A Multi-center, Single-arm, and Open-label Phase Ib/II Study Exploring the Safety/Tolerability, Pharmacokinetics, and Efficacy of GFH018 in Combination With Toripalimab in the Treatment of Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumor
Sponsor: Genfleet Therapeutics (Shanghai) Inc.

 
Clinical Study Protocol 
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CLINICAL STUDY PROTOCOL 
Protocol Title: 
A multi-center, single-arm, and open-label Phase Ib/II study exploring 
the safety/tolerability, pharmacokinetics, and efficacy of GFH018 in 
combination with Toripalimab in the treatment of patients with 
advanced solid tumors  
Protocol Number: 
GFH018X0201 
Study Phase: 
Phase Ib/II 
Brief Title: 
Phase Ib/II study of GFH018 in combination with Toripalimab in the 
treatment of patients with advanced solid tumors 
Sponsor: 
Genfleet Therapeutics 
Version Number: 
3.0 
Release Date: 
18-Nov-2022 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document contains the confidential information of Genfleet Therapeutics.  
This document must not be disclosed to anyone other than the site study staffs and members 
of the institutional review board/independent ethics committee/institutional scientific review 
board or equivalent.  
The information in this document cannot be used for any purpose other than the evaluation or 
conduct of the clinical investigation without the prior written consent of Genfleet 
therapeutics. 

 
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Sponsor's Signature Page 
 
 
Protocol title: A multi-center, single-arm, and open-label Phase Ib/II study exploring 
the safety/tolerability, pharmacokinetics, and efficacy of GFH018 in combination with 
Toripalimab in the treatment of patients with advanced solid tumors 
Protocol Number: GFH018X0201 
Version Number and Date:3.0, 18-Nov-2022 
 
 
This study will be conducted in accordance with the requirements of this clinical study 
protocol, International Council for Harmonization Good Clinical Practice Guideline 
(ICH-GCP), 
and 
relevant 
national 
laws 
and 
regulations. 
 
This study will comply with the Declaration of Helsinki and take necessary measures 
to ensure the safety and interests of the subjects. 
 
 
Sponsor: Genfleet Therapeutics 
 
Signature of sponsor: 
 
  
 
 
Name and Title (print) 
Name (signature) 
Date (DD /MM/YYYY) 
 
 
 
 

 
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Investigator's Signature Page 
Protocol title: A multi-center, single-arm, and open-label Phase Ib/II study exploring 
the safety/tolerability, pharmacokinetics, and efficacy of GFH018 in combination with 
Toripalimab in the treatment of patients with advanced solid tumors 
Protocol Number: GFH018X0201 
Version Number and Date: 3.0, 18-Nov-2022 
 
By signing the signature page of this protocol, the investigator confirms and agrees: 
 
I have read the protocol GFH018X0201 entitled “A multi-center, single-arm, and open-
label Phase Ib/II study exploring the safety/tolerability, pharmacokinetics, and efficacy 
of GFH018 in combination with Toripalimab in the treatment of patients with advanced 
solid tumors”.  
I agree to conduct study and comply the ICH-GCP and applicable national or regional 
regulations/guidelines.  
I agree to ensure that all associates, colleagues, employees assisting in this study at my 
site are informed about their obligations. 
I agree to ensure that the confidential information contained in this document will not 
be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Genfleet Therapeutics. 
 
 
  
 
 
Principal investigator  
(print) 
Principal investigator  
(signature) 
Date  
(DD/MM/YYYY) 
 
 
 

 
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Protocol Change Summary (Nov2022) 
This protocol is amended to include osteosarcoma and triple-negative breast cancer 
(TNBC) as two new subgroups in phase II. Specific requirements for previous 
immunotherapy of nasopharyngeal carcinoma subjects have been added. Tumor types 
with potential benefit will be expanded at the discretion of the sponsor and leading 
investigators. Minor changes have been made to correct some inconsistency in the 
protocol. 

 
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Protocol Change Summary (Apr2022) 
This protocol is amended to add new strengths for GFH018 (20mg and 80mg). Hs-CRP 
and cysteine protease inhibitor (Cystatin C) are removed from the laboratory tests of 
cardiac markers due to inconvenience and limitation of clinical application. 20mg BID 
is removed from the recommended adjustment scheme of GFH018 considering the 
limited potential benefit at this dose. The dose delay for a patient to withdraw from the 
study treatment (from the intended day of the next scheduled dose) is adjusted from 21 
days to 28 days as a cycle. 

 
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Protocol Change Summary (Mar2022) 
This protocol is amended to include following changes: to add more tumor types in 
phase II part; to summarize updated clinical data from FIH study GFH018X1101; 
GFH018 7-day on/7-day off dosing regimen has been removed; study assessment 
schedule has been adjusted; blood sampling schema has been added and other 
modifications of study procedures have been made. 
Summary of changes from protocol V1.2 to V 2.0: 
Section #  
Description of Change 
Rationale(s) 
3.3 & 4.1 & 7.5 
Add three types of tumor 
(i.e. thymic carcinoma, 
endometrial cancer, and 
extranodal NK/T-cell 
lymphoma) in phase II part. 
Based on the preclinical and 
clinical data, TGF-β 
inhibitors combined with 
anti-PD-(L)1 therapy might 
have a synergistic antitumor 
effect on thymic carcinoma, 
endometrial cancer, and 
extranodal NK/ T cell 
lymphoma   
1.1 & 1.3.2 
Update clinical results of 
GFH018 FIH study 
Data of GFH018 monotherapy 
updated 
Study Assessment 
Schedule & 1.2.2.1 
&3.1 & 6.2.3 & 
7.2.1.1 
Remove 7 days on / 7 days 
off dosing regimen 
It will be explored in a study 
combining with concurrent 
radiochemotherapy 
Study Assessment 
Schedule 
Adjust the table frame 
according to study phase Ib 
and II; study procedures 
were modified 
Simplify study procedures 
and clinical operations 
Blood Sampling 
Schema 
Add blood sampling 
schema 
Simplify study procedures 
and clinical operations 
1.2.2.1 & 3.1 
Update starting dose of 
GFH018 
Update based on emergent 
data of GFH018 FIH study 
2 
Remove iRECIST and add 
Lugano 2014 Criteria for 
extranodal NK/T-cell 
lymphoma 
Adjust criteria for tumor 
response evaluation 
4.1 
Tumor tissue specimen 
collection has been changed 
from mandatory to optional 
For patients who meet other 
criteria to have access to 
treatment  
Add “with toxicities left 
from prior anti-tumor 
therapy not resolved to 
baseline or CTCAE grade 1 
(neurotoxicity or alopecia ≤ 
For safety consideration of 
enrolled patients 

 
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grade 2)” 
For phase II part 
hepatocellular carcinoma 
patients: loosen the lower 
limit of platelet 
Considering the 
characteristics of 
hepatocellular carcinoma 
patients, after evaluating the 
safety risks, provision on 
relevant indicator were 
loosened. 
For phase II part cervical 
cancer patients: loosen the 
lower limit of hemoglobin 
Considering the 
characteristics of cervical 
cancer patients, after 
evaluating the safety risks, 
provision on relevant 
indicator were loosened. 
4.2 
Change the exclusion 
criteria for interstitial 
pneumonitis or pneumonitis 
To better meet the 
requirements of clinical 
practice. 
Change washout period 
requirement for traditional 
Chinese medicine 
To better meet the 
requirements of clinical 
practice. 
7.3 
Remove Fibronectin 
evaluation，and add tumor-
infiltrating lymphocytes 
(TILs)  as exploratory 
endpoints 
TIL analysis is a potential 
predictive biomarker 
according to recent 
publications.  
8.2.3 
Time period for collecting 
death events has been 
adjusted 
In accordance with SAE 
collection requirement 
Note: Minor changes have been made throughout the protocol to address consistency 
pertaining to major changes made in the protocol or to clarify. 
 
 

 
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Protocol Change Summary (Jun2021) 
This protocol amendment is to address requests and feedback from the Ethics 
Committee and investigators. The clinical safety and pharmacokinetics information of 
GFH018 has been updated. The requirements for safety monitoring during and after 
Toripalimab administration have been specified. Eligibility criteria has been updated to 
remove the age upper limit and include patients with particular cured early stage cancers. 
Clarification for specific subtype of enrolled esophageal cancer has been made.  
Changes to the Protocol: 
• Section 1.1 Study Background: GFH018 clinical data have been updated to the 
cut-off date of 19May2021. 
• Section 4.1 Inclusion Criteria #1: The age upper limit of 75 years has been 
removed.  
• Section 4.2 Exclusion Criteria #9: Patients with cured prostate cancer or thyroid 
cancer will not be excluded.  
• Section 5.3.2.1 Administration of Toripalimab : It has been specified that the 
patient should be closely monitored during and after the infusion for the first 
and second administration.  
• Section 5.6.2.2 Prohibited Concomitant Therapies: COVID-19 vaccines have 
been removed from the prohibited concomitant therapies list because the 
subjects might benefit from the vaccine.  
• 7.2 Pharmacokinetics: Changes to corresponding sections of the protocol are 
shown in the track changes version of the protocol. A copy of this amended 
protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites 
are required to update and submit for approval a revised Informed Consent that takes 
into account the changes described in this amended protocol. 
 
 

 
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Protocol Synopsis 
Protocol 
number 
GFH018X0201 
Protocol title 
A multi-center, single-arm, and open-label phase Ib/II study exploring the 
safety/tolerability, pharmacokinetics, and efficacy of GFH018 in combination with 
Toripalimab in the treatment of patients with advanced solid tumors 
Brief title 
Phase Ib/II study of GFH018 in combination with Toripalimab in the treatment of 
patients with advanced solid tumors 
Sponsor 
Genfleet Therapeutics 
Study phase 
Phase Ib/II 
Study drug 
Study drug 1 
Code: GFH018 
Dosage form: Tablet 
Strength: 5 mg, 50 mg, 20mg, 
80mg 
Study drug 2 
Code: Toripalimab 
Dosage form: Injection 
Strength: 240 mg (6 mL)/vial; 80 mg (2 mL)/vial; 
100 mg (2.5 mL)/vial 
Study purpose 
and rationale 
The purpose of the study is to evaluate the safety/tolerability, pharmacokinetics, and 
preliminary efficacy of GFH018 in combination with Toripalimab in patients with 
advanced solid tumors. 
Transforming growth factor beta (TGF-β), as a multifunctional cytokine, is secreted 
into the tumor microenvironment or peripheral circulation through a variety of cells, 
mainly including regulatory T cells, fibroblasts, and endothelial cells. TGF-β-bound 
cell membrane receptor TGF-β Receptor II(TGF-βRII), the cytokine forms the 
receptor dimer with TGF-βRI to activate downstream SMAD dependent and 
independent signal transduction pathways, thus performing various biological 
functions. TGF-β signaling pathway in advanced solid tumors potentiates epithelial-
mesenchymal transition (EMT) and metastasis of tumor cells, induces and maintains 
the function of tumor stem cells, inhibits the anti-tumor immune response in the 
tumor microenvironment, and increases angiogenesis and tissue fibrosis in the tumor 
microenvironment, thereby comprehensively promoting tumor progression. TGF-β 
signaling pathway genes are highly expressed in blood and tumors in patients with 
solid tumors such as hepatocellular carcinoma, glioma, colorectal cancer, lung 
cancer, pancreatic cancer, and urothelial carcinoma, and the expression level is 
positively correlated with poorly differentiated cell, pathological malignancy and 
poor prognosis of patients. 
Moreover, numerous studies have demonstrated that the function of CD8+ T cells, 
dendritic cells, B cells, and natural killer cells are positively correlated with the 
clinical response of anti-programmed death receptor-1 (PD-1)/programmed death 
ligand-1 (PD-L1) antibodies, and TGF-β suppresses the function of these immune 
cells. Meanwhile, the function of regulatory T cells and M2 macrophages are 
negatively correlated with the clinical response of anti-PD-1/L1 antibodies, and 
TGF-β promotes the effector function of regulatory T cells and the polarization of 
macrophages to M2 type. Therefore, TGF-β can compromise the response of PD-
1/L1 antibodies by promoting tumor fibrosis, blocking the infiltration of the 
cytotoxic T cells into the tumor, affecting the activity of immune cells, and 
suppressing the immune microenvironment. To sum up, TGF-β signaling pathway 
inhibitors can potentially enhance the response of the immune checkpoint inhibitors. 
During combined treatment, TGF-β signaling in tumor cells, stromal fibroblasts, 
and/or immune cells in the tumor microenvironment is suppressed, thereby 
enhancing the anti-tumor immunity and increasing the anti-tumor effect of the 

 
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immune checkpoint inhibitors anti-PD-1/L1 antibodies. 
As a novel TGF-βRI inhibitor, GFH018 can inhibit tumor growth by inhibiting the 
activity of TGF-βRI kinase to block the signal transduction of TGF-βRI and 
modulate the tumor immune microenvironment. Toripalimab is an anti-PD-1 
antibody approved for advanced melanoma and nasopharygeal carcinoma and for 
urothelial carcinoma in neoadjuvant and adjuvant setting by the National Medical 
Products Administration in China (NMPA). Pivotal studies for other indications are 
under development. Preclinical studies show that GFH018 in combination with PD-
1 or PD-L1 monoclonal antibody can significantly inhibit tumor growth in colorectal 
cancer and pancreatic cancer mouse models showing synergistic effects. 
Study 
objectives and 
endpoints 
This is a phase Ib/II study. 
The objectives and endpoints of phase Ib part (dose escalation) include: 
 
Objectives 
Endpoints 
Primary 
• To evaluate the 
safety/tolerability of 
the combination 
therapy 
• Incidence of dose-limiting toxicity 
(DLT) events 
• Incidence and severity of adverse 
events (AEs), serious adverse events 
(SAEs), adverse events of special 
interest (AESIs), and immune-related 
adverse events (irAEs) 
• Changes in laboratory parameters, 
vital signs, physical examination, 
and electrocardiograms (ECG) 
Secondary 
• To evaluate the 
pharmacokinetic (PK) 
characteristics of 
GFH018 in the 
combination therapy 
• Single dose plasma concentration and 
PK parameters of GFH018, including 
Cmax, Tmax, AUC0-t, AUC0-inf, T1/2, 
CL/F, and Vd/F; repeated doses 
plasma 
concentration 
and 
PK 
parameters of GFH018, including 
Cmax,ss, Cmin,ss, Tmax,ss, AUCtau, T1/2,SS, 
CL/F,SS, Vd/F,SS, and Raccc 
• To evaluate the serum 
concentration and 
immunogenicity of 
Toripalimab in the 
combination therapy 
• Ctrough of Toripalimab; number and 
percentage of subjects who develop 
anti-Toripalimab-antibody 
• To explore the 
efficacy of the 
combination therapy 
• Objective 
response 
rate 
(ORR), 
disease control rate (DCR), time to 
response (TTR), duration of response 
(DOR), 
progression-free 
survival 
(PFS) 
evaluated 
per 
Response 
Evaluation Criteria in Solid Tumors 
(RECIST) 1.1，and overall survival 
(OS)  
Exploratory 
• To explore the 
correlation between 
molecular 
characteristics and 
clinical efficacy 
• PD-L1 expression  
• CD8 + cell density 
• Tumor-infiltrating lymphocytes 
(TILs) characterization 

 
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The objectives and endpoints of phase II part (indication expansion stage) include: 
Objectives 
Endpoints 
Primary 
• To evaluate the efficacy of 
the combination therapy 
• ORR, DCR, TTR, DOR, PFS 
evaluated per RECIST 1.1 or 
Lugano 2014 Criteria (only 
for 
extranodal 
NK/T-cell 
lymphoma), OS 
Secondary 
• To evaluate the safety/ 
tolerability of the 
combination therapy 
• Incidence and severity of 
AEs, SAEs, AESIs, and 
irAEs 
• To evaluate the plasma 
concentration of GFH018 in 
the combination therapy 
• Ctrough of GFH018 
• To evaluate the serum 
concentration and 
immunogenicity of 
Toripalimab in the 
combination therapy 
• Ctrough of Toripalimab; 
number and percentage of 
subjects who develop anti-
Toripalimab-antibody 
Exploratory  
• To explore the correlation 
between molecular 
characteristics and clinical 
efficacy 
• 
PD-L1 expression  
• 
CD8 + cell density 
• 
Tumor-infiltrating 
lymphocytes (TILs) 
characterization 
 
 
 
Study design 
1. 
Phase Ib 
Eligible patients with advanced solid tumors will be enrolled. GFH018 in 
combination with Toripalimab will be administered to evaluate the safety/tolerability. 
Considering a low probability of drug-drug interaction when combining the 
monoclonal antibody with small molecule drug, and no expected overlap of major 
adverse events of these two drugs, the starting dose and dosing regimen of GFH018 
was derived from the safe dose and corresponding dosing regimen explored in 
GFH018X1101 (the dose-escalation phase I clinical study on the safety/tolerability, 
and pharmacokinetics of GFH018 in patients with advanced solid tumors) and have 
been started as 40mg BID 14 days on/14 days off. Toripalimab will be administered 
at the approved dose of 3 mg/kg as an intravenous infusion every 2 weeks. 
The first 28 days of the treatment is the observation period of dose-limiting toxicity 
(DLT) for phase Ib part. The maximum tolerated dose (MTD) will be determined by 
Bayesian optimal interval (BOIN) design. In principle, no dose adjustment is allowed 
during the DLT observation period. The definition of the DLT-evaluable subject is 
the subject who has completed the 28-day observation period and received more than 
75% of the total planned dose of GFH018, as well as the planned complete dose of 
Toripalimab (including the interruption allowed in the protocol), or has experienced 
a DLT during the DLT observation period. In the absence of DLT events, patients 
will receive the treatment until disease progression, intolerable toxicity, or other 
circumstances leading to treatment discontinuation. 
The phase Ib part will employ BOIN design to find the MTD. MTD is defined as the 
dose level at which the incidence of DLT is closest to the target toxicity rate. The 
target toxicity rate for MTD is 0.3, and the planned maximum sample size is 15. 
Subjects will be enrolled and treated in each cohort of size 3 to 6. The BOIN design 
uses the following rules, optimized to minimize the probability of incorrect dose 
assignment, to guide dose escalation/de-escalation of GFH018: 
 
If the observed DLT rate at current dose is ≤ 0.236, escalate the dose to 

 
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the next higher dose level; 
 
If the observed DLT rate at current dose is ≥ 0.359, de-escalate the dose 
to the next lower dose level; 
 
Otherwise, stay at the current dose. 
Subjects in the first cohort have been assigned to receive GFH018 40 mg BID, 14 
days on/14 days off. To assign a dose to next cohort of subjects, conduct dose 
escalation/de-escalation according to the rule displayed in the following table. If the 
current dose is the lowest dose and the rule indicates dose de-escalation, treat the 
new subject at the lowest dose; if the current dose is the highest dose and the rule 
indicates dose escalation, treat the new subject at the highest dose. If none of actions 
(i.e. escalate, de-escalate, or eliminate) is triggered, stay at the current dose for 
treating the next cohort of subjects. Dose escalation procedure will be completed 
early when the suggested next dose level has had ≥ 9 evaluable subjects. 
Dose escalation/de-escalation rule for BOIN design 
(Target toxicity rate = 30%) 
Action 
Number of subjects treated at current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Escalate if # of DLT ≤ 
0 
0 
0 
0 
1 
1 
1 
1 
2 
De-escalate if # of DLT ≥ 
1 
1 
2 
2 
2 
3 
3 
3 
4 
Eliminate if # of DLT ≥ 
NA 
NA 
3 
3 
4 
4 
5 
5 
5 
Definition of DLTs: DLT is defined as an adverse event that occurs within 28 days 
after the first administration, is assessed as related to GFH018 or Toripalimab, and 
meets the following severity. The toxicities will be assessed using the Common 
Terminology Criteria Adverse Events (CTCAE) version 5.0. Criteria for defining 
DLT are listed in the following: 
1) 
Non-hematologic toxicity 
‐ 
Grade 3 or above toxicity, except for the following circumstances: 
i. 
Nausea, vomiting, diarrhea, constipation, or pain that resolves to 
≤grade 2 within 3 days after starting appropriate treatment; 
ii. 
Fatigue, rash, or hypertension that resolves to ≤ grade 2 within 7 
days after starting appropriate treatment; 
iii. 
ALT/AST ≥ grade 3 without total bilirubin ≥ grade 2, or ALT/AST 
≥ grade 3 lasting for less than 14 days;  
iv. 
Other laboratory abnormalities not requiring intervention at the 
discretion of investigator. 
2) 
Hematologic toxicity 
‐ 
Grade 4 neutropenia lasting ≥5 days; grade 3 febrile neutropenia 
(neutrophil count < 1.0 × 109/L with a single temperature > 38.3 °C or a 
sustained temperature > 38 °C for more than 1 hour); 
‐ 
Grade 4 thrombocytopenia lasting ≥5 days, or grade 3 thrombocytopenia 
with ≥ grade 2 bleeding; 
‐ 
Grade 4 anemia lasting ≥ 5 days. 
3) 
Immune-related adverse events (irAEs) 
‐ 
≥ Grade 2 irAE that involves vital organs, such as immune-related 
myocarditis, central nervous system, ocular toxicity, and pneumonia; 
‐ 
Grade 3 irAE of other organs that fails to recover to ≤ grade 2 before the 
planned next Toripalimab administration, except grade 3 endocrine 
abnormalities that can be corrected by hormone replacement therapy;   
‐ 
Grade 4 irAEs 

 
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In addition, for other significant treatment-related toxicity, the investigator and the 
sponsor should decide whether it is assessed as DLT after discussion; the toxicity 
beyond the DLT observation period but in line with the definition of DLT will be 
taken for consideration as an important safety signal to determine the safe dose. 
2. 
Phase II  
Eligible patients with advanced solid tumors of specific types will be enrolled into 
fourteen  indication groups, including hepatocellular carcinoma, cholangiocarcinoma 
or gallbladder cancer (except carcinoma of ampulla), pancreatic cancer, colorectal 
cancer, urothelium carcinoma, cervical cancer, head and neck squamous cell 
carcinoma or esophageal squamous cell carcinoma, nasopharyngeal carcinoma, 
thymic carcinoma, endometrial cancer, osteosarcoma, TNBC and extranodal NK/T-
cell lymphoma. Patients will be treated with the dosing regimen established in phase 
Ib until disease progression, intolerable toxicity, or other circumstances leading to 
treatment discontinuation. In phase II part, dose adjustment and/or interruption of 
GFH018 or Toripalimab is allowed.  
3. 
Study Process 
Both phase Ib part and phase II part of the study can be divided into three periods. 
1) 
Screening period: Day -28 to Day -1 before the first drug administration. 
2) 
Treatment period: Eligible patients will be treated with the combination of 
GFH018 and Toripalimab until disease progression confirmed by RECIST 1.1 
or Lugano Response Criteria 2014 (only for NK/T cell lymphoma), intolerable 
toxicity, or other circumstances leading to treatment discontinuation. During 
the study period, subjects will receive safety monitoring regularly as planned; 
the imaging assessment will be performed every 8 ± 1 weeks (every 6 ± 1 
weeks for hepatocellular carcinoma) in the first year and every 12 ± 1 weeks 
(every 8 ± 1 weeks for hepatocellular carcinoma) from the second year, and 
the efficacy evaluation will be performed by the investigator based on the 
RECIST 1.1 or Lugano 2014  Criteria for NK/T cell lymphoma . The blood 
samples for pharmacokinetic and immunogenic analysis will be collected as 
specified in the protocol. 
3) 
Follow-up period: Patients will be discontinued from the study treatment 
permanently in case of disease progression, intolerable toxicity, or other 
circumstances leading to treatment discontinuation, and will receive the safety 
follow-up (which will be performed 30 days after the last administration, and 
SAE will be collected up to 90 days) and survival follow-up (until the subject 
dies, lost to follow-up, or study ends). Subjects who are discontinued from the 
study treatment for reasons other than disease progression and not start other 
anti-tumor therapies should be followed up for disease progression every 8 ± 
1 weeks (every 6 ± 1 weeks for hepatocellular carcinoma) in the first year and 
every 12 ± 1 weeks (every 8 ± 1 weeks for hepatocellular carcinoma) from the 
second year. 
The end of study is defined as the time when all enrolled patients have been under 
study treatment for at least one year or have been discontinued for any reason 
(whichever occurs first). 
Study 
population 
 
Phase Ib part: Patients with advanced solid tumors. 
 
Phase II part: Patients with advanced solid tumors, including hepatocellular 
carcinoma, cholangiocarcinoma/gallbladder cancer (except carcinoma of 
ampulla), pancreatic cancer, colorectal cancer, urothelium carcinoma, cervical 
cancer, head and neck squamous cell carcinoma, esophageal squamous cell 
carcinoma, nasopharyngeal carcinoma, thymic carcinoma, endometrial 
cancer, osteosarcoma, TNBC and extranodal NK/T-cell lymphoma. 

 
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Inclusion 
criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
1) 
Voluntarily participates in the study and signs the informed consent. 
2) 
Age ≥18 years (inclusive) at the time of signing the informed consent. 
3) 
Has histologically or cytologically confirmed diagnosis of advanced or 
metastatic solid tumors, progressed on at least first line therapy, or not been 
able to tolerate standard therapy due to toxicity or other reasons, or for whom 
no standard anticancer therapy exists. 
 
For nasopharyngeal carcinoma group: patients who haven’t received 
PD1/PDL1 inhibitor, bispecific antibody or any other checkpoint 
inhibitors; documented prior benefit (partial response, complete 
response) to checkpoint PD1/PDL1 inhibitor / bispecific antibody 
monotherapy or combined with chemotherapy and have an interval of > 
6 months between the last dose of checkpoint inhibitor and entering the 
study. 
4) 
Has sufficient organ functions, including: 
a. 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 
109/L, hemoglobin ≥ 9 g/dL, without blood transfusion or granulocyte 
colony-stimulating factor, thrombopoietin, erythropoietin and other 
therapies within 14 days prior to hematology test. 
b. 
Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × 
ULN, alkaline phosphatase (ALP) ≤ 2.5 × ULN; for subjects with tumor 
involvement of the liver who must have TBIL ≤ 3.0 × ULN, AST and 
ALT ≤ 5.0 × ULN. 
c. 
Creatinine (Cr) ≤ 1.5 × ULN, or measured/calculated creatinine 
clearance (CrCl) ≥ 50 mL/min (Cockcroft-Gault formula) if Cr > 1.5 × 
ULN; urine protein < 2+. 
d. 
International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × 
ULN (except for subject receiving anticoagulation treatment, as long as 
INR or PT is within therapeutic range of intended use of anticoagulants). 
5) 
With toxicities from prior anti-tumor therapy resolved to baseline or CTCAE 
grade 1 (neurotoxicity or alopecia ≤ grade 2). 
6) 
Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) ≤ 1. 
Subject with tumor involvement of the liver must have the Child-Pugh score 
of 5-7. 
7) 
Life expectancy ≥ 12 weeks. 
8) 
Female or male subjects of child-bearing potential must agree to use effective 
contraceptive methods from the signing of the informed consent to 90 days 
after the last administration of the study drug. Fertile female subjects must 
have negative pregnancy test results within 7 days before administration. 
Effective contraceptive methods shown as follows:  
 
Abstinence (avoiding heterosexual intercourse). 
 
Use (or make their partner use) reliable and effective methods 
of contraception during heterosexual intercourse, such as: 
i. 
Single method of contraception (any one of the following 
methods is sufficient) 
a) 
Intrauterine device (IUD) 
b) 
Vasectomy in male partner of female subject 
c) 
Subcutaneous implant contraception 
ii. 
Combined condom and oral contraceptive pills. 
Male subjects and partners with azoospermia (caused by vasectomy or 
other underlying conditions) are not required to take contraception. 
Female subjects are considered to be infertile if the following conditions 
were present: 

 
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i. 
Postmenopausal; 
ii. 
Documented hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion at least 6 
weeks prior to screening; 
iii. 
Congenital or acquired infertility. 
9) 
According to the judgment of the investigator, the subject is able to 
communicate well with the investigator to comply with the requirement of 
the protocol. 
In addition, eligible patients in phase II part must meet the following criteria: 
10) Histologically or cytologically confirmed diagnosis of advanced or 
metastatic 
tumors 
of 
specific 
types: 
hepatocellular 
carcinoma, 
cholangiocarcinoma/gallbladder cancer (except carcinoma of ampulla), 
pancreatic cancer, colorectal cancer, urothelium carcinoma, cervical cancer, 
head and neck squamous cell carcinoma, esophageal squamous cell 
carcinoma, nasopharyngeal carcinoma, thymic carcinoma, endometrial 
cancer, osteosarcoma, TNBC and extranodal NK/T-cell lymphoma. 
11) At least one measurable lesion according to RECIST 1.1 or Lugano 2014 
Criteria (only for extranodal NK/T-cell lymphoma). 
12) For hepatocellular carcinoma patients: 
platelet count ≥60x109/L, without thrombopoietin or other therapies within 
14 days prior to hematology test. 
13) For cervical cancer patients: 
hemoglobin ≥ 8 g/dL, without blood transfusion or erythropoietin and other 
therapies within 14 days prior to hematology test. 
Exclusion 
criteria 
Patients eligible for this study must not meet any of the following criteria: 
1) 
Impaired cardiac function or clinically significant cardiac diseases: 
a. 
Clinically significant cardiac diseases within 6 months, for example: 
myocardial infarction, angina, heart failure, severe arrhythmia, 
angioplasty, stent implantation, and coronary artery bypass grafting; 
b. 
Ascending aorta aneurysm or major artery aneurysm history, or 
predisposing conditions that are consistent with development of 
aneurysms (for example, family history of aneurysm, Marfan 
syndrome, evidence of damage to the large vessels of the heart 
documented by computerized tomography [CT] scan with contrast); 
c. 
Abnormalities at screening/baseline, which will be confirmed by the 
cardiologist if necessary: 
i. 
ECG: QT/QTc prolongation (QTcF > 470 ms for females or 
QTcF > 450 ms for males), or other clinically significant 
arrythmia, 
conduction 
abnormalities, 
morphology 
abnormalities; 
ii. 
Doppler 
echocardiography: 
clinically 
significant 
abnormalities, such as left ventricular ejection fraction 
(LVEF) < 50%, moderate or severe heart valve stenosis, and 
moderate or severe heart valve regurgitation; 
iii. 
Troponin > ULN in conjunction with symptoms or other 
abnormal testing indicating myocardial ischemia 
2) 
With acute or chronic infections, including: 
a 
Active infections requiring intravenous treatment; 
b 
Positive human immunodeficiency virus antibody (HIV-Ab), active 
syphilis, active hepatitis B virus infection (positive HBsAg and 
positive HBV-DNA), and active hepatitis C virus infection (positive 
HCV-Ab and positive HCV-RNA) during the screening/baseline 

 
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period; 
c 
Active tuberculosis. 
3) 
With active central nervous system metastases, including symptomatic brain 
metastases, meningeal metastases, spinal cord compression, or requiring 
treatment with glucocorticoids, antiepileptic drugs, anticonvulsant drugs, or 
mannitol. 
4) 
With known active autoimmune diseases or a history of autoimmune diseases 
within 1 year prior to enrollment, such as systemic lupus erythematosus, 
psoriasis, rheumatoid arthritis, inflammatory bowel disease, and Hashimoto's 
thyroiditis. Except for type I diabetes, hypothyroidism or hyperthyroidism 
that can be controlled with only hormone replacement, skin diseases 
requiring no systemic treatment, controlled celiac disease. 
5) 
With clinically significant gastrointestinal diseases, such as intractable 
hiccup, nausea and vomiting, severe peptic ulcer, active gastrointestinal 
bleeding, or other conditions that interfere swallowing the tablets or 
significantly alter the absorption; subjects with hepatocellular carcinoma who 
have severe portal hypertension due to Budd-Chiari syndrome or portal vein 
thrombosis. 
6) 
Uncontrollable or symptomatic ascites, pleural effusion or pericardial 
effusion. 
7) 
History of non-infectious (e.g., drug-induced) ILD requiring systemic steroid 
treatment, or current pneumonitis. 
8) 
With other uncontrolled systemic diseases, such as hypertension and diabetes. 
9) 
Diagnosed with other malignant tumors within 3 years prior to starting study 
drug, except for cured carcinoma in situ of cervix, skin basal cell carcinoma, 
early stages of prostate or thyroid cancer. 
10) With diseases requiring immunosuppressant therapy, or requiring 
prednisone > 10 mg/day or equivalent dose of similar drugs during the study 
period. 
11) Subjects who have been treated with immunosuppressant drugs within 28 
days prior to starting study drug, except for topical and inhaled cortisol and 
systemic cortisol of physiological dose (prednisone < 10 mg/day or 
equivalent dose of similar drugs). 
12) Subjects who have received live vaccine, attenuated vaccine within 28 days 
prior to starting study drug, or plans to receive live vaccine, attenuated 
vaccine during treatment or within 30 days after the last administration. 
13) Subjects who have been treated with radiotherapy, chemotherapy, targeted 
therapy, endocrine therapy, immunotherapy, and other anti-tumor therapies 
(except for traditional Chinese medicines), or other investigational drugs 
within 5 half-life periods or within 28 days (whichever is shorter) prior to 
starting study drug. 
14) Subjects who have been treated with traditional Chinese medicine with 
approved antitumor indications within 2 weeks prior to starting study drug. 
15) Subject who has received major surgeries (except for needle biopsy) that may 
affect the administration or study evaluation within 28 days prior to starting 
study drug. 
16) Subjects who have received strong inhibitor or inducer of CYP3A4 within 5 
half-life periods or within 2 weeks (whichever is shorter) prior to starting 
study drug. 
17) Subjects who have received combined treatment of drugs targeting TGF-β 
and PD-(L)1, including combination of antibody and small molecule or 
bispecific antibody. 

 
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18) Pregnant or lactating women. 
19) With known allergies to the study drugs or components. 
20) The subject is a staff member who is directly related to the investigator of the 
study or his/her family members, or the sponsor. 
21) Other conditions judged by the investigator as inappropriate to participate in 
the study. 
Sample size 
Phase Ib part 
Subjects will be enrolled and treated in cohort size of 3-6. A minimum of 6 DLT-
evaluable subjects are required for the recommended Phase II dosing level. Up to 15 
subjects will be enrolled and treated in the phase Ib part. Additional subjects may be 
enrolled if more dose levels or alternative dosing regimens are to be explored. 
Phase II part 
Ten subjects will be enrolled in each tumor type. Subjects from phase Ib part who 
have received the phase II treatment regimen and meet the phase II part eligibility 
criteria will be counted. Depending on the clinical benefits of each tumor type, the 
sponsor will determine the enrollment of additional 10-20 subjects with the same 
tumor type, i.e., one tumor type can be expended to approximately a total of 20-30 
subjects, tumor types with potential benefit will be expanded to maximal 60 patients 
at the discretion of the sponsor and leading investigators. Otherwise, if none of the 
ten shows response (i.e., complete response or partial response according to RECIST 
1.1 or Lugano 2014 Criteria), the enrollment of subjects with the specific tumor type 
may be stopped. 
Statistical 
analysis 
Analysis population 
 
Full Analysis Set (FAS) consists of all subjects who have received at least 
one dose of study treatment. 
 
Safety Set (SS) includes all subjects from the FAS who have received at least 
one dose of study treatment and had at least one valid post-baseline safety 
assessment. 
 
Dose Determining Set (DDS) consists of all subjects in the SS from phase 
Ib part who have received at least 75% of the total planned dose of GFH018 
and the planned complete dose of Toripalimab (including the interruption 
allowed in the regimen) during the DLT observation period, are considered 
to have sufficient safety evaluation or developed DLT during the DLT 
observation period, and have no major protocol deviations that would impact 
the safety analyses. 
 
Per Protocol Set (PPS) consists of all subjects in the FAS who are in 
compliance with the protocol from phase II part. Subjects who have major 
protocol deviations may be excluded from the PPS based on a study team 
review of all protocol deviations, which will be conducted before final 
database lock. 
 
Pharmacokinetic analysis set (PKAS) consists of all subjects who take at 
least one dose of study treatment and have at least one blood sample 
providing evaluable concentration data. 
Statistical Methods 
The phase Ib and phase II data will be analyzed separately. The summary will be 
presented by dose level and regimen for phase Ib part. The summary will be 
presented by tumor type for phase II part, subjects who have been treated with the 
phase II treatment regimen in phase Ib and meet the phase II eligibility criteria will 
be counted. 
Safety Analysis 
Safety analysis will include AEs, vital signs, physical examination, ECG, and 
laboratory test. Treatment emergent adverse events (TEAEs), study treatment related 

 
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AEs, SAEs, AESI, irAEs, TEAEs leading to interruption of study treatment, TEAEs 
leading to discontinuation of study treatment will be summarized by system organ 
class (SOC) and preferred term (PT). DLTs will be listed and summarized for each 
dose level using DDS. Laboratory parameters, vital signs, and ECGs will be listed 
and summarized by time point.  
Efficacy Analysis 
The number of subjects with the best overall response (BOR) of complete response 
(CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be 
summarized according to the assessment results of each visit. ORR and DCR will be 
summarized. For phase II part, the corresponding two-sided 90% confidence interval 
(CI) for ORR and DCR will be estimated by the Clopper-Pearson method. For phase 
Ib part, DOR, TTR, PFS, and OS will be listed individually by subject. For phase II 
part, when the sample size of analyzed group is ten or more, the Kaplan-Meier 
method will be used to provide median 90% Brookmeyer-Crowley CI. 
Pharmacokinetic Analysis 
The drug plasma or serum concentration data will be summarized and plotted by time 
point for each group. PK parameters will be listed by subject and summarized 
descriptively. 
Immunogenicity analysis 
The number and percentage of subjects with positive anti-drug antibody (ADA) will 
be summarized. 
Interim 
analysis 
No formal interim analysis is planned. 
 
 
 
 

 
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Study Assessment Schedule 
Study Assessment Schedule for phase Ib 
Phase Ib 
Protocol 
Section 
Screening 
Treatment (28 days for each cycle) 
Safety follow-up  
Survival follow-up 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
EOT 
30 days after the 
last administration 
Every 90 days after 
safety follow-up  
Days 
  
D-28 ~ D-1 
D1 
D8 
D15 
D28 
D1 
D15 
D1 
D15 
Within 7 days after 
discontinuation of 
study treatment 
Window (days) 
  
NA 
0 
±2  
±3 
0 
±3  
±3  
±3  
±3  
±3  
±15  
General & Safety 
Informed consent 
15.3 
X 
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion criteria1 
4.1 & 4.2 
X 
X 
  
  
  
  
  
  
  
  
  
  
Demography 
6.1 
X 
  
  
  
  
  
  
  
  
  
  
  
Prior therapies2 
5.6.1 
X 
  
  
  
  
  
  
  
  
  
  
  
Medical history3 
4.1 & 4.2 
X 
  
  
  
  
  
  
  
  
  
  
  
Concomitant therapies 
5.6.2 
 
X（Concomitant therapies should be collected from first administration to the end of safety follow-up period） 
  
Subsequent disease information4 
6.4.2 
  
  
  
  
  
  
  
  
  
X 
X 
X 
Survival information 
6.4.2 
  
  
  
  
  
  
  
  
  
  
  
X 
Physical examination & Weight& 
Height5 
7.1.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Vital signs 
7.1.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Echocardiography6     
7.1.3 
X 
X  
  
  
X 
X 
  
X 
  
X 
X 
  
ECG6 
7.1.3 
X 
X 
X 
X 
X 
X 
 X 
X 
 X 
X 
X 
  
ECOG PS 
7.1.1 
X 
  
  
X 
  
  
X 
  
X 
X 
X 
  
AE  
8.1&8.5 
X（AEs should be collected from informed consent form to 30 days after the last administration of the study treatment） 
  
SAE 
8.2&8.5 
X（SAEs should be collected from informed consent form to 90 days after the last administration of the study treatment） 
Laboratory assessments 
Virus serological test 
7.1.2 
X 
  
  
  
  
  
  
  
  
  
  
  
Pregnancy test7 
7.1.2 
X 
X 
  
  
  
X 
  
X 
  
X 
X 
  
Hematology8 
7.1.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  

 
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Phase Ib 
Protocol 
Section 
Screening 
Treatment (28 days for each cycle) 
Safety follow-up  
Survival follow-up 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
EOT 
30 days after the 
last administration 
Every 90 days after 
safety follow-up  
Days 
  
D-28 ~ D-1 
D1 
D8 
D15 
D28 
D1 
D15 
D1 
D15 
Within 7 days after 
discontinuation of 
study treatment 
Window (days) 
  
NA 
0 
±2  
±3 
0 
±3  
±3  
±3  
±3  
±3  
±15  
Urinalysis8 
7.1.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Blood Chemistry8 
7.1.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Coagulation8   
7.1.2 
X 
X 
  
X 
X 
X 
  
X 
  
X 
X 
  
Thyroid function 
7.1.2 
X 
X 
  
X 
X 
X 
  
X 
  
X 
X 
  
Cardiac markers   
7.1.2 
X 
X 
  
X 
X 
X 
  
X 
  
X 
X 
  
Tumor markers9 
7.1.2 
X 
  
  
  
  
X 
  
X 
  
X 
X 
  
Efficacy assessments  
Radiological imaging and tumor 
assessment10 
7.4 
X 
Study Drug Administration 
GFH018 administration11 
5.3 
  
X 
 
  
  
Toripalimab administration11 
5.3 
  
X 
  
X 
  
X 
X 
X 
X 
  
  
  
Sample collection 
Biomarker tissue sampling12 
  
X 
  
  
  
  
  
  
  
  
  
  
  
PK blood sampling 
  
  
X（Refer to blood sampling schema） 
 
  
  
ADA blood sampling  
  
  
 
  
  
Abbreviations: EOT, End of Treatment; ECOG, Eastern Cooperative Oncology Group; PS, Performance Status; ECG, electrocardiogram; AE, Adverse Event; SAE, 
Serious Adverse Event; PK, pharmacokinetics; ADA, Anti-drug Antibody. 
Note: for the procedures repeated in C1D28 and C2D1, if within the 3-day window, there is no need to repeat it in C2D1. 
1. 
Patient eligibility should be verified at Cycle1 D1. 
2. 
Including prior anti-tumor therapies, and other therapies (within 30 days) prior to the first administration of study treatment. 
3. 
The medical history within 30 days prior to signing of the informed consent, diagnosis and extent of cancer should be collected. 
4. 
Including information on disease progression and subsequent anti-tumor treatment. 

 
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5. 
Height only measured during screening. 
6. 
The results within 2 weeks prior to Cycle1D1 is acceptable and repeated testing at Cycle1D1 is not required. 
7. 
The serum pregnancy test is required at Cycle1D1. For other visits, both serum test and urine test are acceptable. The results within 1 week prior to Cycle1D1 is 
acceptable and repeated testing at Cycle1D1 is not required. 
8. 
The test results within 1 week prior to Cycle1D1 are acceptable and repeated testing at Cycle1D1 is not required. Unscheduled testing may be performed when 
necessary. 
9. 
Specific cancer biomarkers are monitored only for patients with hepatocellular carcinoma, colorectal cancer, and pancreatic cancer. 
10. The results within 4 weeks prior to first administration are acceptable for the baseline if requirements are met, and repeated assessment at baseline is not required. 
Every 8 ± 1 weeks (every 6 ± 1 weeks for hepatocellular carcinoma) in the first year and every 12 ± 1 weeks (every 8 ± 1 weeks for hepatocellular carcinoma) 
from the second year. If a patient discontinues due to reasons other than disease progression and does not start subsequent antitumor therapy, the radiological tests 
will be performed on the scheduled visit until disease progression, initiation of new antitumor therapy or other reasons.  
11. GFH018 tablets will be received on the designated visit day and taken orally as planned. Toripalimab will be given by intravenous infusion every 2 weeks on the 
visit day. 
12. If available, archival formalin-fixed, paraffin-embedded tumor sample shall be submitted before the first administration. 
 

 
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Study Assessment Schedule for phase II 
Phase II 
Protocol 
Section 
Screening 
Treatment (28 days for each cycle) 
Safety follow-up  
Survival follow-up 
Cycle 1 
Subsequent Cycles 
EOT 
30 days after the last 
administration 
Every 90 days after 
safety follow-up 
Days 
  
D-28 ~ D-1 
D1 
D15 
D1 
D15 
Within 7 days after 
discontinuation of study 
treatment 
Window (days) 
  
NA 
0 
±3 
±3  
±3  
±3  
±15  
General & Safety 
Informed consent 
15.3 
X 
  
  
  
  
  
  
  
Inclusion/exclusion criteria1 
4.1 & 4.2 
X 
X 
  
  
  
  
  
  
Demography 
6.1 
X 
  
  
  
  
  
  
  
Prior therapies2 
5.6.1 
X 
  
  
  
  
  
  
  
Medical history3 
4.1 & 4.2 
X 
  
  
  
  
  
  
  
Concomitant therapies 
5.6.2 
 
X（Concomitant therapies should be collected from first administration to the end of safety follow-up period） 
  
Subsequent disease information4 
6.4.2 
  
  
  
  
  
X 
X 
X 
Survival information 
6.4.2 
  
  
  
  
  
  
  
X 
Physical examination & Weight& 
Height5 
7.1.1 
X 
X 
X 
X 
X 
X 
X 
  
Vital signs 
7.1.1 
X 
X 
X 
X 
X 
X 
X 
  
Echocardiography 
7.1.3 
X 
X (According to the clinical practice) 
  
ECG 
7.1.3 
X 
X 
 
X 
  
X 
X 
  
ECOG PS 
7.1.1 
X 
  
X 
  
X 
X 
X 
  
AE  
8.1&8.5 
X（AEs should be collected from informed consent form to 30 days after the last administration of the study treatment） 
  
SAE 
8.2&8.5 
X（SAEs should be collected from informed consent form to 90 days after the last administration of the study treatment） 
Laboratory assessments 
Virus serological test 
7.1.2 
X 
  
  
  
  
  
  
  
Pregnancy test7 
7.1.2 
X 
X 
  
X 
  
X 
X 
  

 
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Phase II 
Protocol 
Section 
Screening 
Treatment (28 days for each cycle) 
Safety follow-up  
Survival follow-up 
Cycle 1 
Subsequent Cycles 
EOT 
30 days after the last 
administration 
Every 90 days after 
safety follow-up 
Days 
  
D-28 ~ D-1 
D1 
D15 
D1 
D15 
Within 7 days after 
discontinuation of study 
treatment 
Window (days) 
  
NA 
0 
±3 
±3  
±3  
±3  
±15  
Hematology8 
7.1.2 
X 
X 
X 
X 
X 
X 
X 
  
Urinalysis8 
7.1.2 
X 
X 
X 
X 
X 
X 
X 
  
Blood Chemistry8 
7.1.2 
X 
X 
X 
X 
X 
X 
X 
  
Coagulation8  
7.1.2 
X 
X 
 
X 
  
X 
X 
  
Thyroid function 
7.1.2 
X 
  
 
X 
  
X 
X 
  
Cardiac markers 
7.1.2 
X 
  
 
X 
  
X 
X 
  
Tumor markers9 
7.1.2 
X 
  
  
X 
  
X 
X 
  
Efficacy assessments  
Radiological imaging and tumor 
assessment10 
7.4 
X 
Study Drug Administration 
GFH018 administration11 
5.3 
  
X 
 
  
  
Toripalimab administration11 
5.3 
  
X 
X 
X 
X 
  
  
  
Sample collection 
Biomarker tissue sampling12 
  
X 
  
  
  
  
  
  
  
PK blood sampling 
  
  
X（Refer to blood sampling schema） 
  
  
ADA blood sampling  
  
  
  
  
Abbreviations: EOT, End of Treatment; ECOG, Eastern Cooperative Oncology Group; PS, Performance Status; ECG, electrocardiogram; AE, Adverse Event; SAE, 
Serious Adverse Event; PK, pharmacokinetics; ADA, Anti-drug Antibody. 
Note: 
1. 
Patient eligibility should be verified at Cycle1 D1. 

 
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2. 
Including prior anti-tumor therapies, and other therapies (within 30 days) prior to the first administration of study treatment. 
3. 
The medical history within 30 days prior to signing of the informed consent, diagnosis and extent of cancer should be collected. 
4. 
Including information on disease progression and subsequent anti-tumor treatment. 
5. 
Height only measured during screening. 
6. 
The results of ECG within 2 weeks prior to Cycle1D1 is acceptable and repeated testing at Cycle1D1 is not required. 
7. 
The serum pregnancy test is required at Cycle1D1. For other visits, both serum test and urine test are acceptable. The results within 1 week prior to Cycle1D1 is 
acceptable and repeated testing at Cycle1D1 is not required. 
8. 
The test results within 1 week prior to Cycle1D1 are acceptable and repeated testing at Cycle1D1 is not required. Unscheduled testing may be performed when 
necessary. 
9. 
Specific cancer biomarkers are monitored only for patients with hepatocellular carcinoma, colorectal cancer, and pancreatic cancer. 
10. The results within 4 weeks prior to first administration are acceptable for the baseline if requirements are met, and repeated assessment at baseline is not required. 
Every 8 ± 1 weeks (every 6 ± 1 weeks for hepatocellular carcinoma) in the first year and every 12 ± 1 weeks (every 8 ± 1 weeks for hepatocellular carcinoma) 
from the second year. If a patient discontinues due to reasons other than disease progression and does not start subsequent antitumor therapy, the radiological tests 
will be performed on the scheduled visit until disease progression, initiation of new antitumor therapy or other reasons. For subjects with extranodal NK/T cell 
lymphoma, the baseline imaging evaluation shall include both PET-CT and diagnostic enhanced CT/MRI of the neck, chest, abdomen, and pelvis, and enhanced 
MRI of the nasopharynx is necessary for nasal type. PET-CT can be used according to the local investigator interpretations in the subsequent evaluations. 
11. GFH018 will be received on the designated visit day and taken orally as planned. Toripalimab will be given by intravenous infusion every 2 weeks on the visit 
day. 
12. If available, archival formalin-fixed, paraffin-embedded tumor sample shall be submitted before the first administration. 
 

 
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Blood Sampling Schema 
Blood sampling schema of GFH018 PK and PK/ADA for Toripalimab in Phase Ib1, 2 
Cycle 
C1 
C2-C4 
Day 
D1 
D8 
D15 
D15 
Timepoints 
Pre-
dose 
post-dose 
0.5h 
1h  
2h 
4h  
8h 
12 h 
Pre-
dose 
post-dose 
0.5h 
1h  
2h 
4h  
8h 
12 h 
Pre-
dose 
Pre-
dose 
Window 
-0.5h 
±10min 
±10min 
±10min 
±15min 
± 30min 
± 30min 
-0.5h 
±10min 
±10min 
±10min 
±15min 
± 30min 
± 30min 
-0.5h 
-0.5h 
GFH018 PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
Toripalimab 
PK/ADA  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Abbreviations: PK, pharmacokinetics; ADA, anti-drug antibody; C, cycle; D, day. 
Note:  
1. The scheduled time points are calculated from the first administration time of GFH018 on that specified day.  
2. The pre-dose 0.5h timepoints of PK for GFH018 and PK/ADA for Toripalimab can be collected at the same time within 0.5 h prior to the combination therapy. 
Blood sampling schema of GFH018 PK and PK/ADA for Toripalimab in Phase II 
Cycle 
C1 
C2-C4 
Day 
D1 
D15 
D15 
Timepoints 
Pre-dose 
Pre-dose 
Pre-dose 
Window 
-0.5h 
-0.5h 
-0.5h 
GFH018 PK 
X 
X 
X 
Toripalimab PK/ADA  
X 
X 
X 
Abbreviations: PK, pharmacokinetics; ADA, anti-drug antibody; PD, pharmacology; C, cycle; D, day. 
Note: The pre-dose 0.5h timepoints of PK for GFH018 and PK/ADA for Toripalimab can be collected at the same time within 0.5 h prior to the combination therapy. 

 
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TABLE OF CONTENTS 
 
Protocol Change Summary (Nov2022) .............................................................................. 4 
Protocol Change Summary (Apr2022) ............................................................................... 5 
Protocol Change Summary (Mar2022) .............................................................................. 6 
Protocol Change Summary (Jun2021) ................................................................................ 8 
Protocol Synopsis ............................................................................................................... 9 
Study Assessment Schedule ............................................................................................. 19 
Blood Sampling Schema .................................................................................................. 25 
TABLE OF CONTENTS ................................................................................................. 26 
LIST OF TABLES ........................................................................................................... 31 
LIST OF FIGURES .......................................................................................................... 31 
ABBREVIATIONS .......................................................................................................... 32 
1 INTRODUCTION ....................................................................................................... 34 
1.1 
Study Background ............................................................................................ 34 
1.2 
Scientific Rationale .......................................................................................... 36 
1.2.1 
Research Rationale ...................................................................................... 36 
1.2.2 
Rational for Dose Selection ........................................................................ 39 
1.3 
Risk/Benefit Assessment ................................................................................. 40 
1.3.1 
Preclinical Toxicology Studies of GFH018 ................................................ 40 
1.3.2 
Clinical Data of GFH018 and Toripalimab ................................................. 41 
1.3.3 
Assessment of Potential Risks and Benefits ............................................... 41 
2 STUDY OBJECTIVES AND STUDY ENDPOINTS ................................................ 42 
3 STUDY DESIGN ........................................................................................................ 44 
3.1 
Overview of Study Design ............................................................................... 44 
3.2 
Phase Ib ............................................................................................................ 44 
3.2.1 
Provisional Dose Levels .............................................................................. 45 
3.2.2 
Escalation/De-escalation Rules ................................................................... 45 

 
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3.2.3 
Definition of DLT ....................................................................................... 48 
3.3 
Phase II............................................................................................................. 49 
3.4 
Study Procedures ............................................................................................. 49 
4 STUDY POPULATION .............................................................................................. 51 
4.1 
Inclusion Criteria ............................................................................................. 51 
4.2 
Exclusion Criteria ............................................................................................ 53 
5 STUDY TREATMENT ............................................................................................... 55 
5.1 
Study Treatment Assignment ........................................................................... 55 
5.2 
Supply of Study Drugs ..................................................................................... 56 
5.2.1 
Strength and Packages of Study Drugs ....................................................... 56 
5.2.2 
Preparation and Dispensing of Study Drugs ............................................... 56 
5.3 
Dose and Administration ................................................................................. 57 
5.3.1 
Dose and Administration of GFH018 ......................................................... 57 
5.3.2 
Dose and Administration of Toripalimab Injection .................................... 58 
5.3.3 
Subject Compliance .................................................................................... 61 
5.4 
Drug Storage .................................................................................................... 62 
5.5 
Records of Administration and Destruction .................................................... 62 
5.6 
Prior and Concomitant Therapies .................................................................... 62 
5.6.1 
Prior Therapies ............................................................................................ 62 
5.6.2 
Concomitant Therapies ............................................................................... 63 
6 STUDY PROCEDURES ............................................................................................. 65 
6.1 
Screening Period .............................................................................................. 65 
6.2 
Treatment Period .............................................................................................. 66 
6.2.1 
Cycle 1 ........................................................................................................ 66 
6.2.2 
Subsequent Cycles ...................................................................................... 67 
6.3 
End-of-Treatment (EOT) Visit ........................................................................ 68 
6.4 
Follow-up Period ............................................................................................. 69 
6.4.1 
Safety Follow-up ......................................................................................... 69 

 
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6.4.2 
Survival Follow-up ...................................................................................... 70 
6.4.3 
Disease Progression Follow-up ................................................................... 70 
6.4.4 
Unscheduled Follow-up .............................................................................. 70 
6.5 
Discontinue/Withdraw from Treatment or Study ............................................ 70 
6.5.1 
Discontinuation of Study Treatment ........................................................... 70 
6.5.2 
Withdraw from the Study ............................................................................ 71 
6.6 
Study Completion and Early Study Termination ............................................. 72 
6.7 
Continue to Use the Study Drug after the Study Ends..................................... 73 
7 EVALUATION ........................................................................................................... 73 
7.1 
Safety Evaluation ............................................................................................. 73 
7.1.1 
Physical Examination .................................................................................. 73 
7.1.2 
Laboratory Assessment ............................................................................... 73 
7.1.3 
Electrocardiogram and Echocardiogram ..................................................... 74 
7.1.4 
Adverse events and Concomitant Therapies ............................................... 75 
7.2 
Pharmacokinetics ............................................................................................. 75 
7.2.1 GFH018 PK Samples Collection ............................................................................ 75 
7.2.2 
Toripalimab PK and ADA Samples Collection .......................................... 77 
7.2.3 
Sample Analysis Methods ........................................................................... 77 
7.2.4 
Calculation of Pharmacokinetic Parameters ............................................... 77 
7.3 
Evaluation of Biomarkers ................................................................................ 77 
7.4 
Evaluation of Tumor Response ........................................................................ 78 
8 REPORT OF ADVERSE EVENTS ............................................................................ 78 
8.1 
Adverse Events (AE) ....................................................................................... 78 
8.1.1 
Definition of AE .......................................................................................... 78 
8.1.2 
Immune-Related Adverse Events (irAE) .................................................... 79 
8.1.3 
Adverse Events of Special Interest (AESI) ................................................. 79 
8.1.4 
Severity Assessment .................................................................................... 79 
8.1.5 
Causality Assessment .................................................................................. 80 
8.2 
Serious Adverse Event (SAE) .......................................................................... 80 

 
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8.2.1 
Definition of SAE ....................................................................................... 80 
8.2.2 
Hospitalisation ............................................................................................. 81 
8.2.3 
Disease Progression and Death ................................................................... 82 
8.2.4 
SAE Reporting Requirements ..................................................................... 82 
8.3 
Pregnancy ......................................................................................................... 83 
8.4 
Hy’s law ........................................................................................................... 84 
8.5 
Collection and Follow-Up of AE/SAE/AESI/Pregnancy Events .................... 84 
9 CLINICAL MONITORING ........................................................................................ 85 
10 STATISTICAL ANALYSIS ....................................................................................... 86 
10.1 
Analysis Sets .................................................................................................... 86 
10.2 
Distribution of Subjects ................................................................................... 86 
10.3 
Protocol Deviations .......................................................................................... 87 
10.4 
Demographic and Baseline Characteristics ..................................................... 87 
10.5 
Treatment Exposure ......................................................................................... 87 
10.6 
Concomitant Medications ................................................................................ 87 
10.7 
Efficacy Analysis ............................................................................................. 87 
10.8 
Safety Analysis ................................................................................................ 88 
10.9 
Immunogenicity analysis ................................................................................. 89 
10.10 
Pharmacokinetic Analysis ................................................................................ 89 
10.11 
Pharmacodynamic Analysis ............................................................................. 89 
10.12 
Sample Size ...................................................................................................... 89 
10.13 
Interim Analysis ............................................................................................... 89 
11 SAFETY MONITORING ............................................................................................ 90 
12 DATA COLLECTION AND MANAGEMENT ......................................................... 90 
12.1 
Data Collection ................................................................................................ 90 
12.2 
Data Management ............................................................................................ 90 
13 SOURCE DATA AND ORIGINAL FILE .................................................................. 91 
14 QUALITY ASSURANCE AND QUALITY CONTROL ........................................... 91 
15 ETHICAL CONSIDERATIONS ................................................................................. 92 
15.1 
Ethical Compliance .......................................................................................... 92 
15.2 
Independent Ethics Committee ........................................................................ 93 
15.3 
Informed Consent............................................................................................. 93 

 
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15.3.1 
Informed Consent Form .............................................................................. 93 
15.3.2 
Informed Consent Procedures ..................................................................... 93 
15.4 
Confidentiality of Patients' Information .......................................................... 94 
15.5 
Future Use of Preserved Specimens ................................................................ 94 
16 PUBLICATION OF STUDY RESULTS .................................................................... 95 
17 REFERENCES ............................................................................................................ 96 
Appendix 1 Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
 
100 
Appendix 2 ECOG Performance Status ......................................................................... 113 
Appendix 3 Operating Characteristics of the BOIN Design .......................................... 114 
Appendix 4 Lugano Response Criteria 2014 for Non-Hodgkin Lymphoma ................. 115 
 
 

 
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LIST OF TABLES 
Table 1 Dose escalation/de-escalation rule for target toxicity rate = 0.3........................... 47 
Table 2 Recommended treatment adjustment scheme of Toripalimab .............................. 60 
Table 3 Inducers and inhibitors of CYP3A4/5 (partial) .................................................... 64 
Table 4 Laboratory test items ............................................................................................ 74 
Table 5 Schedule of pharmacokinetic blood sample collection (14/14) ............................ 75 
Table 6 General guideline on the severity of adverse events ............................................ 79 
Table 7 Criteria for Liver Function Test Abnormalities .................................................... 84 
Table 8 Collection of AE/SAE/AESI/pregnancy events .................................................... 85 
 
LIST OF FIGURES 
Figure 1. Effects of GFH018 combined with PD-L1 or PD-1 antibody on the tumor growth 
of CT26 colon or Pan02 pancreatic cancer model ............................................................. 37 
Figure 2. Overview of study design................................................................................... 44 
Figure 3. BOIN design flow chart ..................................................................................... 46 
Figure 4. Schematic diagram of subject study procedures ................................................ 49 
 
 
 
 

 
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ABBREVIATIONS 
Abbreviations 
Full Name in English 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ADA 
Anti-Drug Antibody 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BOIN 
Bayesian Optimal Interval 
BUN 
Blood Urea Nitrogen 
CK 
Creatine Kinase 
Cl- 
Blood Chlorine 
Cr 
Creatinine 
CR 
Complete Remission 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
DCR 
Disease Control Rate 
DDI 
Drug-Drug Interaction 
DLT 
Dose-Limiting Toxicity 
DOR 
Duration of Response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EMT 
Epithelial-Mesenchymal Transition 
GCP 
Good Clinical Practice 
GLU 
Blood Glucose 
Hb 
Hemoglobin 
HDL-C 
High-Density Lipoprotein cholesterol 
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest Non-Severely Toxic Dose 
ICH-GCP 
International Council for Harmonization 
irAE 
Immune-Related Adverse Events 
LEU 
Leukocytes in Urine 
K+ 
Serum Potassium 
KET 
Urine Acetone Bodies 
LDH 
Lactate Dehydrogenase 
LDL-C 
Low-Density Lipoprotein Cholesterol 
LLOQ 
Lower Limit of Quantification 
MTD 
Maximum Tolerated Dose 
Na+ 
Plasma Sodium 

 
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Abbreviations 
Full Name in English 
NK/T 
Natural killer T cell 
NMPA 
National Medical Products Administration 
NOAEL 
No-Observed-Adverse-Effect Level 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD-1 
Programmed Cell Death 
PD-L1 
Programmed Death Ligand 
PFS 
Progression Free Survival 
PLT 
Blood Platelet 
PK 
Pharmacokinetic 
PRO 
Protein in Urine 
RBC 
Red Blood Cell Count 
RECIST 
The Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommend Phase II Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
T-BIL 
Total Bilirubin 
TGF 
Transforming Growth Factor 
TC 
Total Cholesterol 
TG 
Triglyceride 
TNBC 
Triple-negative breast cancer 
TTR 
Time to Response 
UCG 
Ultrasonic Cardiogram 
ULN 
Upper Limits of Normal 
WBC 
White Blood Cell Count 
 
 
 

 
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1 INTRODUCTION 
1.1 
Study Background 
Transforming growth factor-β (TGF-β) is a multifunctional cytokine, which binds transforming 
growth factor-β receptor II (TGF-βRII) on cell membrane, and subsequently forms a dimer with 
TGF-βRI to activate downstream SMAD dependent or independent signaling. This pathway 
plays a variety of biological functions. In advanced tumors, TGF-β signaling pathway activates 
and promotes epithelial mesenchymal transition (EMT) and metastasis of tumor cells, induces 
and maintains the function of tumor stem cells, inhibits anti-tumor immune response in tumor 
microenvironment, increases angiogenesis in tumor microenvironment, increases tissue 
fibrosis, and comprehensively promotes tumor progression1-2. In a variety of solid tumor 
patients, including hepatocellular carcinoma, glioma, colorectal cancer, lung cancer, pancreatic 
cancer, urothelial cancer and so on, TGF-β signaling pathway genes were found to be highly 
expressed in tumors, and their expression level was positively correlated with the poorly 
differentiated cells and tumor stages, and the poor prognosis of patients3-6. Therefore, targeting 
this signaling pathway may provide a therapeutic opportunity.  
Drugs targeting PD-1/ (PD-L1) pathway have shown a substantial anti-tumor activity. Up to 
date, a number of monoclonal antibody products targeting PD-1 or PD-L1, including 
Toripalimab, have been approved for treating cancer in China and other countries. The approved 
indications include melanoma, non-small cell lung cancer, renal cell carcinoma, classical 
Hodgkin lymphoma, head and neck cancer, bladder cancer (urothelial cancer), gastric cancer, 
liver cancer, High-level microsatellite instability (MSI-H) or Different Mismatch 
Repair(dMMR) colorectal cancer, cervical cancer and esophageal squamous cell carcinoma, 
and others as single agent or combination regimen in different settings. However, overall 
response rate of PD-1/PD-L1 antibodies treating cancer is still limited. Without selecting 
population, the response rates of treating melanoma, Merkel cell carcinoma, Hodgkin’s 
lymphoma and microsatellite unstable tumors are relatively high, ranging from about 40% to 
70%7-10, but the response rate in most other approved tumors is only 10%-25%11-12. Also, 
patients might develop acquired drug resistance even after the initial response. The possible 
reasons include the different expression level of PD-L1 and heterogeneity in tumors13-14. 
Therefore, a variety of combined treatment strategies are being explored to improve the efficacy 
of checkpoint inhibitor. One of the directions is to improve the tumor immune 
microenvironment and increase the chance of immune response. 

 
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With the deepened understanding of the inhibitory effect of TGF-β in tumor immune 
microenvironment, the combination of TGF-β target inhibitor with PD-(L)1 inhibitor or the 
exploration of TGF-β/PD-L1 bispecific antibody have been promoted from preclinical to 
clinical study. Among them, M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein 
from Merck has been explored among patients with cholangiocarcinoma, cervical cancer or 
non-small cell lung cancer. The reported clinical study data show that the combination of 
M7824 can bring durable response, and the safety profile is similar to PD-(L)1 and consistent 
with the expectations of relevant targets15-16.  
GFH018 p-toluenesulfonate (abbreviated as GFH018) is a chemically synthesized small 
molecule and blocks the transduction of TGF-β signaling pathway by inhibiting the activity of 
TGF-βRI kinase. Toripalimab is an anti- programmed cell death (PD-1) recombinant humanized 
antibody which belongs to the human IgG4/Kappa subtype and with increased stability by 
introducing point mutation. Toripalimab has been approved for melanoma, nasopharygeal 
carcinoma and urothelial carcinoma in China, with different setting. Detailed information on 
the chemistry, pharmacology, efficacy, and safety of GFH018 and Toripalimab, has been 
described in the Investigator's Brochure of GFH018 and Toripalimab. 
GFH018 has shown anti-tumor activity as single agent in preclinical efficacy studies, and it also 
shows synergistic effects when combined with PD-(L)1 antibodies. The first human study of 
GFH018 treating patients with advanced solid tumors (GFH018X1101) is in progress.  
39 patients were enrolled into the first in human (FIH) study of GFH018 received the GFH018 
treatment following 14 days on/14 days off regimen as of the cutoff date (Jan 25, 2022). There 
were 4, 3, 4, 7, 4, 4, 6 and 7 subjects in 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 65mg and 85mg 
BID group respectively. The enrollment of patients in the dose escalation part has been 
completed. GFH018 showed a good safety profile. No DLT was observed and the maximal 
tolerated dose (MTD) was not reached. No GFH018-related death was reported, neither was 
serious adverse events (SAE) related to GFH018. No subject discontinued the study treatment 
due to AE. No ≥ grade 2 AESIs were reported in the study. Most TRAE were grade 1-2. Only 
3 G3 treatment-related adverse events (TRAEs) per common terminology criteria for adverse 
events (CTCAE) were reported in 2 subjects. Two of them were reported in 1 subject and the 
PT terms were lymphocyte count decreased and hypocalcaemia, which were not accpomined 
by any clinical symptoms/signs. Another G3 TRAE was proteinuria (routine urine test) and 
repeated by urinary protein using 24-hour urine collection was 1.7 g/24h, grade 2 by CTCAE. 

 
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The most common TRAE summarized by PT incidence (≥ 10%) were in descending order of 
frequency as follows: proteinuria (28.2%), aspartate aminotransferase increased (15.4%), 
alanine aminotransferase increased (12.8%), anemia (12.8%), blood alkaline phosphotase 
increased (10.3%), blood lactate dehydrogenase increased (10.3%), and lymphocyte count 
decreased (10.3%).  
A total of 24 subjects were evaluable for efficacy, 6 patients (1 pelvic paraganglioma, 1 small 
cell lung cancer, 1 breast cancer, 1 cholangiocarcinoma, 1 nasopharyngeal carcinoma and 1 
thymic cancer) achieved a stable disease (SD). The subject who was diagnosed with thymic 
cancer and received GFH018 treatment at the dose level of 65 mg BID achieved SD with tumor 
shrinkage (maximum target lesion decreased by 18.4%). This subject has received the study 
treatment for 185 days with a sustained as an SD as of the data cutoff date. In conclusion, 
GFH018 shows a good safety profile from 5mg to 85 mg BID and preliminary anti-tumor 
efficacy in advanced solid tumors. 
The PK exposure of GFH018 including plasma exposure AUC and peak concentration (Cmax) 
increased linearly with dose (5-85 mg) post single or multiple doses. After 14 days with orally 
administration of GFH018 twice daily, the plasma concentration of GFH018 has reached the 
steady state, and the PK profile was similar to that of single dose. The mean accumulation ratio 
of all dose levels calculated by AUC, Rac (AUC), was 1.06-1.41, which indicated that the 
accumulation of GFH018 was limited after multiple doses. 
The mechanism of action combining GFH018 with PD-(L)1 and data in preclinical, as well as 
the favorable safety profile at completed dose levels from ongoing human study, support this 
study of the combination of GFH018 with Toripalimab in patients with advanced solid tumors. 
1.2 
Scientific Rationale 
1.2.1 
Research Rationale 
As mentioned in the ‘Study background’ session, in addition to the intrinsic tumor-promoting 
functions on tumor cells including EMT and metastasis, TGF-β signaling pathway also 
promotes an immune suppressive anti-tumor microenvironment through a plethora of 
perspectives, including the inhibition of B cells, dendritic cells, NK cells and CD8+ T cells, as 
well as promotion of M2 macrophage polarization, induction of regulatory T cells (Treg) and 
fibrosis17. Our inhouse data of GFH018 demonstrated the inhibition of M2 macrophage 

 
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polarization, Treg cell generation and function. These altogether concert a microenvironment 
to antagonize the efficacy of immune checkpoint inhibitors including PD-1/L1 antibodies.  
This correlation of PD-1/L1 antibody efficacy with microenvironment has been further 
validated. A large number of studies have shown that the functions and activities of CD8+ T 
cells, dendritic cells, B cells and natural killer cells are positively correlated with the clinical 
response of anti-PD-1/L1 antibody. The function and activity of Treg cells and M2 macrophages 
are negatively correlated with the clinical response of anti-PD-1/L1 antibodies18-23. As 
mentioned above, TGF-β promotes tumor fibrosis, thus preventing cytotoxic T cells from 
infiltrating into the tumor nest, to antagonize the response of anti-PD-1/L1 antibody, 
particularly in immune excluded tumor types 24-28. In conclusion, TGF-β signaling pathway 
inhibitors are hypothesized to enhance the response of immune checkpoint inhibitors. 
In the preclinical study of GFH018, the single agent showed tumor inhibition in H22 
hepatocellular carcinoma model and CT26 colorectal cancer model in mice, also showed the 
effect of inhibiting tumor cell metastasis in 4T1-luc2 orthotopic breast cancer model in mice. 
In combination with PD-(L)1 immune checkpoint inhibitor, GFH018 showed synergistic effect 
in the CT26 colorectal cancer model and Pan02 pancreatic cancer model in mice and took effect 
at a lower dose (Figure 1). 
Figure 1. Effects of GFH018 combined with PD-L1 or PD-1 antibody on the tumor growth 
of CT26 colon or Pan02 pancreatic cancer model 

 
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Based on the above inhouse and published data, it is expected that GFH018 combined with PD-
1 monoclonal antibody will play a synergistic role through two non-overlapping pathways, 
reflecting strong anti-tumor activity and acceptable safety profile. This study aims to explore 
and evaluate the safety, efficacy, and pharmacokinetic characteristics of combined therapy with 
Toripalimab in advanced solid tumors. 

 
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1.2.2 
Rational for Dose Selection  
1.2.2.1 
Starting Dose of GFH018 
The GFH018 starting dose of dose escalation in this study was determined based on the 
evaluation 
of 
safety/tolerance, 
pharmacokinetics 
(PK), 
preliminary 
efficacy 
and 
pharmacodynamics data from dose escalation part of study GFH018X1101. 
GFH018X1101 is an ongoing phase I study to evaluate the safety/tolerability and 
pharmacokinetics of GFH018 as monotherapy in patients with advanced solid tumors. The 
planned dose escalation levels of GFH018 in GFH018X1101 is as follow: 
Groups 
Dose Level 
Incremental percentage 
1 
5 mg BID, 14 days on/14 days off 
- 
2 
10 mg BID, 14 days on/14 days off 
100% 
3 
20 mg BID, 14 days on/14 days off 
100% 
4 
30 mg BID, 14 days on/14 days off 
50% 
5 
40 mg BID, 14 days on/14days off 
33% 
6 
50 mg BID, 14 days on/14days off 
25% 
Note: If the MTD is not reached at provisional maximum dose of 50mg BID, higher dose levels may be 
explored (such as 65mg BID, and 85mg BID). 
At the present stage, the evaluation of safety/tolerance for dose level 5mg, 10mg, 20mg,30 mg, 
40mg, 50mg, 65mg, and 85mg have been completed. Based on the data obtained, GFH018 is 
deemed safe at these eight dose levels, without dose-limiting toxicity (DLT) events observed 
and safety signals that need attention.  
The starting dose and dosing regimen of GFH018 in study GFH018X0201 was 40mg BID 14 
days on/14 days off which has been confirmed safe in GFH018X1101 before the enrollment of 
the first subject. 
1.2.2.2 
Rational for Dose Selection of Toripalimab 
Toripalimab has been approved by the National Medical Products Administration (NMPA) for 
the treatment of melanoma, nasopharyngeal carcinoma, and urothelial carcinoma. In this study, 
the approved dosage will be used: 3 mg/kg intravenous infusion once every 2 weeks. 

 
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1.3 
Risk/Benefit Assessment 
1.3.1 
Preclinical Toxicology Studies of GFH018 
GFH018 had no effects on the central nervous or respiratory systems in rats at a single, highest 
test dose of 100 mg/kg (human equivalent dose [HED] of 970 mg). Additionally, GFH018 had 
no effects on cardiovascular system based on the findings of the in vitro cardiac ion channels 
and ex vitro rabbit Purkinje’s fiber action potentials studies at 100 μM, and the dog telemetry 
study at 100 mg/kg (HED of 3240 mg). 
In single dose toxicity studies, the maximum tolerated dose (MTD) was 600 and 180 mg/kg for 
rats and dogs, respectively. 
In the rat 4-week toxicity study, a dose as high as 100 mg/kg/day was well tolerated, and test 
article-related adverse effects were mainly noted in rats at 30 and 100 mg/kg/day. The target 
organs of toxicity in rats were the heart, liver, kidney, bone (femur and sternum), spleen, thyroid, 
adrenal gland, and female reproductive organs. All changes resolved after an 8-week recovery 
period. Therefore, the highest non-severely toxic dose (HNSTD) was determined to be 100 
mg/kg/day (HED of 970 mg). The no observed adverse effect level (NOAEL) was determined 
to be 10 mg/kg/day (HED of 97 mg), which resulted in a calculated human starting dose of 0.16 
mg/kg, or 10 mg based on a 60-kg individual. 
In the beagle dog 4-week toxicity study, a dose of 200/120 mg/kg/day was not tolerated and 
mortality/moribundity were observed. Test article-related adverse effects were mainly observed 
in dogs at 60 and 200/120 mg/kg/day. The target organs of toxicity in dogs were blood vessels 
(multiple organ vasculitis), heart, femur, and immune system (including spleen, thymus, and 
Payer patch). After a 4-week recovery period, all changes were completely recovered. Therefore, 
the HNSTD was determined to be 60 mg/kg/day and the NOAEL was 20 mg/kg/day. 
In the rat 14-week intermittent repeated dose toxicity study, a dose of 100 mg/kg was well 
tolerated. The target organs of toxicity in rats were the heart, liver, bone (femur and sternum), 
female reproductive system (ovary, uterus, and vagina), mammary glands (female), spleen, 
thyroid, and adrenal glands. After a recovery of 8 weeks, all changes completely resolved except 
those findings of bone (femur and sternum), ovary, vagina, and mammary glands. Therefore, 
the HNSTD was determined to be 100 mg/kg (HED of 970 mg). 

 
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1.3.2 
Clinical Data of GFH018 and Toripalimab 
The study (GFH018X1101) which is the dose-escalation phase I clinical study on the 
safety/tolerability, and pharmacokinetics of GFH018 in patients with advanced solid tumors 
after single/multiple administration is still ongoing. As cut-off date of 25th Jan 2022, 39 patients 
had received 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 65mg and 85mg of GFH018 oral tablet 
twice a day, respectively, following a 14-day on/14-day off schedule. No DLT was observed 
and MTD was not reached. No GFH018-related death was reported, neither was SAE related to 
GFH018. No subject discontinued the study treatment due to AE. None of grade 2 or above 
AESIs were reported in the study. Most TRAE were grade 1-2. GFH018 has shown a good 
safety profile from 5mg to 85 mg BID, and there were no additional safety signals to be noted. 
Toripalimab has been approved for three indications (i.e. advanced melanoma and 
nasopharyngeal carcinoma and for urothelial carcinoma in neoadjuvant and adjuvant setting by 
NMPA) since 2018. As of 16 Dec 2020, cumulatively approximately 1,547 subjects received 
Toripalimab monotherapy or combination therapy in studies sponsored by Shanghai Junshi, of 
which 1,124 received monotherapy and 423 received combination therapy. In addition, 1225 
subjects participated in partner-sponsored collaborative and investigator-initiated studies. The 
safety profile of Toripalimab is generally consistent with the known overall safety profile of 
anti-PD-1 products and no new safety signals were identified. Existing risk management 
measures for Toripalimab remain adequate and effective for important identified and potential 
risks, and the risk-benefit profiles remain good.  
1.3.3 
Assessment of Potential Risks and Benefits  
The available data of GFH018 and Toripalimab show good safety profile. Considering the low 
probability of DDI between monoclonal antibody and small molecule drug, it is expected 
overall safety will be acceptable. Given the anti-tumor effect of GFH018 in the preclinical 
studies and the synergistic effect when combined with PD-(L)1 inhibitor, as well as the clinical 
data of Toripalimab, this study is expected to bring benefit in this patient population. Acceptable 
safety profile and promising outcomes are also observed in other ongoing treatment with 
immune checkpoint inhibitors combined with TGF-β. Therefore, the overall benefit/risk 

 
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evaluation is favorable for those patients in this study. 
2 STUDY OBJECTIVES AND STUDY ENDPOINTS 
The study is consisting of Phase Ib/II. The objectives and endpoints of Phase Ib and Phase II 
are as follows. 
The objectives and endpoints of Phase Ib (Dose escalation) include: 
 
Objectives 
Endpoints 
Primary 
objectives 
• To evaluate the 
safety/tolerability of the 
combination therapy 
• Incidence of dose-limiting toxicity 
(DLT) events 
• Incidence and severity of adverse 
events (AEs), serious adverse events 
(SAEs), adverse events of special 
interest (AESIs), and immune-related 
adverse events (irAEs) 
• Changes in laboratory parameters, vital 
signs, physical examination, and ECG 
Secondary 
objectives 
• To evaluate the 
pharmacokinetics (PK) 
of GFH018 in the 
combination therapy 
• Single dose plasma concentration and 
PK parameters of GFH018, including: 
Cmax, Tmax, AUC0-t, AUC0-inf, T1/2, 
CL/F, and Vd/F; repeated doses plasma 
concentration and PK parameters of 
GFH018, including: Cmax,ss, Cmin,ss, 
Tmax,ss, 
AUCtau, 
T1/2,SS, 
CL/F,SS, 
Vd/F,SS, and Racc 
• To evaluate the serum 
concentration and 
immunogenicity of 
Toripalimab in the 
combination therapy 
• Ctrough of Toripalimab; number and 
percentage of subjects who develop 
anti-Toripalimab antibody  
• To explore the efficacy 
of the combination 
therapy 
• Objective response rate (ORR), disease 
control rate (DCR), time to response 
(TTR), duration of response (DOR), 
progression-free 
survival 
(PFS) 
evaluated per Response Evaluation 
Criteria in Solid Tumors (RECIST) 

 
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1.1，and overall survival (OS) 
Exploratory 
objectives 
• To explore the 
correlation between 
molecular characteristics 
and efficacy 
• PD-L1 expression 
• CD8 + cell density  
• Tumor-infiltrating lymphocytes (TILs) 
characterization 
The objectives and endpoints of Phase II part (Extension of indications phase) include: 
Objectives 
Endpoints 
Primary 
objectives 
• To evaluate the efficacy of the 
combination therapy 
• ORR, DCR, TTR, DOR, PFS 
evaluated per to RECIST 1.1 and 
Lugano 2014 Criteria（only for 
extranodal 
NK/T-cell 
lymphoma）, and OS  
Secondary 
objectives 
• To evaluate the safety/tolerance 
of the combination therapy 
• Incidence and severity of AEs, 
SAEs, AESIs, and irAEs  
• To 
evaluate 
the 
plasma 
concentration of GFH018 in the 
combination therapy 
• Ctrough of GFH018 
• To 
evaluate 
the 
serum 
concentration 
and 
immunogenicity of Toripalimab 
in the combination therapy 
• Ctrough of Toripalimab; number and 
percentage 
of 
subjects 
who 
develop 
anti-Toripalimab- 
antibody  
Exploratory 
objectives  
• To explore the correlation 
between molecular 
characteristics and efficacy 
• PD-L1 expression 
• CD8 + cell density  
• Tumor-infiltrating lymphocytes 
(TILs) characterization 

 
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3 STUDY DESIGN 
3.1 
Overview of Study Design 
This is a multi-center, single arm, and open-label study consisting of Phase Ib and II to explore 
the safety/tolerance, pharmacokinetics, and efficacy of combination of GFH018 and 
Toripalimab in patients with advanced solid tumors. 
Figure 2. Overview of study design 
 
Note: Carcinoma of ampulla is excluded from cholangiocarcinoma/gallbladder carcinoma; RP2D =Recommend 
Phase II Dose; Toripalimab:3 mg/kg, intravenous infusion once every 2 weeks. The starting dose of GFH018 in 
this study is 40mg BID 14 days on/14 days off.  
3.2 
Phase Ib 
After the escalation is completed, maximum tolerated dose (MTD) will be identified (if 
applicable) based on isotonic regression. This computation is implemented by the Shinny app 
“BOIN” available at https://www.trialdesign.org/one-page-shell.html#BOIN. Specifically, 
MTD is the dose for which the isotonic estimate of the toxicity rate is closest to the target 
toxicity rate (0.3). 
The Phase II recommended dose（RP2D）of GFH018 combining Toripalimab will be 
determined based on all available information including safety/tolerability, PK and preliminary 
efficacy data from phase Ib part, may be equal or lower than MTD. 

 
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3.2.1 
Provisional Dose Levels 
The provisional GFH018 dose escalation plan in this study will be consistent with the study of 
monotherapy (GFH018X1101). The planned dose levels are as follows: 
    Group 
           Dose level 
  Incremental percentage 
     1 
20 mg BID, 14 days on/14 days off 
          - 
      2 
30 mg BID, 14 days on/14 days off 
         50% 
      3 
40 mg BID, 14 days on/14 days off 
         33% 
      4 
50 mg BID, 14 days on/14 days off 
         25% 
The starting dose and dosing regimen of GFH018 in study GFH018X0201 was 40mg BID 14 
days on/14 days off which has been confirmed safe in GFH018X1101 before the enrollment of 
the first subject.  
If the MTD is not reached at the provisional maximum dose level, the sponsor will 
comprehensively evaluate all the information obtained to determine whether to proceed with 
higher dose exploration. Dose escalation may be terminated at any time based on emerging 
safety concerns without establishing the MTD. 
3.2.2 
Escalation/De-escalation Rules 
The first 28 days of treatment is the observation period of DLT. In principle, the patient will not 
be allowed to conduct dose adjustment during DLT observation period. The definition of DLT-
evaluable subject is subject who have completed the 28-day-observation period and received 
more than 75% of the total planned dose of GFH018 and the planned completed dose of 
Toripalimab (including the interruption allowed per protocol), or developed a DLT event during 
DLT observation period. If in the absence of DLT event, patients will be treated until disease 
progression confirmed by RECIST 1.1 criteria, intolerable toxicity, or other conditions leading 
to treatment discontinuation. 
The Bayesian optimal interval (BOIN) design will be used to find the MTD. MTD is defined 
as the dose level at which the incidence of DLT is closest to the target toxicity rate (i.e., 0.3). 
The BOIN design is implemented in a simple way similar to traditional 3 + 3 design, but is 

 
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more flexible and processes superior operating characteristics that are comparable to those of 
the more complex model-based designs. The result of 10,000 simulations using Shinny app 
‘BOIN’ (available at http://www.trialdesign.org) shows that the design selects the true MTD, if 
any, with high probability and allocates more subjects to the dose levels with DLT rate closest 
to the target toxicity rate of 0.3 (See Appendix 4).  
The target toxicity rate is 0.3 and the planned maximum sample size is 15. Subjects are planned 
to be enrolled and treated in cohorts of size 3-6. As is shown in Figure 3, the BOIN design uses 
the following rule, optimized to minimum the probability of incorrect dose assignment to guide 
dose escalation/de-escalation of GFH018:  
 
If the observed DLT rate at current dose is ≤ 0.236, escalate the dose to the next higher 
dose level; 
 
If the observed DLT rate at current dose is ≥ 0.359, de-escalate the dose to the next lower 
dose level; 
 
Otherwise, stay at the current dose. 
Figure 3. BOIN design flow chart 
 

 
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For the purpose of overdose control, doses 𝑗 and higher levels will be eliminated from further 
examination if Pr (𝑝𝑗>0.3| data) > 0.95 and at least 3 evaluable patients have been treated at 
dose level 𝑗 , where 𝑝𝑗 is the true DLT rate of dose level 𝑗, 𝑗= 1,2,3,4. This posterior probability 
is evaluated based on the beta-binomial model yj ∣pj −binomial(pj) , with yj ∣pj −
binomial(pj), where 𝑦𝑗 is the number of patients experienced DLT at dose level 𝑗. When the 
lowest dose is eliminated, stop the trial for safety. The probability cutoff 0.95 is chosen to be 
consistent with the common practice that when the target DLT rate ≤ 1/6, a dose with 2/3 
patients experienced DLT is eliminated.  
The steps to implement the BOIN design are described as follows: 
1) Subjects in the first cohort are treated at dose level 1. 
2) To assign a dose to the next cohort of subjects, conduct dose escalation/de-escalation 
according to the rule displayed in the Table 1. When using the rule table, please note the 
following: 
a. "Eliminate" means eliminate the current dose and higher dose from the trial to 
prevent treating any further subjects at these doses because they are overly toxic. 
b. When a dose level is eliminated, automatically de-escalate the dose to the next 
lower level. When the lowest dose is eliminated, stop the trial for safety. In this 
case, no dose should be selected as the MTD. 
c. If none of the actions (i.e., escalate, de-escalate, or eliminate) is triggered, treat 
the new subject at the current dose. 
d. If the current dose is the lowest dose and the rule indicates dose de-escalation, 
treat the new subjects at lowest dose until the number of DLTs reaches the 
elimination boundary, at which point terminate the trail for safety. 
e. If the current dose is the highest dose and rule indicates escalation, treat the new 
subjects at the highest dose. 
3) Repeated step 2 until is the maximum sample size of 15 is reached, or stop the enrollment 
if the number of subjects treated at the current reach 9 and the decision according to the 
table is to stay at the current dose according to the rule displayed in the Table 1. 
Table 1 Dose escalation/de-escalation rule for target toxicity rate = 0.3 
Action 
Number of subjects treated at current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 

 
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Escalate if # of DLT ≤ 
0 
0 
0 
0 
1 
1 
1 
1 
2 
De-escalate if # of DLT ≥ 
1 
1 
2 
2 
2 
3 
3 
3 
4 
Eliminate if # of DLT ≥ 
NA 
NA 
3 
3 
4 
4 
5 
5 
5 
3.2.3 
Definition of DLT 
DLT is defined as an adverse event that occurs within 28 days after the first administration, is 
assessed as related to GFH018 or Toripalimab, and meets the following severity. The toxicities 
will be assessed using the Common Terminology Criteria Adverse Events (CTCAE) version 
5.0. Criteria for defining DLT are listed in the following: 
1) Non-hematologic toxicity 
‐ Grade 3 or above toxicity, except for the following circumstances: 
i. 
Nausea, vomiting, diarrhea, constipation, or pain that resolves to ≤ grade 2 
within 3 days after starting appropriate treatment; 
ii. 
Fatigue, rash, or hypertension that resolves to ≤ grade 2 within 7 days after 
starting appropriate treatment; 
iii. 
ALT/AST ≥ grade 3 without total bilirubin ≥ grade 2, or ALT/AST ≥ grade 3 
lasting for less than 14 days;  
iv. 
Other laboratory abnormalities not requiring intervention at the discretion of investigator. 
2) Hematologic toxicity 
‐ 
Grade 4 neutropenia lasting ≥5 days; grade 3 febrile neutropenia (neutrophil count < 
1.0 × 109/L with a single temperature > 38.3 °C or a sustained temperature > 38 °C 
for more than 1 hour); 
‐ 
Grade 4 thrombocytopenia lasting ≥5 days, or grade 3 thrombocytopenia with ≥ grade 
2 bleeding; 
‐ 
Grade 4 anemia lasting ≥ 5 days. 
3) Immune-related adverse events (irAEs) 
‐ ≥ Grade 2 irAE that involves vital organs, such as immune-related myocarditis, central 
nervous system, ocular toxicity, and pneumonia; 
‐ Grade 3 irAE of other organs that fails to recover to ≤ grade 2 before the planned next 
Toripalimab administration, except grade 3 endocrine abnormalities that can be 
corrected by hormone replacement therapy;   

 
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‐ Grade 4 irAEs 
In addition, for other significant treatment-related toxicity, the investigator and the sponsor 
should decide whether it is assessed as DLT after discussion; the toxicity beyond the DLT 
observation period but in line with the definition of DLT will be taken for consideration as an 
important safety signal to determine the safe dose. 
3.3 
Phase II  
Eligible patients with advanced solid tumors of specific types will be enrolled into fourteen 
indication groups, including hepatocellular carcinoma, cholangiocarcinoma or gallbladder 
cancer (except carcinoma of ampulla), pancreatic cancer, colorectal cancer, urothelium 
carcinoma, cervical cancer, head and neck squamous cell carcinoma or esophageal squamous 
cell carcinoma, and nasopharyngeal carcinoma, thymic carcinoma, endometrial cancer, 
osteosarcoma,  TNBC and extranodal NK/T-cell lymphoma29-34. Preclinical data35 have shown 
that TGF-β is highly expressed in Osteosarcoma cells and tissues and is associated with high  
stage, metastasis, and recurrence in vitro and in vivo. A phase I/II study36 of Vactosertib (TGF-
βR1 inhibitor) in treatment of recurrent of refractory osteosarcoma is ongoing (NCT05588648). 
Fibrosis with TGF-β pathway activation has been identified as an independent prognostic 
indicator  in TNBC37. TGF-β-induced EMT is also shown in docetaxel-resistant and paclitaxel-
resistant TNBC cancer cells38. Patients will be treated with the dosing regimen established in 
phase Ib until disease progression, intolerable toxicity, or other circumstances leading to 
treatment discontinuation. In phase II part, dose adjustment and/or interruption of GFH018 or 
Toripalimab is allowed. 
3.4 
Study Procedures 
Studies of Phase Ib and II include three periods. 
Figure 4. Schematic diagram of subject study procedures 
 

 
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1) Screening period: Day -28 to day -1 before the first administration. 
2) Treatment period: Eligible patients will receive combination therapy of GFH018 and 
Toripalimab until the disease progression confirmed by RECIST 1.1 or Lugano 2014 
Criteria (only for extranodal NK/T-cell lymphoma), intolerable toxicity, or other 
conditions leading to the treatment discontinuation. During the study period, patients will 
receive safety monitoring regularly as planned; imaging assessment will be performed 
every 8 ± 1weeks (every 6 ± 1 weeks for hepatocellular carcinoma) in the first year and 
every 12 ± 1 weeks (every 8 ± 1weeks for hepatocellular carcinoma) from the second year. 
Tumor burden assessments will be performed according to RECIST 1.1 or Lugano 2014 
Criteria (only for extranodal NK/T-cell lymphoma) by investigator. The blood samples 
will be collected for pharmacokinetic and immunogenic analysis. 
3) Follow-up period: Patients will be discontinued from the study treatment permanently in 
case of disease progression, intolerable toxicity, or other circumstances leading to 
treatment discontinuation, and will receive the safety follow-up (which will be performed 
30 days after the last administration, and SAE will be collected up to 90 days) and survival 
follow-up (until the subject dies, lost to follow-up, or study ends). Patients who are 
discontinued from the study treatment for reasons other than disease progression and not 
start other anti-tumor therapies should be followed up for disease progression every 8 ± 1 
weeks (every 6 ± 1 weeks for hepatocellular carcinoma) in the first year and every 12 ± 1 
weeks (every 8 ± 1 weeks for hepatocellular carcinoma) from the second year. 
The end of study is defined as the time when all enrolled patients have been under study 
treatment for at least one yeah or have been discontinued for any reason (whichever occurs 
first). 
This study will explore and evaluate the safety and preliminary efficacy of the combination of 
GFH018 and Toripalimab. The biomarkers may contribute to further understand mechanisms 
of drug action and drug resistance. It is expected that this combination will exert synergistic 
anti-tumor effects through dual inhibition of TGF-β and immune checkpoint, and enhance 
immunotherapy by modulating the immune micro-environment providing the basis for further 
clinical development. 
The dose, dosing regimen, study procedures, time points of sample collection may be revised 
based on obtained safety and PK data from the study.  

 
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4 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.  
4.1 
Inclusion Criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
1) Voluntarily participates in the study and signs the informed consent. 
2) Age ≥18 years (inclusive) at the time of signing the informed consent. 
3) Has histologically or cytologically confirmed diagnosis of advanced or metastatic solid 
tumors, progressed on at least first line therapy, or not been able to tolerate standard 
therapy due to toxicity or other reasons, or for whom no standard anticancer therapy 
exists. 
 
For nasopharyngeal carcinoma group: patients who haven’t received PD1/PDL1 
inhibitor, bispecific antibody or any other checkpoint inhibitors; documented prior 
benefit (partial response, complete response) to checkpoint PD1/PDL1 inhibitor / 
bispecific antibody monotherapy or combined with chemotherapy and have an 
interval of > 6 months between the last dose of checkpoint inhibitor and entering 
the study. 
4) Has sufficient organ functions, including: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, 
hemoglobin ≥ 9 g/dL, without blood transfusion or granulocyte colony-
stimulating factor, thrombopoietin, erythropoietin and other therapies within 14 
days prior to hematology test. 
b. Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN, 
alkaline phosphatase (ALP) ≤ 2.5 × ULN; for subjects with tumor involvement 
of the liver who must have TBIL ≤ 3.0 × ULN, AST and ALT ≤ 5.0 × ULN. 
c. Creatinine (Cr) ≤ 1.5 × ULN, or measured/calculated creatinine clearance (CrCl) 
≥ 50 mL/min (Cockcroft-Gault formula) if Cr > 1.5 × ULN; urine protein < 2+. 
d. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN 
(except for subject receiving anticoagulation treatment, as long as INR or PT is 
within therapeutic range of intended use of anticoagulants). 

 
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5) With toxicities from prior anti-tumor therapy resolved to baseline or CTCAE grade 1 
(neurotoxicity or alopecia ≤ grade 2). 
6) Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) ≤ 1. Subject 
with tumor involvement of the liver must have the Child-Pugh score of 5-7. 
7) Life expectancy ≥ 12 weeks. 
8) Female or male subjects of child-bearing potential must agree to use effective 
contraceptive methods from the signing of the informed consent to 90 days after the 
last administration of the study drug. Fertile female subjects must have negative 
pregnancy test results within 7 days before administration. 
Effective contraceptive methods shown as follows:  
 
Abstinence (avoiding heterosexual intercourse). 
 
Use (or make their partner use) reliable and effective methods of 
contraception during heterosexual intercourse, such as: 
i. 
Single method of contraception (any one of the following methods is 
sufficient) 
a. Intrauterine device (IUD) 
b. Vasectomy in male partner of female subject 
c. Subcutaneous implant contraception 
ii. 
Combined condom and oral contraceptive pills. 
Male subjects and partners with azoospermia (caused by vasectomy or other 
underlying conditions) are not required to take contraception. Female subjects are 
considered to be infertile if the following conditions were present: 
i. 
Postmenopausal; 
ii. 
Documented hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion at least 6 weeks 
prior to screening; 
iii. 
Congenital or acquired infertility. 
9) According to the judgment of the investigator, the subject is able to communicate well 
with the investigator to comply with the requirement of the protocol. 
In addition, eligible patients for phase II part must meet the following criteria: 
10) Histologically or cytologically confirmed diagnosis of advanced or metastatic tumors 
of specific types, including hepatocellular carcinoma, cholangiocarcinoma/ 

 
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gallbladder cancer (except carcinoma of ampulla), pancreatic cancer, colorectal cancer, 
urothelium carcinoma, cervical cancer, head and neck squamous cell carcinoma, 
esophageal squamous cell carcinoma, nasopharyngeal carcinoma, thymic carcinoma, 
endometrial cancer, osteosarcoma，TNBC and extranodal NK/T-cell lymphoma. 
11) At least one measurable lesion according to RECIST 1.1 or Lugano 2014 Criteria 
(only for extranodal NK/T-cell lymphoma). 
12) For hepatocellular carcinoma patients: 
platelet count ≥60x109/L, without thrombopoietin or other therapies within 14 days 
prior to hematology test. 
13) For cervical cancer patients: 
hemoglobin ≥ 8 g/dL, without blood transfusion or erythropoietin and other therapies 
within 14 days prior to hematology test. 
4.2 
Exclusion Criteria 
Patients eligible for this study must not meet any of the following criteria: 
1) Impaired cardiac function or clinically significant cardiac diseases: 
a. Clinically significant cardiac diseases within 6 months, for example: myocardial 
infarction, angina, heart failure, severe arrhythmia, angioplasty, stent implantation, and 
coronary artery bypass grafting; 
b. Ascending aorta aneurysm or major artery aneurysm history, or predisposing 
conditions that are consistent with development of aneurysms (for example, family 
history of aneurysm, Marfan syndrome, evidence of damage to the large vessels of the 
heart documented by computerized tomography [CT] scan with contrast); 
c. Abnormalities at screening/baseline, which will be confirmed by the cardiologist if 
necessary: 
i. 
ECG: QT/QTc prolongation (QTcF > 470 ms for females or QTcF > 450 ms 
for males), or other clinically significant arrythmia, conduction abnormalities, 
morphology abnormalities; 
ii. 
Doppler echocardiography: clinically significant abnormalities, such as left 
ventricular ejection fraction (LVEF) < 50%, moderate or severe heart valve 
stenosis, and moderate or severe heart valve regurgitation; 

 
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iii. 
Troponin > ULN in conjunction with symptoms or other abnormal testing 
indicating myocardial ischemia 
2) 
With acute or chronic infections, including: 
a. Active infections requiring intravenous treatment’ 
b. Positive human immunodeficiency virus antibody (HIV-Ab), active syphilis, active 
hepatitis B virus infection (positive HBsAg and positive HBV-DNA), and active 
hepatitis C virus infection (positive HCV-Ab and positive HCV-RNA) during the 
screening/baseline period; 
c. Active tuberculosis. 
3) With active central nervous system metastases, including symptomatic brain metastases, 
meningeal metastases, spinal cord compression, or requiring treatment with 
glucocorticoids, antiepileptic drugs, anticonvulsant drugs, or mannitol. 
4) 
With known active autoimmune diseases or a history of autoimmune diseases within 1 
year prior to enrollment, such as systemic lupus erythematosus, psoriasis, rheumatoid 
arthritis, inflammatory bowel disease, and Hashimoto's thyroiditis. Except for type I 
diabetes, hypothyroidism or hyperthyroidism that can be controlled with only hormone 
replacement, skin diseases requiring no systemic treatment, controlled celiac disease. 
5) 
With clinically significant gastrointestinal diseases, such as intractable hiccup, nausea 
and vomiting, severe peptic ulcer, active gastrointestinal bleeding, or other conditions 
that interfere swallowing the tablets or significantly alter the absorption; subjects with 
hepatocellular carcinoma who have severe portal hypertension due to Budd-Chiari 
syndrome or portal vein thrombosis. 
6) 
Uncontrollable or symptomatic ascites, pleural effusion or pericardial effusion. 
7) 
History of non-infectious (e.g., drug-induced) ILD requiring systemic steroid 
treatment, or current pneumonitis. 
8) 
With other uncontrolled systemic diseases, such as hypertension and diabetes. 
9) 
Diagnosed with other malignant tumors within 3 years prior to starting study drug, 
except for cured carcinoma in situ of cervix, skin basal cell carcinoma, early stages of 
prostate or thyroid cancer. 
10) With diseases requiring immunosuppressant therapy, or requiring prednisone > 10 

 
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mg/day or equivalent dose of similar drugs during the study period. 
11) Subjects who have been treated with immunosuppressant drugs within 28 days prior 
to starting study drug, except for topical and inhaled cortisol and systemic cortisol of 
physiological dose (prednisone < 10 mg/day or equivalent dose of similar drugs). 
12) Subjects who have received live vaccine, attenuated vaccine within 28 days prior to 
starting study drug, or plans to receive live vaccine, attenuated vaccine during 
treatment or within 30 days after the last administration. 
13) Subjects who have been treated with radiotherapy, chemotherapy, targeted therapy, 
endocrine therapy, immunotherapy, and other anti-tumor therapies (except for 
traditional Chinese medicines), or other investigational drugs within 5 half-life periods 
or within 28 days (whichever is shorter) prior to starting study drug. 
14) Subjects who have been treated with traditional Chinese medicine with approved 
antitumor indications within 2 weeks prior to starting study drug. 
15) Subject who has received major surgeries (except for needle biopsy) that may affect 
the administration or study evaluation within 28 days prior to starting study drug. 
16) Subjects who have received strong inhibitor or inducer of CYP3A4 within 5 half-life 
periods or within 2 weeks (whichever is shorter) prior to starting study drug. 
17) Subjects who have received combined treatment of drugs targeting TGF-β and PD-
(L)1, including combination of antibody and small molecule or bispecific antibody. 
18) Pregnant or lactating women. 
19) With known allergies to the study drugs or components. 
20) The subject is a staff member who is directly related to the investigator of the study or 
his/her family members, or the sponsor. 
21) Other conditions judged by the investigator as inappropriate to participate in the study. 
5 STUDY TREATMENT 
5.1 
Study Treatment Assignment 
Each patient is uniquely identified in the study by an identification number, that is assigned 
when the patient is firstly enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the study.  

 
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This is an open-label study with no blinding or randomization. All enrolled patients will receive 
a combination therapy of GFH018 and Toripalimab. All dose changes during the study must be 
recorded on the source document. 
5.2 
Supply of Study Drugs  
5.2.1 
Strength and Packages of Study Drugs  
Study Drugs 
GFH018 tablet 
Toripalimab injection 
Active 
ingredients 
GFH018 
Toripalimab 
Excipients 
Microcrystalline cellulose, mannitol, 
croscarmellose sodium, colloidal silicon 
dioxide, magnesium stearate, etc. 
Citric acid monohydrate, sodium citrate 
dihydrate, sodium chloride, mannitol, 
polysorbate 80 
Type 
Chemical drugs 
Biological product 
Dosage form 
Tablet 
Injection 
Strength 
5 mg, 50 mg, 20mg, 80mg 
240 mg (6 mL)/vial; 80 mg (2 mL)/vial; 100 
mg (2.5 mL)/vial 
Administration 
route 
Oral administration 
Intravenous infusion 
Storage 
requirements 
Stored below 25 ℃, sealed and protected 
from light 
Stored at 2–8 °C away from light, do not 
freeze 
Source 
GenFleet Therapeutics (Zhejiang) Co., Ltd. Shanghai Junshi Biosciences Co., Ltd. 
Packaging and 
labeling 
The study treatment drug is packaged in 
high-density polyethylene (HDPE) bottles 
and provided to each subject. Each HDPE 
bottle is labeled in accordance with local 
regulatory requirements. 
The study treatment drug is packaged in 
neutral borosilicate glass controlled injection 
vials for delivery to the study center. Each 
neutral borosilicate glass controlled injection 
vial is labeled in accordance with local 
regulatory requirements. 
5.2.2 
Preparation and Dispensing of Study Drugs 
The investigator or his/her designee must ensure that all drugs or related items used for study 
treatment are maintained in appropriate temperature conditions during transport. If deviations 
occur, they are to be reported and resolved before proceeding with the study treatment. 
Only patients enrolled in the study may receive the study treatment, and only authorized study 
center staff can provide or administer the study treatment products. All study intervention drugs 

 
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or related items must be stored in a secure and environmentally controlled area that can be 
monitored (manual or automated) in accordance with the storage conditions indicated on the 
label and it is ensured that only the investigator and authorized study center staff have relevant 
access to the study treatment products. 
5.3 
Dose and Administration 
5.3.1 
Dose and Administration of GFH018 
5.3.1.1 
Administration of GFH018 
GFH018 will be administered orally as a continuous twice daily (BID) dosing for 14 days in a 
28 days cycle during the treatment period of the escalation phase and during the entire 
expansion phase. 
GFH018 will be administered orally served with approximately 200 mL warm water. Subjects 
need to be informed of the condition that the tablets must be swallowed in whole and not chewed 
or broken apart. When taking the medication twice daily, the interval is about 12 hours, e.g. 
schedule it around 8:00 am and 20:00 pm, it is recommended to keep the daily medication time 
be consistent. Subjects will be fasted at least 2 hours before administration of drug and remain 
fasted one hour post-dose. If a PK blood sample is collected in the morning, the drug will be 
taken after sampling. 
If a missed dose occurs, the dose can be made up within 4 hours after the scheduled time, the 
actual dosing time will be recorded, and the subsequent dosing time will remain on schedule. 
If it has been more than 4 hours since the missed dose, the dose should be skipped and the 
subject should continue treatment at the scheduled time. All actual dosing times are recorded in 
the subject diary or recorded as "missed doses". If vomiting occurs after administration of the 
drug, no re-dosing of the patient is allowed before the next scheduled dose. 
5.3.1.2 
Dose Adjustment of GFH018 
During the study period, dose adjustment or interruption of GFH018 within the DLT 
observation period is not allowed in principle; if at discretion of the investigator, adjustments 
are deemed necessary in the best interest of the patient, they should be discussed and agreed 
upon with the sponsor; otherwise, the treatment of subject will be discontinued, and the subject 
should be transferred to the follow-up period. 

 
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After observation period of DLT in Phase Ib and during the Phase II study, in the event of an 
adverse event related to GFH018 that meets the definition of DLT in Section 3.2.3 of the 
protocol, the recommended adjustment scheme is: 
1) Temporary interruption of GFH018 is allowed. If recovery to ≤ grade 1 or baseline within 
1 week, stay at the current dose; if recovery to ≤ grade 1 or baseline within 2 weeks, de-
escalate the dose to the next lower dose level; if there is no tendency to recover within 2 
weeks, discontinuation should be considered. 
2) Discontinuation should be considered if a recovering adverse event turns worse after 
administration at a de-escalate dose level, or if a recovered adverse event recurs. 
3) The recommended adjustment scheme of GFH018 is 80mg BID, 60mg BID,  and 40mg 
BID. 
Intra-patient dose escalation of GFH018 is not permitted during the first 4 cycles of treatment. 
After the 4th cycle is completed, individual patients may be considered for treatment at a dose 
of GFH018 higher than the dose to which they were initially assigned. For a patient to be treated 
at a higher dose of GFH018, he or she must have received the lower dose for at least four cycles 
of therapy without a toxicity ≥ CTCAE grade 2 that is at least possibly related to the study 
treatment. Moreover, the higher dose with which the patient is to be treated must be the dose 
that has completed evaluation in a dose-escalation meeting given all available data. When Phase 
II study begins, for subjects who are still receiving treatment in Phase Ib, it will be judged by 
the investigator whether to adjust their treatment regimen to RP2D in the best interest of the 
patient. 
If a patient requires a dose delay of > 28 days from the intended day of the next scheduled dose 
of GFH018 or Toripalimab for other reasons, the patient must be discontinued from the study 
treatment. All dose adjustments must be documented in the source data and recorded in the CRF 
as required.  
5.3.2 
Dose and Administration of Toripalimab Injection  
5.3.2.1 
Administration of Toripalimab  
The duration of the first intravenous infusion of Toripalimab should be at least 60 min. The 
patient should be closely monitored with vital signs every 30±5 minutes during infusion and 
within one hour after the infusion completion. If the patient is well tolerated with the first 

 
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infusion, the time for the second infusion can be reduced to no less than 30 min following with 
one hour observation period. If the patient has good tolerance during the infusion of 30 min,  
all subsequential infusion can be completed within 30 min. Administration by the intravenous 
bolus or a one-time rapid intravenous injection is not allowed. 
Dilution method for Toripalimab injection before administration is as follows: 
Dilution of this drug should be prepared within 24 h after it is taken from the refrigerator. 
Visually inspect the drug for particles and color change before dispensing. The drug should be 
colorless or light-yellow clear liquid, slight opalescence is acceptable. If visible particles or 
abnormal color is observed, the drug should be discarded. 
The drug does not contain preservative. Under the aseptic condition, the required volume of the 
drug is taken and slowly injected into an infusion bag containing 100 ml of normal saline (0.9% 
sodium chloride). It is diluted to a final concentration of 1-3 mg/ml, and the bag is then gently 
turned over and mixed well before intravenous infusion. The infusion tube utilized during 
infusion must be equipped with a sterile core filter without pyrogen and low protein binding 
(with pore size of 0.2 or 0.22 µm). 
The dilution prepared under the aseptic condition can not be stored more than 8h at room 
temperature, including the storage time after dilution and the time for infusion. It can not be 
stored more than 24h at 2-8℃ either. If it needs to be refrigerated, please allow the diluent 
return to room temperature before administration. It can not be frozen for storage either. 
It cannot be mixed or diluted with other drugs.  
The residual drug in the vial cannot be re-used. 
5.3.2.2 
Dose Adjustment of Toripalimab 
The dose of Toripalimab is 3 mg/kg. Intravenous infusion is given once every two weeks. 
The study treatment should be given as far as possible in accordance with the planned dose and 
time. The dose of Toripalimab should not be adjusted within DLT observation period. In the 
sequential cycles, Toripalimab may be interrupted or discontinued permanently based on safety 
and tolerance of individual subjects. The dose adjustment should be conducted based on the 
observed worst toxicity to proceed if many adverse events occurred at one time. It is not 
recommended to increase or decrease dose. 

 
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For details, recommended to refer to latest "Drug Instruction" or "Investigator’s Brochure". The 
following information was extracted from the "Toripalimab Instruction” of the version revised 
on May. 27, 2022. 
Table 2 Recommended treatment adjustment scheme of Toripalimab 
Immune-related 
adverse reactions 
Severity * 
Treatment modification 
regimen 
Pneumonia  
Grade 2 
Withhold until improved to 
Grade 0-1  
Grade 3-4 or recurrent Grade 2 
Permanent discontinuation  
Diarrhea or colitis  
Grade 2-3 
Withhold until improved to 
Grade 0-1  
Grade 4 
Permanent discontinuation  
Hepatitis  
Grade 2, aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) 3-5 times upper 
limit of normal (ULN) or total bilirubin 1.5-3 
times ULN 
Withhold until improved to 
Grade 0-1  
Grade 3-4, AST or ALT > 5 times ULN, or total 
bilirubin > 3 times ULN 
Permanent discontinuation  
Nephritis  
Grade 2-3 blood creatinine increased 
Withhold until improved to 
Grade 0-1  
Grade 4 blood creatinine increased 
Permanent discontinuation  
Endocrine 
disorders  
Symptomatic Grade 2-3 hypothyroidism, 
Grade 2-3 hyperthyroidism, Grade 2-3 
hypophysitis, Grade 2 adrenal insufficiency 
Grade 3 hyperglycemia or type I diabetes 
Withhold until improved to 
Grade 0-1  
Grade 4 hypothyroidism 
Grade 4 hyperthyroidism 
Grade 4 hypophysitis 
Grade 3-4 adrenal insufficiency 
Grade 4 hyperglycemia or type I diabetes 
Permanent discontinuation  
Cutaneous adverse 
reactions  
Grade 3 rash 
Withhold until improved to 
Grade 0-1 
Grade 4 rash, 
Stevens-Johnson syndrome (SJS) or toxic 
epidermal necrolysis (TEN) 
Permanent discontinuation 
Thrombocytopenia  
Grade 3 
Withhold until improved to 
Grade 0-1 
Grade 4 
Permanent discontinuation 
Other 
Grade 2-3 blood amylase increased or lipase 
increased 
Grade 2pancreatitis 
Grade 2 myocarditis a 
Grade 2-3 other initial immune-related adverse 
Withhold until improved to 
Grade 0-1 

 
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reactions 
Grade 4 blood amylase increased or lipase 
increased 
Grade 3-4 pancreatitis 
Grade 3-4 myocarditis 
Grade 3-4 Encephalitis 
Grade 4 other initial immune-related adverse 
reaction 
Permanent discontinuation 
Recurrent or 
persistent adverse 
reactions 
Recurrent Grade 3-4 adverse reactions (except 
endocrine 
diseases); 
Grade 
2-3 
adverse 
reactions not improved to Grade 0-1 within 12 
weeks after last dosing (except endocrine 
diseases) 
Corticosteroids not reduced to ≤ 10 mg/day 
prednisone equivalent within 12 weeks after the 
last dosing 
Permanent discontinuation 
Infusion reaction  
Grade 2 
Reduce the dripping speed 
or 
suspend 
the 
administration, 
and 
consider 
resuming 
the 
administration and closely 
observing the patient when 
the symptoms are relieved 
Grade 3-4 
Immediately 
and 
permanently 
discontinue 
the transfusion and treat 
symptomatically 
* Graded according to NCI-CTCAE v5.0 
** The safety of restarting Toripalimab after myocarditis is improved to grade 0-1 through treatment is unclear. 
5.3.3 
Subject Compliance 
GFH018 is taken and recorded by the subject after received on the designated visit day. Subject 
will be required to return all unused GFH018 tablets from the previous cycle on the designated 
visit day and return the completed subject diary. The number of tablets returned by the subject 
will be counted, recorded, and archived. 
Toripalimab injection will be infused at the study center on the designated visit day. The study 
center will complete drug preparation and record infusion information according to the drug 
instruction. The documentation system of the clinical study center should include all 
information related to the preparation and administration of the drugs. 

 
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5.4 
Drug Storage 
The investigator or other authorized staff of study center, such as pharmacist, will ensure that 
all study drugs are stored in a secure and access-controlled area that meets the storage 
conditions described in Section 5.2.1 and that their storage meets applicable regulatory 
requirements. The subject should follow the guide of investigators or authorized staff to store 
correctly after receiving GFH018 tablet. If non-conforming storage conditions are identified, 
the investigator should contact the sponsor for guidance. 
5.5 
Records of Administration and Destruction 
The study center must maintain records of the supply of research drugs, including receipt, 
distribution, use, recovery, loss or other whereabouts. The subject should follow the guide of 
investigator to return all unused GFH018 tablets and packages to the investigator at the 
designated follow-up date and return the finished Subject diary card. Toripalimab will be 
administrated in visit time and it will be recorded by the authorized investigators. 
The unused study drug and packages will be recycled and destroyed by sponsor after making 
an inventory or destroyed by authorized study center. The sponsor or the personnel authorized 
by it will provide the guide about destroying the unused study drug to the study center. If it is 
authorized to destroy at the study center, the investigator should ensure that all recovery and 
destruction is conducted and documented in accordance with the appropriate regulatory 
guidelines and regulations. 
5.6 
Prior and Concomitant Therapies 
5.6.1 
Prior Therapies 
Please refer to Section 4.2 for prohibited therapies before the enrollment of the study. 
After signing of the informed consent, the prior anti-cancer therapies will be recorded, including 
setting, regimen, start date, stop date, best response, reason for discontinuation. 
All other prior therapies that were being taken 30 days before the first administration will be 
documented. 

 
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5.6.2 
Concomitant Therapies 
All concomitant medications and treatments are to be collected from the enrollment through the 
end of safety follow-up period.  
In general, the use of concomitant medication, procedures and non-drug therapies deemed 
necessary for the care of the patient are permitted during the study. Using of medications that 
may significantly affect the evaluation of the study results, such as safety and tolerance, should 
be avoided. In case of serious adverse reactions or serious adverse events or deterioration of the 
original condition or other serious diseases, the investigator should promptly administrate 
corresponding medication as clinically indicated. The subject should withdraw from the study 
if he/she meets the withdrawal criteria. 
5.6.2.1 
Permitted/Caution Concomitant Therapies 
The investigators should follow the underly principles and cautiously use concomitant 
therapies, to ensure the safety of the subjects. 
1) Corresponding treatment is permitted in the study period, depending on the investigator's 
judgment and relevant guidelines (e.g., American Society of Clinical Oncology (ASCO) 
Guidelines). For example, palliative local radiotherapy for symptomatic relief is permitted 
for painful bone lesions, these lesions should be present at the time of enrollment and are 
not the only target lesion. Investigator should make judgement and record whether the use 
of radiotherapy is associated with disease progression before radiotherapy. 
2) Allow to use topical steroid and inhaled corticosteroid. Allow to use systemic 
corticosteroids (i.e., prednisone ≤ 10 mg/day) at a physiologically alternative dose. Allow 
to use corticosteroids in short period to prevent (e.g., contrast agent irritability) or treat 
non-autoimmunity diseases (e.g., the delayed anaphylaxis due to contact allergens), or to 
address the adverse reaction of study drugs. 
If the investigator cannot determine whether the concomitant therapy affects the subject safety, 
or whether it affects the judgment for the safety and tolerance of the subjects after 
administration, or whether it affects the eligibility of the subjects to participate in the study after 
administration, the investigator should consult the sponsor before therapy initiation. 

 
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5.6.2.2 
Prohibited Concomitant Therapies 
During the course of the study, the subject should not receive following therapies: 
1) Any other anti-tumor therapies (chemotherapy, immunotherapy, biologic products, 
extensive radiotherapy, hormone therapy, targeted therapy, surgery, and traditional Chinese 
medicine with approved antitumor indications), including research-based therapies. Taking 
antagonism GnRH to treat PC (prostatic cancer), orally contraceptive and hormone 
replacement therapy are allowed. 
2) Any immunosuppressant or systemic corticosteroids for immunosuppressive effects except 
using for adverse events during the study. 
3) Use the drug of G-CSF (granulocyte colony-stimulating factor) as the prophylactic. Such 
drugs can be only used for treatment of adverse events under the judge of the investigator. 
4) Live vaccine or attenuated vaccine (COVID19 vaccine will be allowed if there is no 
interference to the study in the discretion of investigator). 
5) Any other drugs under clinical investigation other than the treatment in this study. 
6) Based on preclinical study, GFH018 is mainly metabolized by CYP3A. To avoid drug-drug 
interactions, the strong inducers and inhibitors of CYP3A4/5 are forbidden. In addition, the 
moderate inhibitor or inducer of CYP3A4/5 should be used with caution. Some typical 
drugs are listed as follows: 
Table 3 Inducers and inhibitors of CYP3A4/5 (partial) 
Interaction mechanism 
Drug name 
Strong inducer 
Carbamazepine, phenytoin, rifampicin, and St. John's wort 
Strong inhibitor 
Clarithromycin, ritonavir, indinavir, ketoconazole, and itraconazole 
Moderate inducer 
Bosentan, Modafinil, Nafcillin, and Thioridazine Hydrochloride 
Moderate inhibitor 
Cimetidine, Ciprofloxacin, Grapefruit, Verapamil, and Imatinib 
1) Other lifestyle requirements: Grapefruit-based fruits and beverages (e.g., citrus, 
grapefruit, or grapefruit juice) are prohibited from at least 7 days prior to the first dose 
until the end of study treatment; products containing caffeine or xanthines (e.g., coffee, 
tea, cola drinks, and chocolate) will not be permitted for 6 hours prior to each dose until 

 
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final pharmacokinetic (PK) samples have been collected. Alcohol will not be permitted 
for 24 hours prior to each dose until final PK samples have been collected. 
6 STUDY PROCEDURES 
An institutional review board/independent ethics committee (IRB/IEC) approved informed 
consent form (ICF) must be dated and signed prior to any screening procedures.  
All procedures of the study should be conducted within the time window specified in the 
assessment schedule. If procedures of the study cannot be completed on time or as required 
under special cases, the investigator will take all necessary measures to ensure the safety and 
benefits of subjects, and record the reasons and interventions. In addition, the investigator needs 
to notify the study team of unexpected situations in time. 
6.1 
Screening Period 
The screening period starts once a patient has provided written informed consent to participate 
in the study and ends on the day of study entry. Screening assessments must be performed 
within 28 days prior to starting study treatment: 
• 
The ICF must be dated and signed prior to any screening procedures 
• 
Demographic data including date of birth, sex, and race will be collected  
• 
Medical history within 30 days prior to signing of the informed consent, and diagnosis 
and extent of cancer (including histopathology, cytological diagnosis, and clinical 
staging, tumor-related symptoms, and imaging findings) 
• 
Height and Weight 
• 
Prior therapies: prior anti-cancer therapies will be recorded, including setting, regimen, 
start date, stop date, best response, reason for discontinuation. All other prior therapies 
that were being taken 30 days before the first administration will be documented. 
• 
Physician examination 
• 
Vital signs (blood pressure, respiratory rate, pulse, and temperature) 
• 
ECOG PS 
• 
ECG 
• 
Echocardiography 
• 
Laboratory tests (See Table 4 in Section 7.1.2)  

 
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• 
If done, they will be assessed by the investigator as normal or abnormal and details 
about abnormality will be entered in the CRF 
• 
Radiological imaging and tumor assessment as necessary 
• 
AE/SAE reporting 
• 
Biomarker sampling or collection 
• 
Determine patient eligibility based on the inclusion/exclusion criteria 
This study allows one-time re-screening of subjects. Subjects should be re-consented when re-
screening. A new identification number will be assigned to the re-screened subject. Once the 
subject is re-screened, a new 28-day screening window will begin. All screening assessments 
are allowed to be repeated once during a screening process. For subjects who have failed 
screening, detailed information at least including demographics, diagnosis of disease, reasons 
for screening failure, and SAEs should be documented. 
6.2 
Treatment Period 
Patients will be treated with GFH018 and Toripalimab. A treatment cycle is defined as 28 days. 
Tumor assessment based on RECIST 1.1 and Lugano 2014 Criteria (only for extranodal NK/T-
cell lymphoma) will be performed every 8 ± 1 weeks (every 6 ± 1 weeks for hepatocellular 
carcinoma) in the first year and every 12 ± 1 weeks (every 8 ± 1 weeks for hepatocellular 
carcinoma) from the second year.  
6.2.1 
Cycle 1 
Day 1 
• 
Reassess inclusion/exclusion criteria before starting study treatment 
• 
Physical examination and weight 
• 
Vital signs 
• 
Laboratory tests (See Table 4 in Section 7.1.2) 
• 
ECG Echocardiogram (for phase II period, conducted as clinically indicated), no need 
to repeat tests them within the allowed time window 
• 
AE/SAE reporting 
• 
Concomitant therapies 
• 
GFH018 PK blood sampling  
• 
Toripalimab PK and ADAblood sampling 

 
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• 
GFH018 and Toripalimab administration 
Day 8(±2) (only for phase Ib) 
• 
Physical examinations and weight 
• 
Vital signs 
• 
Laboratory tests (See Table 4 in Section 7.1.2) 
• 
ECG 
• 
AE/SAE reporting 
• 
Concomitant therapies 
• 
GFH018 PK blood sampling  
• 
GFH018 administration 
Day 15(±3) 
• 
Physical examinations and weight 
• 
Vital signs 
• 
ECOG PS 
• 
Laboratory tests (See Table 4 in Section 7.1.2) 
• 
ECG (only for phase Ib) 
• 
AE/SAE reporting 
• 
Concomitant therapies 
• 
GFH018 PK blood sampling (phase II part only)  
• 
Toripalimab PK and ADA blood sampling  
• 
Toripalimab administration 
Day 28 (only for phase Ib) 
• 
Physical examination and weight 
• 
Vital signs 
• 
Laboratory tests (See Table 4 in Section 7.1.2)  
• 
ECG 
• 
Echocardiogram 
• 
AE/SAE recording 
• 
Concomitant therapies. 
6.2.2 
Subsequent Cycles 
The following procedures will be performed on Day 1 and Day 15 of the subsequent cycles: 

 
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Day 1(±3) 
• 
Physical examination and weight 
• 
Vital signs 
• 
Laboratory tests (See Table 4 in Section 7.1.2)  
• 
ECG 
• 
Echocardiogram (for phase II period, conducted as clinically indicated)  
• 
AE/SAE recording 
• 
Concomitant therapies 
• 
GFH018 and Toripalimab administration. 
Day 15(±3) 
• 
Physical examination and weight 
• 
Vital signs 
• 
ECOG PS 
• 
Laboratory tests (See Table 4 in Section 7.1.2) 
• 
ECG (only for phase Ib) 
• 
AE/SAE recording  
• 
Concomitant therapies 
• 
GFH018 PK blood sampling (Cycle 2-4) 
• 
Toripalimab PK and ADA blood sampling (Cycle 2-4) 
• 
Toripalimab administration 
6.3 
End-of-Treatment (EOT) Visit 
For patient who has confirmed disease progression based on the RECIST 1.1 or Lugano 2014 
Criteria (only for extranodal NK/T-cell lymphoma), or meets any of the criteria described in 
Section 6.5.1, the EOT visit should occur as soon as possible (within 7 days) after making the 
decision of discontinuation. Radiological test within 6-8 weeks will not require additional 
image test. Monitoring tests for AE will be at the discretion of investigator. If a patient 
discontinues due to reasons other than disease progression and does not start subsequent 
anticancer therapy, the radiological tests will be performed on the scheduled visit (i.e., every 8 
± 1 weeks or every 6 ± 1 weeks in the first year; every 12 ± 1 weeks or every 8 ± 1 weeks since 
the second year) until disease progression, start of new anticancer therapy or other reasons.  

 
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The following procedures should be performed at the EOT visit:  
• 
Vital signs 
• 
Physical examination and weight 
• 
ECOG PS 
• 
ECG 
• 
Echocardiogram (for phase II period, conducted as clinically indicated) 
• 
Laboratory tests (See Table 4 in Section 7.1.2) 
• 
AE/SAE reporting 
• 
Concomitant therapies 
• 
Collection of subsequent disease information and subsequent anti-tumor treatment  
If the EOT visit is conducted within the time window of the safety follow-up, it shall be carried 
out according to the safety follow-up visit, and the same examination items do not need to be 
repeated. 
6.4 
Follow-up Period 
6.4.1 
Safety Follow-up 
After the EOT visit, the subject starts the follow-up period. Tumor assessment performed within 
6 weeks (for hepatocellular carcinoma) or 8 weeks is acceptable and repeated assessment is not 
required. But AE related assessment could be performed according to the investigator' 
judgment. The safety follow-up visit should occur 30 (± 3) days after the last administration, 
subjects will return to the study center for a safety follow-up visit. The following procedures 
will be performed: 
• 
Vital signs 
• 
Physical examination 
• 
ECOG PS 
• 
Laboratory tests (See Table 4 in Section 7.1.2) 
• 
ECG 
• 
Echocardiogram (for phase II period, conducted as clinically indicated) 
• 
AE/SAE reporting 
• 
Concomitant therapies 
• 
Collection of subsequent disease information and subsequent anti-tumor treatment  

 
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After the safety follow-up visit, AEs will not be collected actively, but all treatment-related AEs 
must be followed up to resolve, recover to baseline, or the investigator judges it a stable and 
irreversible condition. 
6.4.2 
Survival Follow-up 
Following the safety follow-up period, there will be a survival follow-up. Subjects will be 
followed up every 90 (±15) days until death, lost to follow-up, or the study ends (whichever 
occurs first). Investigator may inquire subjects, their family members, or local physicians 
through email or telephone to obtain survival information (including date and cause of death), 
disease status, and subsequent anti-cancer treatment. The follow-up information needs to be 
recorded in the source data. 
6.4.3 
Disease Progression Follow-up 
If a patient discontinues due to reasons other than disease progression and does not start 
subsequent anticancer therapy, the radiological tests will be performed on the scheduled visit 
(i.e., every 8 ± 1 weeks or every 6 ± 1 weeks in the first year; every 12 ± 1 weeks or every 8 ± 
1 weeks since the second year) until disease progression, start of new anticancer therapy or 
other reasons. 
All subjects will be permitted to continue treatment beyond initial RECIST 1.1-defined or 
Lugano 2014 (only for extranodal NK/T-cell lymphoma) progression if the investigator judged 
that the subject is beneficial to treatment without safety concern.  
6.4.4 
Unscheduled Follow-up 
If it is necessary judged by investigator for safety concerns, AEs follow-up, or clinical 
symptoms suggesting disease progression, the investigator may arrange unscheduled follow-up 
for further examination and evaluation. 
6.5 
Discontinue/Withdraw from Treatment or Study  
6.5.1 
Discontinuation of Study Treatment 
Patients may voluntarily withdraw from the study treatment or be dropped from it at the 
discretion of the investigator at any time. If withdrawal occurs, the investigator must determine 

 
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the primary reason for a patient’s premature withdrawal from the study treatment. Patients may 
be withdrawn from the study treatment prematurely for one of the following reasons: 
• 
Disease progression 
• 
Adverse event(s) 
• 
Start other anti-cancer treatment 
• 
Non-compliance 
• 
Pregnancy 
• 
Subject request 
• 
Lost to follow-up 
• 
Death 
• 
Withdrawal of consent 
• 
Investigator decision 
• 
Study terminated by sponsor 
Patients who discontinue study treatment should be scheduled for an EOT visit within 7 days 
after making the decision of discontinuation. If a patient discontinues due to reasons other than 
disease progression and does not start subsequent anticancer therapy, the radiological tests will 
be performed on the scheduled visit (i.e., every 8 ± 1 weeks or every 6 ± 1 weeks in the first 
year; every 12 ± 1 weeks or every 8 ± 1 weeks since the second year) until disease progression, 
start of new anticancer therapy or other reasons.  
Investigators may provide suggestions or alternative treatment for subjects based on their actual 
conditions. 
6.5.2 
Withdraw from the Study 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Reasons for removal of a subject from the study are： 
• 
Withdrawal of consent 
• 
Death 
• 
Lost to follow-up 
• 
Study terminated by sponsor 

 
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If the subject fails to return to the study center for follow-up visit as scheduled, the investigator 
should make efforts to contact them in time and reschedule the missed visit as soon as possible. 
The investigator should ask about the reason for dropping out and ask the subject to return to 
the center as much as possible to complete the visit and follow up the unresolved AEs. If 
possible, every effort should be made to record the outcome of the subject in any case. 
If the subject refuses to come back to the research center for further visit, the investigator should 
continue to track and collect information of their disease and survival, unless the subject 
withdraws informed consent. In this case, no more study evaluations will be performed, and no 
more information should be collected. 
All attempts to make contact should be recorded on the source document. 
6.6 
Study Completion and Early Study Termination 
The end of study is defined as the time when all enrolled subjects have been under study 
treatment for at least one yeah or have been discontinued for any reason (whichever occurs 
first).  
This study may also be discontinued early or interrupted. This may be due to decision of the 
authority, opinion of the Ethics Committee, suggestion from SMC, or decision of the sponsor. 
Additionally, the sponsor reserves the right to stop the research and development of GFH018. 
Reasons for early termination and interruption of the study may include but not limited: 
• 
Determined unexpected, significant, or unacceptable risks to the subject. 
• 
The results of the efficacy support early termination of the study. 
• 
Non-compliance to the study. 
The party that decides to discontinue/interrupt the study will give a written notice to record the 
reasons for the discontinuation or interruption to the investigator, sponsor, and regulator. If the 
study is early discontinued or interrupted, the investigator should immediately notify the Ethics 
Committee. 
Once the above-mentioned drug safety and protocol compliance issues that caused the 
discontinuation have been resolved and approved by the sponsor, Ethics Committee or 
regulatory agency, the study will be reinitiated. 

 
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6.7 
Continue to Use the Study Drug after the Study Ends 
If the investigator judges that the subject will get benefit continuing the treatment after study 
completion, the subject may be allowed to continue to be treated with GFH018 and/or 
Toripalimab after fully informed and reconsent until the treatment discontinuation criteria are 
met (see Section 6.5.1). Study drugs will be provided through other extended studies or other 
programs provided by the sponsor. 
7 EVALUATION 
The procedures required by the protocol should be performed as planned to ensure that the 
examination results can be evaluated in a timely manner. If it cannot be completed on time as 
required under special cases, the investigator will take all necessary measures to ensure the 
safety and benefits of subjects. The investigator should record the reasons and remedial 
measures and notify the study team in time. 
7.1 
Safety Evaluation 
Safety evaluation includes vital signs, physical examination, laboratory assessments, ECG, 
echocardiogram, AEs, SAEs, and concomitant therapies. 
7.1.1 
Physical Examination 
The physical examination may be performed by a physician, physician’s assistant, or nurse 
practitioner licensed to perform assessment. The subject's vital signs (respiration, pulse, blood 
pressure, and body temperature) will be recorded. The physical examinations include 
examination of general appearance, weight and examinations of disease-related systems if 
indicated based on medical history and/or symptoms, and ECOG PS will be recorded based on 
the examination results.  
If necessary, a complete physical examination will be performed, including general appearance, 
skin and lymph nodes, head and neck, chest, abdomen, spine and limbs, nervous system, 
genitals, anus and rectum examination and weight. 
7.1.2 
Laboratory Assessment 
Hematology, urinalysis, blood chemistry, coagulation, thyroid function, cardiac markers, tumor 
markers, and pregnancy test will be performed based on the schedule of study procedures. The 

 
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laboratory testing will be completed in the local laboratory. In the screening/baseline period, 
test of viral serology will be required to assess the eligibility for enrollment. Tumor markers 
other than which are listed in the Table 4 may be collected if available. 
Table 4 Laboratory test items 
Test item 
Observation index 
Hematology 
Count of red blood cell (RBC), concentration of hemoglobin (HGB), hematocrit (HCT), Mean 
corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), count of white blood cell (WBC), count of platelet (PLT), 
Absolute neutrophil count (ANC), lymphocyte (LY) count, monocyte (MO) count, eosinophil 
(EO) count, basophil (BA) count, percentage of neutrophils, percentage of lymphocytes, 
percentage of monocytes, percentage of eosinophils, and percentage of basophils 
Urinalysis 
White urine cells (LEU), urine nitrite (NIT), pH of urine, urine specific gravity (SG), urine 
protein (PRO), urine glucose (GLU), urine ketone body (KET), urobilinogen (UBG), urinary 
bile red pigment (BIL), urine occult blood (BLD), and 24-hour urine protein (if necessary) 
Coagulation 
Prothrombin time (PT), activated partial thromboplastin time (APTT), and international 
normalized ratio (INR) 
Blood 
chemistry 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase 
(ALP), lactate dehydrogenase (LDH), glutamyl transpeptidase (GGT), urea (UREA)/urea 
nitrogen, blood creatinine (CREA), total protein (TP), albumin (ALB), total bilirubin (TBIL), 
direct bilirubin (DBIL), creatine kinase (CK), amylase/pancreatic amylase (AMY/p-
AMY),lipase, blood glucose, total cholesterol (TCHO), low-density lipoprotein cholesterol 
(LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), phosphate, 
calcium, sodium, chlorine, and potassium 
Virus 
serology test 
Hepatitis B surface antigen (HBsAg), anti-hepatitis C virus antibody (anti-HCV), HIV 
antibody, Treponema pallidum antibody; If HBsAg positive, then add test of HBVDNA; If anti-
HCV positive, then add test of HCVRNA. 
Thyroid 
function  
Free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) 
Cardiac 
markers 
Troponin, brain natriuretic peptide (BNP) or NT-proBNP 
Tumor 
markers 
AFP (hepatocellular carcinoma only), CEA (colorectal cancer only), CA199 (pancreatic cancer 
only) 
Pregnancy 
test 
Female subjects in child-bearing period undergo serum β-HCG pregnancy test at baseline, and 
both serum test and urine test are acceptable at other visits 
7.1.3 
Electrocardiogram and Echocardiogram 
A standard 12-lead electrocardiogram (ECG) and echocardiogram will be completed according 
to the date and time requirements specified in the schedule of the study. 

 
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Standard 12-lead ECGs should be taken in supine, after at least 10 minutes rest. Recording of 
specific ECG parameters, include but are not limited to heart rate, QT, QTcF, and PR. Single 
ECGs will be performed at all timepoints. Triplicate 12-lead ECG will be performed when 1) 
QTcF 450≥ msec at screening; 2) in case of a post-screening QTcF interval ≥450 msec or an 
increase of ≥30 msec from baseline. These ECGs should be at least 10 min interval to ensure 
the accuracy of the examinations, and the average of the triplicate measurements will be 
recorded and used for evaluation. 
Echocardiography should include at least the condition of the heart valve, aortic valve, and 
systolic and diastolic function in the heart. During the study period, the consistency of test items 
should be ensured as much as possible. 
7.1.4 
Adverse events and Concomitant Therapies 
The evaluation of adverse events includes term of event, severity (grading based on NCI 
CTCAE version 5.0), starting and ending time, whether it is an immune-related adverse event, 
whether it is a serious adverse event, relevance to study treatment (GFH018 or/and 
Toripalimab), the adjustment of study treatment and outcomes. 
After signing of the informed consent until the completion of the safety follow-up visit, the AEs 
that occurred during the period will be recorded in the original medical records and collected 
in the CRF. Comedication/treatments received by the subject during the study treatment period 
will be recorded in the original medical records and collected in the CRF. 
7.2 
Pharmacokinetics 
7.2.1 GFH018 PK Samples Collection 
7.2.1.1 
For the 14 days on/ 14 days off Dosing Regimen 
1. Phase Ib 
As shown in the table of PK blood sampling schedule (see Table 5 Schedule of pharmacokinetic 
blood sample collection (14/14)), blood samples will be collected on Cycle 1 Day 1 and Day 8, 
and Cycle 2, Cycle 3, and Cycle 4 Day 15 for PK analysis. 
Table 5 Schedule of pharmacokinetic blood sample collection (14/14) 

 
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Cycle 
Day 
Volume of blood 
collected /(mL) 
Scheduled time 
point  
Description 
1 
1 
~ 3 
0 h 
Pre-dose in the morning 
1 
1 
~3 
0.5 h (± 10 min)  
Post-dose in the morning 
1 
1 
~ 3 
1 h (± 10 min)  
1 
1 
~ 3 
2 h (± 10 min)  
1 
1 
~ 3 
4 h (± 15 min)  
1 
1 
~ 3 
8 h (± 30 min)  
1 
1 
~ 3 
12 h (± 30 min)  
1 
8 
~ 3 
0 h 
Pre-dose in the morning 
1 
8 
~ 3 
0.5 h (± 10 min)  
Post-dose in the morning 
1 
8 
~ 3 
1 h (± 10 min)  
1 
8 
~ 3 
2 h (± 10 min) 
1 
8 
~ 3 
4 h (± 15 min)  
1 
8 
~ 3 
8 h (± 30 min)  
1 
8 
~ 3 
12 h (± 30 min)  
2, 3, 4 
15 
~ 3 
0 h 
Pre-dose in the morning 
2. Phase II 
Blood samples will be collected pre-dose in the morning of Cycle 1 Day 1 and Day 15, and 
Cycle 2, Cycle 3, and Cycle 4 Day 15. 
7.2.1.2 
Unscheduled Sampling  
In addition to the samples in the schedule, it may be necessary to collect GFH018 additional 
blood samples for subjects with unexpected AE and/or SAE related to the study treatment. In 
this case, it is necessary to record the sampling date and specific time points, as well as the 
details for the last administration.  
Every effort should be made to collect PK samples according to the date and time points 
specified in the protocol. The collection of PK samples with exact dates and clock times of drug 
administration and sample collection will be recorded on the appropriate blood collection CRF. 
If the blood sample cannot be obtained within the planned time, the investigator should contact 
the sponsor at the first time to discuss possible remedial measures. 
For details of sample preparation and processing, please refer to the laboratory manual. 

 
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7.2.2 
Toripalimab PK and ADA Samples Collection 
Pre-dose PK and ADA blood samples of Toripalimab will be collected on the Cycle 1 Day 1 
and Day 15, and Cycle 2, Cycle3 and Cycle 4 Day 15. For details, please refer to "Laboratory 
Manual". 
7.2.3 
Sample Analysis Methods 
The PK samples of the GFH018 will be analyzed with a validated liquid chromatography-
tandem mass spectrometry method, with the lower limit of qualification (LLOQ) of 20 ng/ml 
or less. 
The PK sample of Toripalimab will be analyzed by the validated electrochemiluminescence 
method, with LLOQ of 2.56 ng/ml or less. ADA will be detected by another chemiluminescence 
method. 
For details of processing method of biological samples, please refer to the "Laboratory 
Manual". 
7.2.4 
Calculation of Pharmacokinetic Parameters 
The non-compartmental model will be used to calculate the PK parameters of GFH018 after 
single and multiple doses. The PK parameters include Cmax, Tmax, AUC0-t, AUC0-inf, T1/2, CL/F 
and Vd/F for single dose, while Cmax,ss, Cmin,ss, Tmax,ss, AUCtau, T1/2,ss, CL/F,ss, Vd/F,ss and Racc 
for repeated doses. 
The drug concentration data below LLOQ before Tmax will be marked as 0 when calculating PK 
parameters, and BQL after Tmax will not be included in the calculation of PK parameters. The 
linear trapezoidal method will be used to calculate AUC. During the calculation of T1/2, the data 
of at least 3 time points after Tmax should be used. T1/2 will not be reported if the adjusted R2 
value of the regression analysis is <0.75. 
7.3 
Evaluation of Biomarkers  
During the study, the formalin-fixed, paraffin-embedded specimens of tumor tissue from 
patients will be collected before starting study treatment evaluation. The PD-L1 expression, 
CD8 + cell density and TILs in tumor tissue will be analyzed to explore potential predictive 
biomarkers. 
For details of sample preparation and processing, please refer to the "Laboratory Manual". 

 
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7.4 
 Evaluation of Tumor Response 
The evaluation of tumor response will include all known or suspected sites by radiologic 
techniques. Imaging includes computed tomography (CT) or magnetic resonance imaging 
(MRI) scanning of chest, abdomen or pelvic cavity; brain CT or MRI is used for the known or 
suspected brain metastasis of the subjects; bone scanning and/or bone X-ray are/is used for the 
known or suspected bone metastasis of the subjects. For subjects with extranodal NK/T cell 
lymphoma, the baseline imaging evaluation shall include both PET-CT and diagnostic enhanced 
CT/MRI of the neck, chest, abdomen, and pelvis, and MRI of the nasopharynx is necessary for 
nasal type. PET-CT can be used according to the local investigator interpretations in the 
subsequent evaluations. 
An imaging examination and tumor evaluation will be performed every 8 ± 1weeks (every 6 ± 
1 weeks for hepatocellular carcinoma) in the first year and every 12 ± 1 weeks (every 8 ± 
1weeks for hepatocellular carcinoma) from the second year. The same method of assessment 
and the same technique should be used to characterize each individual and reported lesion at 
baseline and during follow up. The evaluation of anti-tumor activity will be conducted in the 
screening period and treatment process through radiology, according to the study flow chart; it 
shall be also evaluated when the disease progression (such as symptom deterioration) is 
suspected or the subject withdraw (if the subject receives the imaging examination within 4 
weeks, it will not be necessary to repeat the examination). 
The tumor response will be assessed based on the RECIST 1.1 (Appendix 1) and Lugano 2014 
Criteria (Appendix 4) by investigator. Radiographic imaging examination of all subjects must 
meet the RECIST 1.1 or Lugano 2014 Criteria (only for extranodal NK/T cell lymphoma). All 
data shall be properly preserved and can be verified by source and peer review. 
8 REPORT OF ADVERSE EVENTS 
8.1 
Adverse Events (AE) 
8.1.1 
Definition of AE 
The time period for collecting AEs for each subject begins from the time that the subject 
provides written informed consent, until the end of safety follow-up (30 calendar days after the 
last administration of investigational products) (see Section 8.5 for details). An AE for the 
purposes of this protocol is defined as the appearance of undesirable sign(s), symptom(s), or 

 
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medical condition(s), whether or not considered related to the investigational product. 
Whenever possible, a diagnosis should be reported instead of underlying signs and symptoms. 
Examples of AEs include, but are not limited to:  
• Aggravation of existing (prior to enrollment of study) medical conditions/ diseases 
(including exacerbation of symptoms, signs, laboratory abnormalities); 
• Any new occurrence of AEs: any adverse medical conditions that newly occur 
(including symptoms, signs, newly diagnosed diseases); 
• Abnormal laboratory test findings of clinical significance. 
8.1.2 
Immune-Related Adverse Events (irAE) 
Based on the mechanism of Toripalimab, immune-related adverse events may occur during the 
study. When adverse events occur, investigators need to make a comprehensive judgment 
according to the symptoms, signs and laboratory examination results of the subjects. In the 
absence of alternative causes (such as infection or disease progression), all inflammation-
related events such as myocarditis, enteritis, pneumonia, dermatitis, hepatitis, and endocrine 
diseases require consideration of immune-related possibilities. Early recognition and timely 
treatment are needed to avoid potential major complications. For irAE and other management 
guidelines and principles of special adverse events that may be related to Toripalimab, please 
refer to "Investigator's Brochure". 
8.1.3 
Adverse Events of Special Interest (AESI) 
The AESI of this study is cardiotoxicity ≥ Grade 2, such as increased cardiac markers, and 
abnormal electrocardiogram or echocardiography with clinical significance. 
8.1.4 
Severity Assessment 
For severity of each AE, refer to the 5-grade scale developed from CTCAE v5.0. For AEs not 
included in CTCAE v5.0, the severity of each AE will be graded based on the general guidelines 
in Table 6. 
Table 6 General guideline on the severity of adverse events 

 
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Grade 
Clinical description of severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living. Instrumental activities of daily living refer to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
3 
Severe or medically significant but not immediately life-threatening; hospitalisation or 
prolongation of hospitalisation indicated; disabling; limiting self-care activities of daily living. 
Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden. 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to adverse event. 
8.1.5 
Causality Assessment 
An investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that investigational products caused or contributed to an AE, such as whether the 
occurrence of AE follows a reasonable time sequence to administration of investigational 
product, the properties of investigational products toxicological and pharmacological effects of 
investigational products, the use of concomitant medications, underlying diseases, medical 
history, family history, dechallenge and rechallenge reactions, etc. Generally, the facts 
(evidence) or arguments to suggest a causality should be provided. 
The causality of AE with GFH018 and Toripalimab administration will be assessed as “related” 
and “unrelated”. If the investigator considers that the AE is related to Toripalimab, this AE 
should be determined whether it is immune related adverse event.  
8.2 
Serious Adverse Event (SAE) 
8.2.1 
Definition of SAE 
An SAE is any untoward medical occurrence during the study as one of the followings: 
• Death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation; 
• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
• Constitutes a congenital anomaly/birth defect; 

 
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• Is considered to be medically significant 
Medical and scientific judgement should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalisation but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or 
development of drug dependency or drug abuse. 
8.2.2 
Hospitalisation 
Hospitalisation is defined as any initial admission (even less than 24 h) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission. 
Hospitalisation does not include the following: 
• Rehabilitation facilities; 
• Nursing homes; 
• General emergency admission (less than 24h); 
• Same-day surgeries (as outpatient/same-day/ambulatory procedures). 
Hospitalisation or prolongation of hospitalisation in the absence of a precipitating clinical AE 
is not in itself an SAE. Examples include: 
• Admission for treatment of a preexisting condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (e.g., for workup of a 
persistent pretreatment laboratory abnormality); 
• Administrative admission (e.g., for yearly physical examination); 
• Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol); 
• Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery); 
• Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject; 
• Admission exclusively for the administration of blood products. 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 

 
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during the reporting period should be reported if the AE requirements are met, and the resulting 
appendectomy should be recorded as treatment of the AE. 
8.2.3 
Disease Progression and Death 
Clinical symptoms of progression of malignancies may be reported as adverse events if the 
symptom cannot be determined as exclusively due to the progression of the underlying 
malignancy, or does not fit the expected pattern of progression for the disease under study. If it 
is clearly consistent with the suspected progression of the underlying cancer, it will not be 
reported as adverse events. Progression of malignancy itself will be not reported as an AE.  
Clinical symptoms of progression of malignancies that meet SAE criteria may be reported as 
SAEs if the symptom cannot be determined as exclusively due to the progression of the 
underlying malignancy, or does not fit the expected pattern of progression for the disease under 
study. An event which meets serious criteria of SAE (except death event) due sole to the 
progression of underlying malignancy should not be reported as a SAE.  
Any death event occurred in clinical trials from the subject's signing the informed consent until 
90 days after the last administration must be reported as SAE, regardless of whether the 
investigator evaluates a possible association with progression of malignancies. The term ‘death’ 
should not be reported as an SAE term, but rather as an outcome of an event. The cause of 
death, medical conditions/disease (including exacerbation of symptoms, signs) should be used 
to be recorded in the eCRF and reported as SAEs; if the cause of death is unknown at the time 
of report, it should be recorded as “unknown cause of death”. 
8.2.4 
SAE Reporting Requirements 
All SAEs should be reported to Genfleet/designated CRO drug safety department by the 
investigator on the report form (signed and dated) within 24 h of investigator awareness, 
regardless of whether this is an initial report or a follow-up report. The investigator should also 
report the SAEs to relevant organizations in a timely manner as required by local regulations. 
In countries or regions outside China, SAEs should be reported in accordance with the most 
stringent standards in accordance with local regulations. 
SAEs occurring in a subject after the active collection period has ended are reported to 
Genfleet/designated CRO drug safety department if the investigator becomes aware of them; at 

 
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a minimum, all SAEs that the investigator believes have at least a reasonable possibility of 
being related to investigational products must be reported. The detailed record content of SAE 
should include symptoms, severity, causality with investigational products, time of onset, time 
of treatment, action taken with investigational products, follow-up time and way as well as 
outcome. If the investigator considers that a SAE is not related to investigational products while 
potentially related to the study conditions (e.g., termination of the original treatment or 
complications during the study), the relationship should be described in detail in the narrative 
section of SAE report form. 
The sponsor’s email to receive safety reports (for SAEs or exposure during pregnancy) in this 
study: 
• Public mailbox for drug safety of Genfleet: drugsafety@genfleet.com 
• Public mailbox for drug safety of Tigermed: pv@tigermedgrp.com 
• Drug safety fax of Tigermed: +86 -21-33275864 
8.3 
Pregnancy 
If a female subject becomes pregnant during the clinical study, the subject must discontinue 
study treatment and be removed from the study; if a male subject's partner becomes pregnant 
during the clinical study, the subject may continue the clinical study. The investigator shall 
report to the sponsor within 24 hours of being informed of the pregnancy event by completing 
the report form. 
The investigator should follow up on the pregnancy outcome (e.g., any early termination of 
pregnancy, or a live birth) until 1 month after delivery, and notify the sponsor the pregnancy 
outcome. If the pregnancy outcome meets the criteria for an SAE (i.e., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly), the 
investigator should follow the procedures for reporting SAEs. 
If a subject experiences an SAE during pregnancy, the SAE should be reported following the 
procedures for reporting SAEs. 

 
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8.4 
Hy’s law 
Increased values in AST and/or ALT concurrent with abnormal elevations of TBIL that meet all 
of the following 3 criteria in the absence of other etiologies should be reported as SAEs. Needs 
to be reported following by SAE report process. 
Table 7 Criteria for Liver Function Test Abnormalities  
Conditions of satisfaction 
Criteria 
Abnormal ALT or AST 
Baseline within normal range: ALT or AST in 
treatment stage > 3 × ULN; 
Baseline within abnormal range: ALT or AST in 
treatment stage > 3 × baseline level. 
Abnormal TBIL 
Baseline within normal range: treatment stage TBIL 
in treatment stage > 2 × ULN; 
Baseline within abnormal range: treatment stage 
TBIL in treatment stage > 2 × baseline level. 
Alkaline phosphatase < 2 ×ULN (or no other information available) 
Subjects who present with abnormal values in AST and/or ALT concurrent with abnormal 
elevations of TBIL during the treatment or follow-up period should return to the investigational 
site and be evaluated as soon as possible. This evaluation should include laboratory tests, 
detailed history, physical assessment and information of concomitant treatments. In addition, 
the condition of tumor affecting the liver shall be considered. 
8.5 
Collection and Follow-Up of AE/SAE/AESI/Pregnancy Events 
AE collection starts from the time that the subject signs the informed consent to participate in 
the study and continues until the end of safety follow-up (30 calendar days after the last 
administration of the investigational product). 
At each study visit period, the investigator shall assess whether the subject has experienced an 
adverse event. All adverse events should be followed until they are resolved, or returned to 
baseline, or be stable, or judged by the investigator to be irreversible, or be reasonably explained 
(e.g., lost to follow-up, death), or until the event is conclusively confirmed to be unrelated to 
the study treatment or study procedure at the end of the safety follow-up period. Every effort 

 
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should be made to ensure that subjects achieve optimal outcomes and receive a clear evaluation 
of causal relationship. 
All AEs should be documented in detail on the AE page of the CRF, including term of event, 
severity (grading according to CTCAE version 5.0), starting and ending time, whether it is an 
irAE or AESI, whether it is a serious adverse event, and causality of investigational products 
(GFH018 or/and Toripalimab), the action taken of investigational product, and outcomes. 
Table 8 Collection of AE/SAE/AESI/pregnancy events 
Abbreviations: AE = adverse events, SAE = serious adverse events, AESI = adverse events of special interest.  
9 CLINICAL MONITORING 
In order to ensure that the rights and interests of patients are protected, the data obtained in the 
study is accurate, complete and reliable, and the study is in compliance with the approved 
protocol/revised protocol, ICH-GCP, and applicable regulatory requirements, the study site will 
be monitored by the sponsor or its authorized agent. During the study, the field monitor will 
visit the site regularly to check the completeness of patient records, the accuracy of entries on 
the eCRFs, the adherence to the protocol to Good Clinical Practice, the progress of enrollment, 
and to ensure that study drug is being stored, dispensed, and accounted for according to 
specifications. 
The detailed planning and the implementation of clinical monitoring will be recorded in this 
study monitoring plan (SMP). 
Period 
Requirements of collection 
From the subject's signing the 
informed consent until the end of the 
safety follow-up period 
All AE/SAE/AESI/pregnancy events 
Pregnancies: collection starts from the first administration of the 
investigational product. 
From the end of the safety follow-up 
period to 90 days after the last 
administration 
All SAE/AESI/pregnancy events. 
After the above period 
SAEs/AESIs which are considered related to the investigational 
product. 

 
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10 STATISTICAL ANALYSIS 
The phase Ib and phase II data will be analyzed separately. The summary will be presented by 
dose level and regimen for phase Ib part. The summary will be presented by tumor type for 
phase II part, subjects who have received the phase II treatment regimen in phase Ib and meet 
the phase II eligibility criteria will be counted. 
The detailed methods for the summary and statistical analysis of the data collected by this study 
will be included in the Statistical Analysis Plan (SAP). 
10.1 Analysis Sets  
• 
Full Analysis Set (FAS) consists of all subjects who have received at least one dose of study 
treatment. 
• 
Safety Set (SS) includes all subjects from the FAS who have received at least one dose of 
study treatment and had at least one valid post-baseline safety assessment. 
• 
Dose Determining Set (DDS) consists of all subjects in the SS in phase Ib part who have 
received at least 75% of the total planned dose of GFH018 and the planned complete dose 
of Toripalimab (including the interruption allowed in the regimen) during the DLT 
observation period, are considered to have sufficient safety evaluation or developed DLT 
during the DLT observation period, and have no major protocol deviations that would 
impact the safety analyses. 
• 
Per Protocol Set (PPS) consists of all subjects in the FAS who are in compliance with the 
protocol in phase II part. Subjects who have major protocol deviations may be excluded 
from the PPS based on a study team review of all protocol deviations, which will be 
conducted before final database lock. 
• 
Pharmacokinetic analysis set (PKAS) consists of all subjects who take at least one dose of 
study treatment and have at least one blood sample providing evaluable concentration data. 
10.2 Distribution of Subjects  
Summary the distribution of subjects who participated in the screening. Summarize and list the 
conditions of participating in screening, receiving study treatment, reason for discontinuation 
of study treatment, reason for end of study, inclusion in each analysis set. 

 
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10.3 Protocol Deviations 
Compliance with the protocol will be assessed by the number and proportion of patients with 
major protocol deviations. Protocol deviations will be identified prior to database lock and will 
be listed and summarized. 
10.4 Demographic and Baseline Characteristics 
Demographic and other baseline characteristics including age, gender, height, weight, medical 
conditions, etc. will be listed individually by patient, and summarized by treatment assigned 
using descriptive statistics (continuous data) or contingency tables (categorical data) for the 
FAS. 
10.5 Treatment Exposure 
The actual dose and duration of study treatment as well as the dose intensity and the relative 
dose intensity will be listed and summarized. Categories for relative dose intensity will be 
specified. The number and proportion of patients within each category will be presented. 
10.6 Concomitant Medications 
Concomitant medications will be coded using World Health Organization Drug Dictionary 
(WHODD). A summary of concomitant medications by anatomical therapeutic chemical (ATC) 
and preferred term (PT) will be provided. 
10.7 Efficacy Analysis 
The efficacy endpoints include objective response rate (ORR), disease control rate (DCR), 
duration of response (DOR), time to response (TTR), progression-free survival (PFS), and 
overall survival (OS). The efficacy endpoints are defined as follows: 
 
ORR: The proportion of subjects with a best overall response (BOR) of complete 
response (CR) or partial response (PR). 
 
DCR: The proportion of subjects with a BOR of CR, PR or stable disease (SD). 
 
DOR: Time from first evidence of CR or PR to disease progression or death from any 
cause, whichever occurs first. 
 
TTR: Time from start of study treatment until the first evidence of CR or PR. 
 
PFS: Time from start of study treatment until disease progression or death from any 
cause, whichever occurs first. 
 
OS: Time from start of study treatment until death due to any cause. 

 
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For Phase Ib part, the efficacy analysis will be based on FAS. The number of subjects with the 
BOR of CR, PR, SD, progressive disease (PD) will be summarized according to the assessment 
results of each visit. ORR and DCR of each group will be also calculated. A by-subject list of 
DOR, TTR, PFS, and OS will be provided. 
For Phase II part, the efficacy will be analyzed based on FAS and PPS. FAS will be used for 
primary analysis, sensitivity analysis will be performed based on PPS. The number of subjects 
with the BOR of CR, PR, SD, PD will be summarized according to the assessment results of 
each visit. ORR and DCR will be calculated, the corresponding two-sided 90% confidence 
intervals (CI) will be estimated by the Clopper-Pearson method. When the sample size of 
analyzed group is ten or more, the Kaplan-Meier method will be used to provide median 90% 
Brookmeyer-Crowley CI for DOR, TTR, PFS, and OS. 
10.8 Safety Analysis 
All safety analysis will be based on SS except for DLTs which based on DDS.  
Adverse events 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of treatment-emergent adverse events (TEAEs), study 
treatment related adverse events, serious adverse events (SAEs), adverse events of special 
interest (AESIs), immune-related adverse events (irAEs), TEAEs leading to study treatment 
interruption and study treatment discontinuation will be summarized by the system organ class 
(SOC) and preferred term (PT). The list of AEs will be provided. DLTs will be listed and 
summarized for each dose level using DDS. 
Laboratory tests 
All laboratory parameters and change from baseline will be summarized by time point. Shift 
table by baseline and worst post-baseline will be provided. 
Vital signs 
Vital sign parameters and change from baseline will be summarized by time point. A by-subject 
listing of vital sign will be provided. 
ECG 

 
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ECG parameters and change from baseline will be summarized by time point. A by-subject 
listing of ECG parameters will be provided. 
10.9 Immunogenicity analysis 
The number and percentage of subjects with positive anti-body antibody (ADA) will be 
summarized. 
10.10 Pharmacokinetic Analysis  
The drug plasma or serum concentration data will be summarized and plotted by time point for 
each group. PK parameters will be listed and summarized descriptively.  
10.11 Pharmacodynamic Analysis 
If necessary, the correlation between the PD parameters and efficacy may be explored. 
10.12 Sample Size 
Phase Ib 
Subjects will be enrolled and treated in cohort of size 3-6. A minimum of 6 DLT-evaluable 
subjects should be included in the selected treatment regimen for Phase II. Up to 15 subjects 
will be enrolled and treated for Phase Ib. Additional subjects may be enrolled if more dose 
levels or alternative dosing regimens are to be explored. 
Phase II 
Ten subjects will be enrolled in each tumor type. Subjects who have received the phase II 
treatment regimen in the phase Ib part and meet the phase II part eligibility criteria will be 
counted. Depending on the clinical benefits of each tumor type, the sponsor will determine the 
enrollment of additional 10-20 subjects with the same tumor type, i.e., a tumor type can be 
expended to approximately a total of 20-30 subjects, tumor types with potential benefit will be 
expanded to maximal 60 patients at the discretion of the sponsor and leading investigators. If 
none of the ten shows response (i.e., complete response or partial response according to 
RECIST 1.1 or Lugano 2014 Criteria), the enrollment of subjects with the specific tumor type 
may be stopped. 
10.13 Interim Analysis 
No formal interim analysis is planned for this study. 

 
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11 SAFETY MONITORING  
The sponsor team and the investigators will review drug safety data on an ongoing basis from 
the first visit for the first subject until the end of the study, and make decision of dose escalation 
for the phase Ib part. 
If it is assessed that the safety of the subject cannot be ensured or that the limits of his or her 
tolerance have been reached, administration of this study will be hold immediately until the 
subject’s risk-benefit ratio has changed and that continued study treatment is beneficial to the 
subject. 
12 DATA COLLECTION AND MANAGEMENT 
The sponsor is responsible for the clinical study data management of this study and Electronic 
Data Capture (EDC) will be used for data collection and management. 
12.1 Data Collection 
This study will use Electronic Data Capture (EDC) for data collection. The investigator or the 
designated staff will enter the data required by the protocol into the Electronic Case Report 
Forms (eCRF). Site staff will not be given access to the EDC system until they have been 
trained. Automatic validation programs check for data discrepancies in the eCRFs and allow 
modification or verification of the entered data by the staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
PK and PD samples drawn during the course of the study will be collected from the study sites 
and analyzed by a Sponsor contracted laboratory. Designated investigational site staff will enter 
the information required by the protocol into the appropriate eCRFs. The monitor will review 
the eCRFs for accuracy and completeness and instruct site personnel to make any required 
corrections or additions. 
12.2 Data Management 
Sponsor or designated CRO staff will review the data entered by investigational staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 

 
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investigational site via the EDC system. Designated study site staff are required to respond 
promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHODD, which employs the Anatomical Therapeutic Chemical classification system. Medical 
history/current medical conditions and adverse events will be coded using the MedDRA 
terminology. 
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked and made available for data analysis. Authorization is required prior to making 
any database changes to locked data. 
13 SOURCE DATA AND ORIGINAL FILE 
In accordance with ICH E6, relevant regulations and the requirements of the study institution 
for the protection of subjects' personal information, each study center is required to keep records 
related to this study properly. As part of Genfleet's sponsoring or participating in the study, each 
study center shall allow Genfleet's authorized representatives and regulatory agencies to inspect 
(and, if permitted by law, copy) clinical records for quality review, audit, evaluation of safety, 
study progress, and data validity. 
Source data is all the information necessary to reconstruct and evaluate a clinical study and is 
the original record of clinical findings, observations or other activities. Examples of these 
original documents and data records include, but are not limited to: hospital records, laboratory 
records, memoranda, subject diary cards, pharmacy dispensing records, recordings of 
consultation sessions, recorded data from automated instruments, photocopied or transcribed 
records verified as accurate and complete, microfilm, photographic negatives, microfilm or 
diskettes, x-rays, and documents and records of subjects maintained in participating 
pharmacies, laboratories, and medical and technical departments. 
14 QUALITY ASSURANCE AND QUALITY CONTROL 
To ensure the quality of the study, the clinical study plan will be discussed and developed by 
the sponsor and the investigator before the study officially starts. And to confirm that the 
relevant study staff participating in the study have undergone appropriate GCP training. 

 
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Each study center must manage study drugs in accordance with SOPs, including receipt, 
storage, dispensing, recycling, and destruction process. 
According to the GCP guidelines, the necessary steps should be taken during the design and 
implementation phases of the study to ensure that the data collected are accurate, consistent, 
complete, and credible. All observed results and abnormal findings in clinical studies shall be 
verified and recorded in a timely manner to ensure the reliability of the data. The instruments, 
equipment, reagents, standards, etc. used for various tests in clinical study shall follow strict 
quality standards and ensure that they are in proper working condition. 
The investigator enters the information required by the protocol into the CRF, and the supervisor 
verifies that it is completed completely and accurately and directs the study center staff to make 
any necessary revisions and additions. 
Drug regulatory authorities, Ethics Committees, sponsors' monitors and/or auditors may 
conduct systematic inspections of clinical study-related activities and documents to evaluate 
whether the study is conducted in accordance with the study protocol, SOPs, and relevant 
regulatory requirements, and whether study data are recorded in a timely, truthful, accurate, and 
complete manner. The audit shall be performed by staff who are not directly involved in the 
clinical study. 
15 ETHICAL CONSIDERATIONS  
15.1 Ethical Compliance 
This clinical study must follow the International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (CIOMS, 2002), the current ICH-GCP, the Declaration of Helsinki, 
and applicable regulations. The study protocol, protocol revisions, “Informed Consent Form” 
and other relevant documents such as enrollment advertisements shall be provided to the Ethics 
Committee before the study. Prior approval must be obtained from the relevant regulatory 
authorities and the hospital ethics committee before this study can be initiated. 
Neither party may unilaterally modify this study protocol without the consent of both the 
sponsor and the investigator. The modified protocol can only be implemented after approval by 
the Ethics Committee. If the investigator has to enter the protocol deviation process in order to 
eliminate obvious and immediate harm to the subject, the Ethics Committee and the sponsor 

 
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must be notified in writing immediately after the deviation process is implemented, along with 
an explanation and documentation of any protocol deviation made. 
Any changes made to this study protocol during the clinical study shall be submitted to the 
Ethics Committee and, if necessary, other study documents should also be revised accordingly 
and submitted and/or approved in accordance with the requirements of the Ethics Committee. 
It is the responsibility of the investigator to submit regular interim reports in accordance with 
the relevant requirements of the Ethics Committee and to inform the Ethics Committee that the 
study has been completed after the end of the study. 
15.2 Independent Ethics Committee 
The protocol, “Informed Consent Form”, enrollment materials and all patients materials will be 
submitted to the Ethics Committee for review and approval. Patients are enrolled only after the 
protocol and “Informed Consent Form” are approved. Any revision of the protocol must be 
reviewed and approved by the Ethics Committee before implementation. All revisions to the 
“Informed Consent Form” must also be approved by the Ethics Committee, and the Ethics 
Committee will decide whether patients who have signed the previous, older version of the 
informed consent form are required to sign the new version again. 
15.3 Informed Consent 
15.3.1 
Informed Consent Form 
Informed Consent Form described the research process in detail and fully explained to the 
subjects the risks of the study. Informed consent form must be obtained before conducting any 
study procedures.  
15.3.2 
Informed Consent Procedures 
Informed consent process begins before a patient agrees to participate in a clinical study and 
continues throughout the course of the clinical study. The investigator or the authorized staff 
should inform the patient that “Informed Consent Form ” has been approved by the EC/IRB 
and that it is the responsibility of the investigator to provide the patients with a complete and 
comprehensive description of the purpose of the project, how the study will be conducted, the 
effects of the drug, the risks and possible benefits of participation in the study, and that the 
patient should be promptly informed of any new information regarding information about the 
study drug. Patients should be informed that they can withdraw unconditionally at any time 

 
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during the experiment. Patients should be informed that the investigator and sponsor have the 
right to read, preserve, and statistically process the subject's trial data in accordance with legal 
requirements. Patients should have adequate time for consultation and consideration before 
signing informed consent. Subjects could only participate in the study after signing an 
“Informed Consent Form”. Patients may withdraw consent at any time during the entire course 
of the clinical study. If the patient cannot read the “Informed Consent Form”, an informed 
explanation needs to be completed in the presence of a neutral third-party witness and verbal 
consent obtained from the patient, and both the investigator and the witness completing the 
explanation need to sign the name and date on the “Informed Consent Form”. An original copy 
of the “Informed Consent Form” will be retained by the patients. Even if the enlisted patients 
decline to participate in this study, their rights will be fully protected and the quality of their 
medical care will not be affected in any way. 
15.4 Confidentiality of Patients' Information 
Procedures for the confidentiality of Patients' information are strictly enforced by the 
investigator, other staff in the study, the sponsor, and their agents. Confidential information 
covers patients' clinical information and biological samples. Therefore, study protocols, 
documents, data, and all other study information will be taken to preserve confidentiality. All 
relevant study information should not be disclosed to any third party without sponsor’s 
authorization. 
Authorized representative of the sponsor, EC, and regulatory authorities may perform audits or 
inspections documents and records that is required to maintain by the investigator, which 
include, but are not limited to: medical records and subjects' IP records. The site should allow 
access to these records. 
It is the responsibility of the investigator to maintain the subject's anonymity. Subjects may be 
identified on case report forms or other documents only by capital letters, numbers, and/or 
codes, not by the subject's name. The investigator must maintain Identification code Form that 
records the subject's code, name and home address. The investigator must prevent data being 
linked to the identity of the patient. 
15.5 Future Use of Preserved Specimens 
Not applicable. 

 
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16 PUBLICATION OF STUDY RESULTS 
The investigator should keep information and data related to this study confidential and should 
not cite or publish relevant study results or information without the consent of the sponsor. If 
the investigator plans to publish any study-related data and information, the original, abstract 
or full text of all planned publications (posters, invited presentations or guest lectures) must be 
agreed to by the sponsor and provided to the sponsor at least 30 days prior to submission of the 
document for publication or other release. 
 
 

 
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17 REFERENCES 
1. Neuzillet C, Tijeras-Raballand A, Cohen R, et al. Targeting the TGF-β pathway for cancer 
therapy. Pharmacol Ther 2015; 147:22-31. 
2. Gramont A, Faivre S, Raymond E. Novel TGF-β inhibitors ready for prime time in onco-
immunology. OncoImmunology 2017; 6: e1257453. 
3. Michitaka Nakano, Yoshikane Kikushige, Kohta Miyawaki, et al. Dedifferentiation process 
driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer. 
Oncogene. 2019;38(6):780-793. 
4. An Y, Gao S, Zhao WC, et al. Transforming growth factor-β and peripheral regulatory cells 
are negatively correlated with the overall survival of hepatocellular carcinoma. World J 
Gastroenterol 2018; 25: 2733-2740. 
5. Peng L, Yuan XQ, Zhang CY, et al. High TGF-β1 expression predicts poor disease 
prognosis in hepatocellular carcinoma patients. Oncotarget 2017; 8: 34387-34397.  
6. Calon A, Lonardo E, Berenguer-Llergo A, et al. Stromal gene expression defines poor-
prognosis subtypes in colorectal cancer. Nat Genet 2015; 47:320-329.  
7. Armand, P., Engert, A., Younes, A., Fanale, M., Santoro, A., Zinzani, P.L., Timmerman, 
J.M., Collins, G.P., Ramchandren, R., Cohen, J.B., et al. (2018). Nivolumab for 
relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic 
cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 
205 trial. J. Clin. Oncol. 36, 1428-1439. 
8. Hamid, O., Robert, C., Daud, A., Hodi, F.S., Hwu, W.J., Kefford, R., Wolchok, J.D., Hersey, 
P., Joseph, R., Weber, J.S., et al. (2019). Five-year survival outcomes for patients with 
advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann. Oncol. 30, 582-
588. 
9. Le, D.T., Durham, J.N., Smith, K.N., Wang, H., Bartlett, B.R., Aulakh, L.K., Lu, S., 
Kemberling, H., Wilt, C., Luber, B.S., et al. (2017). Mismatch repair deficiency predicts 
response of solid tumors to PD-1 blockade. Science 357, 409-413. 
10. Nghiem, P., Bhatia, S., Lipson, E.J., Sharfman, W.H., Kudchadkar, R.R., Brohl, A.S., 

 
Clinical Study Protocol 
 GFH018X0201 
 
Version number: 3.0 
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Page 97/118 
 
Friedlander, P.A., Daud, A., Kluger, H.M., Reddy, S.A., et al. (2019). Durable tumor 
regression and overall survival in patients with advanced Merkel cell carcinoma receiving 
pembrolizumab as first-line therapy. J. Clin. Oncol. 37, 693-702. 
11. Mok, T.S.K., Wu, Y.L., Kudaba, I., Kowalski, D.M., Cho, B.C., Turna, H.Z., Castro, G., Jr., 
Srimuninnimit, V., Laktionov, K.K., Bondarenko, I., et al. (2019).Pembrolizumab versus 
chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic 
non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 
3 trial. Lancet 393, 1819-1830. 
12. Motzer, R.J., Penkov, K., Haanen, J., Rini, B., Albiges, L., Campbell, M.T., Venugopal, B., 
Kollmannsberger, C., Negrier, S., Uemura, M., et al. (2019a). Avelumab plus axitinib 
versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1103-1115. 
13. Callahan MK, Postow MA, Wolchok JD. Targeting T cell co-receptors for cancer therapy. 
Immunity 2016;44:1069-1078. 
14. Zhang J, Dang F, Ren J, Wei W. Biochemical Aspects of PD-L1 Regulation in Cancer 
Immunotherapy. Trends Biochem Sci. 2018;43(12):1014-1032. 
15. Jiang Y, Zhao X, Fu J, Wang H. Progress and Challenges in Precise Treatment of Tumors 
With PD-1/PD-L1 Blockade. Front Immunol. 2020;11:339. Published 2020 Mar 12. 
doi:10.3389/fimmu.2020.00339. 
16. Lind H, Gameiro SR, Jochems C, et al Dual targeting of TGF-β and PD-L1 via a 
bifunctional anti-PD-L1/TGF-βRII agent: status of preclinical and clinical advances 
Journal for ImmunoTherapy of Cancer 2020;8:e000433. 
17. Derynck, R., Turley, S.J. & Akhurst, R.J. TGFβ biology in cancer progression and 
immunotherapy. Nat Rev Clin Oncol 18, 9–34 (2021). 
18. Petitprez, F., de Reyniès, A., Keung, E.Z.B cells are associated with survival and 
immunotherapy response in sarcoma. Nature. 2020. 577: 556-560.  
19. Helmink, B.A., Reddy, S.M., Gao, J. et al. B cells and tertiary lymphoid structures promote 
immunotherapy response. Nature. 2020. 577: 549-555.  
20. Cabrita, R., Lauss, M., Sanna, A. et al. Tertiary lymphoid structures improve 
immunotherapy and survival in melanoma. Nature. 2020. 577: 561-565.  

 
Clinical Study Protocol 
 GFH018X0201 
 
Version number: 3.0 
Confidential 
Page 98/118 
 
21. Mayoux et al. Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy 
Sci. Transl. Med. 2020. 12: eaav7431.  
22. Fairfax, B.P., Taylor, C.A., Watson, R.A. et al. Peripheral CD8+ T cell characteristics 
associated with durable responses to immune checkpoint blockade in patients with 
metastatic melanoma. Nat Med. 2020. 26: 193-199. 
23. Wenjuan Dong, Xiaojin Wu, Shoubao Ma, et al. The Mechanism of Anti-PD-L1 Antibody 
Efficacy against PD-L1-Negative Tumors Identifies NK Cells Expressing PD-L1 as a 
Cytolytic Effector. Cancer Discov 2019. 9:1-16 
24. Daniel R Principe, Alex Park, Matthew J Dorman, et al. TGFβ Blockade Augments PD-1 
Inhibition to Promote T-Cell-Mediated Regression of Pancreatic Cancer. Mol Cancer Ther. 
2019;18(3):613-620.  
25. Sanjeev Mariathasan, Shannon J Turley, Dorothee Nickles, et al. TGFβ attenuates tumour 
response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 
2018;554(7693):544-548.  
26. Daniele V F Tauriello, Sergio Palomo-Ponce, Diana Stork, et al. TGFβ drives immune 
evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554(7693):538-
543. 
27. Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon 
cancer metastasis. Nature 554, 538-543 (2018). 
28. Martin, C. J. et al. Selective inhibition of TGFβ1 activation overcomes primary resistance 
to checkpoint blockade therapy by altering tumour immune landscape. Sci. Transl Med. 12, 
eaay8456 (2020). 
29. Zhang B, Miao T, Shen X, et al. EB virus-induced ATR activation accelerates 
nasopharyngeal carcinoma growth via M2-type macrophages polarization. Cell Death Dis. 
2020 Sep 11;11(9):742.  
30. Yu L, Ke J, Du X, Yu Z, Gao D. Genetic characterization of thymoma. Sci Rep. 2019 Feb 
20;9(1):2369.  
31. Go JH. Altered expression of Smad proteins in T or NK-cell lymphomas. Cancer Res Treat. 
2008 Dec;40(4):197-201. doi: 10.4143/crt.2008.40.4.197. Epub 2008 Dec 31.  

 
Clinical Study Protocol 
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Version number: 3.0 
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Page 99/118 
 
32. Zhang B, Miao T, Shen X, et al. EB virus-induced ATR activation accelerates 
nasopharyngeal carcinoma growth via M2-type macrophages polarization. Cell Death Dis. 
2020 Sep 11;11(9):742.  
33. Zhang L, MacIsaac KD, Zhou T, et al. Genomic Analysis of Nasopharyngeal Carcinoma 
Reveals TME-Based Subtypes. Mol Cancer Res. 2017 Dec;15(12):1722-1732.  
34. Dwivedi SK, McMeekin SD, Slaughter K, et al. Role of TGF-β signaling in uterine 
carcinosarcoma. Oncotarget. 2015 Jun 10;6(16):14646-55.  
35. Ma K, Zhang C, Li W. TGF-β is associated with poor prognosis and promotes 
Osteosarcoma progression via PI3K/Akt pathway activation. Cell Cycle. 2020 
Sep;19(18):2327-2339. doi: 10.1080/15384101.2020.1805552. Epub 2020 Aug 17. 
Retraction in: Cell Cycle. 2022 Apr;21(8):879. 
36. https://www.clinicaltrials.gov/ct2/show/NCT05588648?term=NCT05588648&draw=2&r
ank=1 
37. Jalalirad M, Haddad TC, Salisbury JL, et al. Aurora-A kinase oncogenic signaling mediates 
TGF-β-induced triple-negative breast cancer plasticity and chemoresistance. Oncogene. 
2021 Apr;40(14):2509-2523. 
38. Zhang M, Zhang YY, Chen Y, et al. TGF-β Signaling and Resistance to Cancer Therapy. 
Front Cell Dev Biol. 2021 Nov 30;9:786728. 

 
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Appendix 1 Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST v1.1) 
39. (E.A. Eisenhauer, P. Therasse, J. Bogaerts, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1),European Journal of Cancer,2009;228-
247.) 
1. Measurability of tumor at baseline 
1.1 Definition 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
Measurable lesions 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix II on 
imaging guidance). 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 
20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be P15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed (see Schwartz et al. in this Special Issue15). See also notes be- 
low on ‘Baseline documentation of target and non-target lesions’ for information on lymph node 
measurement. 
Non-measurable lesions 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with P10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal dis- ease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 

 
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abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques. 
Special considerations regarding lesion measurement 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. How- ever, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non- 
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Lesions with prior local treatment: 
• 
A lesion located at a site that has been radiated or otherwise treated regionally is generally 
treated as a non-measurable lesion unless the lesion shows definite progression. The study 
protocol shall describe in detail the conditions under which these lesions are measurable. 
1.2 Specifications by methods of measurements 

 
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Measurement of lesions  
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed 
at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. See Appendix II for more details. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. As is described in 
Appendix II, when CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans). More details concerning the use of both CT and MRI for 
assessment of objective tumor response evaluation are provided in Appendix II. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed the same technique and measurements will be taken from one assessment to the next 

 
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(described in greater detail in Appendix II). If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT or MRI is ad- vised. If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient 
to be considered in complete response. Because tumor markers are disease specific, instructions 
for their measurement should be incorporated into protocols on a disease specific basis. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer), have been published.16–18 In addition, the Gynecologic Cancer 
Intergroup has developed CA125 progression criteria which are to be integrated with objective 
tumor assessment for use in first-line trials in ovarian cancer.19 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can re- main). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
2. Tumor response evaluation 
2.1 Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 

 
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Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.2 Special notes on the assessment of target lesions  
Lymph nodes: Lymph nodes. Lymph nodes identified as target lesions should always have the 
actual short axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if complete 
response criteria are met, since a normal lymph node is defined as having a short axis of <10 
mm. Case report forms or other data collection methods may therefore be designed to have 
target nodal lesions recorded in a separate section where, in order to qualify for CR, each node 
must achieve a short axis <10 mm. For PR, SD and PD, the actual short axis measurement of 
the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each sub- 
sequent evaluation, even when very small (e.g.,2 mm). How- ever, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
‘too small to measure’. When this occurs, it is important that a value be recorded on the case 
report form. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less likely 
that this rule will be used for lymph nodes since they usually have a definable size when normal 
and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node 
is believed to be present and is faintly seen but too small to measure, a de- fault value of 5 mm 
should be assigned in this circumstance as well). This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness). The 

 
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measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error. To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even 
if it is below 5 mm. 
Lesions that split or coalesce on treatment. As noted in Appendix II, when non-nodal lesions 
‘fragment’, the longest diameters of the fragmented portions should be added together to 
calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each individual 
lesion. If the lesions have truly coalesced such that they are no longer separable, the vector of 
the longest diameter in this instance should be the maximal longest diameter for the ‘coalesced 
lesion’. 
2.3 Evaluation of non-target lesions 
This section provides the definitions of the criteria used to deter- mine the tumor response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered progression). 
2.4 Special notes on assessment of progression of non- target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy (see 
examples in Appendix II and further details below). A modest ‘increase’ in the size of one or 

 
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more non-tar- get lesions is usually not sufficient to quality for unequivocal progression status. 
The designation of overall progression solely on the basis of change in non-target disease in the 
face of SD or PR of target disease will therefore be extremely rare. 
When the patient has only non-measurable disease. This circum- stance arises in some phase 
III trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. Some illustrative examples are shown 
in Figs. 5 and 6 in Appendix II. If ‘unequivocal progression’ is seen, the patient should be 
considered to have had overall PD at that point. While it would be ideal to have objective criteria 
to apply to non-measurable dis- ease, the very nature of that disease makes it impossible to do 
so, therefore the increase must be substantial. 
2.5 New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it 
is not. 

 
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A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans con- firm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm: 
a. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, 
this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not PD. 
2.6 Missing assessments and inevaluable designation  
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a patient had a baseline sum of 50 mm with three measured lesions and at follow-

 
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up only two lesions were assessed, but those gave a sum of 80 mm, the patient will have 
achieved PD status, regardless of the contribution of the missing lesion. 
2.7 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may 
not have a total sum of ‘zero’ on the case report form (CRF). 
In trials where confirmation of response is required, re-peated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression. For 
example, in most trials it is reasonable to consider a patient with time point responses of PR-
NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in 
Tables 1–3. 
Conditions that define ‘early progression, early death and inevaluability’ are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis 
or scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by dis- ease specific medical literature for the indication. However, it 

 
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must be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
 
Table 1 – Time point response: patients with target (+/-non-target) disease 
Target lesions 
Non-target-lesions 
New lesions 
Overall response 
CR 
CR  
No  
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. 
Table 2 – Time point response: patients with non-target disease only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD  
No 
Non-CR/non-PDa  
Not all evaluated  
No 
NE 
Unequivocal PD  
Yes or No 
PD  
Any 
Yes  
PD 
 
CR = complete response, PD = progressive disease, and NE = inevaluable. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised.  
Table 3 – Best overall response when confirmation of CR and PR required. 
Overall response 
Overall response 
BEST overall response 

 
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First time point 
Subsequent time point 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. 
a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. However, 
sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and 
in fact the patient had PR, not CR at the first time point. Under these circumstances, the original CR should 
be changed to PR and the best response is PR. 
2.8 Confirmatory measurement/duration of response 
Confirmation 

 
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In non-randomized trials where response is the primary end- point, confirmation of PR and CR 
is required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials (see the paper by Bogaerts et al. However, in 
all other circumstances, i.e., in randomized trials (phase II or III) or studies where stable disease 
or progression are the primary endpoints, confirmation of response is not required since it will 
not add value to the interpretation of trial results. However, elimination of the requirement for 
response confirmation may increase the importance of central review to protect against bias, in 
particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive dis- ease 
is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum 
on study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. 
If the proportion of patients achieving stable disease for a minimum period of time is an 
endpoint of importance in a particular trial, the protocol should specify the minimal time 
interval required between two measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity and standard 

 
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practice. However, these limitations of the precision of the measured endpoint should be taken 
into account if comparisons between trials are to be made. 
2.9 PFS/TTP 
PFS or TTP is the main endpoint in many studies of advanced cancer. If the protocol requires 
all patients to have measurable lesions, the evaluation of progression is relatively simple. More 
and more studies allow patients with measurable lesions and non- measurable lesions to enter 
the study. In this situation, the clinical findings of disease progression in patients without 
measurable lesions must be described in detail. Because the progression date often has definite 
deviation, the observation time arrangement of each study group shall be the same. 
40.   

 
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Appendix 2 ECOG Performance Status 
Score 
Criteria 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, office work). 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 

 
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Appendix 3 Operating Characteristics of the BOIN Design 
Table A-1 shows the operating characteristics of the trial design based on 10,000 simulations of 
the trial with the following trial and design specifications using Shinny app “BOIN”  available 
at http://www.trialdesign.org. The operating characteristics show that the design selects the true 
MTD, if any, with high probability and allocates more patients to the dose level with the DLT 
rate closest to the target toxicity rate of 0.3. 
Parameters 
Value 
Number of doses 
4 
Starting dose 
1 
Max sample size 
15 
Cohort size 
3 
Stop trial if # patients assigned to single dose reaches 
9 
Use accelerated titration 
False 
Target toxicity probability 
0.3 
Use the default alternatives to minimize decision errors 
True 
Alternative (unacceptable high toxicity) for optimization 
Default 
Alternative (unacceptable low toxicity) for optimization 
Default 
Eliminate dose threshold (pE) 
0.95 
Number of repetitions per scenario 
10000 
Random number generator seed 
2021 
Table A-1. Operating characteristics of the BOIN design 
 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Number of 
Patients 
% Early 
discontinuation  
Scenario 1 
 
 
 
 
11.8 
12.72 
True DLT Rate 
0.3 
0.47 
0.55 
0.64 
Selection% 
65.94 
17.13 
3.92 
0.29 
% Pts Treated 
65.8 
29.5 
4.5 
0.3 
Scenario 2 
 
 
 
 
14.4 
0.38 
True DLT Rate 
0.11 
0.3 
0.45 
0.67 
Selection% 
23.77 
49.54 
24.37 
1.94 
% Pts Treated 
38.3 
42.7 
17 
2 
Scenario 3 
 
 
 
 
14.9 
0 
True DLT Rate 
0.02 
0.13 
0.3 
0.47 
Selection% 
1.03 
25.87 
52.74 
20.36 
% Pts Treated 
23.1 
34.8 
32 
10.1 
Scenario 4 
 
 
 
 
14.9 
 
True DLT Rate 
0.05 
0.1 
0.15 
0.3 
Selection% 
1.22 
8.67 
38.64 
51.43 
% Pts Treated 
24.3 
28.3 
28 
19.4 
Note: “% Early discontinuation” refers to early stopping due to excessive DLT. 

 
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Appendix 4 Lugano Response Criteria 2014 for Non-Hodgkin Lymphoma 
PET should be performed with contrast enhanced diagnostic CT and can be performed simultaneously 
or as separate procedures.  
Response 
Site 
PET-CT (Metabolic 
response) 
CT (Radiologic response)d 
Complete 
response 
Lymph nodes 
and 
extralymphatic 
sites 
Score 1, 2, 3a with or 
without a residual mass 
on 5-point scale (5-PS)b,c 
All of the following: 
Target nodes/nodal masses must regress 
to ≤1.5 cm in longest transverse 
diameter of a lesion (LDi) 
No extralymphatic sites of disease 
Non-measured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-
avid disease in marrow 
Normal by morphology; if 
indeterminate and flow cytometry IHC 
negative 
Partial 
response 
Lymph nodes 
and 
extralymphatic 
sites 
Score 4 or 5b with 
reduced uptake compared 
with baseline. No new 
progressive lesions. 
At interim these findings 
suggest responding 
disease. 
At end of treatment these 
findings may indicate 
residual disease. 
All of the following: 
≥50% decrease in SPD of up to 6 target 
measureable nodes and extranodal sites 
When a lesion is too small to measure 
on CT, assign 5 mm x 5 mm as the 
default value. 
When no longer visible, 0x0 mm 
For a node >5 mm x 5 mm, but smaller 
than normal, use actual measurement 
for calculation 
Non-measured 
lesion 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by >50% in 
length beyond normal 
New lesions 
None 
None 

 
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Response 
Site 
PET-CT (Metabolic 
response) 
CT (Radiologic response)d 
Bone marrow 
Residual uptake higher 
than uptake in normal 
marrow but reduced 
compared with baseline 
(diffuse uptake 
compatible with reactive 
changes from 
chemotherapy allowed). 
If there are persistent 
focal changes in the 
marrow in the content of 
a nodal response, 
consider further 
evaluation with biopsy, 
or an interval scan. 
Not applicable 
No response 
or stable 
disease 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
Score 4 or 5b with no 
significant change in 
FDG uptake from 
baseline at interim or end 
of treatment. No new or 
progressive lesions. 
<50% decrease from baseline in SPD of 
up to 6 dominant, measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
Non-measured 
lesion 
Not applicable 
No increase consistent with progression 
Organ 
enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive 
disease 
  
  
  
Individual target 
nodes/nodal 
masses, 
extranodal 
lesions 
Score 4 or 5b with an 
increase in intensity of 
uptake from baseline 
and/or 
New FDG-avid foci 
consistent with 
lymphoma at interim or 
end-of-treatment 
assessment e 
Requires at least one of the following 
PPD progression: 
An individual node/lesion must be 
abnormal with: 
LDi >1.5 cm and 
Increase by ≥50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions >2 cm 
In the setting of splenomegaly, the 
splenic length must increase by >50% 
of the extent of its prior increase 
beyond baseline. If no prior 
splenomegaly, must increase by at least 
2 cm from baseline 
New or recurrent splenomegaly 

 
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Response 
Site 
PET-CT (Metabolic 
response) 
CT (Radiologic response)d 
Non-measured 
lesion 
None 
New or clear progression of preexisting 
nonmeasured lesions 
New lesions 
New FDG-avid foci 
consistent with 
lymphoma rather than 
another etiology (eg, 
infection, inflammation). 
If uncertain regarding 
etiology of new lesions, 
biopsy or interval scan 
may be considered e 
Regrowth of previously resolved 
lesions 
A new node >1.5 cm in any axis 
A new extranodal site >1.0 cm in any 
axis; if <1 cm in any axis, its presence 
must be unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to lymphoma 
Bone marrow 
New or recurrent FDG-
avid foci 
New or recurrent involvement 
Footnotes 
aScore 3 in many patients indicates a good prognosis with standard treatment, especially if at the 
time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may 
be preferable to consider score 3 as an inadequate response (to avoid under-treatment). 
bSee PET Five-Point Scale (5-PS). 
cIt is recognized that in Waldeyer’s ring or extranodal sites with high physiological uptake or with 
activation within spleen or marrow, e.g. with chemotherapy or myeloid colony stimulating factors, 
uptake may be greater than normal mediastinum and/or liver. In this circumstance, CMR may be 
inferred if uptake at sites of initial involvement is no greater than surrounding normal tissue even if 
the tissue has high physiological uptake. 
dFDG-avid lymphomas should have response assessed by PET-CT. Diseases that can typically be 
followed with CT alone include CLL/SLL and marginal zone lymphomas. 
eFalse-positive PET scans may be observed related to infectious or inflammatory conditions. Biopsy 
of affected sites remains the gold standard for confirming new or persistent disease at end of therapy. 
PET 5-Point Scale (5-PS) 
1 
No uptake above background 
2 
Uptake ≤ mediastinum 
3 
Uptake > mediastinum but ≤ liver 
4 
Uptake moderately > liver 
5 
Uptake markedly higher than liver and/or new lesions 
X 
New areas of uptake unlikely to be related to lymphoma 
 
SPD – Sum of the product of the perpendicular diameters for multiple lesions 
 
LDi – Longest transverse diameter of a lesion 
 
SDi – Shortest axis perpendicular to the LDi 
 
PPD – Cross product of the LDi and perpendicular diameter 
Measured dominant lesions – Up to 6 of the largest dominant nodes, nodal masses and extranodal lesions selected 
to be clearly measurable in 2 diameters. Nodes should preferably be from disparate regions of the body, and should 
include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs, 
e.g., liver, spleen, kidneys, lungs, etc, gastrointestinal involvement, cutaneous lesions of those noted on palpation. 
Non-measured lesions – Any disease not selected as measured, dominant disease and truly assessable disease 
should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected 

 
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as dominant, measurable or which do not meet the requirements for measurability, but are still considered abnormal. 
As well as truly assessable disease which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses and other lesions that cannot be confirmed and followed by imaging.