A Phase II Clinical Study of Cadonilimab (AK104) Combined With Chemotherapy in the Treatment of PD-1 Inhibitor Resistant Nasopharyngeal Carcinoma
Phase: PHASE2
Conditions: Nasopharyngeal Carcinoma
Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

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Clinical research project of Union
Hospital Affiliated to Tongji Medical
College, Huazhong University of Science
and Technology
Project name
A Phase II clinical study
of Candonilimab
(AK104) combined with chemotherapy in
PD-1 inhibitor-resistant nasopharyngeal
carcinoma
Scheme number
AK104-IIT
Version number
V1.0
Release date
2022.9.18
Principal
investigator
Yang Kunyu
Specialized
department
Department of Head and Neck Oncology,
Wuhan Union Cancer Cente

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Estimated
starting and
ending date
2022.9.22-2025.9.22
Scheme signature page
Project name: A Phase II clinical study of Candonilimab (AK 104)
combined
with
chemotherapy
in
the
treatment
of
PD-1
inhibitor-resistant nasopharyngeal carcinoma
Version number/Version date: V1.0
I have read and understood the research plan, confirmed that the
plan includes the necessary contents for the research implementation,
and made clear the responsibilities of the researcher related to the
research plan.As the principal investigator, I will provide copies of this
protocol
and
all
relevant
information
to
all
researchers
who
participate in this study.I will discuss this information with them to
ensure that they fully understand how the research protocol will be
implemented.I agree and will perform my duties strictly in accordance
with the applicable laws and regulations, Helsinki Declaration, clinical
trial quality management practice and this study protocol.

3
Principal Investigator's Signature (print) :
Principal Investigator's Signature/Date:
Clinical Research Unit:

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catalogue
Scheme signature page............................................................................................ 错误！未定义书签。
scenario summary......................................................................................................................................6
Principal Investigator Data......................................................................................................................12
Flow chart of the study............................................................................................................................12
Acronym table......................................................................................................................................... 13
1. Introduction......................................................................................................................................... 16
1.1 Research Background................................................................................................................16
1.1.1 Basic overview (necessary)............................................................................................ 16
1.1.2 Previous research basis of this study (if any)................................................................. 16
1.2 Study type (necessary)...............................................................................................................17
1.3 Study Basis (necessary).............................................................................................................19
1.4 Risk / benefit assessment (necessary)........................................................................................22
1.4.1 Known potential risks.....................................................................................................22
1.4.2, the probability of injury.................................................................................................22
1.4.3, the extent of the injury...................................................................................................18
1.4.4 Known potential benefits................................................................................................23
1.4.5 Assessment of potential risks / benefits..........................................................................18
1.4.6 Discussion.......................................................................................................................24
2. Study objective / endpoint (flexible withdrawal according to the characteristics of the project)....... 25
3. Study design........................................................................................................................................ 26
3.1 Overall design (necessary)........................................................................................................ 26
3.2 Sample size (necessary).............................................................................................................26
3.3 Blinding and unblinding procedures (if any).............................................................................27
3.4 Definition of Study Start, End, and Completion (if any).......................................................... 21
3.5 Study design discussion (if so, pay special attention to its reasons or basis)............................21
4. Study population (necessary).............................................................................................................. 27
4.1 Diagnostic criteria (if any).........................................................................................................27
4.2 Inclusion criteria (must)............................................................................................................ 27
4.3 Exclusion criteria (must)........................................................................................................... 28
4.4 Group method of subjects (if any).............................................................................................23
234.6 Subject Exit Criteria (if any)................................................................................................. 30
4.7 Recruitment of subjects (if any)................................................................................................ 30
5. Study intervention (if any)...................................................................................................................24
5.1 Description of the study intervention........................................................................................ 24
5.2 Research drugs or medical devices or diagnostic reagents or questionnaires, etc.................... 24
5.3 Study intervention discussion....................................................................................................24
5.4 Study intervention-related matters (if any)................................................................................24
6. Concomitant medication, permitted drugs, careful use of drugs, prohibited drugs, and concomitant
therapy (if any) 2
7. Items and number of proposed clinical and laboratory examinations (if any)....................................24
8. Study steps (if any)..............................................................................................................................24
9. Evaluation............................................................................................................................................31
9.1 Primary and secondary endpoints / outcome evaluation (necessary)........................................31

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9.2 Safety evaluation (necessary)....................................................................................................32
9.3 Other evaluations (if any)..........................................................................................................25
10. Adverse events and serious adverse events (necessary)....................................................................32
11. Statistical analysis and statistical methods (necessary).....................................................................32
12. Medical treatment and protection of the subjects (necessary)...........................................................34
12.1 Assessment of risk in study, and risk management measures and plan (necessary)............... 34
12.2 Medical treatment and protection of subjects during the study (if any)..................................28
12.3 Medical and protection after study procedure (if any)............................................................ 29
13. Supporting documentation and precautions...................................................................................... 38
13.1 Informed consent process (if any)........................................................................................... 43
13.2 Privacy Protection (must)........................................................................................................43
13.3 Collection and use of Specimens and Data (necessary).......................................................... 34
13.4 Quality Control and Quality Assurance (necessary)............................................................... 46
13.5 Data processing and record keeping (necessary).....................................................................46
13.5.1 Data collection and management..................................................................................46
13.5.2, and the study data were retained................................................................................. 46
13.6 Publication and Data Sharing Agreements (if any).................................................................36
13.7 Conflict of interest statement (must)....................................................................................... 48
14. References (must)..............................................................................................................................48

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scenario summary
Research name
A Phase II clinical study of calbenizimumab (AK 104) plus
chemotherapy for PD-1 inhibitor-resistant nasopharyngeal
carcinoma
Research profile
AK 104 is a humanized immunoglobulin G1 (IgG 1)
bispecific antibody (BsAb) with crystalliable fragment (Fc)
mutations to eliminate the Fc-receptor and
complement-mediated cytotoxic effects. AK 104 is able to
bind both programmed cell death receptor-1 (PD-1) and
cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and
block the interaction of PD-1 / programmed cell death
ligand-1 (PD-L1), PD-1 / PD-L2, CTLA-4 / B7.1, and
CTLA-4 / B7.2.
AK 104 is a tetravvalent IgG-ScFv bispecific antibody.
AK 104 contains a point mutation in its constant region that
prevents the binding of the complement protein C1q and the
Fc γ receptor involved in the cytotoxic effect. AK 104 is
expressed in a Chinese hamster ovary cell line with a total
molecular weight including oligosaccharides of about 200
kDa.
purpose of research
fundamental purpose
· To evaluate the safety and efficacy of carbenilizumab
plus chemotherapy (platinum-based) second-line
treatment of PD-1 inhibitor-resistant NPC based on
RECIST v l.1 Objective response rate (ORR) and PFS as
assessed.
Secondary purpose

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·
To evaluate DoR, DCR, TTR, TTP, and OS in PD-1
inhibitor-resistant NPC with capradilimumab plus
chemotherapy (platinum-based).
·
To evaluate the pharmacokinetics of carradilizumab
plus chemotherapy (Pharmacokinet ics, PK).
·
To assess the immunogenicity of caldradilizumab in
combination with chemotherapy.
·
To evaluate the correlation of PD-Ll expression with
efficacy in immunohistochemical detection of tumor
samples.
· To evaluate the association of EB virus (EBY) DNA
copy number in blood and antitumor activity of
caadilimumab in subjects with advanced NPC.
To assess health-related quality of life (HRQoL) in subjects
treated with carradiniilizumab plus chemotherapy
research design
This study is a Phase II clinical study of carradilimumab (AK
104) plus chemotherapy for PD-1 inhibitor-resistant
nasopharyngeal cancer to evaluate the safety and efficacy of
carradilimumab plus chemotherapy as second-line and above
treatment for PD-1 inhibitor-resistant nasopharyngeal cancer.
This study is a single-arm, phase II clinical study with
approximately 30 PD-1 inhibitor-resistant NPC subjects
scheduled to be enrolled. PD-Ll CPS (<50% vs> 50%,
subjects whose PDLl expression was not evaluated were
classified as <50%) were used as the stratification factor. The
study will have a safe lead-in period of approximately 6
PD-1 inhibitor-resistant subjects, and the investigator will
conduct an preliminary safety assessment. If the safety and

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tolerance are good and initial efficacy signals are observed,
the extended enrollment phase will enter. Efficacy analysis
will be performed for approximately 15 subjects. If 6 of the
15 subjects are not tolerated, subject enrollment may be
stopped after the investigator discussion. After poor safety,
the investigator decided to revise or stop the study. For 4-6
cycles, the use of calduilizumab until the investigator
determines that there is no clinical benefit (based on the
comprehensive judgment of RECISTv1.1 imaging
assessment and clinical symptoms), toxicity intolerance,
completion of 24 months of treatment, or satisfaction of other
criteria for treatment termination in the regimen, whichever
occurs first.
•
Subject treatment protocol:
•
Caradilizumab (200 mg, administered on Day 1,
Q3W until no longer clinical benefit) + platinum-based
chemotherapy, Q3W, 4-6 cycles), treatment cycle every 3
weeks (21 days).
Total number of
enrolled patients
30 Cases
Number of research
groups
Number of control
groups
The number of the study group was 30 cases
diagnose
nasopharyngeal darcinoma
Selection criteria
Selection criteria:
Subjects must meet all of the following inclusion criteria to
be enrolled in the study:

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Voluntary signed the written ICF.
1)
Age was over 18 and 75 at the time of enrollment,
acceptable for both men and women.
2)
The Eastern Cooperative Oncology (ECOG) physical
performance score was 0 or 1.
3)
Expected survival is greater than 3 months.
4)
Histologically
or
cytologically
confirmed
nasopharyngeal carcinoma.
5)
The subject had previously failed treatment with PD-1
inhibitor
and
had
no
indication
for
radical
local
treatment.
6)
According to the efficacy evaluation criteria of solid
tumors RECIST v l. And l with at least one measurable
lesion.
Exclusion criteria
Research
intervention
This study is a Phase II clinical study of carradilimumab
(AK 104) plus chemotherapy for PD-1 inhibitor-resistant
nasopharyngeal cancer to evaluate the safety and efficacy of
carradilimumab plus chemotherapy as second-line and above
treatment for PD-1 inhibitor-resistant nasopharyngeal cancer.
AK 104 has been approved for marketing and is not
approved for nasopharyngeal cancer. The reasons for this
study intervention in NPC are as follows: 1. Clinically, more
and more NPC patients develop PD-1 inhibitor resistance.2.
A large amount of research evidence shows that the
combination of PD-1 antibody and CTLA-4 antibody avoids
the dark side of PD-1 antibody to some extent and effectively
reduces the occurrence of PD-1 inhibitor resistance in

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tumors. PD-1 and CTLA-4 complement each other and do
not repeat in regulating immune responses, with mechanisms
preventing T cell depletion and promoting T cell activation,
respectively.
When
the
PD-1
pathway
and
CTLA-4
modulation target the two pathways (Pardoll, 2012), they
have more effective anti-tumor activity than single-agent
therapy.
evaluation criterion:
Main end point:
Secondary end
point:
safety
evaluation:
Main end point
Safety: Incidence and severity of adverse events (AEs),
clinically significant abnormal laboratory findings.
Based on the following data in RECIST v i. The ORR as
assessed by the I.
Based on the following data in RECIST v i. I of the assessed
PFS.
Secondary end point
According to the RECIST vi. The DoR, DCR, TTR, TTP,
and OS as assessed by I.
PK characteristics:
including
serum
concentrations
of
cadadiniilimumab
at
different
time
points
after
cadadinibizumab administration.
Immunogenicity assessment: Number and percentage of
subjects presenting with detectable antimicrobial antibodies
(ADA).
To evaluate the correlation of PD-Ll expression with
efficacy
in
immunohistochemical
detection
of
tumor
samples.
To evaluate the association of EB virus (EBY) DNA copy
number in blood and antitumor activity of caadilimumab in
subjects with advanced NPC.

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Health-related
Quality
of
Life
Assessment
HRQoL-as
measured using the European Organization for Research and
Treatment of Cancer Quality of Life Questionnaire-Core 30
(EORTCQLQ-C30) and EORTCQLQ-H & N35.
statistical method:
sample
capacity:
analytic set:
Primary
Efficacy Endpoint:
Safety end:
A total of 30 subjects are planned to be enrolled as a
single-arm, phase II clinical study. This study used historical
data as a control with no formal statistical hypothesis.
efficiency analysis
The primary study endpoint of this study was according
to the RECIST v l. And l the ORR and PFS assessed.
Analysis of the primary endpoint was performed after the last
subject who met the statistical and imaging assessment
requirements had completed at least 24 weeks of follow-up
(or disease progression). The ORR and OCR analyses will be
performed based on the full analysis set, with their 95%
exact two-sided confidence intervals
estimated by the
Clopper Pearson method. The time to reach the event
endpoint (OOR, PFS, and OS) was analyzed by the
Kaplan-Meier method. The PFS and OS analyses will be
performed based on the randomized analysis set. The
graphical analysis will include a spider map of the percent
change in target lesion tumor load from baseline over time,
and a waterfall plot of the best percentage of change in target
lesion tumor load from baseline.
safety
The safety analysis will be based on the safety analysis set,
which includes all enrolled subjects who have received any
study drug. Summary statistics for AEs will be summarized
for all adverse events, adverse events related to study drug,

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serious adverse events (SAEs) and for AEs and AESIs
leading to discontinuation. Will be based to the National
Cancer Institute Common Terminology Criteria for Adverse
Events (National Cancer Inst i tute Common Tem1inology
Criteria for Advers e Events, NCI CTCAE) Version 5.0
grades the AEs, And adopt the International Medical
Dictionary for Regulatory Activities (Medical Dictionary for
Regulatory Activities, Med DRA) For encoding. Laboratory
abnormal findings and toxicity levels will be summarized per
version NC I CTCAE 5.0. In the cross table of clinical
laboratory examinations, the change in baseline CTCAE
grade and highest-severity grade after baseline will be shown
and grade CTCAE 3 or 4 clinical laboratory abnormalities
will be listed.
Study duration
Three years
Participation time of
the subjects
Three years
Study unit / site
Department of Head and Neck Oncology, Cancer Center,
Union
Hospital,
Huazhong
University
of
Science
and
Technology
Principal Investigator Data
Name, qualification, and contact information of the principal investigator

Qualifications include physician practicing license, or pharmacist qualification
certificate, nurse practitioner practicing license and other professional technical
certificates, professional title certificate, GCP certificate, and other clinical trial
related training certificates
Flow chart of the study

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Acronym table
abbreviation
The full text of Chinese
AASLD
, The American Society for the Study of Liver
Diseases
ADA
Anti-drug antibodies
AE
adverse event
AESI
Adverse events, and of special interest
ALP
alkaline phosphatase
ALT
glutamic-pyruvic transaminase
ANC
Absolute neutrophil count
AST
glutamic-oxalacetic transaminase
AUC
Area under the concentration-time curve
BCLC
The Barcelona liver cancer clinical staging system
CI
confidence interval
CL
clearance
CNS
C. N. S
CR
complete remission
CRA
Clinical study monitor
CRO
contract research organization
CrCl
CC
CT
computerized tomographic scanning
DCR
Disease control rate
DLT
dose-limiting toxicity

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dMMR
Mismatch repair-defective type
DoR
Relieve duration
ECG
electrocardiogram
ECOG
The Eastern US Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data acquisition
EFS
Event-free survival
Fc
FC
FDA
The US Food and Drug Administration
FFPE
Formalin was fixed fixed and embedded in paraffin
wax
GCP
Practice management of drug clinical trials
GLP
Good Laboratory Practice for Drug Non-clinical
Studies
HBV
HBV
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICF
informed consent
ICH
International
Conference
on
coordination
requirements for human medicines
IEC
Independent ethics committee
Ig
immunoglobulin
IgG1
Immunoglobulin G1
IHC
immunohistochemistry
irAE
Immune-related adverse events
IRB
The Institutional Review Board
IV
I.V
IVIG
Intravenous immunoglobulin was administered
LFT
liver function test

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LLN
lower limits of normal
mAb
monoclonal antibody
MedDRA
The International Medical Dictionary for Regulatory
Activities
MRI
nuclear magnetic resonance
MSI-H
Height microsatellite instability type
NCI CTCAE
US National Cancer Institute Common Terminology
Criteria for Adverse Events
NHC
The
National
Health
and
Family
Planning
Commission of the People's Republic of China
NMPA
The National Medical Products Administration
NSAID
non-steroid anti-inflammatory drug
NSCLC
nonsmall-cell lung cancer
ORR
Objective mitigation rate
OS
Overall survival
PD
PD
PD-1
Programmed cell death-1
PD-L1
Promed cell death ligand-1
PD-L2
Promed cell death ligand-2
PFS
Progression-free survival
PK
pharmacokinetics
PR
partial remission
Q2W
Once every 2 weeks
QTcB
QT interval corrected by heart rate using the Bazett
formula
QTcF
QT interval
corrected by heart
rate using
the
Fridericia formula
RECIST
Criteria for efficacy evaluation in solid tumors
RO
Receptor share
SAE
Serious adverse events
SAP
Statistical analysis plan
SD
stable disease

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1. foreword
1.1 research background
1.1.1
General overview (must)
AK 104 is a humanized immunoglobulin G1 (IgG 1) bispecific antibody (BsAb)
with crystalliable fragment (Fc) mutations to eliminate the Fc-receptor and
complement-mediated cytotoxic effects. AK 104 is able to bind both programmed cell
death receptor-1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)
and block the interaction of PD-1 / programmed cell death ligand-1 (PD-L1), PD-1 /
PD-L2, CTLA-4 / B7.1, and CTLA-4 / B7.2.
AK 104 is a tetravvalent IgG-ScFv bispecific antibody. AK 104 contains a
point mutation in its constant region that prevents the binding of the complement
protein C1q and the Fc γ receptor involved in the cytotoxic effect. AK 104 is
expressed in a Chinese hamster ovary cell line with a total molecular weight including
oligosaccharides of about 200 kDa.
Therefore, this study aimed to evaluate the efficacy and safety of
cadradinilizumab combination chemotherapy in patients with PD-1 inhibitor-resistant
NPC and to determine its PK and immunogenicity characteristics to provide evidence
for subsequent studies.
SID
Subjects number
t1/2
half-life period
TTR
To ease the time
TBil
total bilirubin
TIL
TIL
TSH
TSH
ULN
Upper limit of normal value
WHO-DD
The World Health Organization Dictionary of Drugs

17
1.1.2
The existing preliminary research basis of this study (if any)
AK 104 in Australia enrolled subjects with advanced solid tumors that failed
standard therapy, and dose escalation decisions followed a "3 + 3 + 3" design. Phase
AK104 Ia / Ib clinical study was AK 104 first used in human study. As of 30 April
2020, the phase AK104 Ia study has enrolled 92 subjects with advanced solid tumors
after the standard treatment failure, Including NSCvarious tumor types LC, gastric
cancer, pancreatic cancer, mesothelioma, triple-negative breast cancer,
neuroendocrine cancer, endometrial cancer and so on, The lowest dose of AK 104
treatment was 0.2 mg / kg Q2W, The ascending doses of 0.5mg / kg Q2W, 1mg / kg
Q2W, 2mg / kg Q2W, 4mg / kg Q2W, 6mg / kg Q2W, 10mg / kg Q2W, A fixed dose
of 450mg Q2W and 15mg / kg Q3W. Of these, 18 subjects were enrolled at 10mg / kg
Q2W and 3 subjects at 15mg / kg Q3W.
In terms of safety, as of 30 April 2020, at all dose levels, only one dose of
1.0mg / kg dose subject experienced a dose-limiting toxicity (DLT) event: Grade 3
AST increase. Among them, 18 subjects were treated with 10mg / kg Q2W, the
incidence of grade 3 / 4 TRAE was 22.2%, respectively fever, hyperthyroidism,
polyneuropathy, nephritis, all occurred in 1 subject; currently AK 104 in China is
undergoing 10mg / kg Q2W dose climbing, no DLT events. Three subjects were on
15mg / kg Q3W and did not develop grade 3 TRAEs; TRAEs included anemia (grade
2), facial rash (grade 1), and thyroid dysfunction (grade 1). In terms of efficacy, as of
30 April 2020, the ORR and DCR reached 56.9% in 51 subjects.
Including two phase Ib / II clinical studies, both were multicenter, open-label,
phase Ib / II clinical studies conducted in China. One was to evaluate the safety,
tolerability, PK profile, immunogenicity, pharmacodynamics, and antitumor activity
of AK 104 alone in advanced solid tumors and AK 104 in combination with
oxaliplatin and capecitabine (mXELOX) in the first-line treatment of locally advanced
or metastatic gastric adenocarcinoma or gastric esophageal adenocarcinoma. The
study consisted of 3 phases, namely, dose escalation and extension Phase (Phase I)
and dose confirmation Phase (Phase II). To evaluate the safety and efficacy of AK
104 monotherapy (6mg / kg, 10mg / kg, 450mg Q2W) for advanced solid tumors and

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AK 104 (4mg / kg, 6mg / kg and 10mg / kg Q2W) combined with mXELOX in
first-line treatment for advanced gastric cancer or gastric esophageal adenocarcinoma.
As of 30 April 2020,107 solid tumors were received AK 104 monotherapy (6mg / kg
and 450mg Q2W), of whom 15 of them were advanced NSCLC who failed systemic
therapy. For safety, see the AK 104 safety summary below. In terms of efficacy, as of
April 30,2020, the ORR and 63.6% in 44 subjects with standard treatment failure. In
the cohort of AK 104 combined with mXELOX for advanced gastric cancer or
gastroesophageal adenocarcinoma, of 19 evaluable subjects, 2 CR, 11 PR, 5 SD, ORR
reached 68.4% and 9 DCR reached 94.7%.
Another phase Ib / II clinical study of AK 104 in China was to evaluate the
efficacy of efficacy, safety, PK characteristics, immunogenicity, and relevant
biomarkers of AK 104 in selected patients with advanced or metastatic solid tumors.
Subjects will be classified into the following cohort: Cohort A: locally advanced or
metastatic non-small-cell lung cancer with failed systemic therapy and without
immunotherapy; Cohort B: locally advanced or metastatic non-small-cell lung cancer
with failed systemic therapy and refractory to PD-1 / PD-L1 antibodies; Cohort C:
Locally advanced or metastatic non-small-cell lung cancer that relapsed after failed
systemic therapy and anti-PD-1 / PD-L1 antibodies; Cohort D: local progression or
metastatic melanoma after failure of standard therapy. All the subjects received
AK104 6 mg / kg Q2W. As of 30 April 2020, cohort A has enrolled 19 subjects with
locally advanced or metastatic NSCLC with systemic treatment failure and without
immunotherapy. Safety is described below. In terms of efficacy, considering the
above two studies in China, 34 (15 + 19) Chinese subjects with systematically failed
advanced NSCLC received 6mg / kg Q2W or 450mg Q2W, with an ORR of 16.0% (4
/ 25) of 25 evaluable subjects.
Combined with the above three clinical trials in Australia and China, as of 30
April 2020 in all subjects receiving AK 104 alone (N=228), TEAE was 88.6%, TRAE
was 64.5%, Grade 3 TRAE was 12.7%, the incidence of drug-related SAEs was 11%,
causing study withdrawal of TRAE of 6.6%, and TRAE was 0. TRAEs at 5% of all
subjects and Grade 3 TRAEs in 2 subjects are summarized below:

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The results preliminarily showed that AK 104 had a good safety profile and
tolerability, as well as antitumor activity
1.2
Type of study (necessary)
This study is an interventional study, and all the drugs used in the study are
already marketed. The target population is the second-line resistant NPC population,
and there is no standard treatment plan in the diagnosis and treatment guidelines and
principles. By exploring effective treatment options in such a patient population.
There is clear preliminary study information on the efficacy and safety of any of the
individual drugs used in this study protocol. This study is a single-arm exploratory
study.
1.3
Study rationale (must)
NPC is dominated by poorly differentiated and undifferentiated carcinoma, with
more than half of the patients with advanced disease at initial diagnosis, and about
10% of patients with distant metastasis. According to global cancer statistics in 2012,
the age-standardized incidence (ASR) was 6.4 per 100000 and 2.4 per 100000,
respectively. In China, there are 60,000 new cases of nasopharyngeal cancer and
34,000 deaths each year. Therefore, nasopharyngeal cancer is a serious disease that
endangers human health.

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The traditional treatment of NPC includes surgical treatment, radiotherapy and
chemotherapy. Radiation therapy has always been the main treatment method because
of its deep anatomical site, complex anatomical structure that limit the surgical
approach,
and
its
sensitive
to
radiation.
Studies
have
shown
that
with
intensity-modulated conformate radiotherapy (IMRT) combined with chemotherapy,
the 5-year local recurrence-free rate is estimated to be 90%, but the 5-year overall
survival rate is only about 80%, and distant metastasis has become the main cause of
treatment failure.
The treatment of advanced or recurrent nasopharyngeal carcinoma is mainly
platinum-containing systemic chemotherapy, and the standard treatment regimen for
locally advanced nasopharyngeal carcinoma is cisplatin concurrent chemoradiation.
Synchronous chemoradiotherapy is important in improving the treatment results of
local advanced NPC, but concurrent chemoradiotherapy often leads to complications
such as xerostomia, trismus, and secondary tumors, which seriously reduces the
quality of life of patients. Therefore, the study of novel therapies that can both
improve patient disease-free survival and reduce treatment-related complications is of
great clinical value. And the emerging immunotherapy provides more treatment
options for NPC patients.
According to the report, NPC is closely associated with EB virus infection, and
the tumor has high expression of PDL 1, suggesting that PDI blockade is an ideal
treatment option for NPC. PD-1 is a negative immunomodulator molecule that
mediates tumor immunosuppression in the local tumor microenvironment. The
KEYNOTE-028 phase Ib study (NCT 02054806) evaluated the clinical efficacy of the
immune checkpoint blockade agent pembrolizumab in the treatment of recurrent /
metastatic NPC. Twenty-seven patients with recurrent / metastatic NPC with positive
PD-L1 expression receiving 10mg / kg pembrolizumab once every 2 weeks achieved
an ORR of 25.9% by investigator assessment, a median response duration of 17.1
months, and one additional unconfirmed partial response. Five of the confirmed
partial responses (26.3%) in 19 subjects assessed by the Independent Imaging
Evaluation Committee (IRRC). Pembrolizum ab The median overall survival for the

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treatment of recurrent / metastatic NPC was 16.5 months, and the overall 1-year
survival rate was 63%. In some other cytotoxic and noncytotoxic drug studies, overall
1-year survival is reported at around 45%.
Another phase II study
(NCT02339558) evaluated the clinical efficacy of the
immune checkpoint blocker nivolumab in the treatment of recurrent / metastatic
NPC.44 patients with recurrent / metastatic NPC treated with 3mg / kg nivolum ab
every 2 weeks achieved ORR of 20.5% by investigator assessment, median remission
continuation of 9.3 months, median overall survival of 17.1 months and overall 1-year
survival rate of 59%. ORR reached 33% in 18 PD-L1 positive patients; in 23 PDL 1
negative cases. This shows that the application of PD-1 inhibitors in NPC patients has
a solid theoretical basis and sufficient practical basis as a support. However, with the
gradual and widespread application of PD-1 inhibitors in clinical practice, PD-1
inhibitor resistance has also become another therapeutic challenge.
Resistance to tumor PD-1 inhibitors became the biggest obstacle to the clinical
application of anti-PD-1 / anti-PD-L1. So far, because of the clinical unpredictability
of anti-PD-1 / anti-PD-L1 and the non-reproducible resistance in the laboratory. In the
context of widespread clinical and extensive use of anti-PD-1 / anti-PD-L1 worldwide,
tens of thousands of tumor patients develop PD-1 inhibitor resistance. Therefore,
improving the mechanism of drug resistance of PD-1 inhibitors inducing tumor drug
resistance is imminent and crucial. The solution of this problem greatly helps to
clarify how to develop new treatments or use combination therapies to eliminate PD-1
inhibitor resistance.
Little research has been done on the biological mechanisms of resistance to
tumor PD-1 inhibitors. Most previous studies have shown that the high expression of
PD-L1 on the surface of DCs can inhibit the T cell immune response through the
PD-1 / PD-L1 pathway.
CD28 and CTLA-4, PD-1 are receptors expressed by T cells. During T cell
activation, CD28 plays the "refueling" role, CTLA-4 plays the "front brake" role, and
PD-1 plays the "rear brake" role. Upon recognition of the antigen peptide / major
histocompatibility complex (MHC) by the T cell receptor (TCR), the binding of CD80

22
or CD86 to CD28 generates a costimulatory signal that promotes T cell activation.
After T-cell activation, the co-inhibitory receptor CTLA-4 was upregulated, along
with the expression of other inhibitory receptors on the T-cell surface, including PD-1.
CTLA-4 binds more strongly to CD80 than CD28, thus resulting in CD80 endocytosis
and downregulation of both antigen presentation capacity and T cell activity. Thus
triggering PD-1 inhibitor resistance. Meanwhile, the researchers found that the
combination of PD-1 / PD-L1 antibody and anti-CTLA-4 antibody (Ipilimumab and
Opdivo-IO regimen) had significantly enhanced tumor-infiltrating T cell function on
day 25 than mice treated with anti-CTLA-4 alone or PD-L1 antibody alone or control.
The combination of PD-1 antibody and CTLA-4 antibody can be considered to avoid
the dark side of PD-1 antibody to some extent, effectively reducing the occurrence of
tumor resistance to PD-1 inhibitors. PD-1 and CTLA-4 complement each other and do
not repeat in regulating immune responses, based on their mechanisms preventing T
cell depletion and promoting T cell activation, respectively. When the PD-1 pathway
initially occurs at the tumor locus, CTLA-4 modulation of T cells suppresses
activation and spread that occurs at the site of antigen presentation in the lymphoid
region, yet this distribution of CTLA-4 and PD-1 is far from unique. Target the two
pathways may require additional activity or synergistic activity (Pardoll, 2012), and
combination therapy are more effective than monotherapy.
Therefore,
this
study
aimed
to
evaluate
the
efficacy
and
safety
of
cadradinilizumab combination chemotherapy in patients with PD-1 inhibitor-resistant
NPC and to determine its PK and immunogenicity characteristics to provide evidence
for subsequent studies.
1.4 Risk / benefit assessment (must)
1.4.1
Known potential risks
The irAE is defined as an AE associated with drug exposure, consistent with an
immune-mediated mechanism of action, and without a clear alternative etiology.
Based on the mechanism of action of AK 104 targeting PD-1 and CTLA-4 leading to
T cell activation and proliferation, it is possible that irAE could be observed during
the conduct of this study. The underlying irAE may be similar to the adverse events

23
seen with anti-PD-1 / L1 drugs, including immune-mediated colitis, dermatitis,
pneumonia, hepatitis, encephalitis, nephritis, and endocrine disorders.
Based on the severity of toxicity occurring in treatment according to NCI
CTCAE 5.0 grade, AK 104 treatment adjustments will be performed to manage
potential irAEs.
·
The maximum interval allowing an AK 104 pause is 12 weeks. If
not returning to AK 104 within 12 weeks, the subject permanently
discontinued AK 104 and, if applicable, considered systemic corticosteroids
(such as prednisone or intravenous equivalent) for persistent low grade or
severe (grade 3) events.
·
If symptoms recur or worsen during the glucocorticoid reduction, the dose
was increased until the symptoms stabilized or improved, and then gradually
rereduced at a slower rate.
·
For events that do not respond to systemic corticosteroids, more potent
immunosuppressive agents (e. g. infliximab, maccohenyl esters, etc.) should
be considered after discussion with the medical monitor.
·
For
multiple
low-grade
AEs
(no
treatment
termination
is
required
separately), AK 104 will be terminated at the discretion.
·
After discontinuation of study drug for Grade 3 or 4 events, if the subject
responded well and the toxicity resolved rapidly, AK 104 could be resumed
after discussion with the medical monitor.
· For abnormal laboratory findings, suspension or permanent termination
should be determined based on concomitant clinical symptoms / signs and the
clinical judgment of the investigator.
1.4.2
Known potential benefits
As a population resistant to PD-1 inhibitors, only chemotherapy is used clinically, and
the effective rate is less than 20%. If combined with A K104 and chemotherapy,
patients are highly likely to obtain the most effective treatment from this combination
treatment.

24
1.4.3 discuss
Two phase Ib / II clinical studies. One was to evaluate the safety, tolerability,
PK profile, immunogenicity, pharmacodynamics, and antitumor activity of AK 104
alone in advanced solid tumors and AK 104 in combination with oxaliplatin and
capecitabine (mXELOX) in the first-line treatment of locally advanced or metastatic
gastric adenocarcinoma or gastric esophageal adenocarcinoma. In terms of efficacy,
as of April 30,2020, the ORR and 63.6% in 44 subjects with standard treatment
failure. In the cohort of AK 104 combined with mXELOX for advanced gastric cancer
or gastroesophageal adenocarcinoma, of 19 evaluable subjects, 2 CR, 11 PR, 5 SD,
ORR reached 68.4% and 9 DCR reached 94.7%.
Tumor PD-1 inhibitor resistance is increasingly emerging in a large number of
NPC patients. Regarding the biological mechanism of resistance to tumor PD-1
inhibitors associated with the upregulation of CTLA-4 expression. CTLA-4 binds
more strongly to CD80 than CD28, thus resulting in CD80 endocytosis and
downregulation of both antigen presentation capacity and T cell activity. Thus
triggering PD-1 inhibitor resistance. Meanwhile, the researchers found that the
combination of PD-1 / PD-L1 antibody and anti-CTLA-4 antibody (Ipilimumab and
Opdivo-IO
regimen)
resulted
in better tumor control
in mice treated
with
anti-CTLA-4 alone or with PD-L1 antibody alone or control. The combination of
PD-1 antibody and CTLA-4 antibody can be considered to avoid the dark side of
PD-1 antibody to some extent, effectively reducing the occurrence of tumor resistance
to PD-1 inhibitors. AK 104 is able to bind both programmed cell death receptor-1
(PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and block the
interaction of PD-1 / programmed cell death ligand-1 (PD-L1), PD-1 / PD-L2,
CTLA-4 / B7.1, and CTLA-4 / B7.2.
Therefore, this study aimed to evaluate the efficacy and safety of cadradinilizumab
combination chemotherapy in patients with PD-1 inhibitor-resistant NPC and to
determine its PK and immunogenicity characteristics to provide evidence for
subsequent studies.

25
2. Study objective / endpoint (necessary, flexible withholding
according to project characteristics)
2.1., for the purpose of the study
2.1.1 Main study objectives
To
evaluate
the
safety
and
efficacy
of
carbenilizumab
plus
chemotherapy
(platinum-based) second-line treatment of PD-1 inhibitor-resistant NPC based on
RECIST v l.1 Objective response rate (ORR) and PFS as assessed.
2.1.2 Secondary study objectives
·
To evaluate DoR, DCR, TTR, TTP, and OS in PD-1 inhibitor-resistant NPC with
capradilimumab plus chemotherapy (platinum-based).
·
To evaluate the pharmacokinetics of carradilizumab plus chemotherapy
(Pharmacokinet ics, PK).
·
To assess the immunogenicity of caldradilizumab in combination with
chemotherapy.
·
To evaluate the correlation of PD-Ll expression with efficacy in
immunohistochemical detection of tumor samples.
·
To evaluate the association of EB virus (EBY) DNA copy number in blood and
antitumor activity of caadilimumab in subjects with advanced NPC.
·
To assess health-related quality of life (HRQoL) in subjects treated with
carradiniilizumab plus chemotherapy
2.2 Study Endpoints
2.2.1 Primary Study Endpoints
·
Safety:, incidence and severity of adverse events (AEs), clinically significant
abnormal laboratory findings.
·
Based on the following data in RECIST v i. The ORR as assessed by the I.
·
Based on the following data in RECIST v i. I of the assessed PFS.

26
2.2.2 Secondary Study Endpoints
·
According to the RECIST vi. The DoR, DCR, TTR, TTP, and OS as assessed by
I.
·
PK characteristics: including serum concentrations of cadadilimumab at
different time points after cadilimumab administration.
·
Immunogenicity assessment: Number and percentage of subjects presenting
with detectable antimicrobial antibodies (ADA).
·
To evaluate the correlation of PD-Ll expression with efficacy in
immunohistochemical detection of tumor samples.
·
To evaluate the association of EB virus (EBY) DNA copy number in blood and
antitumor activity of caadilimumab in subjects with advanced NPC.
· Health-related Quality of Life Assessment HRQoL-as measured using the
European Organization for Research and Treatment of Cancer Quality of Life
Questionnaire-Core 30 (EORTCQLQ-C30) and EORTCQLQ-H & N35.
3. research design
3.1
Overall design (must)
This study is a Phase II clinical study of carradilimumab (AK 104) plus
chemotherapy for PD-1 inhibitor-resistant nasopharyngeal cancer to evaluate the
safety and efficacy of carradilimumab plus chemotherapy as second-line and above
treatment for PD-1 inhibitor-resistant nasopharyngeal cancer. This study is a
single-arm, phase II clinical study with approximately 30 PD-1 inhibitor-resistant
NPC subjects scheduled to be enrolled. PD-Ll CPS (<50% vs> 50%, subjects whose
PDLl expression was not evaluated were classified as <50%) were used as the
stratification factor. The study will have a safe lead-in period of approximately 6
PD-1 inhibitor-resistant subjects, and the investigator will conduct an preliminary
safety assessment. If the safety and tolerance are good and initial efficacy signals are
observed, the extended enrollment phase will enter. Efficacy analysis will be
performed for approximately 15 subjects. If 6 of the 15 subjects are not tolerated,

27
subject enrollment may be stopped after the investigator discussion. After poor safety,
the investigator decided to revise or stop the study. For 4-6 cycles, the use of
calduilizumab until the investigator determines that there is no clinical benefit (based
on the comprehensive judgment of RECISTv1.1 imaging assessment and clinical
symptoms), toxicity intolerance, completion of 24 months of treatment, or satisfaction
of other criteria for treatment termination in the regimen, whichever occurs first.
•
Subject treatment protocol:
•
Carradilizumab (200 mg, administered on day 1 of each cycle, Q3W until no
longer had clinical benefit) + platinum was based chemotherapy, 1 treatment cycle
every 3 weeks (21 days).
3.2 Sample size (necessary)
Thirty subjects are planned to be enrolled in this study
4. Study population (necessary)
Patients with nasopharyngeal carcinoma who had received a previous PD-1
inhibitor-containing regimen, presented with disease progression and no indication for
radical local treatment
4.1
Diagnostic criteria (if any)
Histologically or cytologically confirmed nasopharyngeal carcinoma.
4.2 Inclusion criteria (must)
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
Voluntary signed the written ICF.
1)
Age was over 18 and 75 at the time of enrollment, acceptable for both men and
women.
2)
The Eastern Cooperative Oncology (ECOG) physical performance score was 0
or 1.
3)
Expected survival is greater than 3 months.
4)
Histologically or cytologically confirmed nasopharyngeal carcinoma.
5)
The subject had previously failed treatment with PD-1 inhibitor and had no
indication for radical local treatment.

28
6)
According to the efficacy evaluation criteria of solid tumors RECIST v l. And l
with at least one measurable lesion.
4.3 Exclusion criteria (must)

Declaration that all baseline subjects meeting any of the exclusion criteria will be
excluded from the study
1)
Other than NPC, the subject had any other malignancy within 2 years prior to
enrollment. Subjects who have been cured by local treatment of other tumors,
such as basal or cutaneous squamous cell carcinoma, superficial bladder cancer,
cervix or breast in situ carcinoma, are not excluded.
2)
Attreatment the investigational drug within 4 weeks prior to the first study
administration.
3)
Having active autoimmune diseases requiring systemic therapy over the past
two
years
(e.
g.
use
of
modifying
medication,
corticosteroids,
immunosuppressive therapy), alternative therapy (e. g., thyroxine, insulin, or
physiological corticosteroid replacement therapy for adrenal or pituitary
insufficiency) is not considered a systemic therapy.
4)
History of immunodeficiency; test positive for HIV antibodies; ongoing use of
systemic corticosteroids or other immunosuppressants.
5)
Active TB should be excluded in subjects with suspected active TB (TB).
6)
Known history of allogeneic organ transplantation and allogeneic HSCT.
7)
For subjects with untreated active hepatitis B (HBsAg positive with
HBV-DNA over 1 000 copies / ml (200 IU / ml) or above the lower limit of
testing, whichever higher), anti-hepatitis B treatment was required during study
treatment; subjects with active hepatitis C (HCV antibody positive and
HCV-RNA levels above the lower limit of testing).
8)
Major surgery or severe trauma within 30 days prior to the first dose, or a
major surgical planner within 30 days after the first dose (at the discretion of the
investigator); a minor local procedure (excluding transperipheral venous

29
puncture central venous catheterization) within 3 days prior to the first dose.
9)
The presence of CNS metastases.
10)
Current uncontrolled concurrent conditions, including but not limited to
symptomatic congestive heart failure (grade 2 or above under the New York
Heart Association functional classification), unstable angina, acute myocardial
ischemia, poorly controlled arrhythmia, decompensated cirrhosis, nephrotic
syndrome, uncontrolled metabolic disorders, severe active peptic ulcer disease
or gastritis, or psychiatric / social conditions that may limit study requirements
or affect the subject's ability to provide written informed consent.
11) There was a past history of myocarditis, cardiomyopathy, and malignant
arrhythmia. Unstable angina, congestive heart failure, or vascular disease (such
as aortic aneurysm or peripheral venous thrombosis requiring surgical repair)
within 2 months before the first dose, Or other cardiac lesions that may affect
the safety evaluation of the study drug (e. g. poorly controlled arrhythmias,
Myocardial infarction or ischemia); presence of esophageal-gastric varices
within 6 months before the first dose, Severe ulcer, The wound has not healed,
gastric-intestinal perforation, abdominal pain, Gastrointestinal obstruction,
History of intra-abdominal abscess or acute gastrointestinal bleeding; any
arterial thromboembolic event within 6 months prior to the first dose, NC I
CTCAE
5.0
grade
3
and
above,
Transient
cerebral
ischemic
attack,
cerebrovascular accident, Hypertensive crisis or hypertensive encephalopathy;
acute exacerbation of chronic obstructive pulmonary disease within 1 month
before the first dose; current presence of hypertension with SBP> 160mmHg or
DBP <100mmHg after oral antihypertensive medication.
12)
History of severe bleeding tendency or coagulation opathy; blood symptoms of
significant clinical significance within 1 month before the first dose, including
but not limited to gastrointestinal bleeding, hemoptysis, screening imaging
showing tumor wrapping around important blood vessels or significant necrosis
and emptiness, and the investigator believes that participation in the study may

30
cause bleeding risk;
13)
No response of prior anti-tumor therapy, defined as not returning to Grade 0 of
NC l CTCAE 5.0 or 1, or the level specified in the inclusion / exclusion criteria,
except for sequelae of alopecia, neurotoxicity associated with prior lead therapy.
Subjects with irreversible toxicity not expected to worsen after study drug
administration (e. g. hearing loss) may be included in the study after
consultation with the medical monitor. Long-term toxicity from radiotherapy,
subjects not recoverable as judged by the investigator may be included in the
study after consultation with the medical monitor.
14)
Live vaccination was administered within 30 days before the first dose, or was
planned to be administered during the study period.
15)
Known allergy to any component of any study drug; known history of severe
hypersensitivity to other monoclonal antibodies.
16)
Known history of mental illness, substance abuse, alcohol abuse, or drug use.
17)
Pregnant or lactating women.
18)
Prior or current presence of any disease, treatment, laboratory abnormalities
that may confuse the findings, affect the subject's full participation, or
participation in the study may not be in the subject's best interest at the time.
19) Local or systemic disease due to nonmalignancy, or disease or symptoms
secondary to tumor, and can lead to higher medical risk and / or uncertainty in
survival evaluation, such as leukemic response (white cell count> 20 X 109 / L
or malmalignant manifestations (such as known weight loss of more than 10%
in the 3 months prior to screening).
4.4
Subject Exit Criteria (if any)
①Treatment failure as specified in the protocol occurs.
②Unacceptable treatment toxicity occurs.
③Diseases that may significantly affect clinical status assessment or require
interruption of treatment.
④Patients may withdraw from this study at any time and for any reason.

31
Withdrawal procedure: Patients should be asked about the reason for their withdrawal
and any adverse events occurring and, if possible, should be observed and evaluated
by the investigator. Serious or unexpected adverse reactions should be followed-up.
Once the patient withdraws or discontinues the trial, the investigator should try to
obtain information about the patient. The investigator should do his best to complete
the final evaluation and record their efforts. The results of these evaluations and
observations, together with the description of the reasons for patient withdrawal, must
be recorded in the original data. The primary reasons for withdrawal or
discontinuation must be documented in the case report form (CRF) and the relevant
follow-up study steps (discharge visit) completed whenever possible.
5. appraise
5.1 Primary and secondary endpoints / outcome evaluation
Main end point
·
The ORR was based on the RECIST 1.1 assessment.
·
The PFS based on the RECIST 1.1 assessment.
Secondary end point
·
According to the RECIST vi. The DoR, DCR, TTR, TTP, and OS as assessed by
I.
·
PK characteristics: including serum concentrations of cadadilimumab at different
time points after cadilimumab administration.
·
Immunogenicity assessment: Number and percentage of subjects presenting with
detectable antimicrobial antibodies (ADA).
·
To assess the correlation of PD-L1 expression with efficacy in tumor samples by
immunohistochemical detection.
·
To evaluate the association of EB virus (EBY) DNA copy number in blood and
antitumor activity of caadilimumab in subjects with advanced NPC.
Health-related Quality of Life Assessment HRQoL-as measured using the
European Organization for Research and Treatment of Cancer Quality of Life
Questionnaire-Core 30 (EORTCQLQ-C30) and EORTCQLQ-H & N35.

32
5.2
Safety evaluation (necessary)
Safety:, incidence and severity of adverse events (AEs), clinically significant
abnormal laboratory findings.
6.
Adverse events and serious adverse events (must)
All treated patient (APaT) population was used for the safety data analysis for
this study. All treated patient populations included all patients receiving at least 1
dose of study medication.
6.1 Adverse events
Definition: Any adverse medical event between the entry of the patient and the
last follow-up, whether causally related to the trial drug.
Adverse events were truthfully recorded during the trial, including the time,
severity, duration, measures taken and outcome of the adverse events.
The severity criteria for adverse events: according to the WHO evaluation
criteria for adverse drug reactions (Annex 4). The adverse reactions listed in the
table are indicated in the following case:
●Mild: it does not affect the normal function of the subject.
●Moderate: to affect the normal function of the subjects to some extent.
●Severe severity: obviously affecting the normal function of the subjects.
Criteria for determining the relationship between adverse events and trial
drug:
The Investigator should assess the possible association between the adverse
event and the trial drug according to the following criteria:
Positive concern: the timing of the reaction, the timing of the known type of
response of the test drug, improvement after withdrawal, and
repeated administration reappeared.
Related to: the timing of the reaction, the known type of response to the trial
drug, and the patient's clinical status or other treatments.
Probably unrelated: the timing of the reaction does not match the chronological
order of the medication, the response is not quite within the known

33
type of response given by the trial drug, or because of the patient's
clinical status or other treatments.
No: The time of the response does not conform to the chronological order of
the medication, the response has the response type known to the
non-trial drug, the patient's clinical status or other treatment
methods may also produce the response, the improvement of the
disease state or the elimination of other treatment methods, and the
reuse of other treatment methods.
It cannot be determined that there is no clear relationship between the time of
the reaction and the chronological order of the medication, the
response is similar to the known type of response of the test drug,
and other drugs used may also cause the same response.
6.2 Serious Adverse Events
6.2.1 Determination of serious adverse events
die
Life is in danger
Leading to a prolonged hospitalization or hospital stay
Permanent or severely disabling condition

Lead to congenital malformations, defects
6.2.2 Any serious adverse reaction occurring during the clinical trial or within 30 days
of the last treatment, whether it is related to the drug, should be immediately
and orally reported to the study director, the Ethics Committee and the
sponsor within 24 hours.
6.2.3 The investigator should follow up for serious adverse reactions until the
symptoms disappear or the condition is stable.

34
7. Statistical analysis and statistical methods (necessary)
7.1, and the analysis set
7.1.1, and the enrollment analysis set
The enrollment analysis set included all subjects who signed the ICF into the
study.
7.1.2 Full Analysis set
The full Analysis set (FAS) included all subjects who had received at least one
dose of study drug and had measurable lesions at baseline (as defined by RECIST
v1.1).
7.1.3 Safety Analysis Set
The Safety Analysis Set (SS) includes all subjects who have received at least one
study medication. Analysis was performed based on the treatment that the subject
actually received.
7.1.4 Pharmacokinetic analysis set
Pharmacoanalysis Set (PKS): Subjects who had received at least 1 study drug
and had at least 1 effective postdose plasma concentration data.
7.1.5 Immunogenicity analysis set
The immunogenicity analysis set included all subjects who were randomized and
used at least one study drug, pre-medication and at least one post-medication
immunogenicity assessment data.
8. Medical treatment and protection of the subjects (necessary)
8.1
Assessment of risk in the study and risk management measures and plan
(necessary)
In order to better protect the safety and interests of the subjects, the protocol of
the trial is strictly followed and the quality of the trial data is ensured. The test site
must be equipped with necessary medical rescue equipment, first-aid drugs and
emergency measures. When necessary, an emergency medical emergency team shall
be set up to deal with emergency medical events and accidental disasters in

35
accordance with relevant standard operating procedures. Closely observe possible
adverse events, especially non-expected adverse events,
timely analysis and
communication, and record adverse events. Establish linkage procedures with the
hospital intensive care unit for subject transfer and care. Establish communication and
communication between researchers and laboratories and cooperative units to ensure
timely communication and treatment of possible adverse events.
8.2 Infusion reaction
Subjects will be monitored for signs and symptoms of infusion reactions (e. g.,
fever and / or chills, flushing and / or pruritus, changes in heart rate and blood
pressure, dyspnea or chest discomfort, rash, etc.) and systemic allergic reactions (e. g.,
generalized urticaria, angioedema, asthma, hypotension, tachycardia).
In this study, to avoid confounding the potential safety signals regarding the
assessment of the infusion response:
1) Primary prophylaxis is not allowed for infusion reactions (in subjects without
infusion events).
2) The investigator may decide regarding appropriate secondary prevention (that is,
preventing reactions related to infusion after the initial episode):
·
An
acetaminophen
/
paracetamol
and
/
or
antihistamide
(e.
g.
diphenhydramine) may be administered approximately 30 minutes before the
start of a subsequent infusion, and / or glucocorticoids or equivalent drugs
according to the diagnostic routine at each center.
·
Non-sedating antihistamines (e. g. cetirizine) may be considered for subjects
with repeated infusion reactions.
·
If the symptoms persist, the corticostertherapy should be considered.
·
According to the routine of each center, the investigator may at his
discretion decide whether to administer piperidine / morphine sulfate and
promethazine or the equivalent prior to the start of the subsequent infusion.
Readministration of pretreated agents may be required during the infusion;
therefore, this should be considered in determining the dose of pretreated agents. Any

36
significant reactions and use requirements related to corticosteroids must be discussed
with the medical monitor.
In the event of a level 2 infusion reaction, the infusion rate of AK 104 can be
reduced by 50% or interrupt the infusion until the event resolves (up to 6 hours) and
restart the infusion at 50% of the initial infusion rate after event resolution until the
infusion is completed. Once the infusion rate of AK 104 is reduced by 50% or the
infusion is interrupted due to the infusion reaction, all subsequent infusion must be
continued at the reduced infusion rate. If the subject has a second level 2 infusion
reaction at a slower infusion rate, the infusion should be stopped. If the subject has a
grade 3 or 4 infusion reaction at any time, the AK 104 treatment must be stopped.
If severe hypersensitivity (grade CTCAE 3 or 4) is observed during the infusion,
the infusion will be stopped immediately and no further AK 104 treatment will be
given. Supportive treatment is provided according to the standard medical practice. If
subjects develop symptoms or signs of systemic anaphylaxis or type 1
hypersensitivity during AK 104 administration, they will be treated with appropriate
drugs and medical devices that will always be available at all sites. Glucocorticoids,
epinephrine, allergic drugs (antihistamines) or equivalent should be readily available.
The subject should be informed to report to the investigator on any delayed response.
Guidelines for toxicity management of AK 104 treatment related to infusion
reactions are shown in the table below. In case of multiple low-grade AEs (permanent
AK 104 treatment is not required separately), the permanent AK 104 treatment will be
determined at the discretion of the investigator.
Table 1 Treatment adjustments for infusion response symptoms caused by AK
104
NCI-CTCAE grade
Regarding the treatment adjustment for AK
104
Level 1 mild
Minor,
temporary
reaction;
no
infusion
Reduce the AK 104 infusion rate by 50% and
closely monitor any deterioration.
The total infusion time of AK 104 should not

37
interruption; no treatment.
exceed 120 minutes.
Level 2 moderate
Treatment or infusion interruption is required,
but
symptomatic
treatment
(such
as
antihistamines,
NSAID,
corticosteroids,
intravenous infusion), rapid effect; preventive
administration of <24 hours.
Interrupt the AK104 infusion.
The infusion was restarted at 50% of the
previous infusion rate at times when the
infusion response had subsided or the severity
had dropped to at least level 1, and any
deterioration was monitored closely.
If the subject has a second level 2 infusion
reaction at a slower infusion rate, the infusion
should be discontinued and the subject must be
withdrawn from AK 104 treatment.
Grade 3 or 4 is serious or life-threatening
Grade 3: delay in symptom relief (e. g.
symptomatic
treatment
and
/
or
infusion
interruption, lack of rapid response); relapse
after symptom improvement; sequelae requiring
hospitalization.
Grade 4: life-threatening; requiring urgent
treatment.
The
AK
104
infusion
was
stopped
immediately, and the subject's infusion tube
was disconnected.
Subjects must immediately withdraw from AK
104 treatment and must not receive any further
AK 104 treatment.
8.3 Complications of infection
Bacterial, mold, tuberculosis virus infection and some special microorganisms
of each system.
Countermeasures: Most of the above situations can be alleviated by themselves or
improved after symptomatic treatment, and in rare cases, they may be life-threatening;
the prevention measures include eliminating contraindications, strictly following the
treatment procedures and specifications, strictly monitoring the subjects, and treating
the symptoms according to the doctor.

38
8.4 Immune-related adverse events (irAE)
The irAE is defined as an AE associated with drug exposure, consistent with an
immune-mediated mechanism of action, and without a clear alternative etiology.
Based on the mechanism of action of AK 104 targeting PD-1 and CTLA-4 leading to
T cell activation and proliferation, it is possible that irAE could be observed during
the conduct of this study. The underlying irAE may be similar to the adverse events
seen with anti-PD-1 / L1 drugs, including immune-mediated colitis, dermatitis,
pneumonia, hepatitis, encephalitis, nephritis, and endocrine disorders. Subjects should
be monitored for the signs and symptoms of an irAE. In the absence of other
alternative causes (e. g., infection or PD), immune-related causes associated with
signs or symptoms of colitis, dermatitis, pneumonia, hepatitis, encephalitis, nephritis,
and endocrine disorders should be considered.
Based on the severity of toxicity occurring in treatment according to NCI
CTCAE 5.0 grade, AK 104 treatment adjustments will be performed to manage
potential irAEs.
·
The maximum interval allowing an AK 104 pause is 12 weeks. If they could
not return to the reuse of AK 104 within 12 weeks, the subject permanently
discontinued AK 104 and entered the follow-up phase. Except: AK 104 was
suspended for more than 12 weeks or AK 104 for more than 12 weeks due to
AEs that may be unrelated or unrelated to AK 104. In this case, a discussion
with the medical monitor is needed to decide whether the AK 104 treatment
can be continued.
Generally, it is recommended to manage irAEs according to the following
principles. Subjects should be comprehensively evaluated, excluding any other
alternative etiology (e. g. disease progression, concomitant medication, infection, etc.).
Serological, immunological, and histological (biopsy) data should be used to support
the diagnosis of irAE, as appropriate.
·
If applicable, systemic corticosteroids (e. g., prednisone or intravenous
equivalent) should be considered for persistent low-grade or severe (grade 3)
events.

39
·
If symptoms recur or worsen during the glucocorticoid reduction, the dose
was increased until the symptoms stabilized or improved, and then gradually
rereduced at a slower rate.
·
For events that do not respond to systemic corticosteroids, more potent
immunosuppressive agents (e. g. infliximab, maccohenyl esters, etc.) should
be considered after discussion with the medical monitor.
·
Termination of study drug treatment is not mandatory for grade 3 or 4
inflammatory reactions (e. g., sites of metastatic disease, lymph nodes).
·
Doctors in other fields (such as cardiology or autoimmune diseases) should
be arranged to make appropriate treatment decisions.
·
For
multiple
low-grade
AEs
(no
treatment
termination
is
required
separately), AK 104 will be terminated at the discretion.
·
After discontinuation of study drug for Grade 3 or 4 events, if the subject
responded well and the toxicity resolved rapidly, AK 104 could be resumed
after discussion with the medical monitor.
·
For abnormal laboratory findings, suspension or permanent termination
should be determined based on concomitant clinical symptoms / signs and the
clinical judgment of the investigator.
AK 104 dose adjustment and toxicity management principles for immune-related
AEs are shown in the following table for irAEs or when specific toxicities exist, refer
to the management of immune-related adverse events in patients treated with immune
checkpoint inhibitors: Clinical Practice Guidelines of the American Society for
Clinical Oncology (Brahmer et al., 2018) processing. Guidelines for the diagnostic
assessment of immune-related adverse events are detailed in the appendix.
Table 2: The recommended principles for dose adjustment and toxicity
management of AK 104 immune-related AEs
Immune-related
AEs
Toxicity level
Measures
taken against
AK 104
Management of irAE
(corticosteroids
and
other treatments)
Monitoring
and
follow-up

40
pneumonia
Level 2
Suspension of
medication
Corticosteroid
hormone (initial dose
of
1-2mg
/
kg
prednisone
or
equivalent),
then
tapered thereafter
The
subject
was
monitored for the
symptoms
and
signs
of
pneumonia
Subjects
with
suspected
pneumonia
by
imaging
evaluation
and
were
started
on
corticosteroid
hormone therapy
Prophylactic
use
of
antibiotics
to
prevent
opportunistic
infections
Grade 3 – 4, or
recurrent grade
2
Permanent
withdrawal
of
drugs
Diarrhea
/
enteritis
Level 2-3
Suspension of
medication
Corticosteroid hormone
(initial dose of 1-2mg /
kg
prednisone
or
equivalent),
then
tapered thereafter
Participants
were
monitored
for
symptoms
and
signs
of
gastroenteritis
(diarrhea,
abdominal
pain,
hematology,
blood, stool, with
or without fever)
or
bowel
perforation
(peritoneal
irritation
or
intestinal
obstruction)
Subjects
with
grade
2
diarrhea
and
suspected
enteritis
should
consider
consulting
a
gastroenterologist
for endoscopy to
exclude enteritis
Level 4
Permanent
withdrawal
of
drugs
AST/ALT
Level 2
Suspension of
Corticosteroid
(initial
Monitor
liver

41
Elevated or with
an
elevated
bilirubin
medication
dose
0.5-1mg
/
kg
prednisone
or
equivalent), tapered
function
(weekly
or more frequently
until liver enzymes
return to baseline
or remain stable)
Level 3
Suspend
or
permanently
Corticosteroid
hormone (initial dose
of
1-2mg
/
kg
prednisone
or
equivalent),
then
tapered thereafter
Level 4
Permanent
withdrawal
of
drugs
Corticosteroid
hormone (initial dose
of
1-2mg
/
kg
prednisone
or
equivalent),
then
tapered thereafter
Type 1 diabetes
mellitus
(T1DM)
or
hyperglycemia
New
T1DM
or
hyperglycemia
(related to cell
failure)
Suspension of
medication
T1DM subjects were
started
on
insulin
replacement
therapy
and
hyperglycemic
subjects were started
on antidiabetic agents
The
subject
was
monitored
for
blood glucose, or
other
symptoms
and
signs
of
diabetes
hypophysitis
Level 2
Suspension of
medication
Use of corticosteroid
hormones
and,
if
clinically
indicated,
initiate
hormone
replacement therapy
Monitor
for
symptoms
and
signs
of
hypophysitis
(including
pituitary
and
adrenal
dysfunction)
Level 3-4
Suspend
or
permanently
hyperthyrea
Level 2
cont.rem
Treatment
with
nonselective
receptor
blockers
(e.
g.
propranolol)
or
thioamide
(if
appropriate)
Monitor
for
the
symptoms
and
signs
of
thyroid
disease
Level 3-4
Suspend
or
permanently
hypothyrea
Level 2-4
cont.rem
Thyroid
hormone
replacement
therapy
was initiated based on
standard therapy (e. g.
L
Thyroxine
or
triiodothyronine)
Monitor
for
the
symptoms
and
signs
of
thyroid
disease

42
Nephritis
and
renal
insufficiency
Level 2
Suspension of
medication
Corticosteroid
hormone (initial dose
of
1-2mg
/
kg
prednisone
or
equivalent),
then
tapered thereafter
Monitor
for
changes
in
renal
function
Level 3-4
Permanent
withdrawal
of
drugs
carditis
Level 1
Suspension of
medication
Corticosteroid
hormones
were
used
based on the type and
severity of the AE
Ensure
adequate
evaluation
to
confirm the cause
and or to exclude
other causes
Level 2
Suspend
or
permanently
Level 3-4
Permanent
withdrawal
of
drugs
All of the other
irAEs
Level
2,
that
could
not
be
tolerated
or
persisted
Suspension of
medication
Corticosteroid
hormones
were
used
based on the type and
severity of the AE
Ensure
adequate
evaluation
to
confirm the cause
and or to exclude
other causes
Level 3
AEs based on
type
of
AE
suspension or
permanent
withdrawal
include
but
are not limited
to
Guillain-Barre
syndrome,
encephalitis,
etc
Grade
4
or
recurrent grade
3
Permanent
withdrawal of
drugs
1. Suspension or permanent withdrawal will be decided after discussion between the investigator
and the medical supervisor
pay attention to:

43
When the AE returns to grade 0-1 or baseline, corticosteroid hormones began to be gradually
reduced for more than 4 weeks;
For AK 104 suspension: restart AK 104 if the AE returns to Grade 0-1 or baseline with
corticosteroid tapering (10mg prednisone or equivalent dose) and if the AE does not resolve
within 12 weeks after the last dose or 12 weeks;
For severe and life-threatening irAEs, intravenous corticosteroids and sequential oral hormone
therapy should be started, and if corticosteroids are not effective, other immunosuppressants
should be considered;
For subjects with grade 3-4 immune-related endocrine disorders requiring AK 104 suspension, allow
medication to resume when the AE returns to level 2 and is controlled by hormone replacement therapy
or achieves metabolic stability (e. g., T1DM).
Where the above principles are inconsistent with the toxicity management
guidelines related to other immune checkpoint inhibitors or the local standard clinical
practice, the investigator organizes the meeting to discuss the corresponding toxicity
management.
8.5 Non-immune-related adverse events
AK 104-associated AE should often be attributed to an immune-mediated
mechanism, namely irAE. For AK 104-related grade 3 or above non-immune-related
AEs assessed by the investigator, AK 104 administration may be suspended and
treated clinically. When the adverse event is relieved or improved, the medication
may be continued according to the judgment of the investigator. No dose interruption
may be required for AEs specifically unrelated to AK 104 or for laboratory
abnormalities that are not clinically significant. All toxicities were graded according
to NCI CTCAE 5.0. Non-immune-related reactions were handled according to the
diagnostic routine of each study center.
9. Supporting documents and precautions
9.1
Informed Consent Process (if any)
Prior to subject participation, the investigator has the responsibility to fully
explain the study purpose, methods, expected benefits and potential hazards to the
subject for further voluntary written consent from the subject or his legal
representative (if permitted by local regulations). Legal representative refers to the
individual or institution who has obtained the authorization of the subject or the

44
authorization of the law. The informed consent form should be written in the native
language of the potential subject population.
The investigator should follow the relevant regulatory requirements, GCP and
the ethical principles derived from the Declaration of Helsinki. IEC / IRB approval
should be obtained before the informed consent form and its revision are provided to
potential subjects. The investigator should ensure that each subject was informed that
they could voluntarily terminate the study at any time and that each subject had the
opportunity to ask questions and time to think about the information obtained.
Informed consent form should be obtained before the subject participates in the
study and documented in the site. The ICF shall be signed by the subject or his legal
representative (if permitted by local regulations) and the name and date by the
investigator. The original signed ICF should be kept at the study site and provided
with a copy of the signed consent form by the subject or their legal representative.
The date of giving the informed consent should be recorded in the medical record and
the case report form.
If the subject or his legal representative (if permitted by local regulations) is not
reading, a fair witness should be present throughout the informed consent discussion.
The witness should sign the ICF after the subject or his legal representative agrees the
subject to participate in the study and sign the ICF (if possible). Signing the ICF
indicates that the witness confirmed that the information in the ICF and any other
written information had been fully explained to the subject or his legal representative,
that they had clearly understood this information, and that the subject or his legal
representative agreed to sign the written informed consent.
The informed consent form approved by the IRB / IEC should describe any
incentives for the subjects to participate in the study.
9.2
Privacy protection (must)
In clinical trials and collection and processing of patient personal data, strictly
abide by the clinical trial privacy protection procedures, data protection legislation
and ethical standards, implement the safeguard procedures to protect the subject's
personal data, to prevent loss or theft, unauthorized access, improper use, copying,

45
transmission or tampering, modification, retention or damage. During centralized
screening, independent space is needed to conduct separate informed consent after
group knowledge, to ensure that subjects can ask questions and get answers without
concern. The physical examination as well as the electrocardiogram requires
independent space to avoid exposing the subject's body parts. In the process of
clinical trial, various forms, such as physical examination records, electrocardiogram
records, PK blood collection records, local laboratory sample collection records, drug
distribution forms, etc., should be distinguished by the unique number conforming to
the project requirements in the clinical trial, and no personal information of the
subjects, such as name, gender, etc. After the bedside card is numbered instead of
name, the subject wears a chest plate, mark the item number, subject number, and
identify with the chest plate during operation. When sent to external institutions and
departments (such as the third-party testing platform), the sample is identified with
the only code that cannot reflect the subject's personal information. Quality control
checks shall be performed for all documents before sending email, transmitting data
or entering them into the system. Keep the password and permission for access to the
clinical trial system, such as browsing the electronic medical record system and
laboratory sheet, etc., only by qualified staff. In case of any privacy disclosure, timely
correct and strengthen management and take preventive measures to prevent such
situation from happening again. Any documents and data reflecting the personal
information of subjects in a relatively fixed position, and timely sorting and archive,
only authorized personnel can write or browse, not in large areas or open area,
unauthorized personnel can not access to any medical records related to the study, for
blinded studies, unblinded personnel can not access to any subject's medical records.
The research data should be kept in the archives room and managed by special
personnel. The archived documents should be locked in time. Only those with
authority can borrow them, and lend and return them need to be registered. When the
results are published, report with the group synthesis data rather than the individual
data of the subject. When describing the special situation of the individual, there is no
personal information that can identify the subject, and it can be coded instead.

46
9.3
Quality Control and Quality Assurance (must)
The investigator / site is required to open direct access to the source data /
documents allowing study related monitoring, audit, IRB / IEC review and regulatory
audit. Direct access includes permits for examination, analysis, validation, and
replication of any records and reports critical to the evaluation of clinical studies.
9.4 Data processing and record keeping (must)
9.4.1 Data collection and management
9.4.1.1 Data acquisition
All data collected during the study will be recorded in the subject's
individual-specific case report form. The designated person will provide the case
report form and instructions for completing the case report form, and any
modifications will be automatically recorded through the Audit Traces function of the
EDC system.
The case report form should be kept up to date to help the monitor review
subject status throughout the study. The case report form should be filled in as soon as
possible after the follow-up, and questions should be answered as soon as possible.
The case report form should be completed, reviewed as soon as the last subject follow
up and signed by the investigator.
Each subject who has signed the ICF and has passed all the screening steps
must have a completed case report form. If the subject is not treated, the cause must
be recorded in the case report form.
All external data (e. g. data generated from the central laboratory, PK process,
PD process) are integrated with the subject's case report form data based on the data
management plan.
Subject number and the date of study participation should be recorded by the
investigator in the subject's medical / study file along with the study code. The
investigator should also record the following information in the medical / study files:
written and verbal confirmation of informed consent, subject clinical status, date of
each study follow-up, administration date of study medication, concomitant

47
medication, copies of all relevant reports and laboratory test results, comments on the
results, and any AEs mentioned.
The investigator signed the name and date at the designated location of the case
report form via the electronic signature function of the EDC system. These signatures
indicate that the investigator has checked or reviewed the data, data queries and site
notification, and agreed to the form.
All information and other materials used by subjects and researchers must be in
clear and understandable vocabulary and language.
9.4.1.2 Data management
To ensure the quality of clinical data for all subjects and sites, subject data will
be reviewed for clinical data management. When checking the case report form data
electronically and manually, and electronically using the internal programmed data
rules electronically, edit the checks and questions established for data entry in the
EDC system. Post-entry verification was performed as described in the Data
Management Plan. The doubt arising by the rules and raised by the auditor will arise
within the EDC application. This review process will check the consistency,
omissions and any apparent differences in subject data. In addition, data compliance
with the protocol and the GCP will be reviewed. To address all issues arising during
the clinical data management review, case sheet questions will be addressed and
resolved within the EDC application.
Data obtained from external (e. g. central laboratory) will be consistent with the
clinical database. Serious adverse events in the clinical database will be consistent
with the safety database.
All AEs were encoded using MedDRA. Concomitant medications and previous
oncology treatments selected per the World Health Organization Drug Dictionary
(WHO-DD) reference catalogue are also documented in the Case Report Form.
9.4.2
Study data retained
The investigator will keep a signed list of appropriately qualified persons with
research responsibilities. All persons authorized to enter or modify to the case report
form are included in the signature list.

48
Source documents refer to the original documents, data and records from which
the subject's case report form data are obtained. These documents include, but are not
limited to, hospital records, clinical and outpatient medical records, laboratory testing
and pharmacy records, diaries, microfilms, X-rays, and letters. It is the responsibility
of the investigator and investigator to maintain a complete central documentation
archiving system (trial master document) for all study related (critical) documents for
ready inspection by representatives of the appropriate regulatory authorities. Key
documents include:
Subject file, containing the completed CRF informed consent form and a copy
of the supporting source document (if available). For studies using EDC, at the end of
the study, a PDF file (portable document format) was generated for each subject's data
(case report form, doubt), kept in the trial master file.
Study documents, containing copies of the protocol and all amendments,
investigator's manual, and relevant critical documents required before the start of the
clinical study.
Records related to study medication, including site receipt, accountability notes,
final reconciliation and correspondence.
In addition, all the original documents supporting the entries in the case report
form must be retained and easily accessible. All key documents will be maintained by
the research institution until at least 5 years or more after completion of the study (if
specified in other applicable regulations or requirements). No study documents will be
destroyed until written consent between the investigators.
9.5 Conflict of interest statement (must)
See the Interest and Conflict Statement document
10. References (must)
·
Mojgan Ahmadzadeh, Laura A Johnson, Bianca Heemskerk, John R
Wunderlich,
Mark
E
Dudley,
Donald
E
White,
Steven
A
Rosenberg.Tumor antigen-specific CD8 T cells infiltrating the tumor

49
express high levels of PD-1 and are functionally impaired.Blood.2009
Aug 20;114(8):1537-44. doi: 10.1182/blood-2008-12-195792. Epub
2009 May 7.
·
Philipp Holliger, Peter J Hudson.Engineered antibody fragments and
the rise of single domains.Nat Biotechnol.2005 Sep;23(9):1126-36.
doi: 10.1038/nbt1142.
·
Michael A Curran, Welby Montalvo, Hideo Yagita, James P
Allison.PD-1 and CTLA-4 combination blockade expands infiltrating
T cells and reduces regulatory T and myeloid cells within B16
melanoma
tumors.Proc
Natl
Acad
Sci
U
S
A.2010
Mar
2;107(9):4275-80. doi: 10.1073/pnas.0915174107. Epub 2010 Feb 16.
· Drew M.Pardoll.The blockade of immune checkpoints in cancer
immunotherapy.Nature Reviews Cancer volume 12, pages252–264
(2012).