
 
7.3 Dose modifications  
KN046 will be withheld for ≥ Grade 3 drug-related toxicity, including laboratory abnormalities with 
the exception of laboratory abnormalities that are not clinically significant or that do not meet the 
criteria of adverse event, and severe or life-threatening AEs (i.e. anemia grade 3, lymphocytopenia 
grade 3-4, hypercholesterolemia grade 3-4, hypertriglyceridemia grade 3-4).  
 
If a dose of KN046 is withheld due to toxicity, subjects may resume dosing with KN046 when toxicity 
has improved to ≤ Grade 1.  


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In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment will 
be discontinued. With the agreement between investigator and Sponsor Medical Monitor, subjects 
with a laboratory adverse event at Grade 2 after 12 weeks may continue treatment only if 
asymptomatic and controlled, for example, hypothyroidism or Type I diabetes controlled by 
replacement treatments.  
 
Subjects who require corticosteroids to manage drug-related adverse events must be at an equivalent 
dose of ≤ 10 mg per day of prednisone to resume dosing with KN046. In case of an inability to reduce 
the corticosteroid dose for managing a drug-related adverse event to the equivalent of ≤ 10 mg 
prednisone per day within 12 weeks of last KN046 dose, patient will go off treatment.  
 
For a subject who experiences a recurrence of the same serious adverse event at the same grade or 
greater after rechallenge of KN046, study medication will be discontinued.  
 
In addition, if any of below drug-related adverse events occur, KN046 treatment will be permanently 
discontinued:  
• 
≥ Grade 3 immune related pneumonitis; 
• 
Recurrence of ≥ Grade 2 immune related pneumonitis lasting ≥ 4 weeks after appropriate medical 
interventions;  
• 
≥ Grade 2 immune related CNS toxicities lasting ≥ 4 weeks after appropriate medical 
interventions;  
• 
≥ Grade 3 immune related colitis;  
• 
≥ Grade 3 uveitis or optic neuritis;  
• 
≥ Grade 3 immune related hepatitis with ALT/AST > 8 x ULN OR TBIL > 3 x ULN;  
• 
≥ Grade 3 immune related nephritis or renal dysfunction.  
• 
≥ Grade 2 myocarditis 
• 
≥ Grade 2 myositis 
Table 7-1 
Guideline on KN046 dose modification 
Toxicity 
Grade 
Withheld 
treatment 
Resume 
treatment 
Dose / schedule 
for 
resuming 
treatment  
Discontinuation of 
treatment  
Hematological 
toxicity  
1, 2 
No 
Not applicable  
Not applicable  
Not applicable  
3 
(except 
for 
isolate event of 
grade 
3 
neutropenia) 
Yes 


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Toxicity 
Grade 
Withheld 
treatment 
Resume 
treatment 
Dose / schedule 
for 
resuming 
treatment  
Discontinuation of 
treatment  
4 
Yes 
Toxicity resolves 
to ≤Grade 1 or 
baseline within 12 
weeks 
of 
last 
KN046 dose 
Resume 
at 
planned dose and 
increase the dose 
interval by 1 week 
at 
each 
occurrence  
Permanent 
discontinuation if 
toxicity does not 
resolve to ≤Grade 
1 
or 
baseline 
within 12 weeks of 
last KN046 infusion 
Non-
hematological 
toxicity with the 
exception 
for 
alopecia of any 
Grade and Grade 2 
fatigue which will 
be 
treated 
as 
Grade 1 adverse 
reaction (with the 
exception of those 
reported in 7.3) 
1 
No 
Not applicable  
Not applicable  
Not applicable  
2 
Yes 
Toxicity resolves 
to ≤Grade 1 or 
baseline within 4 
weeks 
of 
last 
KN046 dose 
Resume 
at 
planned dose and 
dose interval  
Permanent 
discontinuation if 
toxicity does not 
resolve to ≤Grade 
1 
or 
baseline 
within 12 weeks of 
last KN046 infusion 
Toxicity resolves 
to ≤Grade 1 or 
baseline beyond 4 
weeks and within 
12 weeks of last 
KN046 dose 
Resume 
at 
planned dose and 
increase the dose 
interval by 1 week 
at 
each 
occurrence  
3, 4 
Yes 
Toxicity resolves 
to ≤Grade 1 or 
baseline within 12 
weeks 
of 
last 
KN046 dose 
Resume 
at 
planned dose and 
increase the dose 
interval by 1 week 
at 
each 
occurrence  
Permanent 
discontinuation if 
toxicity does not 
resolve to ≤Grade 
1 
or 
baseline 
within 12 weeks of 
last 
KN046 
infusion; 
Permanent 
discontinuation 
should 
also 
be 
considered for any 
life-threatening or 
severe 
adverse 
reactions  
Note: if increased Grade 3 or 4 CPK occurs, myocardial enzymes (CPK, CK, Tn1, TnT) should also be measured. KN046 will be 
permanently discontinued in case of elevation on treatment-related myocardial enzymes  
Infusion related reactions, hypersensitivity reactions, and immune related adverse event should be 
handled according to the guidelines provided in Sections 7.5.1 and Appendix A, respectively.  
7.4. Concurrent medications and therapies  
7.4.1 Permitted medications and procedures  
Any medications considered necessary for subjects’ welfare and will not interfere with KN046 may be 
given at the investigator’s discretion. Other drugs to be used for prophylaxis, treatment of 
anaphylactic reactions, infusion-related reactions, severe hypersensitivity reaction are described in 
Sections 7.5.1. The investigator will record all concomitant medications taken by the subject from 28 
days prior to first trial treatment, during the study till 90 days after last KN046 dose.   


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7.4.2 Prohibited medications and procedures  
The following treatments must not be administered during the study:  
• 
Anticancer treatment other than the investigational drug (for example, cytoreductive therapy, 
radiotherapy, immunotherapies, or cytokine therapy);  
• 
Concurrent systemic therapy with steroids or other immunosuppressive agents with the 
exception of the treatment of irAEs, prophylactic use to prevent allergic reactions to the contrast 
for imaging evaluation, for the prevention of acute infusion-related reactions, or administration 
of steroids for hormone replacement at doses ≤10 mg or equivalent of prednisone per day. 
Steroids with no or minimal systemic effect (topical, intranasal, intra-ocular, or inhalation) are 
allowed;  
• 
Immunosuppressive drugs with the exception for the treatment of irAEs;  
• 
Other investigational drug;  
• 
Major surgery;  
 
If the administration of a nonpermitted concomitant drug becomes necessary during the study, the 
subject will be withdrawn from treatment with KN046.  
7.5. Special precautions  
As a routine precaution, subjects enrolled in this study must be observed for 2 hours after the 
completion of infusion of KN046 in an area with resuscitation equipment and emergency agents. At 
all times during study drug administration, immediate emergency treatment of an infusion-related 
reaction or a severe hypersensitivity reaction according to institutional standards must be assured, 
for instance, dexamethasone 10 mg and epinephrine in a 1:1000 dilution or equivalents should always 
be available along with equipment for assisted ventilation.  
 
Infusion of KN046 will be stopped in case of ≥Grade 3 hypersensitivity or anaphylactic reaction. The 
treatment recommendations for infusion-related reactions, severe hypersensitivity reactions 
according to the NCI are outlined in Sections 7.5.1. All infusion-related reactions occurring during the 
infusion of KN046 or within 2 hours after completion of the administration of KN046 should be 
reported as AE of interest (See Section 13).  
 
Investigators should monitor subjects closely for potential irAE, which may manifest at the earliest 
after the first dose of treatment. Such events may consist of autoimmune hepatitis, diarrhea and 
colitis, arthritis, persistent rash, glomerulonephritis, cardiomyopathy or inflammatory eye conditions 
etc. Details for irAE management please refer to Section Appendix A.  
7.5.1 
Infusion-related reactions and hypersensitivity reactions  
Infusion-related reactions could manifest as fever, chills, rigors, diaphoresis or headache. 
Hypersensitivity reactions could manifest as impaired airway, decreased oxygen saturation (<93%), 
confusion, lethargy, hypotension, pale or clammy skin and cyanosis.  
 
Management of infusion-related reactions and hypersensitivity caused by KN046 is provided in below 


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table.  
 
If a hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf (refer to: Emergency Treatment of Anaphylactic 
Reactions: Guidelines for Healthcare Providers, 2008). Subjects should be instructed to report any 
delayed reactions to the Investigator immediately.  
 
If severe immediate systemic hypersensitivity occurs, the subject should be placed on a monitor 
immediately and receive epinephrine and corticosteroid infusion as appropriate. The intensive care 
unit should be alerted for possible transfer if required.  
 
If the subject is suspected to have systemic hypersensitivity reaction, the investigator is advised to 
collect plasma histamine, C-reactive protein (CRP) and the presence of drug-specific immunoglobulin 
E within 30 minutes of system onset, and urinary methyl histamine within 24 hours of onset of 
symptoms, as well as unplanned ADA and PK samples. For subjects with chest pain, ECG, myocardial 
enzymes (CPK, CK, Tn1, TnT) and BNP are recommended within 30 minutes of the onset of symptoms. 
 
If investigator determines that the benefit of the continued administration outweighs the risk, the 
KN046 treatment is allowed to continue and the prophylactic medical must be administered 30-45 
minutes prior to the administration of all subsequent dosing cycles. Examples of prophylactic dosing 
regimens are: diphenhydramine 25~50 mg IV, cimetidine 300 mg IV and acetaminophen 650 mg po.  
 
If the subject's hypersensitivity reaction includes bronchospasm or dyspnea, montelukast 10 mg PO 
is recommended as part of a prophylactic regimen. Investigators can use medical judgment to 
determine whether steroids need to be added to a preventive regimen. Encourage discussion with 
immunologists to determine treatment options.  
Table 7-2 Guideline on management of infusion-related reactions and systemic hypersensitivity reactions 
NCI-CTCAE Grade  
Treatment Modification for KN046 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease the KN046 infusion rate by 50% and 
monitor closely for any worsening.  
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDs, narcotics, i.v. fluids); 
prophylactic medications indicated for  24 hours. 
Stop KN046 infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any worsening.  
  
Once the KN046 infusion rate has been 
decreased by 50% due to an infusion-related 
reaction, it must remain decreased for all 
subsequent infusions. At next cycle, a 
premedication regimen of diphenhydramine 
25~50 mg IV, cimetidine 300 mg IV and 
acetaminophen 650 mg po is mandatory 30 to 60 


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NCI-CTCAE Grade  
Treatment Modification for KN046 
minutes prior to each dose of KN046). If subject 
developed symptomatic bronchospasm, 
premedication with montelukast (10 mg PO) is 
mandatory as part of premedication regimen 
mentioned above. At the discretion of 
investigator, premedication of corticosteroid can 
also be considered. If a subject has a recurrence 
of ≥grade 2 infusion related reactions despite the 
premedications as well as decreased infusion 
rate, the subject should be withdrawn from 
KN046 treatment.  
It’s also suggested to the investigator discuss 
with the allergist locally.  
Grade 3 or Grade 4 – severe or life-threatening 
Grade 3: Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
clinical sequelae. 
Grade 4: Life-threatening consequences; urgent 
intervention indicated. 
Stop the KN046 infusion immediately and 
disconnect infusion tubing from the subject. 
Subjects have to be withdrawn permanently from 
KN046. 
Note: once the subject develops infusion related reactions, additional appropriate medical therapy may 
include but is not limited to: IV fluids, antihistamines, NSAIDS, acetaminophen and narcotics. Increase 
monitoring of vital signs as medically indicated until the subject is deemed medically stable in the opinion of 
the investigator. If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted 
at 50% of the original infusion rate (e.g. from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until 
symptoms resolve and the subject should be premedicated for the next cycle.  
i.v.=intravenous, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Event, 
NSAIDs=nonsteroidal anti-inflammatory drugs. 
 
 
7.6  Packaging and labeling of the investigational medicinal product  
The Sponsor’s Clinical Trial Supply Chain department will supply the investigational medicinal product, 
KN046.  
 
Packaging and labeling of KN046 will be in accordance with applicable regulatory requirements and 
Good Manufacturing Practice guidelines. KN046 will be packed in boxes containing a suitable number 
of vials. The information on the KN046 will be in accordance with approved submission documents.  
KN046 will be shipped in transport cool container (2°C to 8°C), according to the storage and shipping 
conditions. Shipments will be monitored with temperature control devices. 
 
7.7  Preparation, handling and storage of the investigational medicinal product  
KN046 drug product must be diluted with sterile 5% dextrose in water supplied in an infusion bag. 
Detailed information on preparation of the dilutions and subsequent administration will be provided 
in the Manual of Preparation.  
 
The study drug must be stored at 2°C to 8°C until use, with a temperature log maintained daily. The 


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study drug must be stored carefully and safely from other drugs that can only be accessed by 
investigators and authorized site personnel.  
 
7.8 Investigational medicinal product accountability  
The Investigator is responsible for ensuring accountability for KN046, including reconciliation of drugs 
and maintenance of drug records. 
 
Upon receipt of study drugs, the Investigator (or designee) will check for accurate delivery and 
acknowledge receipt by signing (or initialing) and dating the documentation provided by the Sponsor 
and returning it to the Sponsor. A copy will be retained for the Investigator Site File.  
 
Dispensing of study drugs will be carefully recorded on the appropriate drug accountability forms 
provided by the Sponsor and an accurate accounting will be available for verification by the Clinical 
Research Associate (CRA) (or equivalent) at each monitoring visit.  
 
Study drug accountability records will include:  
• 
Confirmation of study drug delivery to the study site;  
• 
The inventory at the site of study drug provided by the Sponsor and prepared at the site;  
• 
The use of each dose of study drug by each subject;  
• 
Destruction of unused study drug;  
• 
Dates, quantities, batch number, expiry dates and formulation, as well as the subjects’ Study 
Identifier Numbers.  
 
The investigator should maintain records that adequately document:  
• 
That the subjects were provided the doses specified by the Clinical Trial Protocol / 
Amendment(s);  
• 
That all study drug provided by the Sponsor was fully reconciled.  
 
Unused study drug must not be discarded or used for any purpose other than this study. Any study 
drug that has been dispensed to a subject must not be re-dispensed to a different subject. The CRA 
will periodically collect the study drug accountability forms and will check all returns (both unused 
and used containers) before authorizing their destruction by the site.  
 
At the conclusion or termination of this study, site personnel and the CRA will conduct a final product 
supply inventory on the Drug Accountability Forms and all unused containers will be destroyed. 
Instructions for destruction of study drug will be provided to the site. The CRA will be supplied with a 
copy of the Drug Accountability Forms for filing. This documentation must contain a record of clinical 
supplies used, unused and destroyed, and shall include information on:  
• 
All administered units;  
• 
All unused units;  
• 
All destroyed units (during the study);  
• 
All destroyed units at the end of the study;  
• 
Date(s) of destruction(s);  
• 
Name and signature of the Investigator/pharmacist.  
In addition, it must be ensured at each study site that the study drug MUST NOT BE used:  
• 
After the expiry date;  
• 
After the retest date, unless the study drug is reanalyzed and its retest date extended.  


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This is to be closely monitored by the CRA. 
 
7.9 Assessment of investigational medicinal product compliance  
In this study, subjects will receive the KN046 at the study site. Well trained medical staff will monitor 
and perform administration of KN046. Details of each administration of KN046 including the date, 
time, and dose will be recorded on the eCRF. The Investigator will make sure that the information 
entered onto the eCRF regarding administration is accurate for each subject. Any reason for 
noncompliance should be documented. 
 
Noncompliance is defined as a subject missing > 3 cycles or 12 weeks of KN046 for nonmedical 
reasons. Should these situations occur, the subject should be withdrawn from KN046 treatment (See 
Section Error! Reference source not found.).  
 
7.10  Duration of Follow Up 
 
Subjects will be followed for 2 years after removal from study or until death, whichever occurs first.  
Subjects removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  
 
7.11. Measures to Minimize Bias: Randomization and Blinding 
This is an open-label trial. There is no blinding. 
 
8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 
Participants are free to withdraw from participation in the study at any time. 
 
8.1 Criteria for subject withdrawal  
 
A subject must be withdrawn from KN046 in the event of any of the following:  
• Confirmed PD per RECIST 1.1 and the investigator consider that continuing KN046 treatment will 
not benefit (note: subject receiving KN046 may continue past the initial determination of PD if the 
subject meets the criteria of clinically stable);  
• Significant clinical deterioration (clinical progression) is defined as new symptoms that are 
deemed by the investigator to be clinically significant or significant worsening of existing 
symptoms;  
• Therapeutic failure requiring urgent additional anticancer drug;  
• Unacceptable toxicity (if a subject does not occur RECIST 1.1 defined confirmed PD, the subject 
will be asked to continue tumor assessment until RECIST 1.1 defined PD is confirmed);  
• Occurrence of pregnancy;  
• Use of a nonpermitted concomitant drug as defined in Section 7.4.2 where the predefined 
consequence is withdrawal from KN046;  


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• Withdrawal of the subject’s consent to continue KN046 (if a subject withdraws consent, the 
subject will be asked to continue tumor assessments if RECIST 1.1 defined confirmed PD does not 
occur);  
• Noncompliance.  
• Withdrawal of the subject’s consent. If the subject withdraws consent, it must be clearly stated if 
the subject is also withdrawing their consent from the post-treatment follow-up assessments;  
• Participation in any other therapeutic study during the Treatment Phase of this study; however, 
subjects will continue to be followed for new anticancer therapy and for survival;  
• Lost to follow-up.  
 
In case of withdrawal from the study, the assessment schedule for end-of-treatment visit should be 
performed if possible and focus on the most relevant assessments. Subjects will be asked to continue 
safety and long-term follow-up, which includes the collection of data on survival and subsequent 
anticancer therapy.  
The investigator must determine the primary reason for the subject’s withdrawal as completely and 
accurately as possible. The reason for participant discontinuation or withdrawal from the study will 
be recorded in the medical record and RedCap. 
8.2 Lost to Follow Up   
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits and 
is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. If treatment cannot be resumed 
within 12 weeks from last administration, patient will go off treatment. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
9. Correlative/Special Studies 
Correlative studies analyzing blood, archival tumor tissue, and new tumor biopsies will run 
concurrently with the study. We will investigate biomarkers to prognosticate response and immune 
related side effects.  All findings will be correlated with patient outcomes.  
We will assess gene expression and immune cell infiltrates at baseline. In case of severe 
autoimmune disorders after initiation of KN046 treatment, tissue-directed biopsies and blood will 


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be drawn for TCR sequencing and to assess circulating levels of cytokines. The primary hypothesis 
will be that treatment will reduce systemic levels of cytokines associated with a suppressive myeloid 
environment in patients who develop irAEs. To that end, we will quantify pre and on treatment 
levels of the following cytokines: IL-8, IL-6, and IL-1 all of which have been associated with a non-
permissive tumor microenvironment. As a secondary hypothesis, we will test whether levels of pro-
inflammatory cytokines are increased in a compensatory manner – those studies will focus on IFN-γ, 
IL-12 and IL-2.  
 
9.1. Laboratory Correlative Studies 
Correlative laboratory studies will be collected, sent, and stored to the PI’s laboratory, located on 1300 
York Avenue, 6th floor Room A601, New York, NY 10065.  
 
9.1.1 Laboratory Correlative Study  
    We will obtain baseline neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte counts 
(ALC) since ALC >2000 (26) and NLR <3 (27) have been shown to be correlated with an increased risk 
of irAEs. Levels of multiple cytokines and chemokines reflecting inflammatory immune responses (IL-
6, IL-10, IFN-γ, CXCL10/11, TNFα, CCL2, CCL5, etc.) will be measured using human cytokine array 
(HD71; Eve Technologies). A CYTOX score was identified in melanoma patients, which predicts early 
risk of severe irAEs (28). We will use these laboratory results to validate CYTOX as a biomarker for 
toxicity in patients on immune checkpoint blockade. 
Circulating tumor DNA will be sequentially assessed at baseline, at time of best response and at 
tumor progression. Autoantibodies against Acetylcholine Receptor, striated muscle (anti-SM) and 
muscle-specific kinase (MUSK) will be assessed at baseline. Patients with elevated autoantibodies at 
baseline will be excluded. Blood samples for TCR sequencing will be collected at baseline and if irAE 
occurs. 
 
9.1.1.1 Collection of Specimen(s) 
Serial blood samples will be collected for serum and peripheral blood mononuclear cells (PBMC) at 
baseline and during treatment. Timepoints will be at baseline, after 2 cycles, and at occurrence of 
irAE (if any). 
 
9.1.1.2 Handling of Specimen(s) 
 
Whole blood samples will be stored in -80 C within 16 hours to preserve nucleic acid quality. 
Formalin-fixed paraffin-embedded (FFPE) unstained sections will be stored in +4 C and FFPE blocks will 
be stored at room temperature. 
 
9.2. Special Studies 
9.2.1 Special Correlative Studies  
We hypothesize that additional mutations may appear after chemotherapy that could 
potentially lead to PD-L1 upregulation in thymic carcinomas and therefore induce sensitivity to PD-1 
antibody therapy. Thus we plan to explore whether specific genetic mutations and the number of 
mutations are associated with PD-L1 expression in thymic carcinomas and patients’ response to 
KN046 therapy (targeting CTLA-4 and PD-L1). Attempts will be made to obtain tumor material 
before enrolling onto this study. Samples (fresh or FFPE samples) collected post chemotherapy and 
their normal blood pairs as well as 10 fresh or archived FFPE tumor materials derived from the same 
patients before systemic chemotherapy will be sequenced using NEXTGEN technology focusing on 
all the identified recurrent mutations in thymic carcinomas [33; 38], published cancer driver genes 


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[39] and COSMIC cancer gene census (http://cancer.sanger.ac.uk/cosmic/census). Comparative 
sequencing analysis of the tumor/blood pairs allows us to identify specific somatic mutations and 
the number of somatic mutations in a given tumor. Moreover, comparative analysis of tumor 
samples from the same patient before and after systemic treatment can uncover whether the tumor 
may acquire additional mutations after chemotherapy. The data will be employed to evaluate the 
correlation between the type/number of mutations and PD-L1 expression in the tumors and 
patients’ response to PD-1 antibody therapy. 
 
9.2.1.1 Assessment 
For archival tumor specimens, gene expression profiling (GEP) by Nanostring (12), RNAseq and 
Whole Exome Sequencing (WES) will be performed and results will be correlated with clinical 
outcome and response to therapy. We will obtain normal peripheral blood as a control for WES. 
Tumor specimens will also be evaluated for tumor-infiltrating lymphocyte (TIL) infiltration. The main 
immune cell subsets will be quantified by immunohistochemical analysis for markers of T cells (CD3, 
CD4, CD8, FoxP30), DC (CD11c) and macrophages (CD68), and for expression of PD-L1. 
 
9.2.1.2 Method of Assessment 
Whenever feasible, fresh tissue will be obtained to establish organoids(29, 30). If sufficient 
tumor material is available, attempts will also be made to develop patient-derived xenograft (PDX) 
models. Both organoids and PDX tumors will be characterized with several immunohistochemistry 
markers and by sequencing as described above. Organoids will be subjected to in vitro drug testing 
using a robotic platform that is available in our cancer center through the Weill Cornell Medicine 
Englander Institute for Precision Medicine. PDX models will be subjected to in vivo drug testing. TCR 
sequencing will be performed on tumor, sequential blood samples and non-lesional/lesional tissue 
biopsies in patients who develop autoimmune disorders, using the Adaptive platform (12). 
 
9.2.1.3 Timing of Assessment 
 
On-treatment biopsies would be obtained at time of irAE development if it occurs. 
 
10.  Measurement of Effect 
 
10.1 Response Criteria 
RECIST v1.1 will be applied by the site as the primary measure of tumor assessment and response 
and as the basis for protocol guidelines related to disease status (e.g., discontinuation of study 
treatment).  
 
Radiological scans of all suspected sites of disease will be performed utilizing the same method and 
technique throughout the study. Target lesions should demonstrate the patient’s baseline tumor 
burden and will be selected based on size (i.e., lesions with the longest diameter), and suitability for 
accurate repeat assessment.  
 
The following should be performed:  
• 
PET-CT scans are required for all patients at Screening, at the time of best response, and as 
clinically indicated 
• 
Chest, abdomen, and pelvis CT (Chest CT and Abdomen/Pelvis MRI acceptable) are required for 
all patients every 2 cycles for the first year and then every 4 cycles for the second year. 


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Additional imaging evaluations may be performed at any time if there is symptomatic evidence 
suggesting the possibility of disease progression based on clinical symptoms or physical examination.  
 
10.2 Duration of response 
Among subjects with a confirmed response (PR or CR) per RECIST 1.1, duration of response (DOR) is 
defined as the time from first documented response (PR or CR) to the date of first documented 
disease progression or death due to underlying cancer. DOR will be listed by subject and described 
using Kaplan-Meier curves and relevant statistics if appropriate. 
 
10.3 Progression-Free Survival  
PFS is defined as the duration of time from start of treatment to time of progression. 
 
10.4 Other Response Parameters 
 None  
 
 
11. Data Reporting / Regulatory Considerations 
 
11.1 Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, efficacy, and 
adverse event data for all enrolled subjects.  
 
11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software system 
that is fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool for the 
creation of customized, secure data management systems that include Web-based data-
entry forms, reporting tools, and a full array of security features including user and 
group based privileges, authentication using institution LDAP system, with a full audit 
trail of data manipulation and export procedures.  REDCap is maintained on CTSC-
owned servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported through a 
multi-institutional consortium led by the Vanderbilt University CTSA. 
 
11.2 Regulatory Considerations 
 
11.2.1 Institutional Review Board/Ethics Committee Approval  
 
As required by local regulations, the Investigator will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, before study initiation.  
Before initiation of the study at each study center, the protocol, the ICF, other written material 
given to the patients, and any other relevant study documentation will be submitted to the 
appropriate Ethics Committee. Written approval of the study and all relevant study information 
must be obtained before the study center can be initiated or the IP is released to the Investigator. 
Any necessary extensions or renewals of IRB approval must be obtained for changes to the study, 


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such as amendments to the protocol, the ICF, or other study documentation. The written approval 
of the IRB together with the approved ICF must be filed in the study files.  
The Investigator will report promptly to the IRB any new information that may adversely affect 
the safety of the patients or the conduct of the study. The Investigator will submit written 
summaries of the study status to the IRB as required. On completion of the study, the IRB will be 
notified that the study has ended.  
 
All agreed protocol amendments will be clearly recorded on a protocol amendment form and will 
be signed and dated by the original protocol approving signatories. All protocol amendments will 
be submitted to the relevant institutional IRB for approval before implementation, as required by 
local regulations. The only exception will be when the amendment is necessary to eliminate an 
immediate hazard to the trial participants. In this case, the necessary action will be taken first, 
with the relevant protocol amendment following shortly thereafter.  
Once protocol amendments or consent form modifications are implemented at the lead site, Weill 
Cornell Medicine, updated documents will be provided to participating sites, as applicable. Weill 
Cornell Medicine must approve all consent form changes prior to local IRB submission.  
Relevant study documentation will be submitted to the regulatory authorities of the participating 
countries, according to local/national requirements, for review and approval before the beginning 
of the study. On completion of the study, the regulatory authorities will be notified that the study 
has ended.  
 
11.2.2 Ethical Conduct of the Study  
The Investigators and all parties involved should conduct this study in adherence to the ethical 
principles based on the Declaration of Helsinki, GCP, ICH guidelines and the applicable national 
and local laws and regulatory requirements.  
 
This study will be conducted under a protocol reviewed and approved by the applicable ethics 
committees and investigations will be undertaken by scientifically and medically qualified 
persons, where the benefits of the study are in proportion to the risks. 
 
11.2.3 Informed Consent 
 
The investigator or qualified designee must obtain documented consent according to ICH-GCP 
and local regulations, as applicable, from each potential subject or each subject’s legally 
authorized representative prior to participating in the research study. Subjects who agree to 
participate will sign the approved informed consent form and will be provided a copy of the signed 
document.   
 
The initial ICF, any subsequent revised written ICF and any written information provided to the 
subject must approved by IRB prior to use. The ICF will adhere to IRB requirements, applicable 
laws and regulations. 
 
11.2.4 Compliance with Trial Registration and Results Posting Requirements  
 


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Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to http://www.clinicaltrials.gov. Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by calling a 
central contact number for further information on appropriate trial locations and trial site contact 
information. 
 
11.2.5 Record Retention 
 
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced.  After completion of the study, all documents and 
data relating to the study will be kept in an orderly manner by the Investigator in a secure study 
file.  Essential documents should be retained for 2 years after the final marketing approval in an 
ICH region or for at least 2 years since the discontinuation of clinical development of the IP. In 
addition, all subjects medical records and other source documentation will be kept for the 
maximum time permitted by the hospital, institution, or medical practice.   
 
12. Statistical Considerations 
 
12.1 Study Design/Endpoints 
 
This is an open-label, single arm, single center non-randomized Phase II study to investigate the 
efficacy and safety of KN046 in patients with advanced thymic carcinoma who have progressed on 
prior immune checkpoint inhibitor therapy. Subjects will be treated with KN046 5 mg/kg q2wk.   
 
A Simon's two-stage design will be used.  Under the optimum design criterion, a sample size of 29 is 
required to test a null hypothesis of H₀: π ≤ 0.05 versus an alternative hypothesis of H₁: π ≥ 0.2 with 
a one-sided significance level of 0.047 and 80.11% power, where π is the true proportion of 
successes. This design results in an expected sample size of 17.624 and a probability of early 
termination of 0.599. If the number of responses is less than or equal to 0 out of 10 subjects in the 
first stage then the trial will be stopped. If the trial proceeds to the second stage, 29 subjects in total 
will be studied. If 3 or less responses are observed, then KN046 is rejected. 
 
12.2 Sample Size/Accrual Rate 
 
29 subjects are anticipated to be enrolled in this protocol.  
A Simon's two-stage design will be used. Under the optimum design criterion, a sample size of 29 is 
required to test a null hypothesis of H₀: π ≤ 0.05 versus an alternative hypothesis of H₁: π ≥ 0.2 with 
a one-sided significance level of 0.047 and 80.11% power, where π is the true proportion of 
successes. This design results in an expected sample size of 17.624 and a probability of early 
termination of 0.599. If the number of responses is less than or equal to 0 out of 10 subjects in the 
first stage then the trial will be stopped. If the trial proceeds to the second stage, 29 subjects in total 
will be studied. If 3 or less responses are observed, then KN046 is rejected. A total sample size of 29 
subjects are planned. 
 
 


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12.3 Stratification Factors  
None 
 
 12.4 Analysis of Endpoints 
 
12.4.1 Analysis of Primary Endpoints 
 
Primary endpoint: Response rate. Responses will be assessed according to RECIST 1.1.  
 
For ORR analysis, 95% confidence interval (CI) will be calculated using the Clopper Pearson 
method.  
 
12.4.2 Analysis of Secondary Endpoints 
 
Secondary endpoints: duration of response, PFS, OS, safety and tolerability.  
Safety will be assessed by monitoring all adverse events, including serious adverse events, 
immune-related adverse events (irAEs), infusion reactions, regular monitoring of bloodwork 
(including CPK and troponin levels), vital signs, EKGs, and echocardiograms. Kaplan–Meier 
estimator will be used to estimate PFS and OS.  
 
Safety and tolerability analysis will be performed on SS. The safety endpoints will be tabulated 
using descriptive statistics.  
 
The extent of exposure to KN046 will be characterized by duration (weeks), number of 
administrations, cumulative dose (mg/kg), dose intensity (mg/kg/week), relative dose intensity 
(actual dose given/planned dose), number of dose reductions, and number of dose delays.  
 
Safety assessments will be based on review of the incidence of AEs, adverse drug reactions 
(ADRs), and changes in vital signs, ECGs, body weight, and laboratory values (hematology and 
serum chemistry).  
 
For a single proportion, such as PFS rate, and OS rate, 95% CIs will be calculated using the 
Clopper Pearson method. For time to event variable, for example DOR, PFS and OS analysis, the 
Kaplan-Meier method will be used to estimate parameters (including the median with 
corresponding 2-sided 95% CIs). The PFS and OS rates will be estimated with corresponding 95% 
CIs at appropriate time points, e.g., at 6 and 12 months.  
 
12.4.3. Exploratory Endpoints 
(1) Determine the association of PD-L1 expression in tumor samples and treatment response  
(2) Perform RNAseq and whole exome sequencing (WES), and determine the association of the 
molecular profile with treatment response,  
(3) Identify and validate blood and tumor biomarkers that are associated with efficacy-related 
endpoints or toxicity, 
(4) Develop organoids and PDX models whenever feasible, in order to functionally characterize 
the tumor of origin and perform drug testing 
 
12.4.4 Analysis Population 


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Efficacy Analysis Set (EAS): all subjects who are centrally confirmed diagnosis of thymic carcinoma 
and received at least 1 trial treatment. EAS will be used for efficacy analysis.  
Safety set (SS): all subjects who receive at least one dose of trial treatment and have at least one 
valid post-baseline safety assessment. The statement that a patient has no AE (on the Adverse 
Event eCRF) continues a valid safety assessment.  
Per-protocol set (PPS): consist of a subset of subjects who are compliant with requirements of 
the Clinical Trial Protocol (CTP). The PPS will include subjects who have an adequate tumor 
assessment at baseline, a follow-up tumor assessment >6 weeks after starting treatment, and no 
major protocol deviations 
 
12.5 Interim Analysis 
 
Response will be assessed in the first 10 patients and the study will be continued if responses are 
seen, or discontinued if no responses are seen. 
 
 12.6 Reporting and Exclusions 
 
12.6.1 Evaluation of Toxicity 
All subjects will be evaluable for toxicity from the time of their first treatment with KN046.  
 
12.6.2 Evaluation of Response 
All subjects included in the study will be assessed for response to treatment if they have 
received at least one treatment.  The response rate will be estimated as a binomial proportion 
with 95% exact Clopper-Pearson confidence interval using exact binomial calculation 
 
 
13. Adverse Event Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The investigator will 
be required to provide appropriate information concerning any findings that suggest significant hazards, 
contraindications, side effects, or precautions pertinent to the safe use of the drug or device under 
investigation.  Safety will be monitored by evaluation of adverse events reported by subjects or 
observed by investigators or research staff, as well as by other investigations such as clinical laboratory 
tests, x-rays, electrocardiographs, etc. 
 
13.1 Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, and does not imply any judgment about causality. An adverse event can arise with any use of the 
drug (e.g., off-label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose.  
 
13.1.1 Investigational Agent or Device Risks (Expected Adverse Events) 
 
 
Expected adverse events to monitor for include infusion-related adverse events, hypersensitivity 
reactions and immune-related adverse events.  


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13.1.2 Adverse Event Characteristics and Related Attributions 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
• 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
13.1.3 Recording of Adverse Events 
 
All adverse events will be recorded on a subject specific AE log. The AE log will be maintained by 
the research staff and kept in the subject’s research chart.    
 
13.1.4 Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, which can 
be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Poli
cy.pdf.  
 
 
13.1.6 Events of Special Interest  
 
 
 
See section 2.4.1 
 
13.1.7 Reporting of Pregnancy 
 
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 24 
weeks after product administration, the investigator must immediately notify the Sponsor 
Medical Monitor/designee of this event and complete and forward a Pregnancy Reporting Form 
to sponsor within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures. In the event of a pregnancy in a subject occurring during the course of the study, 
the subject must be discontinued from KN046 administration immediately.  
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Reporting Form. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Alphamab. Information on this pregnancy will be collected on the Pregnancy Reporting Form.  


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Any abnormal outcome must be reported in an expedited manner, while normal outcomes must 
be reported within 45 days from delivery 
 
13.2 Definition of SAE 
 
SAEs include death, life threatening adverse experiences, hospitalization or prolongation of 
hospitalization, disability or incapacitation, overdose, congenital anomalies and any other 
serious events that may jeopardize the subject or require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or research subject and may require medical or surgical 
intervention to prevent one of the outcomes listed as serious 
 
13.2.1 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, which can 
be accessed via the following link:   
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Poli
cy.pdf.  
 
13.2.2 Reporting of SAE to FDA  
 
The Principal Investigator must report any suspected adverse reaction or adverse reaction to 
study treatment that is both serious and unexpected. Unexpected fatal or life-threatening 
suspected adverse reactions represent especially important safety information and must be 
reported to FDA as soon as possible but no later than 7 calendar days following the Principal 
Investigator’s initial receipt of the information. 
 
CDER INDs:  
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Biological Products  
5901-B Ammendale Road  
Beltsville, MD 20705-1266  
 
13.2.3 Reporting of SAE to Jiansu 
 
Institution will send Jiansu copies of any and all serious adverse event reports filed with 
the FDA or other applicable regulatory authorities, as well as copies of any 
correspondence with the FDA or other applicable regulatory authorities, regarding any 


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and all serious adverse events, irrespective of association with the Study Drug(s) in the 
course of the Clinical Trial, within 7 business days of such report or correspondence 
being sent to the FDA or other applicable regulatory authorities.  
 
13.3 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the investigator 
confirms that the AE/SAE has stabilized and no more follow-up is required. This requirement 
indicates that follow-up may be required for some events after the subject discontinues 
participation from the study.  
 
14. Data and Safety Monitoring Plan (DSMP)  
 
• The WCM DSMB will monitor all aspects of the safety of this trial.  
• All applicable adverse events will be captured and reported to the DSMB.  Efficacy data in this 
trial are the biological and imaging endpoints will be batched and not processed until the end 
of the trial so they will not be reported in real time to the DSMB.  
• The study will be submitted to the DSMB for review every 4 months. 
 
15. Stopping Rules 
• If severe autoimmune disorders markedly exceed the expected 15%, the study will be 
terminated. If in the first 10 patients accrued in the stage I of the study, 4 or more patients 
develop severe autoimmune disorders, accrual to the study will be stopped and an assessment 
of safety will be performed with the Sponsor. 
• Treatment stopping rules for an individual patient include: 
• 
Disease progression, 
• 
Significant study intervention non-compliance 
• 
Pregnancy 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• 
Participant lost to follow-up after several attempts to contact subject to schedule 
study visit. 
 
 
 
 
 


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15. References 
1. Kelly RJ, Petrini I, Rajan A, Wang Y, Giaccone G. Thymic malignancies: from clinical management to 
targeted therapies. J Clin Oncol. 2011;29(36):4820-7. 
2. Conforti F, Pala L, Giaccone G, De Pas T. Thymic epithelial tumors: From biology to treatment. 
Cancer Treat Rev. 2020;86:102014. 
3. Kelly RJ, Browne SK, Rajan A, Giaccone G. Thymoma-associated paraneoplastic polymyositis. J Clin 
Oncol. 2010;28(22):e378. 
4. Rajan A, Carter CA, Berman A, Cao L, Kelly RJ, Thomas A, et al. Cixutumumab for patients with 
recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial. 
Lancet Oncol. 2014;15(2):191-200. 
5. Rajan A, Kotlyar D, Giaccone G. Acute autoimmune hepatitis, myositis, and myasthenic crisis in a 
patient with thymoma. J Thorac Oncol. 2013;8(10):e87-8. 
6. Thomas A, Rajan A, Berman A, Giaccone G. Multiorgan autoimmune manifestations associated with 
thymoma. J Thorac Oncol. 2015;10(2):e5-7. 
7. Burbelo PD, Browne SK, Sampaio EP, Giaccone G, Zaman R, Kristosturyan E, et al. Anti-cytokine 
autoantibodies are associated with opportunistic infection in patients with thymic neoplasia. Blood. 
2010;116(23):4848-58. 
8. Lemma GL, Lee JW, Aisner SC, Langer CJ, Tester WJ, Johnson DH, et al. Phase II study of carboplatin 
and paclitaxel in advanced thymoma and thymic carcinoma. J Clin Oncol. 2011;29(15):2060-5. 
9. Giaccone G, Rajan A, Berman A, Kelly RJ, Szabo E, Lopez-Chavez A, et al. Phase II study of belinostat 
in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol. 
2011;29(15):2052-9. 
10. Loehrer PJ, Chen M, Kim K, Aisner SC, Einhorn LH, Livingston R, et al. Cisplatin, doxorubicin, and 
cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an 
intergroup trial. J Clin Oncol. 1997;15(9):3093-9. 
11. Giaccone G, Ardizzoni A, Kirkpatrick A, Clerico M, Sahmoud T, van Zandwijk N. Cisplatin and 
etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study 
of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative 
Group. J Clin Oncol. 1996;14(3):814-20. 
12. Giaccone G, Kim C, Thompson J, McGuire C, Kallakury B, Chahine JJ, et al. Pembrolizumab in patients 
with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol. 2018;19(3):347-55. 
13. Thomas A, Rajan A, Berman A, Tomita Y, Brzezniak C, Lee MJ, et al. Sunitinib in patients with 
chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet 
Oncol. 2015;16(2):177-86. 
14. Sato J, Satouchi M, Itoh S, Okuma Y, Niho S, Mizugaki H, et al. Lenvatinib in patients with advanced 
or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial. Lancet Oncol. 
2020;21(6):843-50. 
15. Wang Y, Thomas A, Lau C, Rajan A, Zhu Y, Killian JK, et al. Mutations of epigenetic regulatory genes 
are common in thymic carcinomas. Sci Rep. 2014;4:7336. 
16. Yost KE, Satpathy AT, Wells DK, Qi Y, Wang C, Kageyama R, et al. Clonal replacement of tumor-
specific T cells following PD-1 blockade. Nat Med. 2019;25(8):1251-9. 
17. Yost KE, Chang HY, Satpathy AT. Tracking the immune response with single-cell genomics. Vaccine. 
2020;38(28):4487-90. 
18. Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational 
load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 
2019;51(2):202-6. 


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19. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and 
location of immune cells within human colorectal tumors predict clinical outcome. Science. 
2006;313(5795):1960-4. 
20. Katsuya Y, Fujita Y, Horinouchi H, Ohe Y, Watanabe S, Tsuta K. Immunohistochemical status of PD-L1 
in thymoma and thymic carcinoma. Lung Cancer. 2015;88(2):154-9. 
21. Weissferdt A, Fujimoto J, Kalhor N, Rodriguez J, Bassett R, Wistuba II, et al. Expression of PD-1 and 
PD-L1 in thymic epithelial neoplasms. Mod Pathol. 2017;30(6):826-33. 
22. Cho J, Kim HS, Ku BM, Choi YL, Cristescu R, Han J, et al. Pembrolizumab for Patients With Refractory 
or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. J Clin Oncol. 2019;37(24):2162-
70. 
23. Rajan A, Heery CR, Thomas A, Mammen AL, Perry S, O'Sullivan Coyne G, et al. Efficacy and 
tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced 
thymoma. J Immunother Cancer. 2019;7(1):269. 
24. Katsuya Y, Horinouchi H, Seto T, Umemura S, Hosomi Y, Satouchi M, et al. Single-arm, multicentre, 
phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study. Eur J 
Cancer. 2019;113:78-86. 
25. Guo W, Wang SJ, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design addressingOckham's 
razor: mTPI-2. Contemp Clin Trials. 2017;58:23-33. 
26. Diehl A, Yarchoan M, Hopkins A, Jaffee E, Grossman SA. Relationships between lymphocyte counts 
and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-
1 checkpoint inhibitors. Oncotarget. 2017;8(69):114268-80. 
27. Eun Y, Kim IY, Sun JM, Lee J, Cha HS, Koh EM, et al. Risk factors for immune-related adverse events 
associated with anti-PD-1 pembrolizumab. Sci Rep. 2019;9(1):14039. 
28. Lim SY, Lee JH, Gide TN, Menzies AM, Guminski A, Carlino MS, et al. Circulating Cytokines Predict 
Immune-Related Toxicity in Melanoma Patients Receiving Anti-PD-1-Based Immunotherapy. Clin 
Cancer Res. 2019;25(5):1557-63. 
29. Dijkstra KK, Voabil P, Schumacher TN, Voest EE. Genomics- and Transcriptomics-Based Patient 
Selection for Cancer Treatment With Immune Checkpoint Inhibitors: A Review. JAMA Oncol. 
2016;2(11):1490-5. 
30. Dijkstra KK, Cattaneo CM, Weeber F, Chalabi M, van de Haar J, Fanchi LF, et al. Generation of Tumor-
Reactive T Cells by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids. Cell. 
2018;174(6):1586-98.e12. 
31. Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities 
from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann 
Oncol. 2018;29(Suppl 4):iv264-iv6. 
32. Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P, Bhatia S, et al. NCCN Guidelines 
Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020. J Natl Compr Canc 
Netw. 2020;18(3):230-41. 
 
 
 


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16. Appendix A: Guidelines on the management of immune related adverse events  
Only the general principles of treatment for relatively common immune-related adverse events are listed 
below. Other immune-related toxicities, including rare but severe immune-related toxicity treatments 
(such as immune-related ocular toxicity and central nervous system toxicity) can be found in ESMO (31) 
and NCCN (32). Subjects who have been treated for more than 3 weeks with steroids recommend the use 
of drugs such as sulfamethoxazole/trimethoprim to prevent opportunistic infections such as 
pneumocystis. 
Table 06-1 
Management of immune related pneumonitis 
CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
Grade 1 
Asymptomatic. 
Radiographic 
changes 
only 
presenting 
as 
ground 
glass 
change, 
non-
specific interstitial 
pneumonia  
• 
Consider delay KN046 
treatment  
• 
Monitor symptoms and 
signs every 2~3 days  
• 
Radiologic findings should 
be followed on serial 
imaging studies at least 
every 3 weeks  
• 
Consider 
pulmonary 
consultation. 
Perform 
bronchoscopy if clinically 
indicated  
 
 
 
 
 
All 
attempts 
should be made 
to rule out other 
causes such as 
metastatic 
disease, 
bacterial 
(eg, 
Legionella, 
Mycoplasma) or 
viral infection  
Grade 2 
Mild/moderate 
new symptoms of 
dyspnea, 
cough, 
chest pain  
• 
Withhold KN046  
• 
Treatment 
with 
KN046 
may 
be 
resumed if the event 
improves to ≤Grade 1 
within 12 weeks and 
corticosteroids 
have 
been reduced to the 
equivalent 
of 
methylprednisolone 
10 mg/day orally or 
less   
• 
Discontinue KN046 if 
upon rechallenge the 
patient develops a 
second 
episode 
of 
≥Grade 2 pneumonia  
• 
Discontinue KN046 if 
Grade 2 pneumonia 
lasting for ≥4 weeks 
despite 
appropriate 
medical intervention  
• 
Rule out other causes such 
as infectious diseases  
• 
Consider 
pulmonary 
function tests  
• 
Consider 
pulmonary 
consultation. 
Perform 
bronchoscopy 
and 
biopsy/bronchoalveolar 
lavage (BAL) if clinically 
indicated  
• 
Start empirical antibiotics 
treatment if suspicion of 
infection 
(fever, 
CRP 
increased, 
neutrophil 
counts increased)  
• 
Consider 
hospitalization 
and monitor signs and 
symptoms every day  
• 
If no evidence of infection 
or no improvement in 
signs and symptoms with 
antibiotics after 48 hours, 
add in prednisolone 1 
mg/kg/day (or equivalent) 
orally 
with 
prolonged 


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CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
taper lasting for at least 4 
weeks  
Grade 3-4 
Severe 
new 
symptoms; 
new/worsening 
hypoxia; 
life 
threatening; 
difficulty 
in 
breathing; 
acute 
respiratory distress 
syndrome (ARDS)  
• 
Discontinue KN046  
• 
Perform 
pulmonary 
function tests  
• 
Pulmonary consultation. 
Recommend to perform 
bronchoscopy 
and 
biopsy/bronchoalveolar 
lavage (BAL) 
• 
Treat with intravenous 
(IV) 
methylprednisolone 
2~4 
mg/kg/day 
(or 
equivalent). 
When 
symptoms 
improve 
to 
Grade 1 or less, a high-
dose oral steroid (eg, 
prednisone 
1~2 
mg/kg/day or equivalent) 
taper should be started 
and continued over no less 
than 4 weeks  
• 
If IV steroids followed by 
high-dose oral steroids 
does not reduce initial 
symptoms within 48~72 
hours, 
treat 
with 
infliximab at 5 mg/kg once 
every 
2 
weeks. 
Discontinue 
infliximab 
upon symptom relief and 
initiate 
a 
prolonged 
steroid taper over 6~8 
weeks. 
If 
symptoms 
worsen 
during 
steroid 
reduction, 
initiate 
a 
retapering 
of 
steroid 
starting at a higher dose of 
80 or 100 mg followed by 
a more prolonged taper 
with 
or 
without 
administration 
of 
infliximab. 
Addition 
of 
mycophenolate mofetil to 
replace infliximab could 


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CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
be 
considered 
if 
the 
subject has liver injury   
• 
Add 
prophylactic 
antibiotics for preventing 
opportunistic infections 
 
 
Table 0-2 
Management of immune related colitis 
CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
Grade 1 
< 4 liquid stools per 
day over baseline  
• 
No change in KN046 
dose  
• 
For 
diarrhea, 
treat 
symptomatically 
(loperamide, 
oral 
hydration, 
electrolyte 
substitution, ADA colitis 
diet and avoid high fiber 
high lactose diet) 
• 
Grade 1 diarrhea that 
persist for > 1 week should 
be 
treated 
with 
the 
addition 
of 
oral 
diphenoxylate 
hydrochloride 
and 
atropine sulfate four times 
daily and budesonide 9 mg 
daily  
• 
Grade 1 diarrhea that 
persist for > 2 weeks 
should consider to add 
treatment 
with 
prednisolone 0.5~1 mg/kg 
(non-enteric coated)  
• 
If 
diarrhea 
persists, 
endoscopy 
is 
recommended  
 
 
 
All 
attempts 
should be made 
to rule out other 
causes such as 
metastatic 
disease, bacterial 
or 
parasitic 
infection, 
viral 
gastroenteritis, 
or 
the 
first 
manifestation of 
an inflammatory 
bowel disease by 
examination for 
stool leukocytes, 
stool 
cultures, 
and a Clostridium 
difficile titer  
Grade 2 
4~6 liquid stools 
per 
day 
over 
baseline, 
or 
abdominal pain, or 
blood in stool or 
nausea 
or 
nocturnal episodes  
• 
Withhold KN046 till ≤ 
Grade 1 
• 
Consultation 
with 
gastroenterologist 
and 
endoscopy 
is 
recommended to confirm 
or rule out colitis for Grade 
2 diarrhea that persists > 1 
week 
or 
Grade 
1~2 


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CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
diarrhea 
with 
rectal 
bleeding   
• 
Grade 2 diarrhea should be 
treated with the addition 
of 
oral 
diphenoxylate 
hydrochloride 
and 
atropine sulfate four times 
daily and budesonide 9 mg 
daily   
• 
Grade 2 diarrhea that 
persists > 1 week or Grade 
2 diarrhea with diffuse 
ulceration and bleeding 
seen on endoscopy is 
recommended to add oral 
prednisolone 0.5~1 mg/kg 
(or 
equivalent) 
with 
prolonged taper lasting for 
at 
least 
4 
weeks 
prednisolone. 
Diffuse 
ulceration and bleeding 
seen 
on 
endoscopy 
represents an increased 
risk for the development of 
bowel 
perforation 
and 
indicates longer taper of 
steroid  
Grade 3-4 
≥7 liquid stools per 
day 
or 
life-
threatening  
• 
Withhold KN046 
• 
KN046 will be 
permanently 
discontinued 
if 
≥Grade 3 colitis is 
confirmed  
• 
Discontinue 
KN046 if unable 
to 
reduce 
corticosteroid 
dose to < 10 mg 
per 
day 
prednisone 
or 
equivalent within 
12 
weeks 
of 
toxicity  
• 
Require hospitalization  
• 
Endoscopy 
is 
recommended to confirm 
or rule out colitis  
• 
Grade 3-4 colitis  
• 
Systemic 
corticosteroids should 
be initiated at a dose 
of 1~2 mg/kg/day of 
prednisone 
or 
equivalent. 
When 
symptoms improve to 
Grade 
1 
or 
less, 
corticosteroid 
taper 
should be started and 
continued 
over 
at 
least 4 weeks  
• 
Grade 3-4 diarrhea   


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CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
• 
Rule 
out 
bowel 
perforation. Imaging 
with plain films or 
computed 
tomography (CT) can 
be useful 
• 
Consider consultation 
with 
gastroenterologist 
and 
confirmation 
biopsy 
with 
endoscopy 
• 
Treat 
with 
intravenous 
(IV) 
steroids 
(methylprednisolone 
125 mg) followed by 
high-dose 
oral 
steroids (prednisone 
1~2 mg/kg once per 
day or equivalent). 
When 
symptoms 
improve to Grade 1 or 
less, 
steroid 
taper 
should be started and 
continued over no 
less than 4 weeks. 
Taper over 6~8 weeks 
in 
patients 
with 
diffuse and severe 
ulceration 
and/or 
bleeding   
• 
If IV steroids followed by 
high-dose 
oral 
steroids 
does not reduce initial 
symptoms within 48~72 
hours, consider treatment 
with 
infliximab 
upon 
symptom relief and initiate 
a prolonged steroid taper 
over 
6~8 
weeks. 
If 
symptoms worsen during 
steroid reduction, initiate a 
retapering 
of 
steroids 
starting at a higher dose of 


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CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
80 or 100 mg followed by a 
more prolonged taper with 
or without administration 
of 
infliximab. 
Caution: 
infliximab is contradicted 
in patients with bowel 
perforation or sepsis  
• 
If 
symptoms 
persist 
despite 
the 
above 
treatment, 
a 
surgical 
consult should be obtained  
 
 
 


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Table 16-3 
Management of immune related endocrinopathies 
CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
Grade 1-2 
• 
Hyperthyroidism 
• 
Hypothyroidism 
• 
Thyroid disorder  
• 
Thyroiditis 
• 
No change in KN046 
dose 
• 
Monitor thyroid function 
or other hormone level 
tests 
and 
serum 
chemistries 
more 
frequently 
(every 
3~6 
weeks) until returned to 
baseline 
values 
or 
clinically stable  
• 
Replacement of thyroid 
hormone 
or 
thyroid 
suppression therapy as 
clinically indicated  
 
 
 
 
 
 
All 
attempts 
should be made 
to rule out other 
causes such as 
brain 
metastases, 
sepsis, 
and/or 
severe infection 
Grade 3-4 
• 
Hyperthyroidism 
• 
Hypothyroidism 
• 
Thyroid disorder 
• 
Thyroiditis 
• 
Withhold 
KN046 
treatment until on 
stable 
replacement 
dose as determined 
by 
resolution 
of 
symptoms 
and 
normalization 
of 
hormone levels  
• 
Consider 
endocrine 
consultation 
• 
Replacement of thyroid 
hormone 
or 
thyroid 
suppression therapy as 
clinically indicated  
Grade 1-4 
• 
Adrenal 
insufficiency 
• 
Hypophysitis 
• 
Hypopituitarism 
• 
Pan-
hypopituitarism 
• 
Withhold 
KN046 
treatment until on 
stable 
replacement 
dose as determined 
by 
resolution 
of 
symptoms 
and 
normalization 
of 
hormone levels 
• 
Consider 
endocrine 
consultation 
• 
Thyroid hormone and/or 
steroid 
replacement 
therapy 
to 
manage 
adrenal insufficiency   
• 
If Grade 1~2 hypophysitis 
is considered, pituitary 
gland imaging should be 
considered 
(magnetic 
resonance imaging [MRIs] 
with 
gadolinium 
and 
selective 
cuts 
of 
the 
pituitary 
can 
show 
enlargement 
or 
heterogeneity 
and 
confirm the diagnosis)  
• 
If adrenal crisis occurs 
(Grade 3~4 hypophysitis 
with clinically significant 
adrenal insufficiency and 
hypotension, 
dehydration, 
and 


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electrolyte abnormalities, 
such as hyponatremia and 
hyperkalemia), it requires 
hospitalization 
and 
intravenous 
methylprednisolone 
should be initiated  
 
Table 0 
Management of immune related hepatitis  
CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
Grade 1 
• 
ALT or AST>1-3 
x ULN 
• 
Subjects 
with 
baseline ALT or 
AST increased, 
toxicity Grading 
worsened 
for 
≤1  
• 
No change in KN046 
dose  
• 
Weekly 
monitor 
liver 
function tests  
 
 
 
 
 
All 
attempts 
should be made 
to rule out other 
causes such as 
medications (eg, 
statins, 
antibiotics), 
alcohol history, 
viral 
infections 
(eg, 
anti-
HAV/HBV/HCV 
antibody, 
HEV 
PCR), other liver 
diseases 
(eg, 
anti-ANA / SMA / 
LKM / SLA / LP / 
LCI, iron studies)  
or metastasis / 
clot  
Grade 2 
• 
ALT or AST 3-5 x 
ULN  
• 
Subjects 
with 
baseline ALT or 
AST increased, 
toxicity Grading 
worsened 
for 
≤1 and ≤5 x 
ULN 
• 
Withhold KN046  
• 
Monitor 
liver 
function 
tests every 3 days 
• 
If no improvement in 
liver function tests, 
treat 
with 
oral 
steroids 
(prednisolone 
1 
mg/kg/ day)  
Grade 3-4 
• 
ALT or AST >5 x 
ULN  
• 
With 
or 
without 
total 
bilirubin 
increased > 3x 
ULN 
• 
Discontinue KN046 
• 
Liver biopsy to establish 
etiology of hepatic injury, 
if necessary  
• 
Treat with high-dose IV 
prednisolone 2 mg/kg/day 
or equivalent for 24~48 
hours. When symptoms 
improve to Grade 1 or less, 
a steroid taper with oral 
prednisone 
at 
1~2 
mg/kg/day (or equivalent) 
should be started and 
continue over no less than 
4 weeks  


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• 
If 
serum 
transaminase 
levels do not decrease 48 
hours after initiation of 
systemic 
steroids, 
oral 
mycophenolate 
mofetil 
500 mg every 12 hours 
may be given. Caution: 
infliximab 
is 
not 
recommended due to its 
potential 
for 
hepatotoxicity  
• 
Several courses of steroid 
tapering may be necessary 
as symptoms may worsen 
when the steroid dose is 
decreased 
 
Table 16-5 
Management of immune related skin toxicity  
CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
Grade 1-2 
• 
Skin rash, with 
or 
without 
symptoms, 
<30% 
body 
surface 
area 
(BSA)  
• 
No change in KN046 
dose   
• 
Symptomatic treatment  
• 
Topical corticosteroids, 
eg 
betamethasone 
0.1% 
cream 
or 
hydrocortisone 1%)  
• 
Urea-containing 
creams in combination 
with oral antipruritics 
(eg, diphenhydramine 
HCl or hydroxyzine HCl)  
• 
At investigator’s discretion, 
treatment with oral steroids 
for Grade 2 events  
• 
Treat as Grade 3 skin 
toxicity if Grade 2 skin 
toxicity 
accompanies 
apparent clinical signs and 
symptoms  
 
 
 
 
All 
attempts 
should be made 
to 
rule 
out 
other 
causes 
such 
as 
metastatic 
disease, 
infection 
or 
allergic 
dermatitis  
Grade 3 
• 
Rash 
covers 
>30% 
BSA or Grade 2 
with 
substantial 
symptoms  
• 
Withhold 
KN046 
treatment  
• 
Dermatology consultation. 
Consider biopsy to confirm 
diagnosis   
• 
Recommend oral steroids 
treatment, starting with 
prednisone 1 mg/kg/day or 
equivalent. 
When 


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symptoms 
improve 
to 
Grade 1 or less, steroid 
taper should be started and 
continued over no less than 
4 weeks  
Grade 4 
• 
Skin 
sloughing >30% 
BSA 
with 
associated 
symptoms (eg, 
erythema, 
purpura, 
epidermal 
detachment)  
• 
Discontinue KN046  
• 
Dermatology consultation. 
Consider biopsy and clinical 
dermatology photograph  
• 
Initiate 
steroids 
at 
methylprednisolone 
1~2 
mg/kg/day or equivalent. 
When symptoms improve 
to Grade 1 or less, steroid 
taper should be started and 
continued over no less than 
4 weeks  


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Table 16-6 
Management of immune related nephritis  
CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
Grade 1 
• 
Creatinine 1.5 x 
baseline or > 
ULN~1.5 x ULN 
• 
No change in KN046 
dose 
• 
Withhold 
KN046 
if 
event 
does 
not 
improve 
with 
symptomatic 
treatment 
• 
Symptomatic treatment 
• 
Monitor 
creatinine 
weekly; resume routine 
creatinine monitoring per 
protocol when it returns 
to baseline  
 
 
 
All 
attempts 
should be made 
to rule out other 
causes such as 
obstructive 
uropathy, 
progression 
of 
disease, or injury 
to 
other 
medications 
Grade 2  
• 
Creatinine 
> 
1.5~3 
x 
baseline or > 
1.5~3 x ULN  
• 
Withhold 
KN046 
treatment 
• 
Discontinue 
KN046 
treatment if elevations 
persists > 7 days or 
worsen 
after 
appropriate 
medical 
interventions  
• 
Renal 
consultation. 
Consider 
ultrasound 
and/or 
biopsy 
as 
appropriate 
• 
Treat 
with 
systemic 
corticosteroids at a dose 
of 
prednisolone 
1~2 
mg/kg/day or equivalent. 
When symptoms improve 
to Grade 1 or less, steroid 
taper should be started 
and continued over no 
less than 4 weeks  
• 
If elevations persist > 7 
days or worsen, treat as 
Grade 3 or 4   
Grade 3-4 
• 
Creatinine > 3 x 
baseline or >3 x 
ULN  
• 
Discontinue KN046 
• 
Renal 
consultation. 
Consider 
ultrasound 
and/or 
biopsy 
as 
appropriate  
• 
Monitor creatinine daily   
• 
Treat 
with 
systemic 
corticosteroids at a dose 
of 
prednisolone 
1~2 
mg/kg/day or equivalent. 
When symptoms improve 
to Grade 1 or less, steroid 
taper should be started 
and continued over no 
less than 4 weeks  
 
 


Protocol # 20-08022493 
Version Date  07/20/2022 
 
Page 81 of 81 
 
Table 0 
Management of immune related myocarditis   
CTCAE v5.0 Grade 
KN046 
Dosing 
Management 
Action and Guidelines  
Diagnostic 
Consideration  
Grade 1 
• 
Abnormal 
in 
cardiac 
tests 
(eg, 
myocardial 
enzymes, ECG) 
• 
Discontinue KN046  
• 
Cardiology consultation  
• 
Exam ECG, troponin, BNP, 
cardiac 
ultrasound 
and 
chest X-ray  
• 
Immediately initiate high-
dose steroid treatment  
• 
Prednisolone 
1~2 
mg/kg/day 
or 
equivalent  
• 
Increase steroid dose 
(eg, 
methylprednisolone 1 
g/day) 
and 
add 
in 
infliximab, 
mycophenolate mofetil 
or 
anti-thymocyte 
globulin if symptoms do 
not promptly respond 
to steroids    
• 
Treat 
cardiovascular 
symptoms 
according 
to 
ACC/AHA guidelines  
• 
Subjects with troponin or 
conduction 
abnormalities 
requires to be treated within 
cardiac ICU  
 
 
 
All 
attempts 
should be made 
to 
rule 
out 
myocardial 
infarction, viral 
myocarditis, 
infectious heart 
valve 
disease 
etc   
Grade 2  
• 
Abnormal 
in 
cardiac 
tests 
with 
mild 
symptoms 
Grade 3-4 
• 
Moderate 
to 
severe cardiac 
dysfunction 
requiring 
intravenous 
treatment or 
life-
threatening