Clinical trial NCT05051241
Conditions: Advanced Solid Tumor
Sponsor: Zhejiang Genfleet Therapeutics Co., Ltd.
Start date: 2019-08-30; Completion date: 2022-08-11
Enrollment: 50 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is the first- in human study of GFH018 comprised of a dose escalation part and a dose expansion part in subjects with advanced solid tumors after single/multiple administration. The study is designed to explore the safety/tolerability, pharmacokinetics, and MTD of GFH018 and to define a RP2D of GFH018.

Detailed description:

Arms: arm 1: 5 mg BID, 14d-on/14d-off arm 2: 10 mg BID, 14d-on/14d-off arm 3: 20 mg BID, 14d-on/14d-off arm 4: 30 mg BID, 14d-on/14d-off arm 5: 40 mg BID, 14d-on/14d-off arm 6: 50 mg BID, 14d-on/14d-off arm 7: 65 mg BID, 14d-on/14d-off arm 8: 85 mg BID, 14d-on/14d-off arm 9: 85 mg BID, 7d-on/7d-off arm 10: 85 mg BID, 14d-on/14d-off
Interventions: intervention 1: GFH018
Intervention descriptions: intervention 1: Subjects will receive GFH018 orally at different dose levels following twice daily, 14-day on/14-day off regimen. Other dose regimens, eg 7d-on/7d-off will also be considered to be explored when the safety/tolerability is confirmed.

Protocol documents:
Prot_000.pdf: 
GenFleet 
 
 
 
 
GFH018 
Clinical Trial Protocol GFH018X1101 
 
A Phase I Study with Single/Multiple Dose Administered to Explore 
the Safety/Tolerability and Pharmacokinetics of GFH018 in the 
Treatment of Subjects with Advanced Solid Tumors 
 
Type: 
Clinical trial protocol 
Version number: 
1.6 
Study phase: 
Phase I 
Status 
Finalized 
Release Date: 
2021-03-02 
 
 
 
Privacy Statement 
The information contained in this clinical trial protocol is confidential and is owned 
by Zhejiang Genfleet Therapeutics Co., Ltd and Genfleet Therapeutics (Shanghai) 
Inc. It may not be disclosed to any third party (group or individual) without prior 
written permission. If you have not obtained prior authorization to hold this plan, 
please contact Zhejiang Genfleet Therapeutics Co., Ltd and Genfleet Therapeutics 
(Shanghai) Inc. in time, and return the plan and a copy thereof.  


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Signature page—Investigator 
 
Protocol Title: 
A Phase I Study with Single/Multiple Dose Administered to 
Explore the Safety/Tolerability and Pharmacokinetics of GFH018 
in the Treatment of Subjects with Advanced Solid Tumors 
Study ID: 
GFH018X1101 
 
This protocol is a confidential document of Zhejiang Genfleet Therapeutics Co., Ltd 
and Genfleet Therapeutics (Shanghai) Inc., and is only disseminated under the premise 
of confidentiality. I confirm that I have read this protocol, I understand and agree with 
the content of the protocol, and I will carry out clinical trial work in accordance with 
this protocol. In addition, I will work in accordance with the ethical principles in the 
Declaration of Helsinki, as well as in accordance with the Good Clinical Trial Practice 
for Drugs and applicable laws and regulations. By signing this document, I agree that 
the undisclosed information contained herein is prohibited without the prior written 
permission of Zhejiang Genfleet Therapeutics Co., Ltd and Genfleet Therapeutics 
(Shanghai) Inc.  
 
Signature of the Investigator: ________________________ 
 
Date:_____________ 
Name: 
  
________________________ 
Title: 
 ________________________ 
Site Name/Address: 
 ________________________________________ 
 
 
 


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Signature page—Sponsor 
 
Protocol Title: 
A Phase I Study with Single/Multiple Dose Administered to 
Explore the Safety/Tolerability and Pharmacokinetics of GFH018 
in the Treatment of Subjects with Advanced Solid Tumors 
Study ID: 
GFH018X1101 
 
This study will be conducted in accordance with the requirements of this clinical 
research protocol and GCP and relevant national laws and regulations. 
This study will comply with the Declaration of Helsinki and treat subjects with the 
highest respect. Necessary measures will be taken to safeguard the safety and interests 
of the subject.  
 
 
Sponsor's signature: ________________________ 
Date:_____________ 
Name:  
________________________ 
Title: 
________________________ 
 


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Abbreviations 
Abbreviation 
Full name 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate transaminase 
ANC 
absolute neutrophil count 
AUC 
Area under the curve 
BID, bid 
up to the 
BNP 
Brain Natriuretic Peptide 
BOR 
Best of Response 
Cmax 
Maximal concentration  
Cmin 
Trough concentration 
CI 
Confidence Interval 
CL 
Clearance 
CLr 
Renal clearance 
CR 
Complete response 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CRR 
Complete Radiological Response 
CV 
Coefficient of Variance 
DLT 
Dose Limiting Toxicities 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transpeptidase 
GLP 
Good Laboratory Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest Non-Severely Toxic Dose 
LLOQ 
Lower Limit of Quantitation 
M1/M2 
Type 1/2 tumor associated macrophage 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NOAEL 
No Observed Adverse Effect Level 
OR 
Objective Response 
ORR 
Objective Response Rate 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Pharmacodynamics 
PFS 
Progression Free Survival 
PI 
Primary Investigator 


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PO, po, p.o. 
Oral administration 
PS 
Physical performance 
PR 
Partial Response 
Racc 
Accumulation ratio 
RDE 
Recommended dose for expansion 
RP2D 
Recommended phase 2 dose 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
TEAE 
Treatment-emergent Adverse Event 
Vd,ss 
Volume of distribution at stead state 
 
 
 
 


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Synopsis  
Protocol ID 
GFH018X1101 
Protocol Title 
A Phase I Study with Single/Multiple Dose Administered to Explore 
the Safety/Tolerability and Pharmacokinetics of GFH018 in the 
Treatment of Subjects with Advanced Solid Tumors 
Version number 
Version 1.6 
Sponsor 
Zhejiang Genfleet Therapeutics Co., Ltd  
Genfleet Therapeutics (Shanghai) Inc. 
Clinical stage 
Phase I 
Investigational 
drugs 
Drug code: GFH018 
Dosage form: tablets 
Specifications: 5 mg and 50 mg 
Study Objectives 
and endpoints 
Study Objective 
Endpoints 
Primary 
 
1) To evaluate the safety and 
tolerability of single/multiple 
administration of GFH018 in 
subjects with advanced solid 
tumors. 
2） Determine the maximum 
tolerated dose (MTD) and/or 
recommended phase II dose 
(RP2D) of GFH018. 
• 
Safety: DLT, incidence and 
severity of AE, SAEs, 
laboratory tests, vital signs, 
ECG, ECHO 
• 
Tolerability: 
dose 
reduction, 
dose 
interruption, 
permanent 
discontinuation 
Secondary 
 
1) 
To 
evaluate 
the 
pharmacokinetic 
characteristics of GFH018 
after 
single/multiple 
administration 
in 
subjects 
with advanced solid tumors. 
2) To evaluate the preliminary 
efficacy 
of 
GFH018 
in 
subjects with advanced solid 
tumors. 
3) To evaluate blood TGF-β 
levels and correlate with the 
clinical responses. 
• 
Pharmacokinetics: 
PK 
parameters (PK parameters 
after 
single 
dose 
administration include Cmax, 
Tmax, AUC0-12h, AUC0-24h,  
AUC0-inf, T1/2, CL/F, Vd/F; 
Steady-state PK parameters 
include Cmax,ss, Cmin,ss, Tmax,ss, 
AUCtau, T1/2, CL/F, Vd/F, 
CLr, Racc） 
• 
Efficacy: BOR, ORR, DCR, 
PFS, 
TTP 
evaluated 
according 
to 
RECIST 
version 1.1 
• 
Pharmacodynamic marker: 
TGF-β levels in peripheral 
blood at baseline and during 


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treatment  
Exploratory 
 
To evaluate possible 
pharmacodynamic marker in 
the blood 
• 
Changes of pSMAD2/3 in 
PBMC (peripheral blood 
single cells). 
Study Design 
This is the first-in-human trial of GFH018, using an open-label, 
non-randomized, single/multi-dose dosing design to evaluate the 
safety, tolerability, pharmacokinetics, and preliminary anti-tumor 
efficacy of GFH018 in subjects with advanced solid tumors.  
This study is divided into two parts: a dose-escalation part aimed at 
determining MTD and/or RDE followed by a dose expansion part 
to confirm the safety of RDE and RP2D and explore the 
preliminary efficacy of GFH018 in the potentially benefited 
population. The RDE will be determined for exploration in 
expansion. Different dosing regimens will be explored, RDE dose 
and optimal dosing regimen will be further confirmed, and RP2D 
will be obtained. Both parts were divided into three periods: 
screening, treatment, and follow-up. 
Part 1: Dose escalation study 
This part is a safety, tolerability, and pharmacokinetic study with a 
modified 3+3 design to determine MTD and/or RDE. According to 
preclinical data, the starting dose is selected as 10 mg/day (5 mg 
administered twice daily). In the first cycle, each group of subjects 
is given a single dose (5 mg as the starting dose) on day 1 and taken 
serial PK sampling. After the first dose on day 1, serial PK blood 
samples will be collected up to 72 h post-dose to obtain the complete 
PK profile of a single dose (the collection point design may be 
modified based on preliminary PK results). Subjects will be 
administered with GFH018 BID, 14d-on/14d-off from day 4. Four 
to six dose levels are planned (refer to Table 3-1). The first cycle is 
defined as 31 days, and subsequent cycles are all defined as 28 days. 
After the last dose of cycle 1 (day 17), serial PK blood samples will 
be collected to obtain PK characteristics at steady state. Starting 
from the third dose level, urine samples from steady state will also 
be collected for PK studies to fully understand GFH018 PK 
characteristics.  
Table 1-1 Dose escalation regimen (provisional dose level) 
Dose 
level 
Regimen 
Incremental percentage 
(%) 


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1 
5 mg bid, 14-d on/14-d 
off 
- 
2 
10 mg bid, 14-d on/14-
d off 
100 
3 
20 mg bid, 14-d on/14-
d off 
100 
4 
30 mg bid, 14-d on/14-
d off 
50 
5 
40 mg bid, 14-d on/14-
d off 
33 
6 
50 mg bid, 14-d on/14-
d off 
25 
During the study, a Safety Monitoring Committee (SMC) composed 
of principal investigators, representatives of contract research 
organizations (CROs) and sponsor representatives will be 
established to review the safety data generated in the study, mainly 
including Dose Limiting Toxicity (DLTs) and all other grade 2 and 
above adverse events per CTCAE v5.0, as well as pharmacokinetic 
and pharmacodynamic data, to determine whether to escalate to the 
next dose level. For a more specific dose escalation decision process 
and definition of DLT, see Section 5.4, "Study Drug Dose 
Escalation Methods".  
The MTD is defined as the highest dose ≤ 1/3 of the incidence of 
DLT. Once the MTD is reached, the dose will not be escalated under 
this dosing regimen (even if not all planned dose groups have been 
completed), and the SMC will review and decide whether to explore 
alternative dosing regimens, such as 7d-on/7d-off, or daily or other 
dose regimens (if the total daily dose is higher than or equal to the 
MTD within 28 days, the dose level needs to be lowered for daily or 
other dosing regimen exploration); On the other hand, if the MTD 
is not reached by escalating to the current highest dose level, the 
SMC will comprehensively evaluate all the data obtained to decide 
whether to proceed with a higher dose level exploration, such as 65 
mg BID, 85 mg BID, etc.    
The RDE will be determined by SMC based on comprehensive data 
such as safety and tolerability, PK, pharmacodynamics, and 
preliminary antitumor efficacy obtained during the dose escalation 


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part. 
At the end of the dose escalation, at least six evaluable subjects in 
the MTD/RDE group should be ensured.  
Part II Dose Expansion  
The primary objective of this part is to confirm the safety of RDE 
dose and explore different dose regimens to ultimately determine 
RP2D. The secondary objective is to initially explore the efficacy in 
potentially benefited populations. 
The 14d-on/14d-off and 7d-on/7d-off dose regimens under RDE 
dose will be explored based on the data from the dose escalation 
part, while the SMC will review the safety, PK, and biomarker data 
then decide whether to also explore other dose regimens at RDE, 
such as daily dosing. This part will further confirm the safety of 
RDE dose and optimal dose regimen and obtain RP2D. At least 12 
subjects (including subjects receiving the same dose during the dose 
escalation part) are required to be enrolled to determine the final 
RP2D.  
Potential benefited tumor types will be selected for dose expansion 
part based on the mechanism of action of the drug and preliminary 
efficacy data in dose escalation part, including hepatocellular 
carcinoma, cholangiocarcinoma/gallbladder cancer, colorectal 
cancer, urothelial cancer, pancreatic, cervical, head and neck 
squamous cell or esophageal cancer, and nasopharyngeal 
carcinoma.  
Definition of DLT 
DLT is defined as an adverse event or abnormal laboratory test 
related to the study drug that occurred during the first cycle (31 
days) and meet the following criteria. All toxicities will be graded 
according to CTCAE version 5.0.  
a) Non-hematologic toxicity 
Grade 3 and above toxicity. Except for diarrhea, nausea, vomiting, 
and rash recovering to grade 2 or less within 3 days of supportive 
care.  
Specific cardiotoxicity 
◼ 
Cardiac structure/function related: 
• 
Grade 2 and above heart valve dysfunction. 
• 
Grade 2 or above left ventricular ejection fraction 


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decreased. 
• 
Radiographic evidence of damage to any heart and great 
vessels. 
◼ 
Biomarkers of cardiac injury related: 
• 
Troponin T or troponin I (hs-cTnT or hs-cTnI) twice the 
baseline and above the upper limit of normal ≥ 2 
consecutive times (the interval ≥3 days). If 
hypersensitivity troponin is not available in the site, 
troponin can be substituted for evaluation according to 
the criteria listed above. 
b) Hematological toxicity 
◼ 
Grade 3 neutropenia with infection. 
◼ 
Grade 4 neutropenia, lasting more than 5 days. 
◼ 
Grade 3 febrile neutropenia (neutrophil count < 1.0×109/L 
with a single temperature > 38.3 °C (101°F) or a sustained 
temperature of ≥ 38 °C (100.4°F) for more than one hour); 
or neutropenic infection requiring clinical intervention. 
◼ 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia 
requiring clinical intervention. 
◼ 
Grade 4 anemia. 
c) Investigator and sponsor need to discuss whether to decide 
whether to be any other clinically significant abnormalities 
of DLT. 
Sample size 
Enroll about 40~60 subjects 
Study population 
Subjects eligible to participate in this study must meet all of the 
following inclusion criteria: 
1. 
Voluntary participation in the study and sign the informed 
consent form. 
2. 
Male or female aged 18–75 years (inclusive). 
3. 
Histologically or cytologically confirmed diagnosis of 
advanced or metastatic solid tumors with progression on, 
intolerance to standard therapy, or no suitable standard 
anticancer therapy available. 
4. 
At least one non-measurable lesion per RECIST 1.1. For 
subjects enrolled in the expansion part, at least one measurable 


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lesion per RECIST 1.1 
5. 
Eastern Cooperative Oncology Group Performance Status 
(ECOG P.S.) ≤ 1. For subjects with liver metastases, Child–
Pugh score of 0–7. 
6. 
Life expectancy ≥ 12 weeks. 
7. 
With sufficient organ functions, including: 
1) 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, or other therapies within 
14 days prior to hematology tests. 
2) 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, TBIL ≤ 3.0 × ULN, AST and ALT 
≤ 5.0 × ULN. 
3) Creatinine (Cr) ≤ 1.5 × ULN, or calculated creatinine 
clearance (CrCl) ≥ 50 mL/min (Cockcroft-Gault formula) 
if Cr > 1.5 × ULN. 
4) International normalized ratio (INR) ≤ 1.5 × ULN. 
8. 
Toxicities left from prior anti-tumor therapy resolved to 
baseline or CTCAE v5.0 Grade 1 (neurotoxicity or alopecia ≤ 
Grade 2). 
9. 
For women of childbearing potential (WOCBP) and male 
subjects with WOCBP partners, agreement to use an effective 
contraception method from the signing of the informed consent 
to 90 days after the last administration of the study drug. For 
WOCBP, negative pregnancy test results within 7 days 
(inclusive) prior to initiation of the study treatment.  
10. Subjects or their legal representatives are able to communicate 
well with the investigators and willing to comply with the 
protocol and complete the study. 
Exclusion Criteria: 
Subjects who meet any of the following exclusion criteria are not 


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allowed to enter this clinical study: 
1. 
With significant cardiovascular diseases: 
a. Baseline QT/QTc prolongation (QTcF > 450 ms). 
b. Baseline ECG abnormalities of clinical significance  
c. Clinically significant cardiovascular diseases within 6 
months, eg: myocardial infarction, angina, congestive 
heart failure, angioplasty, stent implantation, and coronary 
artery bypass grafting, etc. 
d. Abnormal doppler echocardiography confirmed by 
cardiologist such as left ventricular ejection fraction 
(LVEF) < 50%,heart valve stenosis, and ≥G2 valve 
regurgitation. 
e. Ascending aorta aneurysm or major artery aneurysm 
history, or predisposing conditions consistent with the 
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). 
f. Troponin T or I increase of clinical significance. 
2. 
Clinically significant gastrointestinal diseases, such as: 
 
Intractable hiccup, nausea, and vomiting 
 
Chronic gastrointestinal disorders: untreated peptic 
ulcer, Crohn’s Disease, ulcerative colitis, et al. 
 
Unable to swallow. 
 
Severe cirrhosis and gastric varicose veins, hepatic 
encephalopathy 
 
Active gastrointestinal bleeding. 
3. 
With other severe disease, such as: 
a. 
With definitive neurological or mental disorders, 
including epilepsy or dementia. 
b. 
Known positive human immunodeficiency virus 
antibody (HIV-Ab).  
c. 
Active hepatitis B virus infection (positive HBsAg and 
positive HBV-DNA), or active hepatitis C virus infection 
(positive HCV-Ab and positive HCV-RNA. 
d. 
With current or history of interstitial pneumonia. Other 
uncontrolled systemic diseases, such as hypertension 
and diabetes. 
e. 
Other active infections. 
4. 
Uncontrolled ascites, or pleural effusion clinically. 
5. 
Known active autoimmune diseases or with history of 
autoimmune diseases that may recur (such as systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel 


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disease, autoimmune thyroid disease, vasculitis, psoriasis, etc.) 
or subjects at risk (eg, those who have undergone organ 
transplantation and require immunosuppressive treatment). 
However, subjects with well-controlled diabetes mellitus, 
hypothyroidism requiring only hormone replacement therapy, 
skin disorders that do not require systemic therapy (such as 
vitiligo, psoriasis, or alopecia), or who are not expected to 
relapse in the absence of external triggers. 
6. 
Subjects who need to receive glucocorticoids (prednisone >10 
mg/day or equivalent doses of other similar drugs) or other 
immunosuppressants due to certain conditions within 14 days 
before treatment initiation. 
Note: in the absence of active autoimmune disease, the use of 
prednisone or equivalent adrenal drugs at a dose of ≤10 mg/day 
is allowed; subjects are allowed to use topical, ocular, 
intraarticular, intranasal, and inhaled type of glucocorticoid 
therapy (extremely low systemic absorption); short-term (≤ 7 
days) use of glucocorticoids is permitted for prophylaxis (e.g., 
contrast media allergy) or for treatment of non-autoimmune 
conditions (e.g., due to contact allergens) delayed-type 
hypersensitivity). 
7. 
Unstable brain metastasis. For subjects with brain metastases 
unintentionally detected during the screening, if they do not 
cause clinical symptoms and do not require therapeutic 
intervention, they can be discussed with the sponsor's medical 
director to decide whether to be enrolled. 
8. 
Pregnant or lactating women. 
9. 
Treatment with chemotherapy, radiotherapy, targeted therapy, 
endocrine therapy, immunotherapy, or other anti-tumor 
therapies, or other investigational drugs within 28 days prior to 
starting the study drug (For mitomycins and nitrosoureas: 
within 6 weeks. For oral fluorouracils and small molecule 
targeted drugs: within 2 weeks or 5 half-lives of the drug, 
whichever is longer). 
10. Major surgery (needle biopsy not included) within 4 weeks 
prior to treatment initiation. 
11. Administration of a strong inhibitor or inducer of CYP3A4 
within 5 half-life periods or within 2 weeks (whichever is 
longer), or traditional Chinese medicines within 2 weeks prior 
to treatment initiation. 
12. For subjects enrolled in the expansion part, diagnosis of other 
malignant tumors within 3 years prior to starting the study drug, 
except for cured in situ cervical carcinoma and skin basal cell 
carcinoma. 


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13. Other conditions judged by the investigator as inappropriate for 
participation in the study. 
Statistical analysis 
Sample size determination 
In the dose-escalation part, 3 to 6 subjects were enrolled in each dose 
group, and a total of about 20 to 40 subjects are expected to be 
enrolled. If other dose levels need to be explored in addition to the 
predetermined dose level or other dosing regimens need to be 
explored, additional subjects may be enrolled for treatment. 
The second part of the dose expansion phase is planned to enroll 6 
to 12 subjects in each treatment group, with at least 12 subjects 
(including those receiving the same treatment during the dose 
escalation phase) guaranteed in the RP2D dose group for the optimal 
dosing regimen. For an adverse event with an incidence of 10%, the 
probability of observing at least 1 of this adverse event in 12 subjects 
is approximately 72%.  
Statistical Analysis Sett 
• 
Full analysis set (FAS) consists of all subjects who have 
received at least one dose of study treatment. 
• 
Safety Set (SS) consists of all subjects who have received at 
least one dose of study treatment and had at least one valid 
post-baseline safety assessment. 
• 
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. 
• 
Dose determining set (DDS) consists of all subjects who have 
received at least 80% of the total planned dose of GFH018, are 
considered to have sufficient safety evaluation during the 31-
day-observation period or developed DLT during the first 
cycle. 
Statistical methods 
Because the primary objective of this study is to evaluate the safety, 
tolerability, and pharmacokinetic profile of GFH018, no hypothesis 


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testing is performed. The statistical analysis software SAS v9.4 was 
used for statistical analysis, mainly using descriptive statistical 
analysis, and using data lists and summaries and graphs to analyze 
and present data such as safety, tolerability, pharmacokinetics, 
pharmacodynamics and efficacy. 
Safety evaluation 
All AEs will be graded according to CTCAE version 5.0 and be 
coded using MedDRA. All post-treatment AEs/SAEs, grade≥3 AEs, 
treatment-related AEs/SAEs, AEs leading to study drug 
discontinuation, AEs leading to study drug interruption, DLT, and 
AESIs will be summarized by system organ class, preferred term, 
and dose levels. Vital signs, physical examination, laboratory tests, 
and 12-lead ECG values will be analyzed descriptively and 
statistically for changes in observed values and relative baselines.  
Efficacy evaluation 
The disease assessments will be evaluated according to RECIST 1.1. 
Best overall response (BOR), ORR, and DCR will be summarized 
with corresponding 90% confidence intervals for each dose level. A 
waterfall plot will be used to show the best change from baseline in 
tumor size. A by-subject listing of DOR, PFS, and TTP will be 
provided. 
Pharmacokinetic evaluation 
Pharmacokinetic analysis will be based on the PKAS. 
Concentration-time data will be summarized by dose group, while 
descriptive statistical analysis will be performed at each planned 
time point. Individual and average concentration-time curves will be 
provided for each dose group. 
The calculation method of PK parameters is described in Section 
6.2.4. 
Summary statistics of pharmacokinetic parameters for each 
GFH018 dose group are presented in tabular form.  Provides 
geometric mean and coefficient of variation, maximum, median, 
minimum, and arithmetic mean and standard deviation for each PK 
parameter (except Tmax). For Tmax, the median, maximum, and 
minimum values are provided.  


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Evaluation of pharmacodynamic markers 
To assess the changes of TGF-β in the peripheral blood and 
pSMAD2/3 in PBMCs before and after GFH018 treatment.  


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Contents 
Abbreviations ..................................................................................................................... 4 
Synopsis ............................................................................................................................. 6 
Contents ........................................................................................................................... 17 
1. 
Introduction ................................................................................................................... 22 
1.1 TGF-β as a target for anti-tumor drug development .................................................. 22 
1.2 GFH018 Introduction ................................................................................................. 23 
1.2.1 Overview of pharmacological research .................................................................. 23 
1.2.2 Overview of pharmacokinetics ............................................................................... 24 
1.2.3 Overview of toxicological studies .......................................................................... 25 
2. 
Study objectives and endpoints ..................................................................................... 27 
3. 
Study design .................................................................................................................. 29 
3.1 Overview of study design .......................................................................................... 29 
3.2 Rationale of study design ........................................................................................... 31 
3.3 Rationale for dose and regimen selection .................................................................. 31 
3.3.1 Rationale of starting dose selection ........................................................................ 31 
3.3.2 Planned incremental dose group ............................................................................. 32 
3.3.3 Rationale of dosing regimen selection .................................................................... 32 
3.3.4 Risk/benefit assessment .......................................................................................... 32 
4. 
Study population ........................................................................................................... 35 
4.1 Inclusion Criteria ....................................................................................................... 35 
4.2 Exclusion criteria ....................................................................................................... 36 
5. 
Study treatment ............................................................................................................. 39 
5.1 Study drugs ................................................................................................................ 39 
5.1.1 Drug dosage forms and strength ............................................................................. 39 
5.1.2 Package and label of study drugs ........................................................................... 39 


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5.1.3 Storage, management and distribution of study drugs ............................................ 39 
5.1.4 Return and destruction of study drugs .................................................................... 40 
5.2 GFH018 administration ............................................................................................. 40 
5.3 Duration of Treatment ................................................................................................ 41 
5.4 Dose escalation methods ............................................................................................ 41 
5.4.1 DLT definition ........................................................................................................ 41 
5.4.2 MTD/RDE/RP2D definitions ................................................................................. 42 
5.4.3 Dose escalation method .......................................................................................... 43 
5.4.4 Dose escalation decision ......................................................................................... 44 
5.4.5 Intra-patient dose escalation ................................................................................... 44 
5.5 Study drug interruption, dose reduction, and discontinuation ................................... 44 
5.5.1 GFH018 interruption and dose reduction ............................................................... 44 
5.5.2 Study drug discontinuation ..................................................................................... 45 
5.6 Medication and dietary restrictions ............................................................................ 46 
5.6.1 Permitted concomitant medications ........................................................................ 46 
5.6.2 Prohibited concomitant medications ...................................................................... 46 
5.6.3 Permitted medications with caution ....................................................................... 48 
5.6.4 Dietary restrictions ................................................................................................. 48 
5.7 Participant number and treatment assignment ........................................................... 48 
5.7.1 Subject number ....................................................................................................... 48 
5.7.2 Treatment assignment ............................................................................................. 49 
6. 
Study Procedure ............................................................................................................ 50 
6.1 Schedule of Activities ................................................................................................ 50 
6.1.1 Screening period ..................................................................................................... 59 
6.1.2 Treatment period .................................................................................................... 60 
6.1.3 Follow-up period .................................................................................................... 61 


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6.1.4 Loss to follow-up .................................................................................................... 62 
6.2 Evaluation .................................................................................................................. 62 
6.2.1 Safety evaluation .................................................................................................... 62 
6.2.2 Tolerance evaluation............................................................................................... 64 
6.2.3 Efficacy evaluation ................................................................................................. 64 
6.2.4 Pharmacokinetic evaluation .................................................................................... 65 
6.2.5 Pharmacodynamic evaluation ................................................................................. 68 
7 
End of Study and End of Treatment ............................................................................. 70 
7.1 
Definition of End of Study (EoS) ..................................................................... 70 
7.2 
End of Treatment and withdrawal from the study ............................................ 70 
7.3 
Early Study Termination ................................................................................... 70 
8 
Adverse event reporting ................................................................................................ 71 
8.1 Adverse Events .......................................................................................................... 71 
8.1.1 Definition of Adverse Event ................................................................................... 71 
8.1.2 Adverse events collection and documentation ....................................................... 73 
8.1.3 Handling of adverse events..................................................................................... 74 
8.2 Serious Adverse Events.............................................................................................. 75 
8.2.1 Definition of Serious Adverse Events .................................................................... 75 
8.2.2 SAE reporting requirements ................................................................................... 77 
8.3 Causality assessment .................................................................................................. 78 
8.4 Pregnancy ................................................................................................................... 79 
8.5 Other special situation reports ................................................................................... 79 
8.6 Expedited reporting of adverse events of special interest .......................................... 80 
9 Data Management ................................................................................................................. 81 
9.1 CRF Data Collection .................................................................................................. 81 
9.2 Data Security .............................................................................................................. 81 


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9.3 Site Monitoring .......................................................................................................... 81 
9.4 Data Quality Management ......................................................................................... 82 
10 
Statistical analysis ......................................................................................................... 83 
10.1 Analysis sets ............................................................................................................. 83 
10.2 
Analysis method ............................................................................................... 83 
10.2.1 Demographic and baseline characteristics ............................................................ 83 
10.2.2 Primary endpoints ................................................................................................. 83 
10.2.3 Secondary endpoints ............................................................................................. 84 
10.3 
Sample size ....................................................................................................... 85 
11 Ethics .................................................................................................................................. 86 
11.1 Institutional Review Board/ Independent Ethics Committee ................................... 86 
11.2 Ethical Conduct of the Study ................................................................................... 86 
11.3 Patient Information and Consent .............................................................................. 87 
11.4 Confidentiality of Patient’s Information .................................................................. 87 
11.5 Inspection ................................................................................................................. 87 
12 Publication of Study Results .............................................................................................. 87 
References ............................................................................................................................... 89 
Appendix 1 Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) ...................... 90 
Appendix 2 ECOG Performance Status ............................................................................................. 103 
 


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Contents of Tables 
Table 3-1 Dose escalation regimen (provisional dose level) ..................................................... 7 
Table 2-1 Study objectives and endpoints ............................................................................... 27 
Table 3-1 Dose escalation regimen (provisional dose level) ................................................... 30 
Table 5-1 Inducers and inhibitors of CYP3A4/5 (partial) ....................................................... 47 
Table 6-1 Schedule of Activities in Dose Escalation ............................................................... 51 
Table 6-2 Schedule of Activities in Dose Expansion ............................................................... 55 
Table 6-3 Specific requirements for the observation indicators of subjects during the screening 
period ....................................................................................................................................... 59 
Table 6-4 Pharmacokinetics Sampling Schema in Dose Escalation Part ................................ 66 
 
Contents of Figures 
Fig 3-1 Study plan (Dose Escalation Part) .............................................................................. 29 
 
 
 
 


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1. 
Introduction 
1.1 TGF-β as a target for anti-tumor drug development 
TGF-β (Transforming growth factor-β, transforming growth factor-β) is a multifunctional 
cytokine that binds to and activates TGF-β receptor II (TGF-βRII) on the cell membrane, and 
then phosphorylates TGF-β receptor I (TGF-βRI). And activate it, and then phosphorylate 
downstream Smad 2/3, conduct signals, regulate gene expression, and play a variety of 
biological functions.  
A large number of studies have shown that in subjects with advanced tumors, the activation of 
TGF-β signaling pathway could promote epithelial-mesenchymal transformation (EMT) and 
metastasis of tumor cells, inhibit the anti-tumor immune response within the tumor 
microenvironment, and increase angiogenesis in the tumor microenvironment, increase tissue 
fibrosis, thereby promoting tumor progression [1-2]. Moreover, in subjects with a variety of solid 
tumors, such as hepatocellular carcinoma, glioma, colorectal cancer, lung cancer, pancreatic 
cancer, urothelial cancer, etc., high expression of TGF-β signaling pathway genes in blood and 
tumors were found, and their expression level were positively correlated with the low 
differentiation and high grade of tumors, and positively correlated with the poor prognosis of 
subjects [3-6].。 In addition, a retrospective analysis of IMvigor211, a phase III study of the PD-
L1 immune checkpoint inhibitor atezolizumab against urothelial carcinoma, found that TGFB1 
gene expression level was inversely correlated with subjects' response to atezolizumab therapy. 
Moreover, TGF-β signaling pathway inhibitors and immune checkpoint inhibitors can improve 
the efficacy of immune checkpoint inhibitors in animal models [7]. Therefore, inhibition of TGF-
β signaling pathway can inhibit tumor growth and progression through a variety of ways, 
including inhibition of tumor metastasis, enhancement of anti-tumor immune response in tumor 
microenvironment, inhibition of tumor angiogenesis, etc., and has great potential to increase 
synergy in combination with PD-1/L1 immune checkpoint inhibitors.  
At present, there are a number of clinical candidates targeting the TGF-β signaling pathway, all 
of which are in the phase I or II clinical stage. According to the mechanism of action, it can be 
divided into: 1) small molecule TGF-βRI inhibitors, including galunisertib (LY2157299), 
LY3200882, TEW-7197; 2) antisense oligonucleotides, which inhibit TGF-β expression, such 


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as trabedersen; 3) anti-TGF-β antibodies, such as SAR439459; 4) immune checkpoint inhibitors 
and TGF-β inhibitors bifunctional (simultaneously targeting PD-L1 and TGF-β pathways) 
fusion proteins, such as M7824.  
Among small molecule TGF-βRI inhibitors, galunisertib developed by Eli Lilly is currently the 
most comprehensively studied clinically, and a number of single-agent and combination (in 
combination with chemotherapy and immunotherapy) clinical trials have been carried out for 
different tumor indications. In a phase II clinical trial of subjects with hepatocellular carcinoma 
for whom sorafenib was not indicated (resistant or intolerant), the median survival was 16.8 
months. and a 20% decrease in plasma TGF-β levels after galunisertib treatment > greater 
benefit from a 20% reduction than ≤ 20% (median survival 21.8 versus 7.9 months). These 
studies demonstrate that blocking the TGF-β signaling pathway through TGF-βRI small 
molecule inhibitors is effective in associated tumors.  
The above data shows that small molecule TGF-βRI inhibitors targeting the TGF-β signaling 
pathway are expected to become an effective, safe and controllable treatment for advanced solid 
tumors. 
1.2 GFH018 Introduction 
GFH018 is a novel TGF-βRI inhibitor that inhibits TGF-β signaling by inhibiting the function 
of TGF-βRI and thereby inhibits tumor growth. GFH018 has been studied in detail in terms of 
pharmacology, preclinical pharmacokinetics and toxicology, and the specific sub-items are 
briefly summarized below.  
1.2.1 Overview of pharmacological research 
GFH018 is a selective TGF-βRI inhibitor that potently inhibits the kinase activity of TGF-βRI 
in vitro with an IC50 of 70.5 nM. Pharmacological studies have shown that GFH018 can 
effectively inhibit Smad 2/3 phosphorylation and block TGF-β signaling pathway activity in 
tumor cells or tissues, and in vitro MOA experiments show that GFH018 can effectively inhibit 
Treg cell polarization and enhance the anti-tumor immune response of proinflammatory M1 
macrophages, inhibit the migration of tumor cells, the proliferation of fibroblasts and 
angiogenesis.  
In vivo activity of GFH018 was performed in mouse syngeneic tumor models, including mouse 


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H22 liver cancer model, mouse CT26 colorectal cancer model, mouse Pan02 pancreatic cancer 
model, and 4T1-luc2 in situ breast cancer metastasis model. GFH018 showed significant anti-
tumor effect in CT26 and H22 models. In the H22 model, it has a significant effect of inhibiting 
tumor growth at doses as low as 15 mg/kg, corresponding to an effective exposure of AUC0-
24 h of 544 h*ng/mL. In the CT26 and Pan02 models, GFH018 showed significant tumor 
suppressive effect and synergistic effect when combined with immune checkpoint inhibitors. 
At the same time, GFH018 also demonstrated anti-metastasis effect in the mouse 4T1-luc2 in 
situ breast cancer  model, which can significantly inhibit the metastasis of tumor mouse breast 
cancer cells to the liver, lung, spleen, kidney and intestine.  
Given that cardiotoxicity is a potential challenge in the development of TGF-βRI inhibitors, 
GFH018 conducted adequate cardiovascular system safety studies and focused on and 
evaluated cardiotoxicity in repeated administration toxicology experiments. GFH018 had no 
significant inhibitory effect on hERG potassium channel, Nav1.5 sodium channel and Cav1.2 
calcium channel at a concentration of 100 μM, and had no significant effect on the action 
potential of rabbit in vivo Purkinje fiber. At a dose of 100 mg/kg (the highest test dose), there 
was no effect on the cardiovascular system of the Beagle dog. The results of 4-week repeated 
administration of rats and dogs showed that rats were susceptible to cardiotoxicity, and no 
cardiotoxic reactions were observed at a dose of 10 mg/kg/day. In the 4-week repeated 
administration toxicity test of dogs, an increase in heart rate (HR) was seen with shortening of 
the RR interval and the PR interval. In addition, GFH018 had no effect on the rat central nervous 
system and respiratory system at a dose of 100 mg/kg (the highest test dose).  
1.2.2 Overview of pharmacokinetics 
Pharmacokinetic studies of GFH018 in preclinical animal species showed good absorption and 
high oral bioavailability (>50%). The systemic exposure increased dose-proportionally in dogs, 
and a slightly higher than dose proportion in rats. GFH018 showed low to medium protein 
binding in different animals and human plasma, and had a weak concentration dependence in 
the concentration range of 2~100 μM, the binding rate decreases slightly with increasing 
concentration. [C14] GFH018 isotope study showed that radioactivity was widely distributed in 
various tissues in rats, and decreased with the rapid decrease of blood radioactivity. Except for 


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intestinal wall, radioactivity in blood and all other tissues was below the detection limit at 24 
hours. The highest radioactivity was observed  in gastrointestinal wall, liver and kidney (about 
4~7 times radioactivity of whole blood), the radioactivity in the heart is close to that of whole 
blood, and there is almost no distribution in the brain. GFH018 is comparatively stable in human 
liver microsomes and hepatocytes, mainly metabolited by CYP3A4. GFH018 has no induction 
or inhibition on CYP enzymes and is not an inhibitor of P-gp, so the possibility of drug 
interactions mediated by metabolic enzymes and transporter P-gp is low. The study of [C14] 
GFH018 excretion in rats showed that the total recovery of GFH018 within 48 hours after oral 
administration was 94.4% of the dose, which was mainly cleared by urine and bile. After a 
single oral administration in biliary intubated rats, the total excretion of bile accounted for 28.33% 
of the administered amount, urine accounted for 42.77%, and the oral absorption rate of 
GFH018 was at least 71.10%.  
1.2.3 Overview of toxicological studies 
SD rats and beagles were selected as relevant species for GFH018 toxicological studies, and 
single, 4-week and 14-week repeated administration toxicity tests were completed. 
Single administration toxicity tests were performed in SD rats and beagles, respectively, and 
the results showed that the maximum tolerated dose (MTD) of rats and dogs was 600 and 180 
mg/kg, respectively. 
Repeated administration toxicity tests were performed for 4 weeks in SD rats and beagles, 
respectively, to observe the toxicity of GFH018, explore the toxic target organs, and observe 
the reversible condition of damage. In rats, SD rats were given 10, 30, or 100 mg/kg/day 
GFH018 orally once daily for 4 weeks with a recovery period of 8 weeks. Animals were well 
tolerated, and the main toxicity occurred in the 30 and 100 mg/kg/day dose groups, manifested 
by salivation, elevated liver function indicators, urine crystallization, and histopathological 
changes. The rat toxic target organs are the heart, liver, kidney, bone (femur, sternum), spleen, 
thyroid, adrenal gland, and female reproductive organs. All changes recover fully after an 8-
week recovery period. Therefore, the highest non-severe toxic dose (HNSTD) in this trial was 
100 mg/kg/day, at which the exposure (Cmax and AUC0-t) of male and female animals after 
the last dose was 46100 ng/ml and 53900 ng*h/mL, 9670 ng/mL and 20200 ng*h/mL, 


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respectively. No toxic response dose (NOAEL) was 10 mg/kg/day, at which the exposure 
(Cmax and AUC0-t) of male and female animals after the last dose was 4450 ng/mL and 3880 
ng*h/mL and 1160 ng*h/mL and 1050 ng*h/mL, respectively.  
In beagles, 20, 60, or 200/120 mg/kg/day GFH018 is given orally once a day for up to 4 weeks, 
with a recovery period of 4 weeks. The intolerability of animals at a dose of 200/120 mg/kg/day 
and death/near-death are mainly related to the infection caused by gallbladder perforation or 
large fluid accumulation in the abdominal cavity caused by the test product or related organ 
insufficiency caused by necrotizing vasculitis. Other test-related toxicities were mainly seen in 
the 60 and 200/120 mg/kg/day dose groups, including decreased blood phosphorus, increased 
heart rate (HR) with shortened RR and PR intervals, and histopathological changes. Toxic target 
organs in dogs are blood vessels (multi-organ vasculitis), heart, femur, and immune system 
(including spleen, thymus, and Patrick's knot). After a 4-week recovery period, all changes were 
fully restored. Therefore, the HNSTD in this trial was 60 mg/kg/day, and the average exposure 
(Cmax and AUC0-t) of male and female animals after the last dose was 31900 ng/mL and 
110150 ng*h/mL, respectively. NOAEL was 20 mg/kg/day, and the average exposure (Cmax 
and AUC0-t) of male and female animals after the last dose was 15350 ng/mL and 39400 
ng*h/mL, respectively.  
In addition, a 14-week repeated intermittent administration toxicity test was performed in rats 
of sensitive species SD. The results showed that SD rats were given 10, 30 or 100 mg/kg 
GFH018 by oral gavage for 14 weeks once a day in intermittent (2 weeks of administration/2 
weeks of discontinuation) for 14 weeks, with a recovery period of 8 weeks. The animals were 
well tolerated, and the main toxicity manifested as salivation, elevated liver function indicators, 
urine crystallization and hematologic changes, and histopathological changes in the ≥100 
mg/kg dose group in the 100 mg/kg group. Toxic target organs are the heart, liver, bone (femur, 
sternum), female reproductive organs (ovaries, uterus, and vagina), breast (female), spleen, 
thyroid, adrenal glands. After an 8-week recovery period, all changes except those in the bone 
(femur, sternum), ovaries, vagina, and mammary glands are fully restored. Therefore, the 
HNSTD in this trial was 100 mg/kg, and the average exposure (Cmax and AUC0-24h) of male 
and female animals after the last dose was 24800 ng/mL and 49450 ng*h/mL.  
 


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2. 
Study objectives and endpoints 
The objectives and the corresponding endpoints are summarized in Table 2-1. 
Table 2-1 Study objectives and endpoints 
Study Objective 
Endpoints 
Primary 
 
1) To evaluate the safety and tolerability of 
single/multiple administration of GFH018 in 
subjects with advanced solid tumors. 
2） Determine the maximum tolerated dose 
(MTD) and/or recommended phase II dose 
(RP2D) of GFH018. 
• 
Safety: DLT, incidence and severity of 
AE, SAEs, laboratory tests, vital signs, 
ECG, ECHO 
• 
Tolerability: 
dose 
reduction, 
dose 
interruption, permanent discontinuation 
Secondary 
 
1) 
To 
evaluate 
the 
pharmacokinetic 
characteristics 
of 
GFH018 
after 
single/multiple administration in subjects 
with advanced solid tumors. 
2) To evaluate the preliminary efficacy of 
GFH018 in subjects with advanced solid 
tumors. 
3) To evaluate blood TGF-β levels and 
correlate with the clinical responses. 
• 
Pharmacokinetics: PK parameters (PK 
parameters 
after 
single 
dose 
administration include Cmax, Tmax, AUC0-
12h, AUC0-24h,  AUC0-inf, T1/2, CL/F, Vd/F; 
Steady-state PK parameters include 
Cmax,ss, Cmin,ss, Tmax,ss, AUCtau, T1/2, CL/F, 
Vd/F, CLr, Racc） 
• 
Efficacy: BOR, ORR, DCR, PFS, TTP 
evaluated according to RECIST version 
1.1 
• 
Pharmacodynamic 
marker: 
TGF-β 
levels in peripheral blood at baseline 
and during treatment  
Exploratory 
 
To evaluate possible pharmacodynamic 
• 
Changes of pSMAD2/3 in PBMC 


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marker in the blood 
(peripheral blood single cells). 
 
 


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3. 
Study design 
3.1 Overview of study design 
This is the first-in-human trial of GFH018, using an open-label, non-randomized, single/multi-
dose dosing design to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-
tumor efficacy of GFH018 in subjects with advanced solid tumors.  
This study is divided into two parts: a dose-escalation part aimed at determining MTD and/or 
RDE followed by a dose expansion part to confirm the safety of RDE and RP2D and explore 
the preliminary efficacy of GFH018 in the potentially benefited population. The RDE will be 
determined for exploration in expansion. Different dosing regimens will be explored, RDE dose 
and optimal dosing regimen will be further confirmed, and RP2D will be obtained. Both parts 
were divided into three periods: screening, treatment, and follow-up.  
Part I Dose Escalation 
The study schema is shown in Figure 3-1 (14-day on/14-day off regimen).  
 
Fig 3-1 Study Schema (Dose Escalation Part) 
This part is a safety, tolerability, and pharmacokinetic study with a modified 3+3 design to 
determine MTD and/or RDE. According to preclinical data, the starting dose is selected as 10 
mg/day (5 mg administered twice daily). In the first cycle, each group of subjects is given a 
single dose (5 mg as the starting dose) on day 1 and taken serial PK sampling. After the first 
dose on day 1, serial PK blood samples will be collected up to 72 h post-dose to obtain the 
complete PK profile of a single dose (the collection point design may be modified based on 
preliminary PK results). Subjects will be administered with GFH018 BID, 14d-on/14d-off from 
day 4. Four to six dose levels are planned (refer to Table 3-1). The first cycle is defined as 31 
days, and subsequent cycles are all defined as 28 days. After the last dose of cycle 1 (day 17), 


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serial PK blood samples will be collected to obtain PK characteristics at steady state. Starting 
from the third dose level, urine samples from steady state will also be collected for PK studies 
to fully understand GFH018 PK characteristics.  
Table 3-1 Dose escalation regimen (provisional dose level) 
Dose level 
Regimen 
Incremental percentage 
(%) 
1 
5 mg bid, 14-d on/14-d off 
- 
2 
10 mg bid, 14-d on/14-d off 
100 
3 
20 mg bid, 14-d on/14-d off 
100 
4 
30 mg bid, 14-d on/14-d off 
50 
5 
40 mg bid, 14-d on/14-d off 
33 
6 
50 mg bid, 14-d on/14-d off 
25 
During the study, a Safety Monitoring Committee (SMC) composed of principal investigators, 
representatives of contract research organizations (CROs) and sponsor representatives will be 
established to review the safety data generated in the study, mainly including Dose Limiting 
Toxicity (DLTs) and all other grade 2 and above adverse events per CTCAE v5.0, as well as 
pharmacokinetic and pharmacodynamic data, to determine whether to escalate to the next dose 
level. For a more specific dose escalation decision process and definition of DLT, see Section 
5.4, "Study Drug Dose Escalation Methods".  
The MTD is defined as the highest dose ≤ 1/3 of the incidence of DLT. Once the MTD is reached, 
the dose will not be escalated under this dosing regimen (even if not all planned dose groups 
have been completed), and the SMC will review and decide whether to explore alternative 
dosing regimens, such as 7d-on/7d-off, or daily or other dose regimens (if the total daily dose 
is higher than or equal to the MTD within 28 days, the dose level needs to be lowered for daily 
or other dosing regimen exploration); On the other hand, if the MTD is not reached by 
escalating to the current highest dose level, the SMC will comprehensively evaluate all the data 
obtained to decide whether to proceed with a higher dose level exploration, such as 65 mg BID, 


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85 mg BID, etc.    
The RDE will be determined by SMC based on comprehensive data such as safety and 
tolerability, PK, pharmacodynamics, and preliminary antitumor efficacy obtained during the 
dose escalation part. 
At the end of the dose escalation, at least six evaluable subjects in the MTD/RDE group should 
be ensured.  
Part II Dose Expansion  
The primary objective of this part is to confirm the safety of RDE dose and explore different 
dose regimens to ultimately determine RP2D. The secondary objective is to initially explore 
the efficacy in potentially benefited populations. 
The 14d-on/14d-off and 7d-on/7d-off dose regimens under RDE dose will be explored based 
on the data from the dose escalation part, while the SMC will review the safety, PK, and 
biomarker data then decide whether to also explore other dose regimens at RDE, such as daily 
dosing. This part will further confirm the safety of RDE dose and optimal dose regimen and 
obtain RP2D. At least 12 subjects (including subjects receiving the same dose during the dose 
escalation part) are required to be enrolled to determine the final RP2D.  
Potential benefited tumor types will be selected for dose expansion part based on the mechanism 
of action of the drug and preliminary efficacy data in dose escalation part, including 
hepatocellular carcinoma, cholangiocarcinoma/gallbladder cancer, colorectal cancer, urothelial 
cancer, pancreatic, cervical, head and neck squamous cell or esophageal cancer, and 
nasopharyngeal carcinoma.  
3.2 Rationale of study design 
Subjects with advanced solid tumors will be enrolled in the study. The study adopts an open-
label, non-randomized, modified 3+3 design, which is the classical design of the first human 
trial of anti-tumor drugs. And the starting dose selection is reasonable, which meets the 
guidelines of drug regulatory authorities. 
3.3 Rationale for dose and regimen selection 
3.3.1 Rationale of starting dose selection 
To support the clinical development of GFH018, adequate preclinical toxicology studies were 


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conducted. GLP-compliant toxicological studies in SD rats and beagles showed that NOAELs 
were 10 mg/kg in rats and 20 mg/kg in dogs after 4 weeks of continuous oral administration. 
Rats were the sensitive species. According to the species-specific model, the human equivalent 
dose is 107 mg/day (60 kg in adult weight), divided by a safety factor of 10, which is equivalent 
to 10 mg/day. Therefore, the starting dose in this study was 10 mg/day.  
3.3.2 Planned incremental dose group 
The planned dose group is shown in Table 3-1 and consists of 5, 10, 20, 30, 40, 50 mg BID, 
14d-on/14d-off. The increasing amplitudes between the dose groups were 100%, 100%, 50%, 
33%, and 25%, respectively.  
Drug concentration measurements will be performed in a timely manner after each dose group 
is completed to obtain pharmacokinetic parameters in the human body as an important 
consideration in the dose escalation part. If the subject's drug exposure level is higher than the 
exposure level under the dose of cardiac NOEL in rat toxicology studies, the safety monitoring 
committee will carefully decide whether to escalate to the next dose based on a comprehensive 
assessment of all obtained safety information and et al. 
3.3.3 Rationale of dosing regimen selection 
To ensure patient safety to the greatest extent, dosing regimens are initially designed to be given 
twice daily for 14d-on/14d-off. This regimen is based on the research and development 
experience of similar drugs [8], which can avoid the occurrence of cardiotoxicity to the greatest 
extent. When the safety of the 14d-on/14d-off regimen has been fully assessed, other regimens 
such as 7d-on/7d-off or daily or other dose regimens will be explored to optimize dose levels 
and regimens.  
3.3.4 Risk/benefit assessment 
GFH018 is a small molecule TGF-βRI inhibitor developed by the sponsor, and based on its 
preclinical pharmacological and toxicity characteristics, it is expected that its risks and benefits 
are similar to the same class. 
Based on preclinical toxicological findings, cardiac safety is an event of special interest for 
small molecule TGF-βRI inhibitors [9]. Currently no clinically significant drug-related cardiac 
adverse events have been reported in many clinical studies of the same class [10-12]. As for 


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GFH018, in the rat 4-week repeated administration experiment with 10, 30 and 100 mg/kg 
GFH018 administered by mouth, the pathological examination results showed that the NOAEL 
and cardiac NOEL levels were 10 mg/kg. When the dose was ≥ 30 mg/kg, cardiac myocardial 
degeneration/necrosis was accompanied by inflammatory cell infiltration, and pathological 
changes related to the test product were still visible in the heart at the end of the 4-week recovery 
period of the 100 mg/kg dose group. Considering that this study is the first-in-human trial of 
GFH018, and cardiotoxicity has also been observed in rats at high doses in previous 
toxicological studies, a series of cardiac safety risk control measures are adopted in the study: 
in addition to the routine exams of electrocardiogram and blood pressure monitoring, a number 
of cardiac safety parameters are added, including imaging (cardiac Doppler ultrasound), blood 
markers (BNP, hypertroponin T, hs-CRP and cysteine protease inhibitor C）； defined heart 
related DLT. The cardiology experts from the study sites will be involved in the interpretation 
and processing of the abnormal cardiac test results.  
According to the results of preclinical toxicological studies, other possible toxicities in addition 
to cardiovascular system toxicity include: 
• 
Gastrointestinal system: In the 4-week GFH018 repeated dosing in dogs, fecal 
discoloration (black or red) was noted in male and female animals in the high-dose 
group during the administration period, and watery stools/loose stools were 
occasionally noted in male animals. Some fecal occult blood tests for both sexes in 
the high-dose group were positive (+~+++), but was recovered during the recovery 
period. 
• 
Immune system: In the 4-week GFH018 repeated dosing in dogs, the 
histopathological examination of the high-dose group showed thymic cortical atrophy, 
splenic lymphocyte necrosis and neutrophil infiltration, mesenteric lymph node 
lymphocyte necrosis, submandibular lymph node lymphocyte necrosis and 
neutrophil infiltration, and Pais' node atrophy. 
• 
Skeletal lesions: In the 4-week GFH018 repeated dosing in rats, thickening of the 
femoral growth plate and increase of the sponge bone beam of the metaphyseal and 
thickening of the sternum cartilage layer and increase of the sponge bone beam were 


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noted in the medium and high dose groups. In the 4-week repeated dosing in dogs, 
pathological examination showed thickening of the femoral growth plate. 
• 
Endocrine system: In the 4-week GFH018 repeated dosing in rats, thyroid follicular 
cell hypertrophy and diffuse hypertrophy of the adrenal cortex were noted in the 
medium- and high-dose groups. 
• 
Reproductive system: In the 4-week GFH018 repeated dosing in rats, reproductive 
toxicity was only observed in the high-dose group, and was characterized by ovarian 
luteal decrease and interstitial cell increase, cervical mucinization, vaginal 
mucinization, and dilation of the milk ducts and acinar with discharge. 
As the first human trial, other unanticipated adverse effects may also occur. 
The study is designed to minimize these risks as much as possible: set strict inclusion criteria, 
strict and specific definitions of DLT, detailed dose adjustments and procedures for termination 
of GFH018, and close clinical safety monitoring. Any adverse events will be treated accordingly 
per protocol and clinical guidelines.  
 


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4. 
Study population 
Subjects with advanced solid tumors will be enrolled in this study, with the first part of the dose 
escalation phase regardless of tumor type, and the second part of the dose extension phase will 
select specific tumors that may benefit from GFH018 treatment, including hepatocellular 
carcinoma, cholangiocarcinoma/gallbladder cancer, colorectal cancer, urothelial cancer, 
pancreatic cancer, cervical cancer, head and neck squamous cell carcinoma or esophageal 
cancer, and nasopharyngeal carcinoma. 
Investigators must ensure that only subjects who meet all of the inclusion criteria and do not 
meet any of the exclusion criteria are enrolled in this study.  
4.1 Inclusion Criteria 
Subjects eligible to participate in this study must meet all of the following inclusion 
criteria: 
1. 
Voluntary participation in the study and sign the informed consent form. 
2. 
Male or female aged 18–75 years (inclusive). 
3. 
Histologically or cytologically confirmed diagnosis of advanced or metastatic solid tumors 
with progression on, intolerance to standard therapy, or no suitable standard anticancer 
therapy available. 
4. 
At least one non-measurable lesion per RECIST 1.1. For subjects enrolled in the expansion 
part, at least one measurable lesion per RECIST 1.1 
5. 
Eastern Cooperative Oncology Group Performance Status (ECOG P.S.) ≤ 1. For subjects 
with liver metastases, Child–Pugh score of 0–7. 
6. 
Life expectancy ≥ 12 weeks. 
7. 
With sufficient organ functions, including: 
5) 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, or other therapies within 14 days prior to 
hematology tests. 
6) Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), aspartate 


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aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN, alkaline 
phosphatase (ALP) ≤ 2.5 × ULN; for subjects with tumor involvement of the liver, 
TBIL ≤ 3.0 × ULN, AST and ALT ≤ 5.0 × ULN. 
7) Creatinine (Cr) ≤ 1.5 × ULN, or calculated creatinine clearance (CrCl) ≥ 50 mL/min 
(Cockcroft-Gault formula) if Cr > 1.5 × ULN. 
8) International normalized ratio (INR) ≤ 1.5 × ULN. 
8. 
Toxicities left from prior anti-tumor therapy resolved to baseline or CTCAE v5.0 Grade 1 
(neurotoxicity or alopecia ≤ Grade 2). 
9. 
For women of childbearing potential (WOCBP) and male subjects with WOCBP partners, 
agreement to use an effective contraception method from the signing of the informed 
consent to 90 days after the last administration of the study drug. For WOCBP, negative 
pregnancy test results within 7 days (inclusive) prior to initiation of the study treatment.  
10. Subjects or their legal representatives are able to communicate well with the investigators 
and willing to comply with the protocol and complete the study. 
4.2 Exclusion criteria 
Subjects who meet any of the following exclusion criteria are not allowed to enter this clinical 
study: 
1. 
With significant cardiovascular diseases: 
a. Baseline QT/QTc prolongation (QTcF > 450 ms) 
b. Baseline ECG abnormalities of clinical significance  
c. Clinically significant cardiovascular diseases within 6 months, eg: myocardial 
infarction, angina, congestive heart failure, angioplasty, stent implantation, and 
coronary artery bypass grafting, etc. 
d. Abnormal doppler echocardiography confirmed by cardiologist such as left 
ventricular ejection fraction (LVEF) < 50%,heart valve stenosis, and ≥G2 valve 
regurgitation. 
e. Ascending aorta aneurysm or major artery aneurysm history, or predisposing 
conditions consistent with the 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). 


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f. Troponin T or I increase of clinical significance. 
2. 
Clinically significant gastrointestinal diseases, such as: 
 
Intractable hiccup, nausea, and vomiting 
 
Chronic gastrointestinal disorders: untreated peptic ulcer, Crohn’s Disease, 
ulcerative colitis, et al. 
 
Unable to swallow. 
 
Severe cirrhosis and gastric varicose veins, hepatic encephalopathy 
 
Active gastrointestinal bleeding. 
3. 
With other severe disease, such as: 
f. 
With definitive neurological or mental disorders, including epilepsy or dementia. 
g. 
Known positive human immunodeficiency virus antibody (HIV-Ab).  
h. 
Active hepatitis B virus infection (positive HBsAg and positive HBV-DNA), or 
active hepatitis C virus infection (positive HCV-Ab and positive HCV-RNA. 
i. 
With current or history of interstitial pneumonia. Other uncontrolled systemic 
diseases, such as hypertension and diabetes. 
j. 
Other active infections. 
4. 
Uncontrolled ascites, or pleural effusion clinically. 
5. 
Known active autoimmune diseases or with history of autoimmune diseases that may recur 
(such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, 
autoimmune thyroid disease, vasculitis, psoriasis, etc.) or subjects at risk (eg, those who 
have undergone organ transplantation and require immunosuppressive treatment). 
However, subjects with well-controlled diabetes mellitus, hypothyroidism requiring only 
hormone replacement therapy, skin disorders that do not require systemic therapy (such as 
vitiligo, psoriasis, or alopecia), or who are not expected to relapse in the absence of 
external triggers. 
6. 
Subjects who need to receive glucocorticoids (prednisone >10 mg/day or equivalent doses 
of other similar drugs) or other immunosuppressants due to certain conditions within 14 
days before treatment initiation. 
Note: in the absence of active autoimmune disease, the use of prednisone or equivalent 
adrenal drugs at a dose of ≤10 mg/day is allowed; subjects are allowed to use topical, 
ocular, intraarticular, intranasal, and inhaled type of glucocorticoid therapy (extremely low 
systemic absorption); short-term (≤ 7 days) use of glucocorticoids is permitted for 
prophylaxis (e.g., contrast media allergy) or for treatment of non-autoimmune conditions 
(e.g., due to contact allergens) delayed-type hypersensitivity). 


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7. 
Unstable brain metastasis. For subjects with brain metastases unintentionally detected 
during the screening, if they do not cause clinical symptoms and do not require therapeutic 
intervention, they can be discussed with the sponsor's medical director to decide whether 
to be enrolled. 
8. 
Pregnant or lactating women. 
9. 
Treatment with chemotherapy, radiotherapy, targeted therapy, endocrine therapy, 
immunotherapy, or other anti-tumor therapies, or other investigational drugs within 28 
days prior to starting the study drug (For mitomycins and nitrosoureas: within 6 weeks. 
For oral fluorouracils and small molecule targeted drugs: within 2 weeks or 5 half-lives of 
the drug, whichever is longer). 
10. Major surgery (needle biopsy not included) within 4 weeks prior to treatment initiation. 
11. Administration of a strong inhibitor or inducer of CYP3A4 within 5 half-life periods or 
within 2 weeks (whichever is longer), or traditional Chinese medicines within 2 weeks 
prior to treatment initiation. 
12. For subjects enrolled in the expansion part, diagnosis of other malignant tumors within 3 
years prior to starting the study drug, except for cured in situ cervical carcinoma and skin 
basal cell carcinoma. 
13. Other conditions judged by the investigator as inappropriate for participation in the study. 
For abnormal laboratory tests, if the investigator deems it necessary, one retest is allowed to 
rule out detection errors. 
 


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5. 
Study treatment 
5.1 Study drugs 
The investigational drug in this study is GFH018 tablets, which will be provided by the sponsor. 
5.1.1 Drug dosage forms and strength 
Dosage form: tablets. 
Strength: 5 mg, 50 mg 
Excipients: microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silica, 
magnesium stearate, etc. 
Shelf life: 36 months 
Storage conditions: Stored below 25 °C, sealed and protected from light 
5.1.2 Package and label of study drugs 
All investigational drugs will be labeled in accordance with the requirements of the Good 
Clinical Practice (GCP). All drugs are shipped as primary materials for research. 
Unified format of drug labels, including clinical trial approval number, protocol number, subject 
identification code, clinical trial drug name (indicating clinical trial specific), dosage, strength, 
storage, batch number, expiration date, sponsor, etc. 
Complete records of all study lot numbers and expiration dates, as well as drug labels, will be 
kept in the sponsor study folder. 
5.1.3 Storage, management and distribution of study drugs 
Study drugs shall be stored, managed and distributed by special personnel of the research center. 
It must be stored in a safe place in accordance with national regulations, in a locked medicine 
cabinet and in accordance with the storage conditions specified in the programme. The storage 
temperature of the study drug needs to be recorded and kept in the corresponding file. 
The person in charge of the research center will confirm in writing that the investigational drug 
has been received and will use the investigational drug within the framework of the clinical 
study in accordance with the protocol requirements. The receipt, distribution and return of 
investigational drugs will be documented in accordance with the detailed procedures of the 
sponsor agreement. 


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Dispensing will be carried out by a member of the research team who will ensure and record 
that subjects receive the dispensing as planned, and that the quantity and date of the drug issued 
and recovered are recorded in the original medical record. At the end of the study, the packaging 
of the study drug was processed uniformly and centrally. 
5.1.4 Return and destruction of study drugs 
The remaining investigational drugs and packaging are collected and destroyed by the sponsor 
or a research center authorized by the sponsor. All recycling and destruction shall be carried out 
in accordance with the corresponding regulations, guidelines and rules and regulations, and 
relevant inspection, verification, signature and recording shall be done. 
5.2 GFH018 administration 
GFH018 is administered orally with approximately 200 mL of warm water. Subjects should be 
advised that the tablet must be swallowed whole, not chewed or broken apart.  
Cycle 1 (14d-on/14d-off): 
• 
Day 1: Eligible subjects will receive their first dose at the study site around 8:00. 
After 20:00 at the evening prior to Day 1, subjects are not allowed to consume food 
and can drink water freely. Fasting and water for half an hour before and half an hour 
after administration in the morning, and drinking water freely after half an hour. 
Subjects are required to be fasted for 1 hour and 3-4 hours after administration for 
breakfast and lunch respectively.  
• 
Day 2-3: No medication administration. 
• 
Days 4-16: Subjects should take the medication twice daily, if possible, around 8:00 
and 20:00, and should take the medication on an empty stomach.  
Day 10: Take the corresponding pre-administration PK blood sample and laboratory 
blood sample before taking the medicine in the morning, and take the study drug at 
the site. After half an hour of observation, subject can leave the site if no 
abnormalities occur. The second dose of GFH018 is taken around 20:00. 
• 
Day 17: After 20:00 on D16, the subjects should be fasted and only can drink water. 
At about 8:00 on D17, the study drug will be administered at the site. Subjects are 


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required to be fasted for half an hour respectively prior to and after medication 
administration (water is not allowed as well). Water is allowed after the periods 
mentioned above. Subjects are required to be fasted for 1 hour and 3-4 hours after 
administration for breakfast and lunch respectively. After taking a 12-h PK blood 
sample in the evening, take the second dose of the day.  
• 
Days 18-31: No medication administration. 
Cycle 2 and subsequent cycles (14d-on/14d-off): 
• 
Days 1-13: Take the drug twice a day around 8:00 am and 20:00. And take the 
medicine on an empty stomach.  
• 
Day 14: Complete PK sampling and lab tests before taking the medication in the 
morning. After administration, the subjects should be observed for half an hour, and 
then can leave the site. The second dose should be taken at about 20:00.  
• 
Days 15-28: No medication administration. 
Vomiting and missed doses: 
It is recommended to keep the daily medication time to be consistent as possible. If a missing 
dose occurs, it can be made up within 4 hours after the scheduled timepoints. In this case, the 
actual dosing time should be recorded, and the subsequent dosing timepoints will remain on 
schedule. If it has been more than 4 hours, the exact dose should be skipped, and the patient 
should continue the subsequent dose treatment at the scheduled timepoints. If vomiting occurs 
after administration, re-dosing is not allowed before the next scheduled dose. All actual dosing 
timepoints are recorded in the subject diary or recorded as ‘missing doses’. 
5.3 Duration of Treatment 
The subjects will continue to receive GFH018 until disease progression, or intolerance to 
toxicity, informed consent withdrawal, or study ends, or death. 
5.4 Dose escalation methods 
5.4.1 DLT definition 
DLT is defined as an adverse event or abnormal laboratory test related to the study drug that 
occurred during the first cycle (31 days) and meet the following criteria. All toxicities will be 


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graded according to CTCAE version 5.0.  
d) Non-hematologic toxicity 
Grade 3 and above toxicity. Except for diarrhea, nausea, vomiting, and rash recovering to grade 
2 or less within 3 days of supportive care.  
Specific cardiotoxicity 
◼ 
Cardiac structure/function related: 
• 
Grade 2 and above heart valve dysfunction. 
• 
Grade 2 or above left ventricular ejection fraction decreased. 
• 
Radiographic evidence of damage to any heart and great vessels. 
◼ 
Biomarkers of cardiac injury related: 
• 
Troponin T or troponin I (hs-cTnT or hs-cTnI) twice the baseline and above the 
upper limit of normal ≥ 2 consecutive times (the interval ≥3 days). If 
hypersensitivity troponin is not available in the site, troponin can be substituted for 
evaluation according to the criteria listed above. 
e) Hematological toxicity 
◼ 
Grade 3 neutropenia with infection. 
◼ 
Grade 4 neutropenia, lasting more than 5 days. 
◼ 
Grade 3 febrile neutropenia (neutrophil count < 1.0×109/L with a single temperature > 
38.3 °C (101°F) or a sustained temperature of ≥ 38 °C (100.4°F) for more 
than one hour); or neutropenic infection requiring clinical intervention. 
◼ 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia requiring clinical 
intervention. 
◼ 
Grade 4 anemia. 
f) Investigator and sponsor need to discuss whether to decide whether to be any other 
clinically significant abnormalities of DLT. 
5.4.2 MTD/RDE/RP2D definitions 
The MTD referred to in this study is defined as the highest dose with a DLT incidence ≤1/3. If 


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the MTD has been obtained in the dose escalation part, it can be used as an RDE for further 
research. If MTD is not obtained, the RDE used in the dose expansion part will be determined 
by the SMC based on comprehensive data such as safety and tolerability, PK, 
pharmacodynamics, and preliminary antitumor efficacy during the dose escalation part. The 
RP2D will be determined based on the data obtained in the dose expansion part.  
5.4.3 Dose escalation method 
The starting dose is 5 mg. The single dose PK sampling will be performed after the first dose. 
Multi-dose will be initiated on day 4 with a regimen of 14d-on/14d-off. The first cycle consists 
of 31 days.  
At least three subjects (but generally no more than six subjects) will be enrolled in each dose 
group. Simultaneous increments of 2 or more dose levels are not permitted to be carried out. 
"Subjects" in the dose escalation part described below are eligible for inclusion in the Dose 
Determination Set, defined as subjects who have completed the first cycle of the study, achieved 
a minimum drug exposure (defined as 80% of the total planned dose received in the first cycle), 
have not undergone dose reduction, and have completed a 31-day safety assessment, or have 
developed DLT within the first cycle. 
1. 
If none of the three subjects in a dose group developed DLT within the first cycle (31 days), 
three new subjects will be enrolled in the next ascending dose group. At the same time, 
subjects in this dose group can continue to receive the current dose of therapy.  
2. 
If two or more of three subjects in a dose group develop DLTs in the first cycle (31 days), 
the dose escalation will be stopped (i.e., the next high-dose group study is not conducted). 
And the next lower dose group will be further tested for safety/tolerability.  
If one of three subjects in a dose group develops DLT in the first cycle (31 days), three 
additional subjects should be added to the dose group: if none of the three additional 
subjects develop DLT, three new subjects will be enrolled in the next ascending dose group; 
If one or more of the three additional subjects develop DLTs, the dose escalation will be 
stopped. And the next lower dose group will be further tested for safety/tolerability. 
3. 
When the next lower dose group is further tested for safety/tolerability, if there are only 
three subjects in this dose group, three additional subjects will be added. If there are already 


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six subjects in this dose group, the dose is the MTD. 
4. 
If the dose reaches the planned highest dose group (50 mg twice daily) and the MTD is 
still not reached, the Safety Monitoring Committee (SMC) will jointly decide whether to 
continue the dose escalation and which is the specific dose based on the safety, efficacy 
and PK data already obtained. 
5. 
At the time of the first enrollment of the dose group, if multiple subjects participate in the 
screening at the same time, the modified 3+3 dose escalation protocol allows enrollment 
of ≥ 3 subjects, but no more than 6 subjects. If no DLT occurs in the enrolled evaluable 
subjects (≥ 3 subjects), it will be escalated to the next dose; If one DLT occurs, new subjects 
will be added to the total of 6 in this dose group, and if more than or equal to two DLT 
occur in 3-6 subjects, the escalation will be stopped. The dose will be reduced to the 
previous dose group.  
5.4.4 Dose escalation decision 
During the study, an SMC composed of principal investigators, representatives of contract 
research organizations (CROs) and sponsor representatives will be established to review the 
safety data generated in the study, mainly for DLTs and all other grade 2 and above adverse 
events per CTCAE v5.0, as well as pharmacokinetic and pharmacodynamic data, and carefully 
evaluate whether to escalate to the next dose level.  
The decision to increment to the next dose will be notified to investigators in writing, 
confirming that the data from the previous dose group has been reviewed and that the SMC 
agrees to proceed with the next higher dose. 
5.4.5 Intra-patient dose escalation 
This study does not allow for intra-patient dose escalation. 
5.5 Study drug interruption, dose reduction, and discontinuation 
5.5.1 GFH018 interruption and dose reduction 
Dose adjustments are not permitted during the first cycle of the dose escalation part. If DLT 
occurs, subject will discontinue from the study drug. 
In cycle 2 and subsequent cycles: 


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• 
When grade 3 hematologic toxicity or grade 2 non-hematologic toxicity occurs, 
GFH018 will be interrupted until the adverse event returns to grade ≤ 1. Subjects will 
restore the former dose level if the adverse event is a return to grade 0-1 within 7 
days of the last dose. If AE recovers to grade 0-1 for more than 7 days, subjects may 
restart GFH018 treatment at a lower dose level if it is judged by the investigator and 
deemed necessary after consulting with the sponsor. If AE recovers to grade 0-1 for 
more than 14 days, GFH018 will be permanently discontinued.  
• 
Special interest of adverse events – cardiac toxicity 
• 
Clinically significant elevation of BNP or NT-proBNP. 
• 
Clinically significant elevation of troponin T (or troponin I). 
• 
Cardiac ultrasound abnormalities, such as heart valve stenosis or worsening of 
regurgitation, or a significant decrease in LVEF that the investigator judged to 
be clinically significant compared to baseline. 
If BNP/NT-proBNP or hs-TnI/hs-TnI clinically increases, repeated testing is warranted. If 
necessary, cardiology consultation is preferred for further evaluation. 
During the trial, only one dose reduction of the drug is allowed. Two dose interruption is 
allowed. If a third occurrence of toxicity requiring dose interruption occurs, the study treatment 
will be permanently discontinued after consultation with the sponsor. 
5.5.2 Study drug discontinuation 
Study drug administration should be permanently discontinued after consultation with the 
sponsor if any of the following applies: 
• 
Grade 4 non-hematologic toxicity. 
• 
Grade 4 neutropenia last for > 7 days. 
• 
AST or ALT ≥ 5 times the upper limit of normal; If subjects with liver metastases have 
a grade 2 AST/ALT increased at the time of enrollment, study drug will be permanently 
discontinued when AST/ALT is ≥ 50% increase compared to baseline last for ≥ 1 week； 
• 
Total bilirubin > 3 times the upper limit of the normal range; If subjects have Gilbert 
syndrome, permanently discontinue the study drug if TBIL increases ≥ 50% compared to the 


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baseline lasting for ≥ 1 week. 
5.6 Medication and dietary restrictions 
5.6.1 Permitted concomitant medications 
In general, treatment that is necessary to ensure the safety of the subject is permitted. 
Concomitant medications used throughout the study should be documented. All drugs used 
from 28 days prior to screening to the end of treatment period should be documented in the 
relevant eCRF with justification for use and details of treatment. 
When treatment-related adverse events occur, subjects should be closely monitored and treated 
adequately. The corresponding drug used should be documented in the eCRF. 
5.6.2 Prohibited concomitant medications 
Subjects may receive other drugs deemed medically necessary by the investigator, but may not 
accept the prohibitions listed as below. If, based on the investigator's assessment, subjects need 
to be treated using any of the treatments described below, please discuss with the sponsor 
whether these subjects need to be excluded from the study. 
• 
Antineoplastic drugs: Do not use any antineoplastic drugs other than study drugs, including 
but not limited to chemotherapy, immunotherapy, targeted therapy, hormone therapy 
(subjects taking hormones that antagonize GnRH for prostate cancer, oral contraceptives, 
subjects with hormone replacement therapy can continue to take GFH018), and traditional 
Chinese medicines approved with anti-tumor indications. 
• 
Any other drugs under clinical investigation other than the treatment in this study. 
• 
Palliative care therapies (e.g., local radiotherapy for pain, or thoracentesis and drainage to 
relieve subjects' symptoms) can be used at any time after completion of the second dosing 
cycle, if necessary, after discussion between the investigator and the sponsor. 
• 
Live vaccines are prohibited during the study. However, inactivated influenza or attenuated 
vaccines may be permitted, and the washout period is not required. The use of other 
inactivated or attenuated vaccines for the prevention of infectious diseases must be 
discussed on a case-by-case basis and discussed with the investigator and sponsor prior to 
administration. Any vaccine used during the study must be documented in the subject's 


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medical records and eCRF. 
• 
According to preclinical pharmacokinetic studies, GFH018 is mainly metabolized by 
CYP3A4 in vivo. In order to avoid drug-drug interactions, the use of strong inducers and 
strong inhibitors of the drug metabolizing enzyme CYP3A4/5 are prohibited, as detailed 
in Table 5-1. If investigators suspect that the drug may have a strong inducing or strong 
inhibitory effect on CYP3A4/5, but it is not listed in Table 5-1, the sponsor can be 
contacted for specific discussion. 
• 
The use of Chinese herbal medicines is prohibited in the first cycle. 
• 
Other treatments prohibited per the inclusion and exclusion criteria.


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Table 5-1 Inducers and inhibitors of CYP3A4/5 (partial) 
Interaction mechanisms 
Drug name 
Strong inducer 
Carbamazepine, phenytoin, rifampicin, St. John's wort 
Strong inhibitors 
Clarithromycin, ritonavir, indinavir, ketoconazole, 
itraconazole 
Moderate inducer 
Bosentan, modafinil, nafcillin, thioridazine hydrochloride 
Moderate inhibitors 
Cimetidine, ciprofloxacin, grapefruit, verapamil, imatinib 
5.6.3 Permitted medications with caution  
• 
Moderate inhibitors and inducers of CYP3A4/5 (see Table 5-1). 
• 
Colony-stimulating factor: subjects should not have been used within 14 days before 
participating in screening; Prophylactic use is not possible in the first cycle, and application 
is allowed when serious adverse reactions occur; The use of subsequent cycles can be 
determined by the investigator in conjunction with clinical practice in accordance with the 
ASCO 2015 guidelines. 
• 
If the dose of warfarin or low molecular weight heparin has been stable for 2 weeks in the 
pre-enrollment patient, >continued use of the anticoagulant is allowed, subject to 
continuous monitoring of INR at the discretion of the investigator. The investigator may 
decide to suspend the use of anticoagulants according to the clinical norms of the research 
center, such as when tumor tissue samples need to be taken. 
5.6.4 Dietary restrictions 
Subjects must abstain from taking grapefruit fruits and beverages for at least 7 days prior to the 
first dose, and from grapefruit fruits and beverages throughout the study period. 
5.7 Participant number and treatment assignment 
5.7.1 Subject number 
Subjects are assigned a screening number after signing the informed consent form, entering the 
screening period, which is determined by a two-digit site code (01, 02, ...). Plus a three-digit 
serial subject number (001,002,...). ) composition. Screening numbers cannot be reused and are 


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unique for each subject.  
Subjects who are eligible for admission will be assigned enrollment numbers in order of 
enrollment, 5001, 5002, 5003, 5004, ....。 Enrollment numbers cannot be reused.  
5.7.2 Treatment assignment 
All enrolled subjects in this study will be treated with GFH018. 
 


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6. 
Study Procedure 
6.1 Schedule of Activities 
Table 6-1 and Table 6-2 are the flowcharts for the dose escalation part and the dose 
expansion part, respectively. 
Screening should be performed within ≤ 28 days before day 1 of the first cycle (excluding 
pregnancy tests, which are required within 72 hours prior to the first dose).  
All visits and operations during the study should be carried out as long as possible according to 
the schedule of the study. The corresponding accepted window is shown in the test flow chart. 
The specific time points and allowable time windows for PK sample collection are shown in 
Table 6-4. 


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Table 6-1 Schedule of Activities in Dose Escalation 
Cycle 
Screening1 
Treatment period 
Follow up 
Cycle 1 
Cycle 2 and subsequent 
cycles 
EoT 
Follow-
up12 
Safety 
Follow-up13 
Days 
-28 to -1 
1 
2 
3 
4 
10 
17 (7/7 
regimen * 
only). 
24 
(14/14 
regimen 
only* ) 
31 
1 
14 
(D21 for 7/7 
regimen) 
28 (±2) 
0-7 days 
after 
EoT 
30 ± 3 days 
after the 
last dose 
Informed consent 
form2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Serum pregnancy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs4* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PE 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Hematology 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
Chemistry 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 


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Cycle 
Screening1 
Treatment period 
Follow up 
Cycle 1 
Cycle 2 and subsequent 
cycles 
EoT 
Follow-
up12 
Safety 
Follow-up13 
Days 
-28 to -1 
1 
2 
3 
4 
10 
17 (7/7 
regimen * 
only). 
24 
(14/14 
regimen 
only* ) 
31 
1 
14 
(D21 for 7/7 
regimen) 
28 (±2) 
0-7 days 
after 
EoT 
30 ± 3 days 
after the 
last dose 
Urinalysis 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
Coagulation5 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Thyroid 
function 
(FT3, FT4, TSH) 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
12-lead ECG6* 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECHO 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
BNP + troponin 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
hsCRP  
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
Cystatin C 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
Adverse events7 
X 
Blood PK sample8 
 
X 
 
 
Urinary PK sample8 
 
X 
 
 


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Cycle 
Screening1 
Treatment period 
Follow up 
Cycle 1 
Cycle 2 and subsequent 
cycles 
EoT 
Follow-
up12 
Safety 
Follow-up13 
Days 
-28 to -1 
1 
2 
3 
4 
10 
17 (7/7 
regimen * 
only). 
24 
(14/14 
regimen 
only* ) 
31 
1 
14 
(D21 for 7/7 
regimen) 
28 (±2) 
0-7 days 
after 
EoT 
30 ± 3 days 
after the 
last dose 
Biomarker sample 
collection9 
 
X 
 
 
Tumor imaging 10 
X 
X 
GFH018 
administration11 
 
X 
 
 
Footnote: 
1. Laboratory assessments results within 3 days prior to C1D1 are not required to be repeated on C1D1. Rescreening is allowed under limited conditions in consultation with 
the sponsor. Only one rescreening is allowed. 
2. Written informed consent should be obtained prior to the implementation of any particular procedure in the protocol. These tests may be used in lieu of screening tests if they 
are performed as part of routine clinical care within a specific time frame (eg, within 28 days prior to day 1 of cycle 1). 
3. Including diagnosis and extent of tumor, history of treatment for the primary diagnosis, etc. The date of the most recent oncology treatment must be recorded. Medical history 
is requested to be collected within 30 days prior to the signing of ICF. 
4. Vital signs include temperature, blood pressure, heart rate, and respiratory rate. 
5. Determination of PT/INR and APTT. In addition to the planned time point, coagulation should be measured throughout the study when relevant clinical indications are 
present. PT/INR and APTT analysis is performed by local laboratories. 
6. Three ECGs (12-lead ECG) will be performed, each at least 5 minutes apart, and the subject should rest for at least 10 minutes before the examination. If clinically indicated, 
the frequency of ECG may be increased. If the drug is planned to be given at the same time on the same day, the specific time point of ECG examination: 2 hours (±30 minutes) 


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after the morning administration. If the drug is not administered on the same day, it can be done between 8:00 and 11:00 am.  
7. Adverse events will be graded according to NCI-CTCAE version 5.0. The severity of all adverse event will be assessed. 
8. Blood and urine samples will be collected for PK analysis of GFH018. The specific time points are shown in Table 6-4. Collection of urine samples is limited to the first 
cycle of the dose escalation, starting with the third dose group.  
9. For blood sampling scheme of pharmacodynamic markers, please refer to 6.2.5.  
10. Tumor imaging (CT or MRI, preferably CT) will be performed within 28 days prior to enrollment and checked approximately every 8 weeks (± 7 days) for the duration of 
the study. The same imaging technique should be used for one subject throughout the duration of the study. 
11. The first cycle dose regimen is, single dose on day 1, no dose on days 2 and 3, starting BID from D4 for 14 days and then stopping the drug for 14d-on/14d-off, 7d-on/7d-
off, daily, or other regimens, a total of 31 days. The dosing regimen for cycle 2 and all subsequent cycles is BID for 14d-on/14d-off, 7d-on/7d-off, or daily for 28 days per cycle.  
12. The EOT date will be the date on which the decision is made to permanently discontinue the study treatment and is not necessarily the actual last dosing date. EOT visits 
should take place within 0-7 days of the EOT date. If the EOT visit occurs within the time window of the safety follow-up, there is no need to repeat the same procedure. 
13. The safety follow-up should be performed 30 (±3 days) after the last dose of study treatment. Subjects who discontinue the study treatment due to intolerable toxicity will 
be followed until toxicities are ≤ grade 1 or stable. 
 
 


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Table 6-2 Schedule of Activities in Dose Expansion  
 
Screening1 
Treatment period 
Follow 
Cycle 1 
Cycle 2 and subsequent cycles 
End 
of 
treatment 
follow-up12 
Safety follow-
up13 
Days 
-28 to -1 
1 
14 (D21 for 
the 7/7 
regimen). 
28 
（±2） 
1 
14 (D21 for 
the 7/7 
regimen). 
28 
（±2） 
0-7 days after 
EoT 
30 ± 3 days 
after the last 
dose 
Informed consent 
form2 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
Medical history3 
X 
 
 
 
 
 
 
 
 
ECOG PS 
X 
 
 
X 
 
 
X 
X 
X 
Serum pregnancy 
X 
 
 
 
 
 
 
 
X 
Vital signs 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
 
X 
 
 
X 
X 
X 
Chemistry 
X 
X 
 
X 
 
 
X 
X 
X 


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Screening1 
Treatment period 
Follow 
Cycle 1 
Cycle 2 and subsequent cycles 
End 
of 
treatment 
follow-up12 
Safety follow-
up13 
Days 
-28 to -1 
1 
14 (D21 for 
the 7/7 
regimen). 
28 
（±2） 
1 
14 (D21 for 
the 7/7 
regimen). 
28 
（±2） 
0-7 days after 
EoT 
30 ± 3 days 
after the last 
dose 
Urinalysis 
X 
X 
 
X 
 
 
X 
X 
X 
Coagulation 5 
X 
 
 
X 
 
 
X 
 
X 
Thyroid function  
(FT3, FT4, TSH). 
X 
 
 
X 
 
 
X 
 
X 
12-lead ECG 6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECHO 
X 
 
 
X 
 
 
X 
 
 
BNP+ troponin 
X 
 
X 
X 
 
 
X 
 
 
hsCRP  
X 
 
X 
X 
 
 
X 
 
 
Cystatin C 
X 
 
X 
X 
 
 
X 
 
 
Adverse events7 
X 
PK blood sample8 
 
X 
 
 
Blood collection 
 
X 
 
 
Tumor imaging10 
X 
 


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Screening1 
Treatment period 
Follow 
Cycle 1 
Cycle 2 and subsequent cycles 
End 
of 
treatment 
follow-up12 
Safety follow-
up13 
Days 
-28 to -1 
1 
14 (D21 for 
the 7/7 
regimen). 
28 
（±2） 
1 
14 (D21 for 
the 7/7 
regimen). 
28 
（±2） 
0-7 days after 
EoT 
30 ± 3 days 
after the last 
dose 
Study 
drug 
administration11 
 
X 
 
 
Footnote: 
1. Laboratory assessments results within 3 days prior to C1D1 are not required to be repeated on C1D1. Rescreening is allowed under limited conditions in consultation with 
the sponsor. Only one rescreening is allowed. 
2. Written informed consent should be obtained prior to the implementation of any particular procedure in the protocol. These tests may be used in lieu of screening tests if they 
are performed as part of routine clinical care within a specific time frame (eg, within 28 days prior to day 1 of cycle 1). 
3. Including diagnosis and extent of tumor, history of treatment for the primary diagnosis, etc. The date of the most recent oncology treatment must be recorded. Medical history 
is requested to be collected within 30 days prior to the signing of ICF. 
4. Vital signs include temperature, blood pressure, heart rate, and respiratory rate. 
5. Determination of PT/INR and APTT. In addition to the planned time point, coagulation should be measured throughout the study when relevant clinical indications are 
present. PT/INR and APTT analysis is performed by local laboratories. 
6. Three ECGs (12-lead ECG) will be performed, each at least 5 minutes apart, and the subject should rest for at least 10 minutes before the examination. If clinically indicated, 
the frequency of ECG may be increased. If the drug is planned to be given at the same time on the same day, the specific time point of ECG examination: 2 hours (±30 minutes) 
after the morning administration. If the drug is not administered on the same day, it can be done between 8:00 and 11:00 am.  
7. Adverse events will be graded according to NCI-CTCAE version 5.0. The severity of all adverse event will be assessed. 
8. Blood and urine samples will be collected for PK analysis of GFH018. The specific time points are shown in Table 6-4. Collection of urine samples is limited to the first 
cycle of the dose escalation, starting with the third dose group.  
9. For blood sampling scheme of pharmacodynamic markers, please refer to 6.2.5.  


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10. Tumor imaging (CT or MRI, preferably CT) will be performed within 28 days prior to enrollment and checked approximately every 8 weeks (± 7 days) for the duration of 
the study. The same imaging technique should be used for one subject throughout the duration of the study. 
11. The first cycle dose regimen is, single dose on day 1, no dose on days 2 and 3, starting BID from D4 for 14 days and then stopping the drug for 14d-on/14d-off, 7d-on/7d-
off, daily, or other regimens, a total of 31 days. The dosing regimen for cycle 2 and all subsequent cycles is BID for 14d-on/14d-off, 7d-on/7d-off, or daily for 28 days per cycle.  
12. The EOT date will be the date on which the decision is made to permanently discontinue the study treatment and is not necessarily the actual last dosing date. EOT visits 
should take place within 0-7 days of the EOT date. If the EOT visit occurs within the time window of the safety follow-up, there is no need to repeat the same procedure. 
13. The safety follow-up should be performed 30 (±3 days) after the last dose of study treatment. Subjects who discontinue the study treatment due to intolerable toxicity will 
be followed until toxicities are ≤ grade 1 or stable. 
 
 
 


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6.1.1 Screening period 
Once a subject has been considered for entry into the study, the nature and content of the study 
must be explained, and an informed consent signed by the subject must be obtained prior to any 
study-related process. 
The screening period is from day -28 to day -1, and the items to be completed during the 
screening period are shown in the research flow chart. The details of each item are shown in 
Table 6-3.  
Table 6-3 Specific requirements for the observation indicators of subjects during the 
screening period 
Parameter 
 
Demographic 
Age, gender, ethnicity, smoking history and alcohol history; Height, 
weight, body mass index 
physical examination 
General condition, skin condition, head/neck, lungs, cardiovascular, liver, 
kidneys, gastrointestinal, lymphatic system, musculoskeletal system, 
limbs, larynx; Weight (no need to repeat measurements when already 
measured in the demographic data item) 
Eligibility criteria 
Verification of inclusion and exclusion criteria 
Medical history 
Previous and present medical history 
Tumor diagnosis and 
confirmation 
Histopathological and/or cytology diagnosis, including clinical staging; 
tumor-related symptoms, pain score, ECOG score; Bone scan and brain 
CT (if applicable) 
History 
of 
oncology 
treatment 
Previous topical or systemic antineoplastic therapy, start and end time, 
optimal response, reason for discontinuation of treatment 
Imaging 
of 
tumors 
(CT/MRI 
of 
chest, 
abdomen, pelvis, and 
any 
other 
suspected 
tumor lesion) 
The imaging modalities used were consistent throughout the study. Tumor 
imaging at baseline and after study entry should be performed in the same 
site/facility. 
Biopsy of tumor or other 
tissue (optional) 
Biopsy is performed only when no other history is available to confirm 
the diagnosis. Biopsy of tumors or other tissues (eg, inflammatory tissue 
obtained without general anesthesia) may be performed during the 
screening period and when other clinically indicated. Biopsy requires 
informed consent from the subject.  
Vital signs 
Temperature, heart rate, respiratory rate, systolic and diastolic blood 
pressure 
Electrocardiogram 
Standard 12-lead ECG 
Echocardiography 
Left ventricular ejection fraction, heart valve function, etc 
Concomitant 
medications 
Previous and current medications 


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Parameter 
 
Adverse events 
 
Laboratory tests 
 
Hematology 
Red blood cell count (RBC), hemoglobin concentration (HGB), 
hematocrit (HCT), mean red blood cell volume (MCV), mean red blood 
cell hemoglobin content (MCH), mean red blood cell hemoglobin 
concentration (MCHC), white blood cell count (WBC), platelet count 
(PLT), neutrophil count (ANC), lymphocyte (LY) count, monocytes (MO) 
count, eosinophil (EO) count, Basophil (BA) count, percentage 
neutrophils, percentage lymphocytes, percentage monocytes, percentage 
eosinophils, percentage basophils 
Urinalysis 
Urine leukocytes (LEU), urine nitrite (NIT), urine pH, urine specific 
gravity (SG), urine protein (PRO), urine glucose (GLU), urine ketone 
bodies (KET), urine bilinogen (UBG), urine bilirubin (BIL), urine occult 
blood (BLD), 24-hour protein1 
Coagulation function 
Prothrombin time (PT), activated partial thromboplastin time (APTT), 
international normalized ratio (INR) 
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), white globular ratio (A/G 
ratio), total bilirubin (TBIL), direct bilirubin (DBIL), creatine kinase 
(CK), pancreatic amylase (AMY), fasting blood glucose (FPG), total 
cholesterol (TCHO), low-density lipoprotein cholesterol (LDL-C), high-
density lipoprotein cholesterol (HDL-C), triglycerides (TG), bicarbonate, 
phosphate, calcium, sodium, chloride, potassium 
Virus testing 
Hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-
HCV), HIV antibody, treponemal antibody 
Thyroid function tests 
Free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-
stimulating hormone (TSH). 
Cardiac markers 
Hypertroponin T (or Hypertroponin I), brain natriuretic peptide (BNP), 
hs-CRP, cysteine protease inhibitor (Cystatin C) 
Pregnancy test 
Serum β-HCG pregnancy test (blood pregnancy test in women of 
childbearing age) 
1 For routine urinalysis, if the result of the fibrine test strip for urine protein is ≥2+, a 24-hour 
urine sample should be collected for analysis. 
6.1.2 Treatment period 
During the treatment period of this study, various examinations will be performed at the 
specified time points in each dosing cycle (see Table 6-1 and Table 6-2 for details). Subjects 
who meet the inclusion criteria could start treatment with GFH018 up to 28 days after the 
screening visit.  
The first cycle dose regimen is, single dose on day 1, no dose on days 2 and 3, starting BID 


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from D4 for 14 days and then stopping the drug for 14d-on/14d-off, 7d-on/7d-off, daily, or other 
regimens, a total of 31 days. The dosing regimen for cycle 2 and all subsequent cycles is BID 
for 14d-on/14d-off, 7d-on/7d-off, or daily for 28 days per cycle.  
For daily or other dosing regimens, subjects will follow the 14d-on/14d-off visits and SoA. 
Subjects will continue to receive GFH018 until disease progression, or intolerance, withdrawal 
of knowledge, or study end, or death. 
All scheduled visits should be completed within the time window specified in the protocol. 
6.1.2.1 Subject substitution 
No subject substitution will be performed in this study. 
6.1.3 Follow-up period 
6.1.3.1 End-of-treatment (EoT) follow-up 
For subjects who discontinue the study drug early, follow up with the EoT within -7 days (as 
soon as possible) after the decision to permanently discontinue the study drug, and the following 
procedures are required to be performed during the follow-up period and the results of the 
assessment are required to be recorded in the eCRF.  
• 
Vital signs 
• 
physical examination 
• 
ECOG  
• 
Hematology, chemistry, urinalysis (see section 6.1.1 for specific items). 
• 
Concomitant medications 
• 
AE 
6.1.3.2 Safety follow-up 
After the EOT visit, the patient enters into the follow-up period. The safety follow-up visit 
should occur 30 (± 3) days after the last study treatment, and patients will return to the study 
center for a safety follow-up visit. The following procedures will be performed:  
• 
Pregnancy test (serum or urine) 
• 
Vital signs 


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• 
physical examination 
• 
ECOG  
• 
Tumor imaging 
• 
Hematology, chemistry, urinalysis (see section 6.1.1 for specific items). 
• 
Thyroid function 
• 
Coagulation 
• 
Combined medications 
• 
AE 
6.1.3.3 Disease progression follow-up 
For subjects who discontinue GFH018 for reasons other than disease progression, tumor 
evaluation should continue at a frequency of every 8 weeks (± 7 days) until disease progression 
or until the end of the study. 
6.1.4 Loss to follow-up 
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
 
 
6.2 Evaluation 
6.2.1 Safety evaluation 
Safety assessment is performed based on medical review of AE and laboratory abnormality. 
Evaluate the toxicity according to CTCAE v5.0.  
The following assessments will be performed throughout the study to confirm the safety and 
tolerability of GFH018: vital signs, clinical laboratory tests, pregnancy tests (if required), 
ECOG PS, tumor imaging, physical examination, ECG, ECHO, frequency and severity of AEs. 
Adverse event of special interest (AESI) 
According to the toxicological results of GFH018, ASEIs include elevated cardiac biomarkers 
BNP or troponin, and abnormal cardiac ultrasound. Therefore, in this study, additional 
monitoring of cardiac safety is required to be performed. In addition to routine blood pressure 


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and electrocardiogram monitoring, a series of cardiac Doppler ultrasonography and heart-
related biomarkers laboratory tests have been added.  
6.2.1.1 Physical examination 
Physical examination will be performed during the screening period, before the first dose on 
day 1 of each cycle, and at safety follow-up. 
A complete PE will include the examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular and neurological. If indicated based on medical history and/or symptoms, rectal, 
external genitalia, breast, and pelvic exams will be performed. 
6.2.1.2 Vital signs 
Vital signs include blood pressure (BP), respiratory rate, pulse rate and body temperature. They 
will be obtained in the same position, either sitting or supine, as appropriate prior to any blood 
collection. 
6.2.1.3 Electrocardiogram 
An electrocardiogram (ECG) will be completed according to the date and time requirements 
specified in the Schedule of Activities. 
Patients need to rest comfortably on their back for at least 10 minutes prior to the first ECG. 
Recording of specific ECG parameters, including but may not be limited to heart rate, QT, 
QTcF, and PR. It will be performed three times at approximately 5 minutes apart at baseline 
and when the results are of clinical significance. Otherwise, ECG will be only performed once 
at each time point.  
The average of the triplicate QTcFs will be used as the baseline QTcF. During the study period, 
the investigator will compare the ECG results with baseline, if there is an increase of ≥30 msec 
from baseline, or a QTcF ≥450 msec in any specified ECG measurement, then another 2 ECG 
measurements are required to be performed to obtain the average value. 
Blood samples scheduled at the same time point should be taken after the ECGs are completed. 
Each ECG tracing should be labeled with the study number, patient number, date, and kept in 
the source documents at the study site. 


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6.2.1.4 Cardiac ultrasound 
A cardiac Doppler ultrasound will be performed during the screening period and on the last day 
of each cycle to assess the structure and function of the heart, including left ventricular ejection 
fraction, valve function, etc. Cardiac ultrasound reports judged by investigators to be abnormal 
and clinically significant will be interpreted by cardiologists if necessary. 
6.2.1.5 Laboratory tests 
Blood and urine samples evaluated by clinical laboratories will be collected in accordance with 
the protocol (see study flow chart for details). 
The following parameters will be measured in this study, the specific test items are shown in 
Table 6-3, and the blood sample collection volume for laboratory tests is shown in Appendix I.  
 
Chemistry 
 
Hematology 
 
Urinalysis 
 
Coagulation function 
 
Thyroid function 
 
Blood tests for cardiac biomarkers 
 
Pregnancy test 
6.2.2 Tolerance evaluation 
Tolerability will be assessed based on the proportion of subjects who experience dose reduction, 
interruption, and permanent discontinuation.  
6.2.3 Efficacy evaluation 
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; brain CT or MRI is used for the known or suspected brain metastasis of the patients; 
bone scanning and/or bone X-ray are/is used for the known or suspected bone metastasis of the 
patients. CT/MRI scans (with preference for CT) should be performed with contrast agent 
enhancement, unless the patient has contraindications. CT/MRI scans of brain, chest, abdomen, 


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and pelvis cavity are acceptable within 28 days prior to the first treatment, and bone scanning 
is acceptable within 42 days prior to the first treatment.  
All subsequent scans will be performed in the same manner as at screening, with the same 
contrast, preferably on the same scanner. Other metastatic disease sites (e.g., bone or brain 
metastases) should be followed at scheduled visits using appropriate imaging, as clinically 
indicated.  
The first tumor assessment will be performed every 8 (±1) weeks thereafter in the first 48 weeks, 
and every 12 (±1) weeks later during the whole study treatment. The tumor assessments will be 
performed at screening and the subsequent visits according to Schedule of Activities. Tumor 
assessment should also be performed when progression of disease is suspected (e.g., worsening 
of symptoms) and when the patient withdraws from treatment (imaging scans performed within 
4 weeks do not need to be repeated). 
For the phase II study, best response confirmation must be performed at least 4 weeks after the 
initial evaluation of complete response (CR) or partial response (PR). 
The tumor response will be assessed based on the RECIST 1.1 (see Appendix 1 Response 
Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)). Tumor responses according to RECIST 
1.1 will be determined according to the local investigator interpretations. All data shall be 
properly preserved and can be verified by source and peer review. 
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 till 
disease progression, start of new anticancer treatment, withdrew consent, lost to FU or study 
termination for other reasons. 
6.2.4 Pharmacokinetic evaluation 
6.2.4.1 Sample collection 
Dose escalation 
After the first dose on day 1 of cycle 1, serial PK blood samples will be collected up to 72 h 
after administration, the complete PK characteristics of a single dose will be obtained, and 


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multiple doses will be started from day 4. The first cycle is 31 days, and subsequent cycles are 
all 28 days. After the last dose of cycle 1 (day 17 or 24), serial PK blood samples will be 
collected to obtain PK characteristics at steady state. In cycles 2 and subsequent cycles, a trough 
sample will be taken prior to administration in the morning on the last dosing day of each cycle 
(day 14 or 21), primarily for the purpose of determining the compliance. 
Unscheduled PK blood sample collection: When an unexpected adverse event occurs, if 
possible, a blood sample at that time is required to be collected for PK as soon as the investigator 
get the information of the event.  
The specific timing of pharmacokinetic blood sample collection for the first and second cycles 
is shown in Table 6-4. 
 Table 6-4 Pharmacokinetics Sampling Schema in Dose Escalation Part 
Cycle 
Days 
Volume of blood 
taken (mL). 
Planned point in time (h) 
1 
1 
3 
Prior to administration 
1 
1 
3 
0.5 h (± 10 min) after administration 
1 
1 
3 
1 h (± 10 min) after administration 
1 
1 
3 
2 h (± 10 min) after administration 
1 
1 
3 
4 h (± 15 min) after administration 
1 
1 
3 
8 h (± 30 min) after administration 
1 
1 
3 
12 h (± 30 min) after administration 
1 
2 
3 
24 h (± 1 h) after administration 
1 
3 
3 
48 h (±1 h) after administration 
1 
4 
3 
72 h (± 1 h) after dosing / D4 before 
administration 
1 
10 
3 
In the morning, before administration 
1 
17 (for 14d-
on/14d-off) or 24 
(for 7d-on/7d-off) 
3 
In the morning, before administration 
1 
17 (for 14d-
on/14d-off) or 24 
(for 7d-on/7d-off) 
3 
 0.5 h (± 10 min) after morning 
administration 
1 
17 (for 14d-
on/14d-off) or 24 
(for 7d-on/7d-off) 
3 
1 h (± 10 min) after morning 
administration 
1 
17 (for 14d-
on/14d-off) or 24 
(for 7d-on/7d-off) 
3 
2 h (± 10 min) after morning 
administration 


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1 
17 (for 14d-
on/14d-off) or 24 
(for 7d-on/7d-off) 
3 
4 h (± 15 min) after morning 
administration 
1 
17 (for 14d-
on/14d-off) or 24 
(for 7d-on/7d-off) 
3 
8 h (± 30 min) after morning 
administration 
1 
17 (for 14d-
on/14d-off) or 24 
(for 7d-on/7d-off) 
3 
12 h (± 30 min) after morning 
administration 
2 
17 (for 14d-
on/14d-off) or 24 
(for 7d-on/7d-off) 
3 
In the morning, before administration 
Starting from the third dose group, urine samples at steady state will also be collected for PK 
studies to fully understand. Urine samples are collected during the morning of the last dosing 
day of the first cycle (D17 or D24), 0-4 hours after administration, and 4-12 hours after 
administration.  
Dose expansion 
On the last dosing day of the first cycle (D14 for 14d-on/14d-off regimen, or D21 for 7d-on/7d-
off regimen), serial PK blood samples will be collected to obtain the PK characteristics at steady 
state, and the specific time points are shown in Table 6-5. 
Table 6-5. Dose extension period pharmacokinetics blood sample collection schedule 
Cycle 
Days 
Volume of blood taken 
(mL). 
Planned point in time (h) 
1 
Last dosing day 
3 
Before administration 
1 
Last dosing day 
3 
0.5 h (± 10 min) after 
administration 
1 
Last dosing day 
3 
1 h (± 10 min) after 
administration 
1 
Last dosing day 
3 
2 h (± 10 min) after 
administration 
1 
Last dosing day 
3 
4 h (± 15 min) after 
administration 
1 
Last dosing day 
3 
8 h (± 30 min) after 
administration 
1 
Last dosing day 
3 
12 h (± 30 min) after 
administration 


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In subsequent cycles, a trough sample is required to be taken before administration in the 
morning of the last dosing day of each cycle (D14 for 14d-on/14d-off regimen, or D21 for 7d-
on/7d-off regimen), primarily for the purpose of determining compliance. 
For daily or other dosing regimens, subjects will follow a 14-day discontinuation of dosing and 
14-day visits and study activities. 
Unscheduled PK blood sample collection: When an unexpected adverse event occurs, if 
possible, a blood sample at that time should be collected for PK as soon as possible.  
6.2.4.2 Sample analysis methods 
The PK sample of GFH925 will be analyzed with the validated bioanalytical method. Any 
results below the lower limit of quantification and any missing samples will be labeled 
accordingly. For details of sample preparation and processing, refer to the Laboratory Manual. 
6.2.4.3 Calculation of pharmacokinetic parameters 
The pharmacokinetic parameters of GFH018 after steady-state administration with single dose 
and multiple doses will be calculated using a NCA model. The PK parameters for single-dose 
administration include Cmax, Tmax, AUC0-12h, AUC0-24h, AUC0-inf, T1/2, CL/F, Vd/F. Steady-state PK 
parameters include Cmax,ss, Cmin,ss, Tmax,ss, AUCtau, T1/2, CL/F, Vd/F, CLr, Racc.  
6.2.5 Pharmacodynamic evaluation 
In this study, blood samples will be collected for evaluation of pharmacodynamic markers. The 
pharmacodynamic markers involved in this study are TGF-β in peripheral blood and 
pSMAD2/3 in PBMC. 
Blood samples for analysis of TGF-β will be collected before treatment and 1 h after the 1st 
dose in cycle 1, and 1 h after the dose in the morning of the last dosing day (D17 or D24) in 
cycle 1; from cycle 2 and within 1year, it will be measured every 3 cycles during the treatment 
of GFH018, i.e. 1 h (±10 minutes) after the dose on the last day of the 4th, 7th, 10th cycle. For 
daily dosing or other dosing regimens, subjects will follow a 14-day on and 14-day off schedule.  


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PBMC for pSMAD2/3 evaluation will be collected before treatment and 1 h after the 1st dose 
in cycle 1, and before drug administration in the morning of the last day each week (every 7 
days, i.e., days 10, 17, 24, 31) since day 4. From cycle 2, please follow the TGF-β blood 
sampling arrangement.  
 


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7 
End of Study and End of Treatment 
7.1 Definition of End of Study (EoS) 
Defined as the time when the last enrolled subject has been under the study treatment for at 
least 1 year or discontinued for any reason (whichever is earlier). 
7.2 End of Treatment and withdrawal from the study 
End of Treatment Criteria: 
• 
Disease progression. 
• 
Intolerable toxicity. 
Withdrawal criteria: 
• 
ICF withdraw. 
• 
Major protocol deviation. 
• 
Investigator’s decision. 
The investigator must fill in the reason for withdrawal in the eCRF and, if possible, contact the 
subject to complete the end-of-treatment assessment, and complete the end-of-treatment follow-
up record form, recording the last medication as much as possible. 
All study-related AEs and SAEs present at the time of study discontinuation must be followed 
up until they are recovered or stable. 
After the subject has completed all the tests at the last visit, the investigator must be informed 
by the subject as soon as possible if a new SAE or pregnancy is detected within 30 days of the 
study drug. 
7.3 Early Study Termination  
This study may also be discontinued early or interrupted. This may be due to decision of the 
authority, opinion of the Ethics Committee (EC) and et al. Additionally, the sponsor reserves 
the right to stop the research and development of GFH925. 
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 EC.  


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8 
Adverse event reporting 
8.1 Adverse Events 
8.1.1 Definition of Adverse Event 
An AE is defined as any untoward medical occurrence or worsening of a pre-existing medical 
condition in a clinical investigation subject that has developed since signing of informed 
consent, which does not necessarily have to have a causal relationship with the medicinal 
product. An AE could therefore be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pretreatment or post-treatment complications 
resulting from protocol-specified procedures, overdose, drug abuse/misuse, or occupational 
exposure. Any pre-existing event that worsens or changes in nature during or as a result of 
participation in a clinical study is also considered an AE. AEs should be reported on the Adverse 
Event eCRF page. 
Severity of all AEs will be graded according to CTCAE v5.0. For those events not listed by 
CTCAE, the following criteria may be used. 
Table 1 Criteria for judging the severity of adverse events not listed in CTCAE 
Grade 
Clinical descriptions 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 (ADL). Instrumental ADL 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; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self 
care ADL. Self care ADL refer to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden. 
4 
Life-threatening consequences; urgent intervention indicated. 


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5 
Death related to AE. 
It is important to distinguish between serious and severe AEs. Severe is a measure of intensity 
and standard definition of serious adverse events is listed in Section 8.2.1 Definition of Serious 
Adverse Events. Severe AEs are not necessarily SAEs. For example, nausea lasting several 
hours is considered severe nausea, but not an SAE. For another example, a stroke causing only 
mild disability is considered a minor stroke but is an SAE. 
Adverse events of signs and symptoms 
All AEs spontaneously reported by the subject or caregiver or answered by the subject after the 
investigator asked "Have you had any new health problems since the last follow-up/visit?" or 
detected by the subject 's voluntary report should be recorded in the eCRF. When collecting 
AEs, the diagnosis record (where possible) should preferably list the signs and symptoms of 
the subject. 
Adverse events based on physical examination and tests 
Results of laboratory tests, cardiac ultrasound, vital signs, ECGs, and other safety assessments 
should be reported as AEs if these parameters worsen from baseline values and meet the criteria 
for AEs. If associated with appropriate clinical signs and symptoms, the sign or symptom should 
be reported as an AE, and relevant laboratory or other results should be provided as additional 
information. Reported investigators should use clinical rather than laboratory terms whenever 
possible (eg, use anemia rather than hemoglobin decreased). Abnormal laboratory findings 
without clinical significance will not be recorded as AEs or SAEs. 
AEs do not include:  
• 
pre-existing diseases, conditions, or laboratory abnormalities that were present or detected 
prior to the Screening Visit that did not worsen further;  
• 
absence of an untoward medical occurrence (eg, hospitalization for elective surgery, social 
reasons, and/or self-convenience reasons);  
• 
any medical condition or clinically significant laboratory abnormality that occurred prior 
to signing of informed consent and is not associated with a protocol-related procedure is 
not considered an AE. This condition is considered pre-existing and should be recorded as 
medical history in the eCRF. 


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8.1.2 Adverse events collection and documentation 
Any AEs (clinical symptoms, signs, or diseases) occurring during the administration of the 
study drug will be recorded in the eCRF, whether or not related to the study drug. 
Time period for collecting adverse events 
AEs should be collected from the time of informed consent through follow-up. The follow-up 
period was 30 days (± 3 days) after discontinuation of study treatment. SAEs occurring during 
the follow-up period should be reported to the sponsor by routine methods.  
After a subject discontinues study drug, investigators are required to collect SAEs related to 
study procedures, and patients who discontinue study drug for reasons other than disease 
progression should be followed for disease progression until disease progression or the end 
of the study as shown in Table 2. 
Table 2 Time period for collecting adverse events 
 
Treatment period 
Follow-up period 
After follow-up 
period 
Collect all new AEs in 
the eCRF 
Yes 
Yes 
No 
Collect 
all 
ongoing 
AEs in the eCRF 
Yes 
Yes 
No 
Collect all treatment-
related SAEs in the 
eCRF 
Yes 
Yes 
Yes 
 
Information required for adverse events 
AEs will be documented by investigators and the following information should be collected for 
each AE: 
• 
Diagnosis/description of AEs 
• 
AEs onset date and end date  


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• 
Severity (CTCAE grade) 
• 
Investigator's judgment of causal relationship to study drug 
• 
Action taken with study drug (none, dose reduction, dose interruption, permanent 
discontinuation, etc.) 
• 
Medication administered for AEs (if yes, corresponding treatment medication information 
should be recorded) 
• 
Whether it is a serious adverse event (SAE) (see Section 8.2 Serious Adverse Events)  
• 
Outcome (recovered, recovering, not recovered) 
8.1.3 Handling of adverse events 
All subjects experiencing AEs, whether considered treatment-related or not, must be 
monitored regularly (if feasible) and medically judged and appropriately managed by 
investigators until the symptoms subside, any abnormal laboratory values return to normal 
or return to baseline or are considered irreversible, or until the changes observed can be 
explained appropriately. 
Grade 3 or 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing, if feasible, and preferably within 3 calendar days of receipt of the initial test result the 
subject should be returned for review and then processed accordingly. 
Cardiac adverse events of special interest 
• 
Clinically significant elevations in cardiac biomarkers BNP or NT-proBNP;  
• 
Clinically significant elevations in high-sensitivity troponin T (or high-sensitivity troponin 
I);  
• 
Abnormal cardiac ultrasound, such as worsening of valvular stenosis or regurgitation from 
baseline, or a clinically significant decrease in LVEF from baseline as judged by the 
investigator. 
If the subject presents clinically significant elevation of cardiac biomarkers BNP or NT-proBNP, 
or clinically significant elevation of high-sensitivity troponin T (or high-sensitivity troponin I), 
reexamination is required and consultation with the cardiology department is requested for 
further evaluation if necessary. 


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Follow-up of unrecovered adverse events 
The investigator should continue to follow up AEs that were not resolved at the last study visit, 
but do not need to be documented in the eCRF. The sponsor had the right to request information 
on subjects who had an AE ongoing at the end of the study, if deemed necessary. 
8.2 Serious Adverse Events 
8.2.1 Definition of Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that occurs from the time the patient 
signs the informed consent through the end of the safety follow-up visit and meets one or more 
of the following criteria:  
• 
results in death, 
• 
is life-threatening (NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the patient was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more severe.),  
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation,  
• 
results in persistent or significant disability/incapacity, or  
• 
is a congenital anomaly/birth defect. 
Important medical events: such events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. Medical and scientific judgement 
should be exercised in deciding whether expedited reporting is appropriate in such situations. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm. 
8.2.1.1 Hospitalization 
An AE resulting in hospitalization (even if less than 24 hours) or prolonged hospitalization in a 
clinical study should be considered an SAE. Hospitalization did not include the following:  
• 
a visit to an emergency department, outpatient clinic, or other hospital department for < 
24 hours and no hospitalization (unless considered an "important medical event" or a life-
threatening event), 


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• 
elective surgery planned prior to signing informed consent, 
• 
planned medical/surgical treatment or monitoring based on the protocol, 
• 
routine health assessments requiring hospitalization, such as routine colonoscopy, 
• 
hospitalization for Grade 1 AEs, including overnight hospitalization for nonmedical 
reasons after study drug administration, 
• 
hospitalization for medical insurance reimbursement,  
• 
hospitalization that had no impact on health status and did not require medical/surgical 
intervention (eg, no residence, financial difficulties, family reasons, management needs, 
etc.).  
 
8.2.1.2 Malignant neoplasm progression  
Clinical symptoms of malignant neoplasm progression may be reported as adverse events if the 
symptoms cannot be determined as exclusively due to the progression of the underlying 
malignant neoplasm or do not fit the expected pattern of progression for the disease under study. 
If it is clearly consistent with the suspected progression of the underlying malignant neoplasm, 
it will not be reported as adverse events. Progression of malignant neoplasm itself will not be 
reported as an AE.  
Clinical symptoms of malignant neoplasm progression that meet SAE criteria may be reported 
as SAEs if the symptoms cannot be determined as exclusively due to the progression of the 
underlying malignant neoplasm or does not fit the expected pattern of progression for the 
disease under study. An event should not be reported as an SAE if it met the criteria for an SAE 
(except for a death event) but is clearly consistent with suspected progression of the disease 
under study. 
Death events that occur during the safety follow-up period must be reported as SAEs, whether 
or not the investigator assesses them as possibly related to disease progression. 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 as SAE 
terms and reported as SAEs; if the cause of death is unknown at the time of report, it should be 


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recorded as ‘unknown cause of death’. 
8.2.2 SAE reporting requirements 
In case of any SAE occurring from the signing of informed consent form by the subject to 30 
days (± 3 days) after the last dose, no matter whether or not it is related to the study drug, the 
investigator shall:  
• 
immediately take appropriate treatment measures for the subject, and report to the sponsor 
within 24 hours after being informed of its occurrence, and timely report to relevant units 
according to regulatory requirements. 
• 
complete the SAE Report Form and complete all applicable sections of the form. The 
investigator should evaluate and record the relationship between SAE and each specific 
study treatment, and send the completed and signed form to the drug safety department of 
the sponsor and the drug safety department of CRO Tigermed as entrusted by the sponsor 
by fax or email within 24 hours:  
• 
Genfleet Drug Safety Public Mailbox: drugsafety@genfleet.com  
• 
Tigermed Drug Safety Public Mailbox: PV@tigermed.net  
• 
Tigermed Drug Safety Fax: 021-33275864 
Follow-up information will use a new SAE Report Form and will be identified as follow-up 
information for previously reported SAEs.  
At the end of the trial or early withdrawal of a subject, unresolved SAEs must be followed up 
until any of the following occurs:  
• 
event resolved;  
• 
event stable;  
• 
event returns to baseline (if available at baseline);  
• 
event is attributable to a drug other than study drug or to factors unrelated to study 
procedures;  
• 
subject lost to follow-up (loss to follow-up is defined in Section 6.1.6).  
If the investigator learns that a subject experienced an SAE, including death, after completing 
the study, and considers the event to be possibly related to the study drug, the investigator 


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should report it to the sponsor.  
8.3 Causality assessment 
The investigator should determine the relationship of AE/SAE to the study drug according to 
the following criteria:  
• 
Definitely related: there was a reasonable temporal sequence between the onset of the AE 
(including laboratory abnormalities), and the administration of the study drug; the study 
drug more reasonably explains the AE than other causes (e.g., the subject 's pre-existing 
disease, environmental or toxic factors, or other treatments the subject received, etc.); and 
the reaction after study drug discontinuation is clinically reasonable. 
• 
Possibly related: there was a reasonable temporal sequence between the onset of the AE 
(including laboratory abnormalities), and the administration of the study drug; the AE is 
equally plausible to be explained by the study drug as for other reasons (e.g., the subject 
's preexisting disease, environmental or toxic factors, or other treatments the subject 
received, etc.); information of the event is lacking or unknown after study drug 
discontinuation. 
• 
Unlikely related: the temporal relationship between the onset of AE (including laboratory 
abnormalities) and the administration of the study drug is unclear; the event may also be 
caused by the clinical state or other treatments (e.g., the subject 's preexisting disease, 
environmental or toxic factors, or other treatments the subject received. 
• 
Definitely unrelated: the AE does not occur in a reasonable temporal sequence from 
administration of the study drug; the AE has other obvious causes (e.g., the subject 's 
preexisting disease, environmental or toxic factors, or other treatments the subject received, 
etc.). 
• 
Unable to judge: the above information was unknown, causal relationship was difficult to 
determine, and the data could not be supplemented.  
The causality relationship will be considered related if the investigator judged the relationship 
to study drug as "definitely related" or "possibly related". And it will be considered related if 
the investigator judged it as " unable to judge" and the investigator will be required to collect 
as much information as possible and make a causality relationship assessment again. The 


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causality relationship will be considered unrelated if judged by the investigator as "definitely 
unrelated" or " unlikely related ". 
8.4 Pregnancy 
Pregnancy reports are used to report any case of pregnancy following maternal or paternal 
exposure to study drug.  
The investigator should report all pregnancy cases identified after the subject first agreed to 
participate in the study (ie, signed informed consent) and throughout the study (including the 
follow-up period after study drug treatment until 30 days [± 3 days] after the last dose of study 
drug) to the sponsor in the form of a pregnancy report within 24 hours of learning of the 
pregnancy report.  
Refer to SAE reporting guidelines for a complete description of the pregnancy reporting 
procedure. 
Pregnancy itself is not considered an AE and artificial elective abortion without medical reasons 
is not required to terminate the pregnancy. Any premature termination of pregnancy (eg, 
spontaneous abortion due to complications or other medical reasons, artificial therapeutic 
abortion) must be reported within 24 hours as an SAE. Medical reasons emerging during this 
process should be recorded as AE terms. Spontaneous abortion is always considered an SAE 
and should be reported as an SAE. Subjects should receive appropriate monitoring and care 
until the end of pregnancy.  
For male study subjects, pregnancy of their female partners must also be reported and reported 
as an SAE. Monitoring of the partner should continue until the end of pregnancy.  
8.5 Other special situation reports 
Other special situation reports include reports of medication errors, abuse, misuse, and overdose. 
In addition, reports of adverse reactions in infants following breastfeeding exposure are 
included.  
Medication error refers to any unintentional error in the prescribing, dispensing, or 
administration of a drug.  
Abuse was defined as persistent or sporadic intentional excessive use of the drug by the subject.  


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Misuse was defined as deliberate and inappropriate use of the drug not in accordance with the 
protocol instructions and prescribing information.  
Overdose was defined as accidental or intentional overdose of study drug. An overdose was 
defined as a dose (accidental or intentional) taken by a subject that exceeded 20% of the 
protocol-specified dose.  All other special situation reports must be faithfully recorded within 
24 hours after the investigator learns of the situation. If the special situation leads to AE or SAE, 
the report should be made in the form of AE or SAE. These reports must include cases involving 
the study drug, but do not apply to concomitant medications. Special situations involving 
concomitant medications will not be reported except for those causing AEs. Any inappropriate 
use of medication prohibited by this protocol should not be reported as "misuse", but may be 
more appropriately documented as a protocol deviation. All clinical sequelae associated with 
these special situation reports should be reported as AEs simultaneously in the form of AE 
reports. If it leads to an SAE, it will be reported in the form of an SAE report. Details of 
symptoms and signs, clinical management, and results will be reported.  
8.6 Expedited reporting of adverse events of special interest 
As described in Section 6.2.1 Safety evaluation, cardiotoxicity is an adverse event of special 
interest in this study. Cardiac related adverse events of Grade 2 or higher should be reported to 
the sponsor within 24 hours of awareness (refer to Section 8.2.2 SAE reporting requirements).  
In addition, during the first cycle (DLT observation period), AEs meeting the criteria for DLT 
should also be reported to the sponsor within 24 hours of awareness of their occurrence (see 
Section 8.2.2 SAE reporting requirements for reporting methods). 
 


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9 Data Management 
9.1 CRF 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. 
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 Principal Investigator is responsible for assuring that the data entered eCRF is  
9.2 Data Security 
The investigator or the designated staff will have an unique account ID in EDC. The 
Investigator need to electronically sign the data to assure that the data entered ineCRF is 
complete, accurate. E-signature will require investigator to provide account ID and password, 
after successfully signed, system will record the date and time of signature. Investigator is not 
allowed to share their account and password with others. For all data modification, EDC will 
have a specific process and requirement to tracking all audit trail. 
9.3 Site Monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, sponsor personnel 
(or designated CRO) will review the protocol and study procedures with the investigators and 
other site staff. During the study, the 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 and GCP, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, prepared and accounted according to the instructions. Key study personnel must be 
available to assist the monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinical medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 


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assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Full verification for the presence of informed consent, 
adherence to the inclusion/exclusion criteria and documentation of SAEs are required. 
Additional checks of the consistency of the source data with the eCRFs are performed according 
to the study-specific monitoring plan.  
9.4 Data Quality Management 
To ensure the data quality, sponsor or designated CRO may take below actions during the study: 
• 
Provide protocol related information if needed 
• 
Provide training to site personnel including but not limited to protocol, EDC entering 
guidance.etc 
• 
Perform site monitoring regularly 
• 
Keep close contact with site personnel via emal or phone to solve protocol problems 
• 
Perform data review to ensure there is no data discrepancy 
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. 
 


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10 Statistical analysis 
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) consists of all subjects who have received at least one dose of study 
treatment and had at least one valid post-baseline safety assessment. 
• 
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. 
• 
Dose determining set (DDS) consists of all subjects who have received at least 80% of the 
total planned dose of GFH018, are considered to have sufficient safety evaluation during 
the 31-day-observation period or developed DLT during the first cycle. 
10.2  Analysis method 
10.2.1 Demographic and baseline characteristics 
Descriptive statistical analysis will be used to summarize demographic and baseline 
characteristics, including age, sex, height, weight, and ECOG performance status scores based 
on FAS. 
10.2.2 Primary endpoints 
The primary objective of this study is to evaluate the safety and tolerability of GFH018, no 
hypothesis testing will be performed. 
10.2.2.1 Safety analysis 
Safety analysis will be based on the SS. 
• 
DLT 
DLT will be summarized for each dose group and a by-subject listing of DLT will be provided. 
• 
AEs 
All AEs will be graded according to CTCAE version 5.0 and be coded using MedDRA. All 
post-treatment AEs/SAEs, grade≥3 AEs, treatment-related AEs/SAEs, AEs leading to study 
drug discontinuation, AEs leading to study drug interruption, DLT, and AESIs will be 
summarized by system organ class, preferred term, and dose levels. 


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• 
Laboratory tests 
Vital signs, physical examination, laboratory tests, and 12-lead ECG will be summarized by 
time point. 
10.2.2.2 Tolerability 
The proportion of subjects who experienced dose reduction, dose interruption, and dose 
discontinuation will be summarized. 
10.2.3 Secondary endpoints 
10.2.3.1 Pharmacokinetic analysis 
Pharmacokinetic analysis will be based on the PKAS. 
Concentration-time data will be summarized by dose group, while descriptive statistical 
analysis will be performed at each planned time point. Individual and average concentration-
time curves will be provided for each dose group. 
The calculation method of PK parameters is described in Section 6.2.4. 
Summary statistics of pharmacokinetic parameters for each GFH018 dose group are presented 
in tabular form.  Provides geometric mean and coefficient of variation, maximum, median, 
minimum, and arithmetic mean and standard deviation for each PK parameter (except Tmax). 
ForTmax, the median, maximum, and minimum values are provided.  
The power function model was used to test whether PK changed proportionally between doses. 
10.2.3.2 Efficacy analysis 
The disease assessments will be evaluated according to RECIST 1.1. 
Best overall response (BOR), ORR, and DCR will be summarized with corresponding 90% 
confidence intervals for each dose level. A waterfall plot will be used to show the best change 
from baseline in tumor size. A by-subject listing of DOR, PFS, and TTP will be provided. 
The efficacy analysis will be based on the FAS. 
10.2.3.3 Pharmacodynamic markers 
For pharmacodynamic markers, changes (or percentage changes) from baseline will be 
summarized by time points.  


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10.3  Sample size 
For dose-escalation part, 3 to 6 subjects are planned to be enrolled in each dose level, a total of 
20 to 40 subjects are planned. Additional subjects may be enrolled if more dose levels or 
alternative dosing regimens are to be explored. 
For dose expansion part, 6 to 12 subjects are planned to be enrolled in each group. A minimum 
of 12 subjects are required for RP2D group (subjects who received RP2D treatment from dose 
escalation part are counted). For an adverse event with an incidence of 10%, the probability of 
observing at least 1 adverse event in 12 subjects is 72%.  
 


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11 Ethics 
11.1 Institutional Review Board/ Independent Ethics Committee 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted IRB/IEC before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all the instructions and procedures found in this protocol 
and to give access to all relevant data and records to the sponsor or designated CRO monitors, 
auditors, the sponsor or designated CRO clinical quality assurance representatives, 
IRBs/IECs/REBs and regulatory authorities as required. 
11.2 Ethical Conduct of the Study 
This clinical study was designed, shall be implemented, and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations, and with the ethical principles laid down in the Declaration of Helsinki. 
The protocol and the proposed informed consent form must be reviewed and approved by 
IRB/IEC before study start. The study can only be conducted after it has been approved by 
related regulatory authorities and IRB/IEC. The sponsors and investigator must not amend this 
study protocol unilaterally without mutual agreement. The amended protocol cannot be 
conducted until being approved by the IRB/IEC. When investigator must change or deviate 
from the study protocol to eliminate the direct and immediate hazards to subjects, they must 
notify the IRB/IEC and sponsors in writing to explain and record all the deviations as soon as 
possible.  
During the clinical study, any amendment made to the study protocol should be submitted to 
the IRB/IEC and Regulatory Authorities, and corresponding amendment to other documents 
can also be made when necessary, then be submitted and/or approved as required by the ethics 
committee and Regulatory Authorities. Investigators are responsible for periodic submission of 
the interim report to the IRB/EC in accordance with relevant requirements and should inform 
the ethics committee when the trial is completed. 


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11.3 Patient Information and Consent 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. Informed consent must 
be obtained before conducting any study-specific procedures (i.e., all the procedures described 
in the protocol). The process of obtaining informed consent should be documented in the patient 
source documents. The date when a patient’s Informed Consent was obtained will be captured 
in eCRFs. 
The sponsor will provide to the investigator, in a separate document, a proposed ICF that is 
considered appropriate for this study and complies with the ICH GCP guideline and regulatory 
requirements. Any changes to this ICF suggested by the investigator must be agreed to by the 
sponsor before submission to the IRB/IEC, and a copy of the approved version must be provided 
to the sponsor monitor after IRB/IEC approval. 
WOCBP should be informed that taking the study medication may involve unknown risks to 
the fetus if pregnancy were to occur during the study and agree that in order to participate in 
the study, they must adhere to the contraception requirement for the duration of the study. If 
there is any question that the patient will not reliably comply, they should not be entered in the 
study. 
11.4 Confidentiality of Patient’s Information 
The investigator must ensure anonymity of the subjects; subjects must not be identified by 
names in any documents submitted to the sponsor or the designated CRO. Signed informed 
consent forms and patient enrollment log must be kept strictly confidential to enable patient 
identification at the site. 
11.5 Inspection 
The sponsor or regulatory authority may inspect and inspect the study during or after the study. 
12 Publication of Study Results 
The sponsor assures that the key design elements of this protocol will be posted in publicly 
accessible databases such as https://euclinicaltrials.eu. In addition, upon study completion and 


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finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.  
If the investigator intends to publish any study-related data and information, they should obtain 
the approval of the sponsor, and provide the manuscript, abstract or full text of all planned 
publications (poster, speech, or lecture) to the sponsor at least 30 days prior to the submission 
of the documents or materials in other forms. 
 


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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. 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. 
4. Peng L, Yuan XQ, Zhang CY, et al. High TGF-β1 expression predicts poor disease 
prognosis in hepatocellular carcinoma subjects. Oncotarget 2017; 8: 34387-34397. 
5. 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. 
6. Xia X, Wu WD, Huang C, et al. SMAD4 and its role in pancreatic cancer. Tumor 
Biol 2015; 36:111-119. 
7. Sanjeev M, Shannon JT, Dorothee N, et al. TGF-β attenuates tumour response to 
PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554: 544–
548. 
8. Gueorguieva I, Cleverly AL, Stauber A, et al. Defining a therapeutic window for 
the 
novel 
TGF-β 
inhibitor 
LY2157299 
monohydrate 
based 
on 
a 
pharmacokinetic/pharmacodynamic model. Br J Clin Pharmacol 2014;77:796-807. 
9. Anderton MJ, Mellor HR, Bell A, et al. Induction of heart valve lesions by small-
molecule ALK5 inhibitors. Toxicol Pathol 2011; 39:916-924. 
10. Rodon J, Carducci MA, Sepulveda-Sánchez JM, et al. First-in-human dose study 
of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 
monohydrate in subjects with advanced cancer and glioma. Clin Cancer Res 2015; 
21: 553-60. 
11. Herbertz S, Sawyer JS, Stauber AJ, et al. Clinical development of galunisertib 
(LY2157299 monohydrate), a small molecule inhibitor of transforming growth 


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factor-beta signaling pathway. Drug Des Devel Ther 2015; 9:4479-4499. 
12. Kovacs RJ, Maldonado G, Azaro A, et al. Cardiac Safety of TGF-β Receptor I 
Kinase Inhibitor LY2157299 Monohydrate in Cancer Subjects in a First-in-Human 
Dose Study. Cardiovasc Toxicol 2015;15:309-323. 
 
 
 
 
 
 
Appendix 1 Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) 
(E.A. Eisenhauer, P. Therasse, J. Bogaerts, et al. New response evaluation criteria in 
solid tumors: 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). 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 
20 mm by chest X-ray. 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed.  


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Non-measurable lesions 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement 
of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques. 
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. However, 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. 


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1.2 Specifications by methods of measurements 
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 ≥ 10 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.  
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. 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).  
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. 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 


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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. 
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 remain). 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. 
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 


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more new lesions is also considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor enough 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 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 can provide an actual measure, that should 
be recorded, even if it is below 5 mm. 


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Lesions that split or coalesce on treatment. 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. A modest ‘increase’ in the size of one or 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 


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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 subjects 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’. 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. 
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 


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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 is 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-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 


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overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that subjects 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. 
Subjects 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 subjects is to be determined by 
evaluation of target and non-target disease as shown in Tab 1. 
Conditions that define ‘early progression, early death and in evaluability’ 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 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. 


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Tab 1 Time point response: subjects 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 
Note: CR = complete response, PR = partial response, SD = stable disease, PD = 
progressive disease, and NE = inevaluable 
Tab 2 Time point response: subjects 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 
Note: 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. 


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Tab 3 Best overall response when confirmation of CR and PR required. 
Overall response 
First time point 
Overall response 
Subsequent time point 
Best overall response 
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 
Note: 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 


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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 
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). 


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The clinical relevance of the duration of stable disease varies in different studies and 
diseases. If the proportion of subjects 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 
consider many parameters including disease types and stages, treatment periodicity and 
standard practice. However, these limitations of the precision of the measured endpoint 
should be considered 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 subjects to have measurable lesions, the evaluation of progression is 
relatively simple. More and more studies allow subjects with measurable lesions and 
non- measurable lesions to enter the study. In this situation, the clinical findings of 
disease progression in subjects 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. 
 


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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. 
 

SAP_001.pdf: 
Genfleet Therapeutics 
SAP 
Protocol Number: GFH018X1101 
    Version 1.0 
 
1 
 
 
 
 
 
 
A Phase I Study to Evaluate the Safety/Tolerability and Pharmacokinetics of 
GFH018 with Single/Multiple Ascending Dose Patients with Advanced Solid 
Tumors 
 
GFH018X1101 
 
 
S tatisicial Analysis Plan 
 
 
 
Version: 1.0 
August-31-2022 
 
 
 
 


Genfleet Therapeutics 
SAP 
Protocol Number: GFH018X1101 
    Version 1.0 
 
2 
 
 
CONTENTS 
 
ABBREVIATIONS LIST ........................................................................................ 4 
1. 
INTRODUCTION ........................................................................................... 7 
2. 
STUDY OBJECTIVES ................................................................................... 7 
3. 
OVERALL STUDY DESIGN ........................................................................ 7 
4. 
STUDY ENDPOINTS ................................................................................... 10 
4.1. 
Safety Variables .......................................................................................................... 10 
4.1.1. Adverse Events ........................................................................................................ 10 
4.1.2. Laboratory Tests ..................................................................................................... 11 
4.1.3. Electrocardiogram (ECG) ...................................................................................... 11 
4.1.4. Echocardiography ................................................................................................... 11 
4.1.5. Physical Examination ............................................................................................. 12 
4.1.6. Vital Signs ................................................................................................................ 12 
4.1.7. Eastern Cooperative Oncology Group (ECOG) Performance Status ............... 12 
4.2. 
Efficacy Variables ...................................................................................................... 12 
4.3. 
Pharmacodynamic Biomarkers ................................................................................ 13 
4.4. 
Pharmacokinetic Parameters .................................................................................... 13 
5. 
STATISTICAL HYPOTHESIS ................................................................... 13 
6. 
SAMPLE SIZE .............................................................................................. 13 
7. 
ANALYSIS DATASETS ............................................................................... 13 
7.1. 
Screening Set ............................................................................................................... 13 
7.2. 
Full Analysis Set (FAS) .............................................................................................. 13 
7.3. 
Safety Set (SS） .......................................................................................................... 13 
7.4. 
Phamacokinetic Analysis Set (PKAS) ...................................................................... 14 
7.5. 
Dose-determining Set (DDS) ..................................................................................... 14 
7.6. 
Protocol Deviation ...................................................................................................... 14 
8. 
STATISTICAL METHOD ........................................................................... 14 
8.1. 
General Statistical Consideration ............................................................................. 14 
8.2. 
Subjects in Study ........................................................................................................ 15 


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8.2.1. Subjects Dispostion ................................................................................................. 15 
8.2.2. Protocol Deviation ................................................................................................... 15 
8.2.3. Demographics and Baseline Characteristics ........................................................ 15 
8.2.4. Medical History/Current Medical Conditions ..................................................... 16 
8.2.5. Prior Anti-Tumor Therapy .................................................................................... 16 
8.2.6. Prior and Concomitant Medications and Surgeries/Procedures ........................ 16 
8.3. 
Treatment Compliance and Exposure...................................................................... 17 
8.4. 
Safety Analysis ............................................................................................................ 18 
8.4.1. Adverse Events ........................................................................................................ 18 
8.4.2. Laboratory Evaluations ......................................................................................... 19 
8.4.3. Vital Signs ................................................................................................................ 19 
8.4.4. 12-Lead Electrocardiogram ................................................................................... 20 
8.4.5. Physical Examination ............................................................................................. 21 
8.4.6. ECOG Score ............................................................................................................ 21 
8.4.7. Echocardiography ................................................................................................... 21 
8.5. 
Efficacy Analysis ........................................................................................................ 21 
8.6. 
Pharmacokinetic Analysis ......................................................................................... 22 
8.7. 
Pharmacodynamic Analysis ...................................................................................... 22 
9. 
INTERIM ANALYSIS .................................................................................. 22 
10. REFERENCES .............................................................................................. 22 
11. ATTACHMENT ............................................................................................ 22 
12. APPENDIX I .................................................................................................. 22 


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Abbreviations List 
Abbreviations 
Definition / Expansion 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AST 
Aspertate Aminotransferase 
AUC 
Area Under the Concentration-Time Curve 
AUC(0-t) 
Area Under the Curve (0-t hour) 
BOR 
Best of Response 
CRF 
Case Report Form 
Cmax 
maximum concentration 
CL 
Clearance 
CR 
Complete response 
d，D 
day 
DCR 
Disease Control Rate 
DLT 
Dose Limited Toxiciyy 
DOR 
Duration of Response 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 


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Abbreviations 
Definition / Expansion 
h 
Hour 
ICH 
International Conference on Harmonization 
kg 
Kilogram 
L 
liter 
LLN 
Low Limit of Normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
OR 
Objective Response 
ORR 
Objective Response Rate 
PD 
Pharmacodynamics 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PS 
Physical performance 
PR 
Partial Response 
RP2D 
Recommended phase 2 dose 
SAE 
Severe Adverse Event 


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Abbreviations 
Definition / Expansion 
SAP 
Satistical Analysis Plan 
SD 
Stable Disease 
T1/2 
half-time 
TEAE 
Treatment-emergent Adverse Event 
Tmax 
Time to maximum concentration 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 


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1. 
INTRODUCTION 
 The analyses described in this SAP are based upon the following study documents: 
 
Study Protocol, Version 1.6 (February 26, 2021) 
 
electronic Case Report Form, Version 6.0 (October 14, 2021) 
 
2. 
STUDY OBJECTIVES 
Primary Objectives 
 
To evaluate the safety and tolerability of single/multiple administration of GFH018 in 
patients with advanced solid tumors 
 
Determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) 
of GFH018 
Secondary Objectives 
 
To evaluate the pharmacokinetic characteristics of GFH018 after single/multiple 
administration in patients with advanced solid tumors 
 
To evaluate the preliminary efficacy of GFH018 in patients with advanced solid tumors 
 
To evaluate the expression level of TGF-β in the peripheral blood of patients with different 
solid tumors, and analyze whether it is related to the clinical response of subjects to GFH018 
Exploratory Objectives 
 
 Evaluate possible blood pharmacodynamic markers 
3. 
OVERALL STUDY DESIGN 
This is the first-in-human trial of GFH018, using an open-label, non-randomized, single/multi-
dose dosing design to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-
tumor efficacy of GFH018 in subjects with advanced solid tumors.  
This study is divided into two parts: a dose-escalation part aimed at determining MTD and/or RDE 
followed by a dose expansion part to confirm the safety of RDE and RP2D and explore the 
preliminary efficacy of GFH018 in the potentially benefited population. The RDE will be 
determined for exploration in expansion. Different dosing regimens will be explored, RDE dose 
and optimal dosing regimen will be further confirmed, and RP2D will be obtained. Both parts were 
divided into three periods: screening, treatment, and follow-up.  
Part I Dose Escalation 
The study schema is shown in Figure1 (14-day on/14-day off regimen). 


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Fig 1 Study Schema (Dose Escalation Part) 
This part is a safety, tolerability, and pharmacokinetic study with a modified 3+3 design to 
determine MTD and/or RDE. According to preclinical data, the starting dose is selected as 10 
mg/day (5 mg administered twice daily). In the first cycle, each group of subjects is given a single 
dose (5 mg as the starting dose) on day 1 and taken serial PK sampling. After the first dose on day 
1, serial PK blood samples will be collected up to 72 h post-dose to obtain the complete PK profile 
of a single dose (the collection point design may be modified based on preliminary PK results). 
Subjects will be administered with GFH018 BID, 14d-on/14d-off from day 4. Four to six dose 
levels are planned (refer to Table 1). The first cycle is defined as 31 days, and subsequent cycles 
are all defined as 28 days. After the last dose of cycle 1 (day 17), serial PK blood samples will be 
collected to obtain PK characteristics at steady state. Starting from the third dose level, urine 
samples from steady state will also be collected for PK studies to fully understand GFH018 PK 
characteristics.  
Table 1 Dose escalation regimen (provisional dose level) 
Dose level 
Regimen 
Incremental 
percentage (%) 
1 
5 mg bid, 14-d on/14-d off 
- 
2 
10 mg bid, 14-d on/14-d off 
100 
3 
20 mg bid, 14-d on/14-d off 
100 
4 
30 mg bid, 14-d on/14-d off 
50 
5 
40 mg bid, 14-d on/14-d off 
33 
6 
50 mg bid, 14-d on/14-d off 
25 
During the study, a Safety Monitoring Committee (SMC) composed of principal investigators, 
representatives of contract research organizations (CROs) and sponsor representatives will be 
established to review the safety data generated in the study, mainly including Dose Limiting 
Toxicity (DLTs) and all other grade 2 and above adverse events per CTCAE v5.0, as well as 
pharmacokinetic and pharmacodynamic data, to determine whether to escalate to the next dose 
level. For a more specific dose escalation decision process and definition of DLT, see Section 5.4 
of Protocol V1.6, "Study Drug Dose Escalation Methods".  


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The MTD is defined as the highest dose ≤ 1/3 of the incidence of DLT. Once the MTD is reached, 
the dose will not be escalated under this dosing regimen (even if not all planned dose groups have 
been completed), and the SMC will review and decide whether to explore alternative dosing 
regimens, such as 7d-on/7d-off, or daily or other dose regimens (if the total daily dose is higher 
than or equal to the MTD within 28 days, the dose level needs to be lowered for daily or other 
dosing regimen exploration); On the other hand, if the MTD is not reached by escalating to the 
current highest dose level, the SMC will comprehensively evaluate all the data obtained to decide 
whether to proceed with a higher dose level exploration, such as 65 mg BID, 85 mg BID, etc.    
The RDE will be determined by SMC based on comprehensive data such as safety and tolerability, 
PK, pharmacodynamics, and preliminary antitumor efficacy obtained during the dose escalation 
part. 
At the end of the dose escalation, at least six evaluable subjects in the MTD/RDE group should be 
ensured.  
Part II Dose Expansion  
The primary objective of this part is to confirm the safety of RDE dose and explore different dose 
regimens to ultimately determine RP2D. The secondary objective is to initially explore the efficacy 
in potentially benefited populations. 
The 14d-on/14d-off and 7d-on/7d-off dose regimens under RDE dose will be explored based on 
the data from the dose escalation part, while the SMC will review the safety, PK, and biomarker 
data then decide whether to also explore other dose regimens at RDE, such as daily dosing. This 
part will further confirm the safety of RDE dose and optimal dose regimen and obtain RP2D. At 
least 12 subjects (including subjects receiving the same dose during the dose escalation part) are 
required to be enrolled to determine the final RP2D.  
Potential benefited tumor types will be selected for dose expansion part based on the mechanism 
of action of the drug and preliminary efficacy data in dose escalation part, including hepatocellular 
carcinoma, cholangiocarcinoma/gallbladder cancer, colorectal cancer, urothelial cancer, 
pancreatic, cervical, head and neck squamous cell or esophageal cancer, and nasopharyngeal 
carcinoma.  


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4. 
STUDY ENDPOINTS 
4.1. 
Safety Variables 
4.1.1. Adverse Events 
Adverse events (AEs) 
The definition of AEs can be found in the section 8.1 of protocol. AEs should be collected from 
the time of informed consent through follow-up. The follow-up period was 30 days (± 3 days) after 
discontinuation of study treatment. SAEs occurring during the follow-up period should be reported 
to the sponsor by routine methods.   
Treatment emergent adverse events (TEAEs) 
TEAEs are defined as adverse events that worsened or occurred following the first dose date of 
study treatment and within 30 days of the last treatment. If missing dates or time prevent a clear 
determination as to whether AE is treatment emergent, the adverse event will be regarded TEAE. 
Treatment related adverse events 
Treatment related AEs are defined as TEAEs definitely related, possibly related to study treatment, 
and the relationship unable to determine.  
Serious adverse events (SAEs) 
The definition of AEs can be found in the section 8.2 of protocol. 
Treatment related SAEs 
Treatment related SAEs are defined as SAEs definitely related, possibly related to study treatment, 
and the relationship unable to determine.  
Adverse event of special interest (AESI) 
According to the toxicological results of GFH018, ASEIs include elevated cardiac biomarkers 
BNP or troponin, and abnormal cardiac ultrasound. 
Adverse events leading to interruption of study treatment 
Adverse events leading to dose reduction of study treatment 
Adverse events leading to discontinuation of study treatment 
Severity of adverse events 
Severity of all AEs will be graded according to CTCAE v5.0 with grade 1 to 5. 


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4.1.2. Laboratory Tests 
Please see Table 2 for the laboratory tests parameters. 
Table 2 Laboratory tests parameters 
Laboratory tests 
Parameters  
Hematology 
Red blood cell count (RBC), hemoglobin concentration (HGB), hematocrit (HCT), mean 
red blood cell volume (MCV), mean red blood cell hemoglobin content (MCH), mean red 
blood cell hemoglobin concentration (MCHC), white blood cell count (WBC), platelet 
count (PLT), neutrophil count (ANC), lymphocyte (LY) count, monocytes (MO) count, 
eosinophil (EO) count, Basophil (BA) count, percentage neutrophils, percentage 
lymphocytes, percentage monocytes, percentage eosinophils, percentage basophils 
Urinalysis 
Urine leukocytes (LEU), urine nitrite (NIT), urine pH, urine specific gravity (SG), urine 
protein (PRO), urine glucose (GLU), urine ketone bodies (KET), urine bilinogen (UBG), 
urine bilirubin (BIL), urine occult blood (BLD), 24-hour protein* 
Coagulation 
function 
Prothrombin time (PT), activated partial thromboplastin time (APTT), international 
normalized ratio (INR) 
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), white globular 
ratio (A/G ratio), total bilirubin (TBIL), direct bilirubin (DBIL), creatine kinase (CK), 
pancreatic amylase (AMY), fasting blood glucose (FPG), total cholesterol (TCHO), low-
density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), 
triglycerides (TG), bicarbonate, phosphate, calcium, sodium, chloride, potassium 
Virus testing 
Hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), HIV 
antibody, treponemal antibody 
Thyroid function 
tests 
Free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone 
(TSH). 
Cardiac markers 
Hypertroponin T (or Hypertroponin I), brain natriuretic peptide (BNP), hs-CRP, cysteine 
protease inhibitor (Cystatin C) 
Pregnancy test 
Serum β-HCG pregnancy test (blood pregnancy test in women of childbearing age) 
* For routine urinalysis, if the result of the fibrine test strip for urine protein is ≥2+, a 24-hour 
urine sample should be collected for analysis. 
4.1.3. Electrocardiogram (ECG) 
ECG includes hearts rate, PR, QRS, QT, QTcF, and the clinical interpretation.  
4.1.4. Echocardiography 
Include left ventricular ejection fraction, heart valve function, and clinical interpretation. 


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4.1.5. Physical Examination  
Physical examination includes General condition, skin condition, head/neck, lungs, cardiovascular, 
liver, kidneys, gastrointestinal, lymphatic system, musculoskeletal system, limbs, larynx; and 
weight. 
4.1.6. Vital Signs 
Vital signs include temperature, blood pressure, heart rate, and respiratory rate.      
4.1.7. Eastern Cooperative Oncology Group (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. 
 
4.2. 
Efficacy Variables 
The clinical efficacy will be evaluated by investigator per RECIST (Response Evaluation Criteria 
in Solid Tumors) 1.1. The efficacy variables including:  
• 
Best overall response (BOR) is defined as the best overall response recorded from the start of 
treatment until disease progression or the last tumor assessment, whichever occurs earlier.  
• 
Overall response rate (ORR) is defined as the proportion of subjects with BOR of complete 
response (CR) or partial response (PR).  
• 
Disease control rate (DCR) is defined as the proportion of subjects with a BOR of CR, PR, or 
stable disease (SD).  
• 
Duration of response (DOR) is defined as the time from first evidence of CR or PR to disease 
progression or death from any cause, whichever occurs first. 


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• 
Progression free survival (PFS) is defined as the time from start of study treatment until 
disease progression or death from any cause, whichever occurs first. 
• 
Time to progression (TTP) is defined as the time from start of study treatment until disease 
progression. 
4.3. 
Pharmacodynamic Biomarkers 
Pharmacodynamic biomarkers includes TGF-β and pSMAD2/3. 
4.4. 
Pharmacokinetic Parameters 
Single-dose paremeters include: Cmax， Tmax， AUC0-12h， AUC0-24h， AUC0-inf， T1/2， 
CL/F，Vd/F. Steady-state parameters include: Cmax,ss ， Cmin,ss ， Tmax,ss ，AUCtau， T1/2， CL/F， 
Vd/F，CLr， Racc. 
5. 
STATISTICAL HYPOTHESIS 
No statistical hypothesis will be tested in this study. 
6. 
SAMPLE SIZE 
Dose escalation part: 
Subjects will be enrolled and treated in cohort of size 3-6. Approximately 20-40 subjects are 
planned to be enrolled. Additional subjects may be enrolled if more dose levels or alternative 
dosing regimens are to be explored. 
Dose expansion part: 
6-12 subjects are planned to be enrolled in each treatment. A minimum of 12 subjects should be 
included in the cohort of RP2D (subjects who have received the same treatment regimen will be 
counted). 
7. 
ANALYSIS DATASETS 
7.1. 
Screening Set 
Screening set: consists of subjects who signed the informed consent. 
7.2. 
Full Analysis Set (FAS) 
FAS: consists of all subjects who have received at least one dose of study treatment. 
7.3. 
Safety Set (SS） 
SS: consists of all subjects who have received at least one dose of study treatment and had at least 
one valid post-baseline safety assessment. 


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7.4. 
Phamacokinetic Analysis Set (PKAS) 
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. 
7.5. 
Dose-determining Set (DDS) 
DDS: consists of all subjects who have received at least 80% of the total planned dose of 
GFH018, are considered to have sufficient safety evaluation during the 31-day-observation 
period or developed DLT during the first cycle. 
 
7.6. 
Protocol Deviation  
Protocol deviations will be defined on a Data Review Meeting  prior to the final database lock. 
8. 
STATISTICAL METHOD 
8.1. 
General Statistical Consideration 
The statistical analysis plan be finalized prior to data base lock. All analyses and data presentations 
will be generated using SAS® Version 9.4 or higher software 
Descriptive summary 
Continuous variables: Descriptive statistics will include the number of non-missing values (n), 
arithmetic mean, standard deviation (SD), median, minimum and maximum values.  
The minimum and maximum values will be displayed to the same decimal precision as the 
source data, the arithmetic mean and median values will be displayed to one more decimal than 
the source data, and the SD value will be displayed to two more decimals than the source data for 
the specific variable. 
Categorical variables: Descriptive statistics will include counts and percentages per category. 
The denominator in all percentage calculations will be the number of participants in the relevant 
analysis set, unless otherwise specified. Percentages will be displayed to one decimal place with 
the following exceptions: 1) percentages will not be displayed for zero frequencies; 2) 
percentages will be displayed as “100%” when percentage is 100%. 
ORR and DCR will be calculated, the corresponding two-sided 90% confidence intervals will be 
estimated by the Clopper-Pearson method. 
Baseline 
Baseline is defined as the last non-missing measurement collected on or before first study drug 
administration. For ECGs, the average of the ECG parameters should be used. 
Censor rule  


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Table 3 below shows the censor rule for PFS： 
Table 3 Censor rule for PFS 
No. 
Situation 
Event or Censor / Analyais date 
1 
PD or death 
Event / PD date or death date 
2 
Have at least one post-baseline 
assessment, no PD, no Death 
Censor / Last imaging date 
3 
No post-baseline assessment and no 
Death 
Censo r/ First dosing date 
Only subjects with the BOR of CR or PR will be included for DOR analysis. DOR will 
apply the same consor rule as PFS. 
Best overall response (BOR) is the best measured response at any time post treatment. Subject 
without any post-treatment assessments will be treated as non-responder. 
8.2. 
Subjects in Study 
8.2.1. Subjects Dispostion 
From screening to study completion, the following summaries will be provided: 
• Summary of the number of patients who screen success for entry into the study and screen 
failure, respectively, and the number of subjects treated with at least 1 dose of GFH018 (All 
enrolled population) 
• Summary of the number and percentage of treatment withdraws by primary reason and overall 
(full analysis set) and the number and percentage of study discontinuation by primary reason and 
overall (full analysis set). 
A by-subject listing of reasons for screen failure reason(s), treatment discontinuation, study 
discontinuation with date and reasons for discontinuation. 
8.2.2. Protocol Deviation 
Deviations will be defined on a Data Review Meeting shortly prior to the final database lock. 
The major protocol deviation will be summarized in the number and percentage of subjects with a 
major protocol deviation by type of deviation based on the FAS.  
Additionally, major protocol deviations will be provided in a data listing. 
8.2.3. Demographics and Baseline Characteristics 
The following demographics and baseline characters will be summarized based on FAS: 
• 
Age (years) at baseline 


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• 
Sex 
• 
Race  
• 
Height (cm)  
• 
Weight (kg) at baseline 
• 
BMI (kg/m2) at baseline 
• 
ECOG Performance Status 
• 
Smoking history  
• 
Alcohol history 
The following baseline characters of Tumor Diagnosis will be summarized: 
• 
Disease diagnosis  
• 
Primary site of cancer 
• 
Time from initial diagnosis to start of study treatment  
• 
TMN stage at screening 
• 
Disease stage  
• 
Any metastatic sites 
8.2.4. Medical History/Current Medical Conditions 
Medical history and current medical conditions will be coded by using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 25.0. Medical history is the medical condition ended 
before the first dose date of study drug and the current medical condition is the medical condition 
ended on or after the first dose date of study drug.. For the FAS, medical history and current 
medical conditions will be summarized descriptively by System Organ Class (SOC) and Preferred 
Term (PT). The corresponding data listing will also be provided. 
8.2.5. Prior Anti-Tumor Therapy 
Prior anti-tumor drug therapies will be coded using World Health Organization Drug Dictionary 
(WHO DD) version 202203 B3. 
Based on the FAS, prior anti-tumor therapies will be summarized, and prior anti-cancer drug 
therapies will be summarized by Anatomical Therapeutic Chemical (ATC) Grade 4 and Preferred 
Term (PT). 
Based on the FAS, a detailed listing of prior anti-tumor therapies will be provided. 
8.2.6. Prior and Concomitant Medications and Surgeries/Procedures 
Prior and concomitant medications will be coded using World Health Organization Drug 
Dictionary (WHO DD) version 202203 B3. Prior and concomitant surgeries and procedures will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 25.0. 
Prior and concomitant medications 


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Prior medications include non-study medications that started and ended prior to the first dose of 
study medication. Concomitant medications include non-study medications with start date on or 
after the date of the first dose of study medication and no later than 30 days after the last dose of 
study medication. Medications will be considered both prior and concomitant if the start date of 
the medication is prior to the first dose of study medication and the end date is on or after the first 
dose of study medication. 
If the start date and/or end date of a non-study medication is missing or partially missing, the non-
complete date should be compared to the first dose date of study medication whenever possible. 
Non-study medication will be considered as concomitant medication unless there is clear evidence 
that the start date of the non-study medication is earlier than the first dose date of study medication. 
If there is clear evidence that the start date of the non-study medication is earlier than the first dose 
date of study medication, the non-study medication will be considered both prior and concomitant 
unless there is clear evidence that the end date is earlier than the first dose date of study medication. 
If there is clear evidence that the end date of the non-study medication is earlier than the first dose 
date of study medication, then the non-study medication will be considered as prior medication. 
Prior and concomitant medications will be summarized by Anatomic Therapeutic Chemical (ATC) 
Grade 4 and Preferred Term (PT) and listed in detail for subjects in the FAS. 
Prior and concomitant surgeries/procedures 
Prior surgeries/procedures include surgeries/procedures (that are not prior anti-cancer therapies) 
with both start and end dates prior to the first dose date of study drug. Concomitant 
surgeries/procedures included surgeries/procedures with start date on or after the first dose date of 
study medication and no later than 30 days after the last dose date of study medication. If the start 
date of a surgery/procedure is before the first dose date of study medication and the end date is on 
or after the first dose date of study medication, then it will be considered both prior and 
concomitant. If the start date and/or end date are missing or partially missing, the criteria for 
judging whether a surgery/procedure is prior or concomitant are the same as for prior and 
concomitant medications. 
Prior and concomitant surgeries/procedures will be summarized by SOC and PT for subjects in the 
FAS and listed in detail. 
8.3. 
Treatment Compliance and Exposure 
Investigate the exposure of study treatment and calculate the duration and amount of exposure, as 
well as dose intensity, of the study treatment GFH018 for subjects in each dose group. 
Duration of exposure 
Duration of exposure (days) = last dose date– first dose date + 1 
Actual dose intensity 
Actual dose intensity (mg/day) = actual total cumulative dose (mg) / actual cumulative days with 
treatment administered (days) 


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Treatment compliance 
Planned cumulative dose: total planned dose before the decision of treatment discontinuation. 
Actual cumulative dose: total actual dose before the decision of treatment discontinuation. 
Treatment compliance (%) = actual cumulative dose / planned cumulative dose × 100% 
Summarize actual total cumulative dose (mg), duration of exposure (days), actual dose intensity 
(mg/day), and treatment compliance (%) for subjects in the SS, and summarize treatment 
interruptions. Categorize treatment compliance by < 80%, 80% to 120%, and > 120%, and 
summarize the number and percentage of subjects under each category. List in detail subjects' first 
and last dose dates, duration of exposure, treatment adjustments, and reasons for the adjustments. 
8.4. 
Safety Analysis 
All safety analyses will be based on the safety set (SS), except for the DLT analysis which will be 
based on the dose-determining set (DDS). Baseline definition for safety analyses are provided in 
Section 8.1. 
8.4.1. Adverse Events 
Adverse events (AEs) will be coded using MedDRA version 25.0 . 
AE summary tables will include only TEAEs, while listings will include all AEs; AE incidence 
will be calculated based on the number of subjects with adverse events, and when a subject 
experiences multiple occurrences of the same AE under the same SOC and PT, the occurrence 
with the most severe grade will be counted. The following summaries and listings will be provided 
for AEs: 
 Summarize the number and percentage of subjects with TEAEs, TEAEs with CTCAE 
Grade ≥ 3, treatment-related adverse events (TRAEs), TRAEs with CTCAE Grade ≥ 3, 
serious adverse events (SAEs), treatment-related serious adverse events (TRSAEs), AESI , 
DLT, TEAEs leading to treatment interruption, TRAEs leading to treatment interruption, 
TEAEs leading to dose reduction, TRAEs leading to dose reduction, TEAEs leading to 
treatment discontinuation, and TRAEs leading to treatment discontinuation. 
 Summary of TEAEs by SOC, PT, and CTCAE Grade 
 Summary of TRAEs by SOC, PT, and CTCAE Grade 
 Summary of SAEs by SOC, PT, and CTCAE Grade 
 Summary of TRSAEs by SOC, PT, and CTCAE Grade 
 Summary of AESIs by SOC, PT, and CTCAE Grade 
 Summary of TEAEs of Grade 3 or Higher by SOC, PT, and CTCAE Grade 
 Summary of TRAEs of Grade 3 or Higher by SOC, PT, and CTCAE Grade 
 Summary of DLTs by SOC, PT, and CTCAE Grade 
 Summary of TEAEs leading to treatment interruption by SOC, PT, and CTCAE Grade 
 Summary of TRAEs leading to treatment interruption by SOC, PT, and CTCAE Grade 
 Summary of TEAEs leading to dose reduction by SOC, PT, and CTCAE Grade 


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 Summary of TRAEs leading to dose reduction by SOC, PT, and CTCAE Grade 
 Summary of TEAEs leading to treatment discontinuation by SOC, PT, and CTCAE Grade 
 Summary of TRAEs leading to treatment discontinuation by SOC, PT, and CTCAE Grade 
 Summary of TEAEs by PT and CTCAE Grade, ordered in descending frequency 
 Summary of TRAEs by PT and CTCAE Grade, ordered in descending frequency 
 Summary of cause of death  
 Listing of adverse events  
 Listing of SAEs 
 Listing of AESIs 
 Listing of DLTs 
 Listing of TEAEs leading to treatment interruption 
 Listing of TEAEs leading to treatment discontinuation 
 Listing of deaths 
8.4.2. Laboratory Evaluations 
By-visit descriptive summary will be provided for hematology, blood biochemistry, urinalysis 
(quantitative measurements), coagulation, thyroid function, and their changes from baseline. 
For hematology, blood biochemistry, coagulation, and cardiac markers, changes in CTCAE grade 
from baseline (Grade 0 to 4, where Grade 0 is non-missing value other than Grade 1-4) to worst 
CTCAE grade after treatment starts (Grade 0 to 4, where Grade 0 means normal) will be 
summarized using shift tables. Test results from both scheduled and unscheduled visits will be 
included. For the tests without corresponding CTCAE grades, results in shift tables will be 
categorized into “lower than normal values and higher than normal values (i.e., both higher than 
normal values and lower than normal values occurred after first dose of treatment)”, “lower than 
normal values”, “normal values”, and “higher than normal values”. CTCAE grading reference 
ranges for laboratory tests are detailed in Appendix I. 
Qualitative descriptive summaries will be provided for urinalysis (qualitative) results measured at 
each visit. A shift table will also be provided by normal, abnormal without clinical significance, 
and abnormal with clinical significance. For urine protein, a shift table by CTCAE grade will also 
be provided. 
Laboratory test results will be listed separately for hematology, urinalysis, coagulation, blood 
biochemistry, virology, thyroid function, cardiac markers, and pregnancy test. 
8.4.3. Vital Signs 
By-visit descriptive summary will be provided for vital sign measurements (body temperature, 
heart rate, respiratory rate, systolic and diastolic blood pressure) and their changes from baseline. 
Changes from baseline to worst post-baseline measurements will be summarized in shift table 
according to the table below (Table 4). The number and percentage of subjects with significant 
changes in vital sign measurements will be summarized for each group. 
Table 4  Criteria for Significant Changes in Vital Signs from Baseline 


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Above Normal 
Below Normal 
Systolic Blood 
Pressure (mmHg) 
increase > = 20 from baseline, 
and > = 160 
Decrease > = 20 from baseline, 
and < = 80 
Diastolic Blood 
Pressure (mmHg) 
increase > = 15 from baseline, 
and > = 100 
Decrease > = 15 from baseline, 
and < = 50 
Heart Rate 
(beats/min) 
increase > = 15 from baseline, 
and > = 100 
Decrease > = 15 from baseline, 
and < = 60 
Respiratory rate 
(breaths/min) 
> 24 
< 8 
Body Temperature 
(⁰C) 
> = 39.1 
- 
 
Vital signs for each subject will be listed in detail, and values with significant changes from 
baseline will be flagged. 
8.4.4. 12-Lead Electrocardiogram 
Descriptive summaries will be provided for each electrocardiogram (ECG) parameter measured at 
each visit and their corresponding changes from baseline (averaged over the three measurements). 
According to Table 5, the number and percentage of subjects with abnormal changes in ECG 
parameters after treatment start will be summarized, and summaries will be provided in shift table 
for the worst change from baseline. ECG results for each subject will be listed in detail. 
Table 5  Criteria for Significant Changes in ECG Indicators from Baseline 
 
Above Normal 
Below Normal 
QTcF (ms) 
> 450 and < = 480 
- 
> 480 and < = 500 
- 
> = 501, or > 60 increase from 
baseline 
- 
QT (ms) 
> 450 and < = 480 
- 
> 480 and < = 500 
- 
>= 501, or > 60 increase from 
baseline 
- 
Heart Rate 
(beats/min) 
> 25% increase from baseline and 
value >= 100 
> 25% decrease from baseline and 
value <= 50 
PR (ms) 
> 25% increase from baseline and 
value > 200 
> 25% decrease from baseline and 
value < 120 


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Above Normal 
Below Normal 
QRS (ms) 
> 25% increase from baseline and 
value > 110 
- 
 
8.4.5. Physical Examination 
Worst changes from baseline in physical examination (normal, abnormal but not clinically 
significant, and abnormal and clinically significant) will be summarized using shift tables. Physical 
examination records will be listed in detail. 
8.4.6. ECOG Score 
ECOG scores will be listed in detail for all subjects. 
8.4.7. Echocardiography 
Descriptive summary will be provided for left ventricular ejection fraction (LVEF) measured at 
each visit and their changes from baseline. Number and percentage of subjects in the following 
categories will be provided: LVEF from 40% ~ 50% or with 10% ~ 19% decrease from baseline, 
LVEF from 20% ~ 39% or with >20% decrease from baseline, and post-baseline LVEF < 20%. 
Worst changes from baseline in valve function measurement (normal, abnormal but not clinically 
significant, and abnormal and clinically significant) will be summarized using shift tables. 
Echocardiography records will be listed in detail. 
8.5. 
Efficacy Analysis 
Efficacy analyses will be performed for subjects in the FAS based on RECIST evaluation. 
A waterfall plot will be presented for the best percentage change from baseline in the sum of target 
lesion diameters. Swim plots will be prepared for all subjects to present subject drug exposure and 
efficacy evaluations at each visit. 
The best overall response (BOR) will be determined and statistically analyzed based on evaluations 
at all visit, and the number and percentage of subjects with BOR of CR, PR, SD, PD, NE, and 
Non-CR/Non-PD will be summarized. Participants with BOR of unknown or none (i.e. no valid 
record of post-baseline tumor assessments) will be considered non-responsive. ORR (CR or PR) 
and DCR (CR, PR or SD) will be calculated based on BOR, respectively, and the Clopper-pearson 
method will be used to estimate ORR and DCR and their 2-sided 90% confidence intervals. 
Time to progression (TTP), duration of response (DOR), and progression-free survival (PFS) will 
be analyzed using the Kaplan-Meier method, with their median and 90% confidence interval will 
be provided. If the number of subjects in a group is less than 10, only DOR, TTP and PFS listings 
will be provided for each subject. 


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Assessments of target lesion, non-target lesion, new lesion, and overall response will be listed in 
detail for each subject and each visit. 
8.6. 
Pharmacokinetic Analysis 
Plasma concentration of study drug will be provided by the central laboratory, and the plasma 
concentration data will be analyzed by the CRO MOSIM in the enterprise version WinNonlin 
software using non-compartmental model to calculate the pharmacokinetic parameters and 
reported independently. Analysis details are presented in the PK Statistical Analysis Report. 
8.7. 
Pharmacodynamic Analysis 
Detailed listings of pharmacodynamic markers and pSMAD2/3 in PBMCs (peripheral single cells) 
and TGF-β measured at each visit will be provided. 
9. 
INTERIM ANALYSIS 
No formal interim analysis is planned. 
10. 
REFERENCES 
NA. 
11. 
ATTACHMENT 
NA. 
12. 
APPENDIX I 
Laboratory 
Test 
Category 
Laboratory test 
indicators 
Altered 
(increased/decreased) 
CTCAE 
Grade 
Criteria for judgment 
Blood 
biochemistry 
Aspartate 
aminotransferase 
(AST) 
Increased 
1 
ULN < value ≤ 3.0 x 
ULN (baseline normal) or 
1.5 x baseline value ≤ 
value ≤ 3.0 x baseline 
value (baseline abnormal) 
 
 
 
2 
3.0 xULN < value ≤ 5.0 
xULN (baseline normal) 
or 3.0 times baseline 
value < value ≤ 5.0 
times baseline value 
(baseline abnormal) 


Genfleet Therapeutics 
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Protocol Number: GFH018X1101 
    Version 1.0 
 
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Laboratory 
Test 
Category 
Laboratory test 
indicators 
Altered 
(increased/decreased) 
CTCAE 
Grade 
Criteria for judgment 
 
 
 
3 
5.0 xULN < value ≤ 
20.0 xULN (baseline 
normal) or 5.0-fold 
baseline value < value ≤ 
20.0-fold baseline value 
(baseline abnormal) 
 
 
 
4 
Value > 20.0 xULN 
(normal baseline) or 
value > 20.0 x baseline 
(abnormal baseline) 
 
 
 
 
 
 
Alanine 
aminotransferase 
(ALT) 
Increased 
1 
ULN < value ≤ 3.0 x 
ULN (baseline normal) or 
1.5 x baseline value ≤ 
value ≤ 3.0 x baseline 
value (baseline abnormal) 
 
 
 
2 
3.0 xULN < value ≤ 5.0 
xULN (baseline normal) 
or 3.0 times baseline 
value < value ≤ 5.0 
times baseline value 
(baseline abnormal) 
 
 
 
3 
5.0 xULN < value ≤ 
20.0 xULN (baseline 
normal); 5.0-fold baseline 
value < value ≤ 20.0-
fold baseline value 
(baseline abnormal) 
 
 
 
4 
Value > 20.0 xULN 
(normal baseline) or 
value > 20.0 x baseline 
(abnormal baseline) 
 
 
 
 
 
 
Alkaline 
phosphatase 
(ALP) 
Increased 
1 
ULN < value ≤ 2.5 
xULN (baseline normal) 
or 2.0 times baseline 
value ≤ value ≤ 2.5 


Genfleet Therapeutics 
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Protocol Number: GFH018X1101 
    Version 1.0 
 
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Laboratory 
Test 
Category 
Laboratory test 
indicators 
Altered 
(increased/decreased) 
CTCAE 
Grade 
Criteria for judgment 
times baseline value 
(baseline abnormal) 
 
 
 
2 
2.5 xULN < value ≤ 5.0 
xULN (baseline normal) 
or 2.5 times baseline 
value < value ≤ 5.0 
times baseline value 
(baseline abnormal) 
 
 
 
3 
5.0 xULN < value ≤ 
20.0 xULN (baseline 
normal) or 5.0-fold 
baseline value < value ≤ 
20.0-fold baseline value 
(baseline abnormal) 
 
 
 
4 
Value > 20.0 xULN 
(normal baseline) or 
value > 20.0 x baseline 
(abnormal baseline) 
 
 
 
 
 
 
Glutamyl 
transpeptidase 
(GGT) 
Increased 
1 
ULN < value ≤ 2.5 
xULN (baseline normal) 
or 2.0 times baseline 
value ≤ value ≤ 2.5 
times baseline value 
(baseline abnormal) 
 
 
 
2 
2.5 xULN < value ≤ 5.0 
xULN (baseline normal) 
or 2.5 times baseline 
value < value ≤ 5.0 
times baseline value 
(baseline abnormal) 
 
 
 
3 
5.0 xULN < value ≤ 
20.0 xULN (baseline 
normal) or 5.0-fold 
baseline value < value ≤ 
20.0-fold baseline value 
(baseline abnormal) 


Genfleet Therapeutics 
SAP 
Protocol Number: GFH018X1101 
    Version 1.0 
 
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Laboratory 
Test 
Category 
Laboratory test 
indicators 
Altered 
(increased/decreased) 
CTCAE 
Grade 
Criteria for judgment 
 
 
 
4 
Value > 20.0 xULN 
(normal baseline) or 
value > 20.0 x baseline 
(abnormal baseline) 
 
 
 
 
 
 
Serum creatinine 
(CREA) 
Increased 
1 
ULN < value ≤ 1.5 
xULN 
 
 
 
2 
1.5 xULN < value ≤ 3.0 
xULN or 1.5 times 
baseline value < value ≤ 
3.0 times baseline value 
 
 
 
3 
3.0 xULN < value ≤ 6.0 
xULN or value > 3.0 
baseline 
 
 
 
4 
Value > 6.0 xULN 
 
 
 
 
 
 
Albumin (ALB) 
Decreased 
1 
3 g/dL ≤ value < LLN or 
30 g/L ≤ value < LLN 
 
 
 
2 
2 g/dL ≤ value < 3 g/dL 
or 20 g/L ≤ value < 30 
g/L 
 
 
 
3 
Values < 2 g/dL or values 
< 20 g/L 
 
 
 
 
 
 
Total bilirubin 
(TBIL) 
Increased 
1 
ULN < value ≤ 1.5 
xULN (baseline normal) 
or 1 x baseline value < 
value ≤ 1.5 x baseline 
value (baseline abnormal) 
 
 
 
2 
1.5 xULN < value ≤ 3.0 
xULN (baseline normal) 
or 1.5 times baseline 
value < value ≤ 3.0 
times baseline value 
(baseline abnormal) 


Genfleet Therapeutics 
SAP 
Protocol Number: GFH018X1101 
    Version 1.0 
 
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Laboratory 
Test 
Category 
Laboratory test 
indicators 
Altered 
(increased/decreased) 
CTCAE 
Grade 
Criteria for judgment 
 
 
 
3 
3.0 xULN < value ≤ 
10.0 xULN (baseline 
normal) or 3.0 times 
baseline value < value ≤ 
10.0 times baseline value 
(baseline abnormal) 
 
 
 
4 
Value > 10.0 xULN 
(normal baseline) or 
value > 10.0 times 
baseline value (abnormal 
baseline) 
 
 
 
 
 
 
Creatine kinase 
(CK) 
Increased 
1 
ULN < value ≤ 2.5 
xULN 
 
 
 
2 
2.5 xULN < value ≤ 5.0 
xULN 
 
 
 
3 
5.0 xULN < value ≤ 
10.0 xULN 
 
 
 
4 
Value > 10.0 xULN 
 
 
 
 
 
 
Total cholesterol 
(TCHO) 
Increased 
1 
ULN < value ≤ 300 
mg/dL or ULN < value 
≤ 7.75 mmol/L 
 
 
 
2 
300 mg/dL < value ≤ 
400 mg/dL or 7.75 
mmol/L < value ≤ 10.34 
mmol/L 
 
 
 
3 
400 mg/dL < value ≤ 
500 mg/dL or 10.34 
mmol/L < value ≤ 12.92 
mmol/L 
 
 
 
4 
Value > 500 mg/dL or 
value > 12.92 mmol/L 
 
Triglycerides 
(TG) 
Increased 
1 
1.71 mmol/L ≤ value < 
3.42 mmol/L or 150 


Genfleet Therapeutics 
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Protocol Number: GFH018X1101 
    Version 1.0 
 
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Laboratory 
Test 
Category 
Laboratory test 
indicators 
Altered 
(increased/decreased) 
CTCAE 
Grade 
Criteria for judgment 
mg/dL ≤ value < 300 
mg/dL 
 
 
 
2 
3.42 mmol/L ≤ value < 
5.7 mmol/L or 3 00 
mg/dL ≤ value < 500 
mg/dL 
 
 
 
3 
5.7 mmol/L ≤ value < 
11.4 mmol/L or 5 00 
mg/dL ≤ value < 1000 
mg/dL 
 
 
 
4 
Value > 11.4 mmol/L or 
value > 1000 mg/dL 
 
 
 
 
 
 
Blood glucose 
Decreased 
1 
3. 0 mmol/L ≤ value < 
LLN or 5 5 mg/dL ≤ 
value < LLN 
 
 
 
2 
2 . 2 mmol/L ≤ value < 
3 . 0 mmol/L or 4 0 
mg/dL ≤ value < 5 5 
mg/dL 
 
 
 
3 
1 . 7 mmol/L ≤ value < 
2 . 2 mmol/L or 3 0 
mg/dL ≤ value < 40 
mg/dL 
 
 
 
4 
Value < 1 . 7 mmol/L or 
Value < 30 mg/dL 
 
 
 
 
 
 
Calcium 
Increased 
1 
ULN < value ≤ 2.9 
mmol/L or ULN < value 
≤ 11.5 mg/dL 
 
 
 
2 
2.9 mmol/L < value ≤ 
3.1 mmol/L or 11.5 
mg/dL < value ≤ 12.5 
mg/dL 


Genfleet Therapeutics 
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Protocol Number: GFH018X1101 
    Version 1.0 
 
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Laboratory 
Test 
Category 
Laboratory test 
indicators 
Altered 
(increased/decreased) 
CTCAE 
Grade 
Criteria for judgment 
 
 
 
3 
3.1 mmol/L < value ≤ 3.4 
mmol/L or 12.5 mg/dL < 
value ≤ 13.5 mg/dL 
 
 
 
4 
Value > 3.4 mmol/L or 
Value > 13.5 mg/dL 
 
 
 
 
 
 
 
Decreased 
1 
2.0 mmol/L ≤ value < 
LLN or 8 . 0 mg/dL ≤ 
value < LLN 
 
 
 
2 
1.75 mmol/L ≤ value < 
2.0 mmol/L or 7. 0 
mg/dL ≤ value < 8 . 0 
mg/dL 
 
 
 
3 
1.5 mmol/L ≤ value < 
1.75 mmol/L or 6. 0 
mg/dL ≤ value < 7 . 0 
mg/dL 
 
 
 
4 
Value < 1.5 mmol/L or 
Value < 6. 0 mg/dL 
 
 
 
 
 
 
Sodium 
Increased 
1 
ULN < value ≤ 150 
mmol/L 
 
 
 
2 
150 mmol/L < value ≤ 
155 mmol/L 
 
 
 
3 
155 mmol/L < value ≤ 
160 mmol/L 
 
 
 
4 
Value > 160 mmol/L 
 
 
Decreased 
1 
130 mmol/L ≤ value < 
LLN 
 
 
 
3 
120 mmol/L ≤ value ≤ 
130 mmol/L 
 
 
 
4 
Value < 120 mmol/L 
 
 
 
 
 


Genfleet Therapeutics 
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Protocol Number: GFH018X1101 
    Version 1.0 
 
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Laboratory 
Test 
Category 
Laboratory test 
indicators 
Altered 
(increased/decreased) 
CTCAE 
Grade 
Criteria for judgment 
 
Potassium 
Increased 
1 
ULN < value ≤ 5 . 5 
mmol/L 
 
 
 
2 
5.5 mmol/L < value ≤ 
6.0 mmol/L 
 
 
 
3 
6.0 mmol/L < value ≤ 
7.0 mmol/L 
 
 
 
4 
Value > 7.0 mmol/L 
 
 
 
 
 
 
 
Decreased 
1 
3 . 0 mmol/L ≤ value < 
LLN 
 
 
 
3 
2.5 mmol/L ≤ value < 
3.0 mmol/L 
 
 
 
4 
Value < 2.5 mmol/L 
Blood 
routine 
Eosinophil (EO) 
count 
Increased 
1 
Value > ULN and value > 
baseline 
 
 
 
 
 
 
Hemoglobin 
concentration 
(HGB) 
Increased 
1 
ULN < value ≤ ULN + 2 
g/d L 
 
 
 
2 
ULN + 20 g/L < value ≤ 
ULN + 40 g/L 
 
 
 
3 
Value > ULN + 40 g/L 
 
 
 
 
 
 
 
Decreased 
1 
100 g/L ≤ value < LLN 
or 10 . 0 g/dL ≤ value < 
LLN or 6 .2 mmol/L ≤ 
value < LLN 
 
 
 
2 
8 0 g/L ≤ value < 100 
g/L or 8. 0 g/dL ≤ value 
< 10 . 0 g/dL or 4 .9 
mmol/L ≤ value < 6 .2 
mmol/L 


Genfleet Therapeutics 
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Protocol Number: GFH018X1101 
    Version 1.0 
 
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Laboratory 
Test 
Category 
Laboratory test 
indicators 
Altered 
(increased/decreased) 
CTCAE 
Grade 
Criteria for judgment 
 
 
 
3 
Value < 80 g/L or value < 
8. 0 g/dL or value < 4.9 
mmol/dL 
 
 
 
 
 
 
Lymphocyte 
(LY) count 
Increased 
2 
20,000/mm 3 ≤ value < 
4000/mm 3 or 20 - < 4 x 
10 9/L 
 
 
 
3 
Value > 20,000/mm 3 
or > 20 x 10 9/L 
 
 
 
 
 
 
 
Decreased 
1 
800/mm 3 ≤ value < 
LLN or < LLN - 0.8 x 10 
9/L 
 
 
 
2 
500/mm 3 ≤ value < 
800/mm 3 or < 0.8 - 0.5 x 
10 9/L 
 
 
 
3 
200/mm 3 ≤ value < 
500/mm 3 or < 0.5 - 0.2 x 
10 9/L 
 
 
 
4 
Value < 200/mm 3 or < 
0.2 x 10 9/L 
 
 
 
 
 
 
Neutrophil count 
(ANC) 
Decreased 
1 
1.5 x 10 9/L ≤ value < 
LLN or 1 500/mm 3 ≤ 
value < LLN 
 
 
 
2 
1.0 x 10 9/L ≤ value < 
1.5 x 10 9/L or 1 000/mm 
3 ≤ value < 1 500/mm 3 
 
 
 
3 
0.5 x 10 9/L ≤ value < 
1.0 x 10 9/L or 5 00/mm 3 
≤ value < 1 000/mm 3 
 
 
 
4 
Value < 0.5 x 10 9/L or 
Value < 5 00/mm 3 
 
 
 
 
 


Genfleet Therapeutics 
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Protocol Number: GFH018X1101 
    Version 1.0 
 
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Laboratory 
Test 
Category 
Laboratory test 
indicators 
Altered 
(increased/decreased) 
CTCAE 
Grade 
Criteria for judgment 
 
Platelet count 
(PLT) 
Decreased 
1 
75.0 x 10 9/L ≤ value < 
LLN or 75000/mm 3 ≤ 
value < LLN 
 
 
 
2 
50.0 x 10 9/L ≤ value < 
75.0 x 10 9/L or 5 
0000/mm 3 ≤ value < 
75000/mm 3 
 
 
 
3 
25.0 x 10 9/L ≤ value < 
50.0 x 10 9/L or 2 
5000/mm 3 ≤ value < 
50000/mm 3 
 
 
 
4 
Value < 25.0 x 10 9/L or 
value < 2 5000/mm 3 
 
 
 
 
 
 
White blood cell 
count (WBC) 
Decreased 
1 
3.0 x 10 9/L ≤ value < 
LLN or 3 000/mm 3 ≤ 
value < LLN 
 
 
 
2 
2.0 x 10 9/L ≤ value < 
3.0 x 10 9/L or 2 000/mm 
3 ≤ value < 3000/mm 3 
 
 
 
3 
1.0 x 10 9/L ≤ value < 
2.0 x 10 9/L or 1 000/mm 
3 ≤ value < 2000/mm 3 
 
 
 
4 
Value < 1.0 x 10 9/L or 
value < 1 000/mm 3 
 
 
 
 
 
Coagulation 
function 
Activated partial 
thromboplastin 
time (APTT) 
Increased 
1 
ULN < value ≤ 1.5 
xULN 
 
 
 
2 
1.5 xULN < value ≤ 2.5 
xULN 
 
 
 
3 
Value > 2.5 xULN 
 
 
 
 
 


Genfleet Therapeutics 
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Protocol Number: GFH018X1101 
    Version 1.0 
 
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Laboratory 
Test 
Category 
Laboratory test 
indicators 
Altered 
(increased/decreased) 
CTCAE 
Grade 
Criteria for judgment 
 
International 
normalized ratio 
(INR) 
Increased 
1 
1.2 < value ≤ 1.5 
 
 
 
2 
1.5 < value ≤ 2.5 
 
 
 
3 
Value > 2.5 
 
 
 
 
 
Urine 
routine 
Urine protein 
Increased 
1 
1 + 
 
 
 
2 
2 +, 3 + 
 
 
 
3 
4 + 
 
 
 
 
 
Note: LLN means lower limit of normal; ULN means upper limit of normal.