A Phase I/II, Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Efficacy of FWD1802in Patients With ER+/HER2- Unresectable Locally Advanced or Metastatic Breast Cancer
Phase: PHASE1
Conditions: Metastatic Breast Cancer, Locally Advanced Breast Cancer, Breast Cancer Stage IV, ER+/HER2- Breast Cancer
Sponsor: Forward Pharmaceuticals Co., Ltd.

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Clinical Study Protocol 
Study Title: 
A phase I open-label dose escalation trial of 
FWD1802 as monotherapy and in combination with 
palbociclib 
in 
patients 
with 
ER+/HER2- 
unresectable locally advanced or metastatic breast 
cancer 
 
Protocol Number: 
FWD1802-001C 
Version/Date: 
1.1/July 13, 2023 
Investigational Product: 
FWD1802 
Study Phase: 
Phase Ⅰ 
Sponsor:  
Shenzhen Forward Pharmaceuticals Co. Ltd 
B406, 19 Gaoxin S. 7th Ave., ShenZhen Hi-Tech 
Industrial Park, ShenZhen, Guangdong Province, 
P.R. China 
Contact: 
Chenggang Zhu 
8618621958197 
zhucg@forward-pharm.com 
Confidential Statement 
The information contained in this document is proprietary to Shenzhen Forward 
Pharmaceuticals Co. Lt. The information is to be used only in connection with review 
of, or participation in, authorized clinical studies of the investigational drug described in 
the protocol. Disclosure of the information to others not under obligations to maintain 
this information in confidence is prohibited without written authorization from Shenzhen 
Forward Pharmaceuticals Co. Lt with the exception that, to the extent necessary to obtain 

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informed consent from those persons to whom the drug may be administered, a general 
protocol description may be disclosed to such potential subjects.  

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Sponsor Statement 
Study Protocol Title: A phase I open-label dose escalation trial of FWD1802 as 
monotherapy and in combination with palbociclib in patients with ER+/HER2- 
unresectable locally advanced or metastatic breast cancer  
Protocol Number: FWD1802-001 
Version Number: 1.1 
Investigational Product: FWD1802 
Sponsor: Shenzhen Forward Pharmaceuticals Co. Lt 
 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and in accordance with the 
following:  
 
The ethical principles that have their origin in the Declaration of Helsinki. 
 
International Conference on Harmonisation E6 Good Clinical Practice Consolidated 
Guideline. 
 
All applicable laws and regulations, including, without limitation, data privacy laws, 
clinical trial disclosure laws, and regulations. 
 
The following signature documents this approval. 
 
Jin Liu 
______________________________   
              ___________________ 
Representative of Sponsor 
 
 
 
 
 
 
 
Date 
 
 
Title CSO 
Shenzhen Forward Pharmaceuticals Co. Lt 
 
 

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Investigator Agreement 
Study Protocol Title: 
Protocol Number: 
Version Number: 
 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
and any other product information provided by the sponsor. 
I agree to conduct this study in accordance with the requirements of this protocol and also 
to protect the rights, safety, privacy, and well-being of study subjects in accordance with 
the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
 All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 
Principle Investigator:  
Name (Print):    
 
 
Clinical Study Center: 
 
Signature      
 
Date 
 
 
 

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Table of Contents 
Emergency Contact Information ............................................................................................  
Sponsor Statement ............................................................................................................... 4 
Investigator Agreement ........................................................................................................ 5 
Table of Contents ................................................................................................................. 6 
List of Tables ..................................................................................................................... 11 
List of Figures .................................................................................................................... 11 
Synopsis ............................................................................................................................. 12 
List of Abbreviations and Definitions of Terms ................................................................ 34 
1 Introduction ..................................................................................................................... 37 
1.1 Background .......................................................................................................... 37 
1.2 Non-Clinical Information ..................................................................................... 38 
1.2.1 Pharmacology ............................................................................................ 38 
1.2.2 Pharmacokinetics ....................................................................................... 39 
1.2.3 Toxicology ................................................................................................. 40 
1.3 Study Rationale .................................................................................................... 41 
1.3.1 Rational for Dose Regimen of Escalation ................................................. 41 
1.4 Benefits and Risks ................................................................................................ 41 
1.4.1 Possible adverse events ............................................................................. 41 
1.4.2 Risk control in trial design ......................................................................... 45 
1.5 Clinical Study Compliance ................................................................................... 46 
2 Objectives ....................................................................................................................... 47 
3 Endpoints ........................................................................................................................ 48 
3.1 Safety and Tolerability ......................................................................................... 48 
3.2 PK Assessment ..................................................................................................... 48 
3.3 Efficacy Assessment ............................................................................................ 48 
3.4 Exploratory endpoints .......................................................................................... 48 
4 Investigational Plan ......................................................................................................... 49 
4.1 Overall Study Design ........................................................................................... 49 
4.2 Methodology ........................................................................................................ 49 
4.2.1 Part A – Dose Escalation of FWD1802 as a Monotherapy ....................... 49 
4.2.2 Part B- Dose Escalation of FWD1802 in combination with palbocilib .... 50 

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4.2.3 Part C – Dose Expansion Study ................................................................. 51 
4.3 Treatment Plan ..................................................................................................... 51 
4.4 Dose Escalation/Stopping Criteria ....................................................................... 51 
4.5 Definition of MTD ............................................................................................... 52 
4.6 Definitions of Dose-Limiting Toxicity (DLT) ..................................................... 53 
4.7 Dose modifications ............................................................................................... 54 
4.7.1 Dose Reductions ........................................................................................ 54 
4.7.2 Dose Escalations ........................................................................................ 55 
4.7.3 Temporary Withdrawal .............................................................................. 55 
5 Study Population ............................................................................................................. 56 
5.1 Number of Subjects .............................................................................................. 56 
5.2 Inclusion Criteria .................................................................................................. 56 
5.3 Exclusion Criteria ................................................................................................. 58 
5.4 Subjects Withdrawal Criteria ............................................................................... 60 
5.4.1 Investigator’s Decision .............................................................................. 60 
5.4.2 Subjects Withdrawing on Their Own ........................................................ 60 
5.5 Criteria for Trial Termination .............................................................................. 61 
5.5.1 Serious Safety Concerns ............................................................................ 61 
5.5.2 Investigator’s Request ............................................................................... 61 
5.5.3 Sponsor’s Request ..................................................................................... 61 
5.5.4 IRB and/or FDA’s Request ........................................................................ 61 
6 Description of Study Treatment ...................................................................................... 62 
6.1 Study Treatment ................................................................................................... 62 
6.2 Administration ...................................................................................................... 62 
6.3 Study Drug Packaging and Labeling .................................................................... 62 
6.4 Study Drug Storage .............................................................................................. 63 
6.5 Study Drug Accountability ................................................................................... 63 
6.6 Study Drug Handling and Disposal ...................................................................... 63 
6.7 Concomitant Medications .................................................................................... 64 
6.8 Assessment of Compliance .................................................................................. 64 
7 Study Procedures ............................................................................................................ 65 
7.1 Subject Identification ........................................................................................... 65 

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7.2 Study Start and End of Study Definitions ............................................................ 65 
7.3 Description of Assessments ................................................................................. 65 
7.3.1 Laboratory Assessments ............................................................................ 65 
7.3.2 Medical History ......................................................................................... 66 
7.3.3 Physical Examination ................................................................................ 66 
7.3.4 Vital Signs ................................................................................................. 66 
7.3.5 Electrocardiogram ..................................................................................... 66 
7.3.6 Echocardiogram ......................................................................................... 66 
7.3.7 18F-FES PET/CT ........................................................................................ 66 
7.4 Study Procedures .................................................................................................. 67 
7.4.1 Screening Period (Day -28~Day -1) for All Subjects ................................ 67 
7.4.2 Treatment Period ....................................................................................... 68 
7.4.3 Post Treatment Follow-up Visit ................................................................ 69 
7.5 Biological Samples ............................................................................................... 70 
7.5.1 PK Samples ................................................................................................ 70 
7.5.2 Sample Preparation .................................................................................... 71 
8 Lifestyle and/or Dietary Management ............................................................................ 72 
8.1 Pregnancy Precautions ......................................................................................... 72 
8.1.1 Definition of Childbearing Potential ......................................................... 72 
8.1.2 Contraception Requirements for Female Subjects of Childbearing 
Potential ...................................................................................................................... 72 
8.1.3 Acceptable Methods Considered Highly Effective ................................... 72 
8.1.4 Unacceptable Birth Control Methods ........................................................ 73 
8.2 Meals and Dietary Restrictions ............................................................................ 73 
8.3 Physical Activity .................................................................................................. 73 
9 Assessments of Adverse Events ...................................................................................... 75 
9.1 Adverse Events ..................................................................................................... 75 
9.1.1 Adverse Event Definition .......................................................................... 75 
9.1.2 Serious Adverse Event Definition ............................................................. 75 
9.2 Relationship of Adverse Event to Study Drug ..................................................... 76 
9.3 Method of Detecting AEs and SAEs .................................................................... 77 
9.4 Recording AEs and SAEs .................................................................................... 77 
9.4.1 All Adverse Events Regardless of Seriousness ......................................... 77 

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9.4.2 Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events and Serious Adverse Events ............................................................. 77 
9.4.3 Grading of Adverse Events ........................................................................ 77 
9.5 Reporting Adverse Events .................................................................................... 78 
9.5.1 All AEs ...................................................................................................... 78 
9.5.2 Follow-Up of AE/SAE .............................................................................. 79 
9.5.3 Post-Study Reporting Requirements ......................................................... 79 
9.5.4 Pregnancy .................................................................................................. 79 
10 Statistics ........................................................................................................................ 81 
10.1 Sample Size Estimate ......................................................................................... 81 
10.2 Analysis Sets ...................................................................................................... 81 
10.2.1 Full Analysis Set (FAS) ........................................................................... 81 
10.2.2 Safety Analysis Set (SS) .......................................................................... 81 
10.2.3 Pharmacokinetic Concentration Set (PKCS) ........................................... 81 
10.2.4 Pharmacokinetic Parameter Set (PKPS) .................................................. 81 
10.2.5 Pharmacodynamics Analysis Set (PDS) .................................................. 81 
10.2.6 Efficacy Analysis Set (EAS) ................................................................... 82 
10.2.7 Interim Analysis ...................................................................................... 82 
10.3 Data Handling Conventions ............................................................................... 82 
10.4 Demographic Data and Baseline Characteristics ............................................... 82 
10.5 Safety Analysis ................................................................................................... 82 
10.5.1 Adverse Events ........................................................................................ 83 
10.5.2 Laboratory Evaluations ............................................................................ 83 
10.5.3 Other Safety Evaluations ......................................................................... 83 
10.5.4 Pharmacokinetic Analysis ....................................................................... 83 
10.6 Pharmacodynamics Analysis .............................................................................. 83 
10.7 C-QT Analysis .................................................................................................... 84 
10.8 Preliminary Efficacy Analysis ........................................................................... 84 
11 Study Conduct Considerations ...................................................................................... 84 
11.1 Quality Check (Study Monitoring) .................................................................... 84 
11.2 Quality Assurance .............................................................................................. 85 
11.3 Study and Site Closure ....................................................................................... 85 
11.4 Record Retention ................................................................................................ 85 

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11.5 Provision of Study Results and Information to Investigator .............................. 86 
11.6 Data Management .............................................................................................. 86 
12 Ethics ............................................................................................................................. 88 
12.1 Regulatory and Ethical Considerations .............................................................. 88 
12.2 Ethics Review ..................................................................................................... 88 
12.3 Written Informed Consent .................................................................................. 89 
12.4 Confidentiality .................................................................................................... 89 
13 Data recordkeeping ....................................................................................................... 90 
13.1 Inspection of Records ......................................................................................... 90 
13.2 Retention of Records .......................................................................................... 90 
14 Financing and Insurance ............................................................................................... 91 
15 Publishing ..................................................................................................................... 92 
16 References and Appendices .......................................................................................... 93 
Appendix 1 ......................................................................................................................... 95 
Appendix 2 ....................................................................................................................... 108 
Appendix 3 ....................................................................................................................... 109 
Appendix 4 ....................................................................................................................... 110 
Appendix 5 ....................................................................................................................... 112 
Appendix 6 ....................................................................................................................... 113 
 
 
 

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List of Tables 
Table 1 Schedule of Events in Part A Dose Escalation ...................................................... 22 
Table 2 Schedule of Events in Part B Dose Escalation ...................................................... 26 
Table 3 Schedule of Events in Part C Dose Expansion...................................................... 30 
Table 4 tarting Dose for Escalation .................................................................................... 41 
Table 5 Adverse Reactions in CONFIRM (≥5% in Either Treatment Group) ................... 43 
Table 6 Adverse Reactions (≥10%) in PALOMA-3 ........................................................... 44 
Table 7 Laboratory Abnormalities in PALOMA-3 ............................................................ 45 
Table 8. The Planned Dose Escalation Levels of FWD1802 in Phase Ia Study ................ 50 
Table 9 Dose reductions guideline for general adverse events .......................................... 54 
Table 10 Laboratory Assessments ...................................................................................... 65 
Table 11 PK Sample Time Points and Time Windows ...................................................... 70 
Table 12 PK Samples Time Windows ................................................................................ 71 
Table 13 Sample Size Estimate for the Study .................................................................... 81 
Table 14 Time Point Response ......................................................................................... 103 
 
List of Figures 
Figure 1 Clinical Design of FWD1802 in Phase I Trial ..................................................... 49 
Figure 2. An example of FWD1802 label .......................................................................... 62 
 
 
 
 
 

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Synopsis 
Investigational 
Product 
FWD1802 
Protocol 
Number 
FWD1802-001C 
Version/Date 
1.1 / Jul 13 2023 
Sponsor 
Shenzhen Forward Pharmaceuticals Co. Lt 
Number 
of 
Subjects 
Approximately 99 patients  
Study 
Population 
A/B: ER+ /HER2- unresectable locally advanced or metastatic breast 
cancer. 
C: ER+/HER2- unresectable locally advanced or metastatic breast cancer 
with ESR1 mutation 
Study 
Objectives 
Primary Objective: 
• 
Establish the recommended phase II dose (RP2D) and/or the 
maximum tolerated dose (MTD) of FWD1802 as monotherapy and 
in combination with palbociclib in patients with ER+/HER2- 
unresectable locally advanced or metastatic breast cancer. 
• 
Explore the safety and tolerability of FWD1802 as monotherapy and 
in combination with Palbociclib. 
Secondary Objective: 
• 
Characterise Pharmacokinetics of FWD1802 as monotherapy and in 
combination with palbociclib.  
• 
Explore the metabolic pathway of FWD1802. 
• 
Explore preliminary efficacy signals. 
Exploratory Objective: 
 
Biomarker of FWD1802 as monotherapy and in combination with 
palbociclib. 
Starting 
Dose 
Selection 
 
 
 
 
 
 
According to ICH S9, considering the safety, efficacy of the nonclinical 
studies, and drug formulation specifications, in a more conservative way, 
25 mg was proposed as the starting dose. The details of starting dose in 
this protocol please refer to Section 1.3.1 Rational for Dose Regimen of 
Escalation 

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Study Design 
Open-label dose escalation trial of monotherapy and combination therapy 
with expansion. 
The overall study design is presented graphically in Figure 1. Detailed 
research procedures can be found in Section 7 Research Procedures.     
 
Part A is an open-label, dose escalation of FWD 1802 as monotherapy, 
approxiamately 27 patients. Dose escalation steps will be determined by 
the Safety Monitoring Committee (SMC), based on 3+3 rule except for 
the accelerated escalation on the 1st dose level. With pharmacokinetic 
(PK), pharmacodynamics (PD), efficacy and safety data, SMC will 
evaluate to guide determination of potentially effective dose for part B 
and C. 
 
Part B is an open-label, dose escalation of FWD 1802 in combination 
with palbociclib fixed dose, approxiamately 12 patients in no more than 
2 dose levels. Dose escalation steps will be determined by SMC, based 
on 3+3 rule. With PK, PD, efficacy and safety data, SMC will evaluate 
to guide determination of potentially effective combination dose. 
 
Part C is an open label, dose expansion of FWD 1802 monotherapy on 
patients with ER+/HER2-/ESR1 mutation, no more than 2 dose levels 
will be evaluated, with 30 patients at the most in either dose level cohort. 
Investigational 
Product 
and 
Administration 
FWD1802 
 
Dosage Formulation: Tablet 
 
Specification: 5 mg, 25 mg, 150 mg 
 
Dosage Regimen: oral, once daily (QD). For details of dosage 
regimen for 8.2 Meals and Dietary Restrictions. 
 
Storage: sealed containers, dry, ≤25℃, keep out of light. 
Inclusion 
Criteria 
1. Patients must understand and voluntarily sign the Informed Consent 
Form (ICF). 
2. Patients ≥ 18 years, female. 
3. Provision of blood sample to test ESR1 mutation status and for other 
biomarker assessment. In part A/B, the ESR1 mutation status will be 
tested retrospectively; In part C, only the patients with ESR1 
mutation positive is eligible (See Appendix 6). 
4. Documented positive oestrogen receptor status of primary or 
metastatic tumour tissue, according to the local laboratory 

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parameters. HER-2 negative. These laboratory parameters are 
consistent with accepted diagnostic guidelines such as the American 
Society of Clinical Oncology (ASCO) / College of American 
Pathologists (CAP) Clinical Practice Guideline for Pathologists 
estrogen (ER) and progesterone receptor (PgR) testing in breast 
cancer (Allison et al., 2020).  
5. Menopausal women according to one of the following criteria: 
 
Prior bilateral ovariectomy; 
 
Patients ≥ 60 years of age; 
 
Patients < 60 years of age presenting an amenorrhea of more 
than 12 months and follicle stimulating hormone (FSH) and 
plasma estradiol levels within the postmenopausal range as 
assessed by the local laboratory in the absence of chemotherapy, 
tamoxifen, tolimifene, or ovarian castration in the past 1 year, 
and no oral contraceptives, hormone replacement therapy, or 
gonadotropin-releasing hormone agonist or antagonist; 
 
Patients < 60 years of age who are taking either tamoxifen or 
tolomifene with two consecutive FSH and estradiol levels in the 
postmenopausal range. 
 
Or premenopausal or perimenopausal female subjects but must 
be willing to receive and maintain an approved luteinizing 
hormone-releasing hormone(LHRH) agonist during the study 
treatment period (LHRH agonist treatment initiated 28 days 
prior to the first study drug treatment); or for males: willing to 
receive and maintain an approved LHRH agonist during the 
study treatment period (LHRH agonist treatment initiated 28 
days prior to the first study drug treatment). 
6. Previous therapy failed or intolerable, or standard therapy not 
available:  
Part A: Previous therapy failed or intolerable, or standard therapy not 
available. 
 
Part B/C: Patients should have received at least 1 line ET, or received 
no 
more 
than 
1-line 
systematic 
chemotherapy 
for 
advanced/metastatic disease, no more than 1 target therapy. 

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7. Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 or 1(See Appendix 6). 
8. At least one measurable lesion according to RECISTv1.1 criteria. 
9. Life expectancy ≥ 12 weeks. 
10. Adequate organ and bone marrow function (no use of hematopoietic 
stimulating factor, no blood transfusion or human albumin within 7 
days prior to screening): 
a) Blood routine: Absolute neutrophil count (ANC) ≥ 1.5×109/L; 
Platelet count (PLT) ≥100×109/L; Hemoglobin (HGB) ≥ 
90 g/L; 
b) Liver function: Serum Total bilirubin (TBIL) ≤ 1.5 Upper 
limit of normal value (ULN); Alanine aminotransferase (ALT) 
and Aspartate transferase (AST) ≤ 3×ULN in subjects without 
liver metastasis; ALT or AST≤ 5×ULN with liver metastasis; 
c) Renal function: Serum creatinine ≤ 1.5×ULN or estimated 
creatinine clearance (CLcr) ≥ 60 mL/min as calculated using 
Cockcroft-Gault formula; 
d) Coagulation function: Activated Partial thromboplastin Time 
(APTT) and international normalized ratio (INR) ≤ 1.5×ULN 
(or within target range if on anticoagulation therapy); 
e) Cardiac function: Echocardiography (ECHO) shows left 
ventricular ejection fraction (LVEF) > 50%. 
11. Women of childbearing potential must have a negative serum 
pregnancy test within 7 days prior to the first dose. Female patients 
of childbearing potential must agree to use effective methods of 
contraception from the time of signature of informed consent, 
throughout the study and for 6 months after the last dose of the 
investigational product, like double barrier methods, condoms, oral 
or injectable contraceptives, intrauterine devices, etc. All female 
subjects will be considered to be of childbearing potential unless they 
are postmenopausal, postmenopausal, or sterilized (hysterectomy, 
tubal resection). 
Exclusion 
Criteria 
1. Documented medical history or ongoing gastrointestinal disease 
(Including difficulty in swallowing capsules, Crohn's disease, 

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ulcerative colitis, or short bowel syndrome) or other malabsorption 
that may affect the absorption of oral study drug. 
2. Participated in other clinical trials of investigational drugs or 
investigational devices within 4 weeks before the first medication; or 
received chemotherapy, targeted therapy, immunotherapy and 
clinical trial medication and other anti-tumor treatment within 4 
weeks, or received radiotherapy, endocrine drugs or Chinese 
traditional medicines with anti-tumor indications 2 weeks prior to the 
first dose, Or receive mitomycin and nitrosourea within 6 weeks 
prior to the first dose 
3. The toxicity of previous anti-tumor treatment has not recovered to 
grade 0 or 1 (except for alopecia, chemotherapy-induced peripheral 
neurotoxicity ≤ grade 2). 
4. Major surgical surgery (except biopsy) or incomplete healing of the 
surgical incision within 4 weeks prior to the first study drug 
treatment. 
5. Known other malignant tumors within 2 years before enrollment 
(except for cervical carcinoma insitu, superficial noninvasive 
bladder tumors, breast ductal carcinoma in situ, prostatic 
intraepithelial neoplasia without evidence of prostate cancer, or 
curatively treated Stage I nonmelanoma skin cancer); 
6. Subjects with unstable or symptomatic or progressive Central 
nervous system (CNS) metastasis. Subjects with a history of brain 
metastases who were clinically stable and who underwent Magnetic 
resonance imaging (MRI) or Computed tomography (CT) Subjects 
with CT (if not suitable for MRI) who confirm no CNS disease 
progression can be enrolled (MRI or CT must be performed at least 
4 weeks after the last brain radiotherapy). 
7. Previous history of interstitial lung disease, drug-induced interstitial 
lung disease, symptomatic interstitial lung disease or any evidence 
of active pneumonia on chest CT scan within 4 weeks prior to the 
first study drug treatment; 
8. Known to interfere with the test requirements of mental illness or 
drug abuse disease; 
9. History of human immunodeficiency virus HIV infection, or active 
bacterial or fungal infection requiring systemic treatment within 14 
days prior to the first study drug treatment. 

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10. Presence of active syphilis infection. 
11. Subjects with known active hepatitis B virus (HBV) or hepatitis C 
virus (HCV) infection with abnormal liver function (Absence of 
infection was defined as HBsAg negative, HBV DNA negative and 
HCV antibody negative), except to: 
 
Subjects who test positive for HBsAg or HBsAb during the 
screening period may be enrolled if the PCR test result for HCV-
RNA is < 500 IU/ml (2000 copies/mL), but receive antiviral 
treatment according to the investigator's assessment and undergo 
PCR for HBV-DNA during the study treatment period; 
 
Subject has a positive test for HCV antibody at screening and 
can be enrolled if the PCR test result for HCV-RNA is negative. 
12. History of clinically significant cardiovascular disease, such as: 
a) Symptomatic congestive heart failure according to New York 
Heart Association Grades (NYHA > Grade 2); 
b) Severe/unstable angina, new angina within last 3 months; 
c) Myocardial ischemia and long-term use of drugs for control; 
according to NYHA, grade Ⅲ-Ⅳ cardiac insufficiency; 
d) Any event of acute myocardial infarction within 6 months 
before screening; 
e) Any grade ≥ 2 supraventricular arrhythmia or ventricular 
arrhythmia requiring treatment or intervention; 
f) 
Any grade atrial fibrillation, coronary/peripheral artery bypass 
graft, or cerebrovascular symptoms including transient 
ischemic attack; 
g) QTcF (Fridericia's correction formula used) > 470 ms; 
h) ECG < 50 bpm. 
13. History of serious allergic reactions to the study drugs or excipients 
used in the protocol. 
14. Women who are pregnant or lactating. 
15. Prior use of an oral selective estrogen receptor degrader (SERD). 

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16. Subjects who use drugs or herbal supplements known to be 
moderate/strong inhibitors of CYP3A2 weeks prior to the first study 
drug treatment. Subjects who use drugs or herbal supplements 
known to be moderate/strong inducers of CYP3A4 weeks prior to the 
first study drug treatment. 
17. Received medications which inhibits the production of stomoch acid 
within 2 weeks or 5 drug half-lives (whichever is longer) prior to the 
first dose of study drugs. 
18. Received medications which inhibits P-gp within 2 weeks or 5 drug 
half-lives (whichever is longer) prior to the first dose of study drugs. 
19. Patients with active or chronic corneal disease, other active eye 
disease requiring ongoing treatment, or any clinically significant 
corneal disease for which drug-induced keratopathy cannot be 
adequately monitored. 
20. Other conditions that the investigator considers inappropriately for 
this study. 
Study 
Procedure 
This study consists of three phases: dose escalation as monotherapy 
phase, combination with palbociclib phase and dose expansion as 
monotherapy phase. Details please refer to 7 Study Procedures. 
Dose/regimen 
 
Part A:  
Dose tiers will start at 25 mg, with daily oral administration. 
Every treatment cycle consists of 28 days. 
Dose-escalation steps will be determined by SMC. The dose level, dose 
frequency, regimen could be modified based on the PK, safety and 
preliminary efficacy.  
The scheduled dose level and patient number as below： 
Dose cohort  
Daily dose (mg) 
Patient number  
1 
25 
1-3 (accelerated escalation) 
2 
75 
3-6 
3 
150 
3-6 
4 
300 
3-6 
5 
450 
3-6 
 
Part B: 
The starting dose of FWD1802 will be the recommended monotherapy 
dose which is deemed safety and decided by SMC based on the 

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comprehensive evaluation from part A based on PK, PD and preliminary 
efficacy. 
The dose level of FWD1802 to be combined with palbociclib is to be 
determined by SMC. 
The palbociclib dose is the fixed approved dose: 125 mg intake daily, for 
consecutive 21 days then off for 7 days, which composes 28-day 
treatment cycle, which is consistent with the 28-day treatment cycle of 
FWD1802.  
Every treatment cycle consists of 28 days. 
The dose level, dose frequency, regimen could be modified based on the 
PK, safety and preliminary efficacy. No more than 2 dose level cohorts 
of FWD 1802 will be selected for the combination with palbociclib. The 
dose adjustment is referred to the SmPC. 
 
Part C: 
No more than 2 dose levels determined from Part A and deemed safety 
by SMC will be explored further in part C in parallel with Part A, the 
planned patient number in every dose level cohort is 30 at the most , 
which will be determined by SMC.Every treatment cycle consists of 28 
days. 
Mode 
of 
administration 
Oral (P.O) 
Test product(s) 
FWD1802 
Combination 
product(s) 
Palbociclib 
DLT Definition 
/ MTD 
evaluation 
period 
DLT Definition: 
All AEs of the specified grades should count as DLTs except those that 
are clearly and incontrovertibly due to disease progression or extraneous 
causes. 
1. Hematological toxicity: 
 
CTCAE Grade ≥4 thrombocytopenia; 
 
CTCAE Grade 4 neutropenia lasting ˃7 days; 
 
CTCAE Grade ≥3 febrile neutropenia, where Grade 3 febrile 
neutropenia is defined as ANC <1000 / mm3 and a single temperature 

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of >38.3°C (101°F) or a sustained temperature of ≥38°C 
(100°F) for more than one hour; 
 
CTCAE Grade 3 thrombocytopenia ( ≥25,000/mm3 and 
<50,000/mm3) associated with bleeding; 
2. Non-hematological toxicity: 
 
Hy’s law, defined as: 
 AST or ALT > 3 x the upper limit of normal (ULN) AND 
 Total bilirubin > 2 x ULN AND 
 Alkaline phosphatase < 2 x ULN AND 
 No other reason for liver injury 
 
ALT or AST >8x ULN, ALT or AST >5x ULN for more than 2 weeks, 
ALT or AST >3x ULN and (TBL >2x ULN or INR >1.5) 
 For patients with hepatic metastases, AST or ALT > 8 x ULN or 
AST or ALT > 5 x ULN for ≥ 14 days 
 
Grade > 3 non-hematologic toxicity with the exception of the 
following 
 Grade 3+ fatigue ≥7 days regardless of baseline grade； 
 Grade 3 nausea and vomiting, lasting ≤ 2 days with optimal 
medical management； 
 Grade 3 diarrhea lasting ≤ 3 days with optimal medical 
management 
 ≥3+ non-hematologic abnormalities should also include 
laboratory values that cause symptoms. 
MTD Evaluation period： 
 
Part A: FWD1802 single dose run-in period (C0:D1-D6 intake on 
D1, then off until D6 ) and 1st 28-day treatment cycle (C1:D1-D28), 
total of 34 days; 
 
Part B: the 1st treatment cycle of FWD1802 in combination with 
palbociclib (C1:D1-D28) 

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Duration 
of 
treatment 
Reiterated treatment cycles of 4 weeks until progression disease based on 
radiological evaluation, undue drug toxicity, withdrawal of consent or 
death, whichever occurs first. 
PK/PD Sample 
Please see Section7.5.1 PK Samples and Section 7.3.7 18F-FES PET/CT. 
Statistical 
Methods 
Descriptive analysis (summary statistics) will be used to describe the 
safety and efficacy endpoints. 
Safety Analysis: 
 
Incidence and severity of adverse events according to the NCI-
CTCAE 
(V5.0) 
will 
be 
summarized 
and 
displayed 
in 
number/percentage. The exposure extent to the study drug will be 
displayed.. 
Efficacy Analysis: 
 
The ORR and its exact 95% Clopper-Pearson confidence interval 
will be calculated. The CBR, DCR will also be calculated similarly. 
All of the time-to-event data (PFS, DOR,OS ) will be estimated using 
Kaplan-Meier method, and the median along with two-sided 95% CI 
will be displayed(use the Greenwood’s formula for estimation of 
standard errors). 
Pharmacokinetic analysis: 
 
A descriptive analysis of the plasma concentration and derived PK 
parameters of FWD1802 and its metabolite (if possible) will be 
conducted by dose level. Plasma concentration patient profiles 
versus time and mean concentration versus time will be displayed. 

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Table 1 Schedule of Events in Part A Dose Escalation 
Items 
Scree
ning1 
Single dose 
Multiple dose  
Follow-up 
4 days 
Cycle 1 
28days 
Cycle 2  
≥Cycle3  
EOT 
2 
SFU 
3 
LTFU4  
Visit Day 
D-
28~ 
D-1 
D 1 
D2~
D4 
 
D1 
D8 
D1
5 
D2
2 
D1 
D15 
D 1 
 
 
 
Evaluation Window 
(Days) 
 
 
0 
 
 
0 
 
 
0 
 
 
0 
 
 
0 
 
± 
1 
 
± 
1 
 
± 
1 
 
± 
3 
 
± 
3 
 
± 
3 
 
± 
7 
 
± 
7 
 
± 
7 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent diseases 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Procedures/Assessments 
Weight 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Body height 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical 
examination5  
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs6 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Score 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG7 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Echocardiogram 
X 
 
 
 
X 
 
 
 
 
 
X 
(Every 
3weeks) 
 
 
 
Laboratory Assessments 
Blood Chemistry 
X 
X* 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology 
X 
X* 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Coagulation 
X 
X* 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
X* 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Virology: HBV, 
HCV, and HIV8  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-1910  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Items 
Scree
ning1 
Single dose 
Multiple dose  
Follow-up 
4 days 
Cycle 1 
28days 
Cycle 2  
≥Cycle3  
EOT 
2 
SFU 
3 
LTFU4  
Visit Day 
D-
28~ 
D-1 
D 1 
D2~
D4 
 
D1 
D8 
D1
5 
D2
2 
D1 
D15 
D 1 
 
 
 
Evaluation Window 
(Days) 
 
 
0 
 
 
0 
 
 
0 
 
 
0 
 
 
0 
 
± 
1 
 
± 
1 
 
± 
1 
 
± 
3 
 
± 
3 
 
± 
3 
 
± 
7 
 
± 
7 
 
± 
7 
PK Assessments 
PK Blood Samples11 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
 
 
Efficacy Assessments 
Tumor Assessmen12 
X 
 
 
 
X (End of every 8 weeks in the first year; and 
every 12 weeks thereafter) 
 
 
 
Biomarker Exploration 
18F-FES PET/CT13 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
FWD1802 Tablet 
 
X 
 
 
Continuous Dosing 
 
 
 
Adverse Events 
X 
 
Concomitant 
Medications and Non-
Drug Supportive 
Interventions 
X 
 
Note: * The tests of hematology, urinalysis, blood biochemistry and coagulation before the first dose administration could be 
exempted if the tests planned during the screening period were performed within 3 days before the first administration on C0D1. 
Other examinations may be conducted if deemed clinically necessary by the investigator. 
1. Screening assessments are performed within 28 days before C0D1. Screening assessments performed no more than 4 days 
before C0D1 will qualify as baseline assessments and need not be repeated, unless otherwise specified. 
2. The end-of-treatment (EOT) will occur at the earliest day possible within 7 days after the last dose of FWD1802 or the 
subject decides to withdraw from study treatment for any reason. 
3. Safety follow-up (SFU) visit should be performed at 28 ±7 days after the last administration and prior to the initiation of a 
new anti-tumor therapy. Subjects who discontinue the study due to an unacceptable adverse event should be followed until 
AE relieves to grade 0-1 or AE is stable. If EOT visit is within the safety follow-up window, no further safety follow-up is 
required.  

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4. LTFU (long term follow-up) visit is for survival follow-up. LTFU visit will performed every 12(±7) weeks after completion 
of SFU (phone contact is acceptable if the patient cannot return to the site). 
5. Physical examination includes examination of whole human body systems (dermatologic, head, eyes, ears, nose, 
mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, extremities, abdomen, back, 
musculoskeletal, orientating neurologic, and psychiatric systems). 
6. Vital signs include temperature, pulse, breathing and blood pressure. On C0D1 and C1D1, the vital signs will be measured 
at pre-morning dose(s), and 0.5 h, 2 h, 4 h, 8 h, 12 h and 24 h after the morning dose(s). On C0D3, C0D4, C1D8, C1D15, 
C1D22, C2D1, C2D15, (C3~Cn) D1, the vital signs will be measured at pre-morning dose(s). Other examinations may be 
conducted if deemed clinically necessary by the investigator. 
7. 12-lead ECG will be performed three times at Screening, 30 min, 20 min and 10 min pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 
4 h, 5 h, 6 h, 8 h, 12 h and 24 h post-dose on C0D1 and C1D1, and the spacing between each ECG examination will be at 
least 1 min. On C1D8, C1D15, C1D22, C2D1, C2D15, (C3~Cn) D1, the 12-lead ECG will be measured at pre-morning 
dose(s) and 2 h after the morning dose(s). Meanwhile, 12-lead ECG will be performed on prematurely withdrawn. If QTcF > 
450 ms (male) or > 470 ms (female), 3 consecutive ECGs should be collected to calculate the mean QTcF value. 
8. Human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis B core antibody, hepatitis C virus antibody, 
and Treponema pallidum antibody. period and may optionally be done at additional time points depending on investigator 
discretion. 
9. Only applicable to women of childbearing age; Subjects must have a negative blood pregnancy test during the screening 
period. Pregnancy tests will be performed anytime during the course of the study, as per investigator’s discretion. Serum or 
urine tests are acceptable based on the site’s standard clinical practice, if a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
10. Infectious disease screening includes polymerase chain reaction for SARS-CoV-2;  
11. Blood will be collected for PK analysis of the FWD1802 Tablet and/or its metabolites (if any), details please refer to 7.5.1 
PK Samples. 
12. Tumor assessment: All patients will undergo MRI, chest, abdomen, pelvis and bone examination at baseline period, and 
subsequent imageological examination included the chest, abdomen, pelvis, and other metastatic sites, if any. The preferred 

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imaging methodology is CT enhanced scan, and using the same imaging examination method and examination conditions 
before and after the same lesion (including scanning slice thickness, contrast agent, etc.). However, If patient has a contrast 
allergy or intolerance to contrast medium, a plain CT scan is allowed. During the treatment period, imageological 
examination and efficacy assessment should be repeated every 8 weeks (± 7 days) from C1D1 for the first 12 months, then 
every 12 weeks (± 7 days) thereafter until disease progression. Each imaging examination should be performed in accordance 
with the original imaging schedule, without adjustment due to dose delay. Tumor assessments will continue until disease 
progression and will not be interrupted due to discontinuation of the study treatment. 
 
CT/MRI examination in the screening period should be confirmed by the sponsor to be acceptable with the test results 
before the C0D1 meeting the requirements (including the test results before the subject signs the informed consent form). 
 
Bone scan should be performed during the screening period. The bone scan during the screening period was performed 
by the sponsor to confirm the results of the research hospital within 42 days before the C0D1 that could meet the research 
requirements ( including the results of the examination before the subject signed the informed consent ). Bone scan was 
performed only when there were clinical indications during the study period. 
 
The investigator may perform off-schedule imaging assessment at any time when disease progression is suspected. 
Subjects with a first CR or PR should be confirmed by imaging confirmation or the next efficacy evaluation after at 
least 4 weeks. 
13. Using 18F-FES PET to monitor the detect in ER target occupation and inhibition. 
 
 

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Table 2 Schedule of Events in Part B Dose Escalation 
Items 
Screening1 
Escalation  
Follow-up 
Cycle 1 
Cycle 2 
≥Cycle3 
EOT 
2 
SFU 3 
LTFU4 
Visit Day 
D28~ D-1 
D1 
D8 
D15 
D22 
D 1 
D15 
D1 
Evaluation Window 
(Days) 
 
0 
±1 
±1 
±1 
±3 
±1 
±3 
±7 
±7 
±7 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent diseases 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Procedures/Assessments 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Body height 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical examination5  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
vital signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Echocardiogram 
X 
X(Every 3weeks) 
 
 
 
Laboratory Assessments 
Blood Chemistry 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
 
 
Coagulation 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
 
 
Virology: HBV, HCV, 
and HIV8  
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy9 
X 
 
 
 
 
 
 
 
 
 
 
COVID-1910  
X 
 
 
 
 
 
 
 
 
 
 
PK Assessments 
PK Blood Samples11 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Efficacy Assessments 
Tumor Assessmen12 
X 
X (End of every 8 weeks in the first year; and every 12 weeks thereafter) 
 
 
 
Biomarker Exploration 
18F-FES PET/CT13 
 
 
 
 
 
X 
 
 
 
 
 

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Items 
Screening1 
Escalation  
Follow-up 
Cycle 1 
Cycle 2 
≥Cycle3 
EOT 
2 
SFU 3 
LTFU4 
Visit Day 
D28~ D-1 
D1 
D8 
D15 
D22 
D 1 
D15 
D1 
Evaluation Window 
(Days) 
 
0 
±1 
±1 
±1 
±3 
±1 
±3 
±7 
±7 
±7 
Administrative Procedures 
Palbociclib Tablet 
 
Each cycle D1-21 for continuous administration, then D22-28 withdrawal 
 
 
 
FWD1802 Tablet 
 
Continuous Dosing 
 
 
 
Adverse Events 
X 
 
Concomitant 
Medications and Non-
Drug Supportive 
Interventions 
X 
 
Note: * The tests of hematology, urinalysis, blood biochemistry and coagulation before the first dose administration could be 
exempted if the tests planned during the screening period were performed within 3 days before the first administration on C1D1. 
Other examinations may be conducted if deemed clinically necessary by the investigator. 
1. Screening assessments are performed within 28 days before C1D1. Screening assessments performed no more than 7 days 
before C1D1 will qualify as baseline assessments and need not be repeated, unless otherwise specified. 
2. The end-of-treatment (EOT) will occur at the earliest day possible within 7 days after the last dose of FWD1802 or the 
subject decides to withdraw from study treatment for any reason. 
3. Safety follow-up (SFU) visit should be performed at 28 ±7 days after the last administration and prior to the initiation of a 
new anti-tumor therapy. Subjects who discontinue the study due to an unacceptable adverse event should be followed until 
AE relieves to grade 0-1 or AE is stable. If EOT visit is within the safety follow-up window, no further safety follow-up is 
required. 
4. LTFU (long term follow-up) visit is for survival follow-up. LTFU visit will performed every 12(±7) weeks after completion 
of SFU (phone contact is acceptable if the patient cannot return to the site). 
5. Physical examination includes examination of whole human body systems (dermatologic, head, eyes, ears, nose, 
mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, extremities, abdomen, back, 
musculoskeletal, orientating neurologic, and psychiatric systems). 

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6. Vital signs include temperature, pulse, breathing and blood pressure. On C1D1, C1D8, C1D15, C1D22, C2D1, C2D15 and 
(C3~Cn) D1, the vital signs will be measured at pre-morning dose(s), and 0.5 h, 2 h, 4 h, 8 h, 12 h and 24 h after the morning 
dose(s). Other examinations may be conducted if deemed clinically necessary by the investigator. 
7. 12-lead ECG will be performed three times at Screening, 30 min, 20 min and 10 min pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 
4 h, 5 h, 6 h, 8 h, 12 h and 24 h post-dose on C1D1, C1D8, C1D15, C1D22, C2D1, C2D15 and (C3~Cn) D1. The 12-lead 
ECG will be measured at pre-morning dose(s) and 2 h after the morning dose(s). Meanwhile, 12-lead ECG will be performed 
on prematurely withdrawn. If QTcF > 450 ms (male) or > 470 ms (female), 3 consecutive ECGs should be collected to 
calculate the mean QTcF value. 
8. Human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis B core antibody, hepatitis C virus antibody, 
and Treponema pallidum antibody. period and may optionally be done at additional time points depending on investigator 
discretion 
9. Only applicable to women of childbearing age; Subjects must have a negative blood pregnancy test during the screening 
period. Pregnancy tests will be performed anytime during the course of the study, as per investigator’s discretion. Serum or 
urine tests are acceptable based on the site’s standard clinical practice, if a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
10. Infectious disease screening includes polymerase chain reaction for SARS-CoV-2;. 
11. Blood will be collected for PK analysis of the FWD1802 Tablet and/or its metabolites (if any), details please refer to 7.5.1 
PK Samples. 
14. Tumor assessment: All patients will undergo MRI, chest, abdomen, pelvis and bone examination at baseline period, and 
subsequent imageological examination included the chest, abdomen, pelvis, and other metastatic sites, if any. The preferred 
imaging methodology is CT enhanced scan, and using the same imaging examination method and examination conditions 
before and after the same lesion (including scanning slice thickness, contrast agent, etc.). However, If patient has a contrast 
allergy or intolerance to contrast medium, a plain CT scan is allowed. During the treatment period, imageological 
examination and efficacy assessment should be repeated every 8 weeks (± 7 days) from C1D1 for the first 12 months, then 
every 12 weeks (± 7 days) thereafter until disease progression. Each imaging examination should be performed in accordance 
with the original imaging schedule, without adjustment due to dose delay. Tumor assessments will continue until disease 
progression and will not be interrupted due to discontinuation of the study treatment. 

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 
CT/MRI examination in the screening period should be confirmed by the sponsor to be acceptable with the test results 
before the C0D1 meeting the requirements (including the test results before the subject signs the informed consent form). 
 
Bone scan should be performed during the screening period. The bone scan during the screening period was performed 
by the sponsor to confirm the results of the research hospital within 42 days before the C0D1 that could meet the research 
requirements ( including the results of the examination before the subject signed the informed consent ). Bone scan was 
performed only when there were clinical indications during the study period. 
 
The investigator may perform off-schedule imaging assessment at any time when disease progression is suspected. 
Subjects with a first CR or PR should be confirmed by imaging confirmation or the next efficacy evaluation after at 
least 4 weeks.. 
12. Using 18F-FES PET to monitor the detect in ER target occupation and inhibition. 
 
 

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Table 3 Schedule of Events in Part C Dose Expansion 
Items 
Screening1 
Expansion 
Follow-up 
Cycle 1 
Cycle 2 
≥Cycle3 
EOT 
2 
SFU 3 
LTFU4  
Visit Day 
D28~ D-1 
D1 
D 1 
D1 
Evaluation Window 
(Days) 
 
0 
±3 
±3 
±7 
±7 
±7 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Concurrent diseases 
X 
 
 
 
 
 
 
Clinical Procedures/Assessments 
Weight 
X 
X 
X 
X 
X 
 
 
Body height 
X 
X 
X 
X 
X 
 
 
Physical examination5  
X 
X 
X 
X 
X 
 
 
vital signs6 
X 
X 
X 
X 
X 
 
 
ECOG Score 
X 
X 
X 
X 
X 
 
 
12-lead ECG7 
X 
X 
X 
X 
X 
 
 
Echocardiogram 
X 
X(Every 3weeks) 
 
 
 
Laboratory Assessments 
Blood Chemistry 
X 
X 
X 
X 
X 
 
 
Hematology 
X 
X 
X 
X 
X 
 
 
Coagulation 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
X 
X 
X 
X 
 
 
Virology: HBV, HCV, 
and HIV8  
X 
 
 
 
 
 
 
Pregnancy9 
X 
 
 
 
 
 
 
COVID-1910  
X 
 
 
 
 
 
 
PK Assessments 
PK Blood Samples11 
 
X 
X 
X 
 
 
 
Efficacy Assessments 
Tumor Assessmen12 
X 
X (End of every 8 weeks in the first year; and every 12 weeks 
thereafter) 
 
 
 
Biomarker Exploration 

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Items 
Screening1 
Expansion 
Follow-up 
Cycle 1 
Cycle 2 
≥Cycle3 
EOT 
2 
SFU 3 
LTFU4  
Visit Day 
D28~ D-1 
D1 
D 1 
D1 
Evaluation Window 
(Days) 
 
0 
±3 
±3 
±7 
±7 
±7 
Administrative Procedures 
18F-FES PET/CT13 
X 
 
X 
 
 
 
 
FWD1802 Tablet 
X 
Continuous Dosing 
 
 
 
Adverse Events 
X 
 
Concomitant 
Medications and Non-
Drug Supportive 
Interventions 
X 
 
Note: * The tests of hematology, urinalysis, blood biochemistry and coagulation before the first dose administration could be 
exempted if the tests planned during the screening period were performed within 3 days before the first administration on C0D1. 
Other examinations may be conducted if deemed clinically necessary by the investigator. 
1. Screening assessments are performed within 28 days before C1D1 dose. Screening assessments performed no more than 7 
days before C1D1 will qualify as baseline assessments and need not be repeated, unless otherwise specified. 
2. The end-of-treatment (EOT) will occur at the earliest day possible within 7 days after the last dose of FWD1802 or the 
subject decides to withdraw from study treatment for any reason. 
3. Safety follow-up (SFU) visit should be performed at 28 ±7 days after the last administration and prior to the initiation of a 
new anti-tumor therapy. Subjects who discontinue the study due to an unacceptable adverse event should be followed until 
AE relieves to grade 0-1 or AE is stable. If EOT visit is within the safety follow-up window, no further safety follow-up is 
required.  
4. LTFU (long term follow-up) visit is for survival follow-up. LTFU visit will performed every 12(±7) weeks after completion 
of SFU (phone contact is acceptable if the patient cannot return to the site). 
5. Physical examination includes examination of whole human body systems (dermatologic, head, eyes, ears, nose, 
mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, extremities, abdomen, back, 
musculoskeletal, orientating neurologic, and psychiatric systems). 

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6. Vital signs include temperature, pulse, breathing and blood pressure. On C1D1, C2D1 and (C3~Cn) D1, the vital signs will 
be measured at pre-morning dose(s), and 0.5 h, 2 h, 4 h, 8 h, 12 h and 24 h after the morning dose(s). Other examinations 
may be conducted if deemed clinically necessary by the investigator. 
7. 12-lead ECG will be performed three times at Screening, 30 min, 20 min and 10 min pre-dose and 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 
4 h, 5 h, 6 h, 8 h, 12 h and 24 h post-dose on C1D1, C2D1 and (C3~Cn) D1. The 12-lead ECG will be measured at pre-
morning dose(s) and 2 h after the morning dose(s). Meanwhile, 12-lead ECG will be performed on prematurely withdrawn. 
If QTcF > 450 ms (male) or > 470 ms (female), 3 consecutive ECGs should be collected to calculate the mean QTcF value. 
8. Human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis B core antibody, hepatitis C virus antibody, 
and Treponema pallidum antibody. period and may optionally be done at additional time points depending on investigator 
discretion 
9. Only applicable to women of childbearing age; Subjects must have a negative blood pregnancy test during the screening 
period. Pregnancy tests will be performed anytime during the course of the study, as per investigator’s discretion. Serum or 
urine tests are acceptable based on the site’s standard clinical practice, if a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
10. Infectious disease screening includes polymerase chain reaction for SARS-CoV-2;. 
11. Blood will be collected for PK analysis of the FWD1802 Tablet and/or its metabolites (if any), details please refer to 7.5.1 
PK Samples. 
15. Tumor assessment: All patients will undergo MRI, chest, abdomen, pelvis and bone examination at baseline period, and 
subsequent imageological examination included the chest, abdomen, pelvis, and other metastatic sites, if any. The preferred 
imaging methodology is CT enhanced scan, and using the same imaging examination method and examination conditions 
before and after the same lesion (including scanning slice thickness, contrast agent, etc.). However, If patient has a contrast 
allergy or intolerance to contrast medium, a plain CT scan is allowed. During the treatment period, imageological 
examination and efficacy assessment should be repeated every 8 weeks (± 7 days) from C1D1 for the first 12 months, then 
every 12 weeks (± 7 days) thereafter until disease progression. Each imaging examination should be performed in accordance 
with the original imaging schedule, without adjustment due to dose delay. Tumor assessments will continue until disease 
progression and will not be interrupted due to discontinuation of the study treatment. 

IND FWD1802 
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 
CT/MRI examination in the screening period should be confirmed by the sponsor to be acceptable with the test results 
before the C0D1 meeting the requirements (including the test results before the subject signs the informed consent form). 
 
Bone scan should be performed during the screening period. The bone scan during the screening period was performed 
by the sponsor to confirm the results of the research hospital within 42 days before the C0D1 that could meet the research 
requirements ( including the results of the examination before the subject signed the informed consent ). Bone scan was 
performed only when there were clinical indications during the study period. 
 
The investigator may perform off-schedule imaging assessment at any time when disease progression is suspected. 
Subjects with a first CR or PR should be confirmed by imaging confirmation or the next efficacy evaluation after at 
least 4 weeks. 
12. Using 18F-FES PET to monitor the detect in ER target occupation and inhibition 
 
 
 

List of Abbreviations and Definitions of Terms 
Abbreviation/ 
Specialist Term 
Definition 
AE 
Adverse event 
AUC 0-t 
Area under the plasma concentration time curve 
AUC0-inf 
The area under the plasma concentration-time curve from time 
0 extrapolated to infinity. 
AF1 
Activation function 1 
CL/F 
Apparent clearance 
Cmax 
Maximum concentration 
CR 
Complete response 
Cave_ss 
Average concentration at steady status 
Cmax_ss 
Maximum concentration at steady status 
Cmin_ss 
Minimum concentration at steady status 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
DBD 
DNA binding domain 
DCR 
Disease control rate 
DF 
Degree of fluctuation 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ER+ 
Estrogen receptor positive 
eCRF 
Electronic case report form 
GCP 
Good Clinical Practice 
GGT 
Glutamyl transpeptidase 
HED 
Human equivalent dose 
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest non-severely toxic dose 

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Abbreviation/ 
Specialist Term 
Definition 
ICH 
Ineternational Council for Harmonization of Techincal 
Requirements for Pharmaceuticals for Human Use 
LBD 
Ligand binding domain 
MAD 
Maximum allowable dose 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose 
NMPA 
National Medical Products Administration 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive Disease   
PFS 
Progress free survival 
PK 
Pharmacokinetics 
PKCS 
Pharmacokinetics concentration set 
PKPS 
Pharmacokinetics parameter set 
QD 
Once-daily 
RP2D 
Recommended Phase II dose 
SAE 
Severe adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SERD 
Selective estrogen receptor downregulator 
SERM 
Selective estrogen receptor modulators 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Classification 
SOP 
Standard Operating Procedure 
t1/2 
Elimination half life 
TEAE 
Treatment emergent adverse event 
Tmax 
Peak time 
UBG 
Urobilinogen 
ULN 
Upper Limits of Normal 

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Abbreviation/ 
Specialist Term 
Definition 
Vd/F 
Apparent volume of distribution 
Vss 
Steady state volume of distribution 
λz 
Elimination rate constant 
 
 
 

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1 Introduction 
1.1 Background 
Breast cancer is a cancer that starts in breast tissue. It happens when cells in the breast 
change and grow out of control. The cells usually form a tumor. In 2020, breast cancer 
became the most commonly diagnosed cancer type in the world; there were more than 2.26 
million new cases of breast cancer and almost 685 000 deaths from breast cancer worldwide. 
Breast cancer was the most common cause of cancer death in women and the fifth most 
common cause of cancer death overall(Organization). Approximately 70% of breast 
cancers are estrogen receptor positive (ER+) and are classified as luminal A or luminal B 
subtype (Lu & Liu, 2020). 
Treatment strategies differ according to molecular subtype. Management of breast cancer 
is multidisciplinary; it includes locoregional (surgery and radiation therapy) and systemic 
therapy approaches. Systemic therapies include endocrine therapy for hormone receptor-
positive disease, chemotherapy, anti-HER2 therapy for HER2-positive disease, bone 
stabilizing agents, poly(ADP-ribose) polymerase inhibitors for BRCA mutation carriers 
and, quite recently, immunotherapy(Harbeck et al., 2019). 
Early stage ER+ breast cancer is usually treated with surgery; in contrast, advanced stage 
breast cancer is commonly associated with metastasis to distant organs and surgical 
treatment is generally no longer an option (Maughan, Lutterbie, & Ham, 2010; Osborne, 
1998). Endocrine therapy (ET) is the first-line treatment available for ER+ breast cancer 
patients and the available drugs are categorized into three major types: selective estrogen 
receptor modulators (SERMs), aromatase inhibitors or SERDs (Lu & Liu, 2020; Shagufta, 
Ahmad, Mathew, & Rahman, 2020). SERMs compete with estrogen for ER binding and 
show mixed agonist/antagonist capabilities in a tissue-specific fashion (Liu, Han, & Smith, 
2013). Aromatase is an enzyme that plays a significant role in the biosynthesis of important 
endogenous estrogens from androgens. Aromatase inhibitors such as anastrozole are 
compounds that are competitive inhibitors of the enzyme aromatase and block the synthesis 
of estrogen by binding to the estrogen receptor (Ahmad & Shagufta, 2015; Ravisekar, 
2007). SERDs create an unstable protein complex that induces ER protein degradation via 
proteasome (Liu et al., 2013). 
Unfortunately, 30−50% of ER positive tumors become resistant to SERM/AI treatment 
after 3−5 years (Lu & Liu, 2020). Clinical resistance associated with progression of disease 
remains a significant therapeutic challenge. Mutations of the ESR1 gene, which encodes 
the ER, have been increasingly recognized as an important mechanism of ET resistance, 
with a prevalence that ranges from 11 to 39% (Reinert, Saad, Barrios, & Bines, 2017). 
Targeted therapy directed to ESR1-mutated clones is an appealing concept, and preclinical 
and clinical development of rationale-based novel therapeutic strategies, new-generation 
SERDs that inhibit these ER mutants has the potential to substantially improve treatment 
outcomes (Reinert et al., 2017). Based on current research (Fribbens et al., 2016), ESR1 
mutations are associated with inferior outcomes with further AI treatment and ESR1-
mutant cancers show selective sensitivity to fulvestrant, the only approved SERD. 

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Direct targeting of ERα is achieved by selective estrogen receptor modulator (SERM) (e.g., 
tamoxifen) and selective estrogen receptor degrader (SERD) (e.g., fulvestrant). SERMs 
compete with estrogen for ER binding and show mixed agonist/antagonist capabilities in a 
tissue-specific fashion. Meanwhile, SERDs create an unstable protein complex that induces 
ER protein degradation via proteasome (Liu et al., 2013). SERDs are therefore considered 
a significant therapeutic approach to treat ER+ BC in both early stage and more advanced 
drug-resistant cases. These types of treatment have demonstrated to improve both survival 
and relapsing times. 
Fulvestrant is currently an important therapeutic approach for the treatment of endocrine-
resistant breast cancers. The poor pharmacokinetic properties of fulvestrant have inspired 
the development of a new generation of oral SERDs to overcome the poor pharmacokinetic 
and drug resistance (Hernando et al., 2021). 
FWD1802 is a novel oral SERD, which binds competitively to the ER, with an affinity 
approximately comparable to that of fulvestrant. FWD1802 acts as a competitive inhibitor 
of the activation of the ER by estradiol, causing the ER to be degraded and thus 
downregulated. In vitro, anti-proliferative effects studies have demonstrated that 
FWD1802 showed a significant growth inhibitory effect in all 3 ER-positive human breast 
cancer cell lines (MCF7, T47D, CAMA1) and 2 MCF7 cell lines with ERα Y537S or 
D538G mutation (MCF7/ERα Y537S and MCF7/ERα D538G) with the relative IC50 
values from 0.0005 μM to 0.0248 μM. Also, FWD1802 exhibits anti-tumor activity in the 
ER-positive or ESR1 Y537S mutation human breast cancer xenograft models. Besides, the 
combination of FWD1802 and Palbociclib significantly inhibited tumor growth with 
greater potency than monotherapy at the same dosage. These results suggest that FWD1802 
has the potential to provide clinical benefit to ER+ /HER2- unresectable locally advanced 
or metastatic breast cancer patients and ER+/HER2- unresectable locally advanced or 
metastatic breast cancer with ESR1 mutation patients as monotherapy and combination. 
1.2 Non-Clinical Information 
1.2.1 Pharmacology  
FWD1802 exhibited significant antagonistic activity against ERα, ERβ, ERα D538G, and 
ERα Y537S in a concentration-dependent manner. FWD1802 exhibited great ERα 
degradation potency and efficiency. FWD1802 had no effect on inducing PR expression 
but significantly down-regulated PR (used as a downstream biomarker of a functional ERα 
signaling pathway) expression in the presence of estradiol.  
In vitro pharmacodynamic studies showed that FWD1802 had significant growth inhibitory 
effects in ER positive human breast cancer cell lines and genetically engineered MCF7 cell 
lines with ERα Y537S or D538G mutation.  
In vivo, FWD1802 (at the dosage ≥1mg/kg) exhibited anti-tumor activity in the ER-
positive or ESR1 Y537S mutation human breast cancer xenograft models. Besides, the 
combination of FWD1802 and Palbociclib significantly inhibited tumor growth with 
greater potency than monotherapy at the same dosage. 

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The in vitro target screening studies showed that there was a low off-target potential of the 
FWD1802. However, because the clinical Cmax cannot be obtained until the phase 1 clinical 
trials, the safety of the compound needs to be further verified by future data. 
There were no test article-related adverse effects on the CNS, respiratory and 
cardiovascular systems. The IC50 for the inhibitory effect of FWD1802 on hERG 
potassium current was 4.51 µM. The safety of the compound on cardiovascular needs to be 
further verified by actual clinical exposure. 
1.2.2 Pharmacokinetics 
FWD1802 demonstrated low permeability across the Caco-2 cell monolayer. The systemic 
exposure of FWD1802 increased dose proportionally with the dose levels and no marked 
accumulation was observed post repeated oral dosing in rats and dogs. FWD1802 showed 
no sex differences at all dose levels when comparing the AUC0-last and Cmax in male and 
female rats or dogs. The systemic exposure of FWD1802-IM02 was relatively stable 
compared to FWD1802, and the two isomers (FWD1802-IM02 and FWD1802) exist as a 
relatively fixed ratio in rats and dogs, with the AUC Ratio values 0.0866~0.121 and 0.0958 
to 0.120, and the Cmax Ratio values 0.0941~0.126 and 0.0793 to 0.105, respectively in all 
PO dose groups. In addition, the same or similar mean PK parameter values for the two 
isomers were observed, including Tmax, T1/2, and so on. Overall, there is the reason to 
consider that the two isomers have same or similar pharmacokinetic behavior in male and 
female SD rats/beagle dogs. 
The binding of FWD1802 to plasma protein were high in rat, monkey and human (>95%), 
very high in dog (>99%), or high to very high in mouse (>98%). Following a single oral 
dose of [14C] FWD1802 at 10 mg/100 µCi/kg to intact rats, FWD1802 distributed widely 
and mainly distributed in lungs, liver, stomach wall and intestine tract wall. The peak 
concentrations of TRA was reached in 4 h post-dose in most tissues and blood. At 72 h 
post-dose, the TRA in blood and brain of male and female rats, and heart of female rats 
were below the limit of quantitation, the TRA in blood and other tissues were all still 
detected measurable concentrations. The TRA exposure (Cmax) in reproductive organ of 
female rats were significantly higher than those of male rats, while the exposure levels in 
other tissues were similar between male and female rats. 
FWD1802 was moderately metabolized in SD rat, cynomolgus monkey and human liver 
microsomes, and slowly metabolized in CD-1 mouse and beagle dog liver microsomes. 
Meanwhile, FWD1802 was highly metabolized in CD-1 mouse, SD rat, and beagle dog 
hepatocytes, moderately metabolized in cynomolgus monkey and human hepatocytes. But 
there was no significant difference in the peak area ratio of FWD1802-IM02 to FWD1802 
in different species liver microsomes or hepatocytes and incubation time. FWD1802 was 
stable in whole blood of different species, SGF within 6 hours, and SIF within 24 hours. 
And there was no significant difference in the peak area ratio of FWD1802-IM02 to 
FWD1802 in blood, SGF or SIF. FWD1802 was mainly unchanged in liver microsomes, 
primarily 
metabolized via N-dealkylation, mono-oxygenation, hydrolysis, 
and 
dedecarboxylation. The metabolites formed in the incubation of human liver microsomes 
were detected in microsomes of at least one of the animal species. In the mouse, rat, dog, 

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monkey, and human hepatocytes, in addition to the unchanged FWD1802, a total of 14 
metabolites of FWD1802 were detected and identified. FWD1802 was mainly metabolized 
via glucuronidation and N-dealkylation. M8 (glucuronidation metabolites) was the 
metabolite only detected in human hepatocytes, accounting for 0.95%. The no detection of 
M8 in animal species might be caused by less metabolism extent in animal species. CYP3A 
was the major metabolic enzyme responsible for the formation of metabolites from 
FWD1802. Based on the metabolites of [14C] FWD1802 identified in SD rat blood, bile, 
urine and feces, the major metabolic clearance pathways of [14C] FWD1802 were 1) 
dehydrogenation to form M1, M2 and M15, excreted from feces via bile; 2) N-dealkylated 
to form M14, or glucuronidation to form M7, mainly excreted from feces via bile; 3) 
unchanged drug directly excreted from feces. The major metabolic pathway of FWD1802 
in beagle dogs blood was oxidative defluorination. 
The excretion route of FWD1802 was mainly via feces, and the excretion rate and recovery 
from male and female rats were similar. 
FWD1802 revealed inhibition CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and 
CYP3A, while no inhibitory effects on CYP1A2. FWD1802 showed no time-dependent 
inhibition on CYP1A2, CYP2B6 and CYP2D6, but it showed time-dependent inhibition 
on CYP2C8, CYP2C9, CYP2C19 and CYP3A. FWD1802 might be an inducer for 
CYP3A4 or CYP2B6, but had no induction potential on CYP1A2. And, FWD1802 
inhibited efflux mediated by P-glycoprotein and BCRP. It was probably a P gp substrate 
but a poor or non-BCRP substrate. Besides, FWD1802 demonstrated inhibition on 
OATP1B1, OATP1B3, OAT1, OCT2, MATE1, or MATE2-K except OAT3. In addition, 
FWD1802 was not a substrate for OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, 
or MATE2-K transporter. 
1.2.3 Toxicology 
For safety evaluation, the MTDs from GLP-compliant single-dose oral toxicity studies 
were 400 or 200 mg/kg for male or female rats, respectively, and 200 mg/kg for dogs. Two 
28-day repeated dose toxicity studies were conducted in rats and dogs. The STD10 in rats 
was considered to be 26 mg/kg/day and the HNSTD in dogs was 15 mg/kg/day.  
FWD1802 when administered once daily for 28 days to rats was well tolerated. Test article-
related adverse changes were limited to decreased food consumption and body weight gain 
in males at 26 mg/kg/day, and anatomic findings within ovaries and uterus in females at 
≥6.5 mg/kg/day which were attributed to the intended pharmacology (selective estrogen 
receptor degrader) of the test article. Test article-related adverse changes in dogs were 
limited to histopathological findings in the reproductive tract in both sexes at ≥2.5 
mg/kg/day. 
In vitro genotoxicity studies showed there was no genotoxicity risk for FWD1802. 
In summary, FWD1802 displayed a high degree of selectivity to ER, causing the ER to be 
degraded and thus downregulated. FWD1802 showed a significant growth inhibitory effect 
in ER-positive human breast cancer cell lines and MCF7 cell lines with ERα Y537S or 

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D538G mutation. FWD1802 monotherapy or combination with Palbociclib exhibit desired 
anti-tumor activity in the ER-positive or ESR1 Y537S mutation human breast cancer 
xenograft models. Besides, the potential toxicity of FWD1802 was well assessed in 
nonclinical safety assessments, and the results support the proposed phase 1 clinical trial 
with appropriate monitoring. 
1.3 Study Rationale 
1.3.1 Rational for Dose Regimen of Escalation  
The starting dose in humans is mainly determined based on the nonclinical information. It 
is based on the ICH guidance which recommends that the starting dose should be either 
1/10 of the severely toxic dose occurring in 10% of animals in rodent toxicity studies 
(STD10) or 1/6 of the highest non-seriously toxic dose (HNSTD) observed in non-rodent 
studies. 
The HNSTD was determined to be 15 mg/kg/day in dogs from the repeated toxicity study. 
Converting from animal dose to human dose normalized by body surface area, the human 
equivalent dose (HED) derived from 1/6 of the dog HNSTD is calculated to be 81 mg/day. 
The STD10 was determined to be 26 mg/kg/day in rats from the repeated toxicity study. 
Converting from animal dose to human dose normalized by body surface area, the human 
equivalent dose (HED) derived from 1/10 of the rat STD10 is calculated to be 25 mg/day. 
The conversion is provided in Table 4. 
Table 4 tarting Dose for Escalation 
 
Animal 
Dose 
HED 
MRSDa 
Toxicity 
Rats 
26 mg/kg/day 
0.42 mg/kg/day 
25 mg/day 
- 
Dogs 
15 mg/kg/day 
1.35 mg/kg/day 
81 mg/day 
a: calculated based on human body weight of 60 kg. 
For the time being, the proposed starting dose 25 mg/day is considered to be a safe dose 
for administration to ER+/HER2- unresectable locally advanced or metastatic breast cancer 
patients. The proposed maximum dose in humans has been provisionally set as 450 mg/day; 
it may be adjusted based on the tolerability of the previous dose level (Part A). 
1.4 Benefits and Risks  
1.4.1 Possible adverse events 
 
Nonclinical Toxicology 
In the 28-day repeat-dose toxicity study conducted in SD rats: test article-related changes 
in food consumption and body weights were noted in all treatment groups. In dosing phase, 
food consumption decreased in males (up to 17.6%) and increased in females (up to 19.2%) 
at ≥6.5 mg/kg/day, when compared with the control group. This reflected in the body 

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weight gain in dosing phase, with a slight decrease in males whereas a slight increase in 
females. As a result, at the end of dosing phase, mean body weights decreased by 12.03-
15.13% in males and increased by 19.96-22.17% in females at ≥6.5 mg/kg/day, when 
compared with the control group. The difference between males and females were 
attributed to the intended pharmacology (selective estrogen receptor degrader) of the test 
article. Following a 4-week recovery, the changes in food consumption and body weight 
gain had a tread of recovery in males at doses of 6.5 and 13 mg/kg/day and females at ≥6.5 
mg/kg/day, indicating reversibility in these groups. In contrast to this, changes in males at 
26 mg/kg/day showed no signs of recovery, and, thus, were considered adverse. Therefore, 
during clinical trials, the body weight of subjects shall be monitored. 
In the 28-day repeat-dose toxicity study conducted in SD rats: at the end of dosing phase, 
test article-related hematology changes were seen in females at ≥6.5 mg/kg/day and limited 
to increased reticulocyte (up to 35.8%) and corresponding increase in red blood cell width 
at ≥6.5 mg/kg/day, increases in neutrophils (up to 71.67%), lymphocytes (up to 77.64%), 
monocytes (up to 98.21%), basophils (up to 150%) and total number of leukocytes at ≥6.5 
mg/kg/day, and increased eosinophils (up to 81.25%) at ≥13 mg/kg/day, when compared 
with the control group. These changes were reversible not being present at the end of 
recovery phase, and lacked correlates in pathology findings, therefore were considered 
non-adverse. Additionally, there were slight increases in erythrocyte, hemoglobin and 
hematocrit at the end of recovery phase, which were considered secondary to the 
reticulocyte increase in dosing phase. Therefore, during clinical trials, the serum 
biochemistry parameters, hematology parameters and any other adverse reactions of 
subjects shall also be concerned. 
In the 28-day repeat-dose toxicity study conducted in beagle dogs: test article-related 
ophthalmic finding were noted in both sexes at 15 mg/kg/day including bilateral 
conjunctiva hyperemia and/or ocular discharge. The ocular discharge was also noted in the 
clinical observations in both sexes at 15 mg/kg/day with higher incidence and the number 
of animals affected than control group. These signs were recoverable during the recovery 
phase. Therefore, during clinical trials, the physical examination should be performed 
regularly to monitor the subject's eye examination.. 
 
Clinical Adverse Effects of FASLODEX® (Fulvestrant) 
As a similar-targeted drug, Fulvestrant is an approved SERD for the treatment of 
endocrine-resistant breast cancers. The most common adverse reactions occurring in ≥5% 
of patients receiving FASLODEX 500 mg were: injection site pain, nausea, bone pain, 
arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, 
asthenia, musculoskeletal pain, cough, dyspnea, and constipation. Increased hepatic 
enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX patients and were not dose-
dependent. 
Comparison of FASLODEX 500 mg and FASLODEX 250 mg (CONFIRM)(FDA, 2021) 
The following adverse reactions (Nevens et al.) were calculated based on the safety analysis 
of CONFIRM comparing the administration of FASLODEX 500 mg intramuscularly once 

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a month with FASLODEX 250 mg intramuscularly once a month. The most frequently 
reported adverse reactions in the FASLODEX 500 mg group were injection site pain (11.6% 
of patients), nausea (9.7% of patients), and bone pain (9.4% of patients); the most 
frequently reported adverse reactions in the FASLODEX 250 mg group were nausea (13.6% 
of patients), back pain (10.7% of patients), and injection site pain (9.1% of patients).  
Table 5 lists adverse reactions reported with an incidence of 5% or greater, regardless of 
assessed causality, from CONFIRM. 
Table 5 Adverse Reactions in CONFIRM (≥5% in Either Treatment Group) 
Adverse Reactions 
FASLODEX 500 mg 
N=361 
% 
FASLODEX 250 mg 
N=374 
% 
Body as a Whole 
Injection Site Pain1 
12 
9 
Headache 
8 
7 
Back Pain 
8 
11 
Fatigue 
8 
6 
Pain in Extremity 
7 
7 
Asthenia 
6 
6 
Vascular System 
Hot Flash 
7 
6 
Digestive System 
Nausea 
10 
14 
Vomiting 
6 
6 
Anorexia 
6 
4 
Constipation 
5 
4 
Musculoskeletal System 
Bone Pain 
9 
8 
Arthralgia 
8 
8 
Musculoskeletal Pain 
6 
3 
Respiratory System 
Cough 
5 
5 
Dyspnea 
4 
5 
1Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral 
neuropathy. 
In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 
mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, 
or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. Grade 
3-4 increases were observed in 1-2% of patients. The incidence and severity of increased 
hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg 
FASLODEX arms. 
Combination Therapy with Palbociclib (PALOMA-3)(FDA, 2021) 
The safety of FASLODEX 500 mg plus palbociclib 125 mg/day versus FASLODEX plus 
placebo was evaluated in PALOMA-3. The data described below reflect exposure to 
FASLODEX plus palbociclib in 345 out of 517 patients with HR-positive, HER2-negative 
advanced or metastatic breast cancer who received at least 1 dose of treatment in 
PALOMA-3. The median duration of treatment for FASLODEX plus palbociclib was 10.8 

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months while the median duration of treatment for FASLODEX plus placebo arm was 4.8 
months.  
Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) 
patients receiving FASLODEX plus palbociclib, and in 6 of 172 (3%) patients receiving 
FASLODEX plus placebo. Adverse reactions leading to discontinuation for those patients 
receiving FASLODEX pluspalbociclib included fatigue (0.6%), infections (0.6%), and 
thrombocytopenia (0.6%).  
The most common adverse reactions (≥10%) of any grade reported in patients in the 
FASLODEX plus palbociclib arm by descending frequency were neutropenia, leukopenia, 
infections, fatigue, nausea, anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, 
alopecia, rash, decreased appetite, and pyrexia.  
The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving 
FASLODEX plus palbociclib in descending frequency were neutropenia and leukopenia.  
Adverse reactions (≥10%) reported in patients who received FASLODEX plus palbociclib 
or FASLODEX plus placebo in PALOMA-3 are listed in Table 6, and laboratory 
abnormalities are listed in Table 7. 
Table 6 Adverse Reactions (≥10%) in PALOMA-3 
Adverse Reactions 
FASLODEX plus Palbociclib 
N=345 
FASLODEX plus Placebo 
N=172 
All Grades 
% 
Grade 3  
% 
Grade 4  
%  
All Grades 
% 
Grade 3  
% 
Grade 4  
%  
Infections and Infestations 
Infections1 
472 
3 
1 
31 
3 
0 
Blood and Lymphatic System Disorders 
Neutropenia 
83 
55 
11 
4 
1 
0 
Leukopenia 
53 
30 
1 
5 
1 
1 
Anemia 
30 
4 
0 
13 
2 
0 
Thrombocytopenia 
23 
2 
1 
0 
0 
0 
Metabolism and Nutrition Disorders 
Decreased appetite 
16 
1 
0 
8 
1 
0 
Gastrointestinal Disorders 
Nausea 
34 
0 
0 
28 
1 
0 
Stomatitis3 
28 
1 
0 
13 
0 
0 
Diarrhea 
24 
0 
0 
19 
1 
0 
Vomiting 
19 
1 
0 
15 
1 
0 
Skin and Subcutaneous Tissue Disorders 
Alopecia 
184 
N/A 
N/A 
65 
N/A 
N/A 
Rash6 
17 
1 
0 
6 
0 
0 
General Disorders and Administration Site Conditions 
Fatigue 
41 
2 
0 
29 
1 
0 
Pyrexia 
13 
<1 
0 
5 
0 
0 
1 Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections 
and infestations.  
2 Most common infections (≥1%)include: nasopharyngitis, upper respiratory infection, urinary tract 
infection, influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, 

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respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, 
paronychia. 
3 Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal 
inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis. 
4 Grade 1 events – 17%; Grade 2 events – 1%. 
5 Grade 1 events – 6%. 
6 Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, 
dermatitis acneiform, toxic skin eruption. 
Additional adverse reactions occurring at an overall incidence of <10.0% of patients 
receiving FASLODEX plus palbociclib in PALOMA-3 included asthenia (7.5%), aspartate 
aminotransferase increased (7.5%), dysgeusia (6.7%), epistaxis (6.7%), lacrimation 
increased (6.4%), dry skin (6.1%), alanine aminotransferase increased (5.8%), vision 
blurred (5.8%), dry eye (3.8%), and febrile neutropenia (0.9%). 
Table 7 Laboratory Abnormalities in PALOMA-3 
Laboratory Parameters 
FASLODEX plus Palbociclib 
N=345 
FASLODEX plus Placebo 
N=172 
All 
Grades 
% 
Grade 3  
% 
Grade 4  
%  
All 
Grades 
% 
Grade 3  
% 
Grade 4  
%  
WBC decreased 
99 
45 
1 
26 
0 
1 
Neutrophils decreased 
96 
56 
11 
14 
0 
1 
Anemia 
78 
3 
0 
40 
2 
0 
Platelets decreased 
62 
2 
1 
10 
0 
0 
Aspartate aminotransferase 
increased 
43 
4 
0 
48 
4 
0 
Alanine aminotransferase 
increased 
36 
2 
0 
34 
0 
0 
 
1.4.2 Risk control in trial design 
In the clinical study, a series of examinations (exams) at the screening and treatment period 
will be conducted. The frequency of the clinical laboratory (lab) tests such as blood 
biochemistry will be increased accordingly, if needed. Additional tests may be added, if 
deemed necessary. Additional risk to subjects include those attributable to study 
participation in general, including risks associated with frequent medical tests and 
laboratory blood draws, and the associated pain and discomfort.   
Strategies to mitigate these risks include close monitoring of adverse events (AEs) and lab 
results. Both individual and trial stopping criteria will be specified, AEs will be assessed in 
this protocol, and AEs of special interest will be paid extra attention. Supportive care and 
risk control management will also be provided to subjects, including appropriate treatment 
of any AEs. The risk to participants in this trial will be minimized by adherence to the 
eligibility criteria, closely clinical monitoring and stopping rules. 
Overall, the nonclinical data showed a positive benefit/risk ratio to support the clinical 
development of FWD1802 with appropriate safety monitoring. Data obtained from this 

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study will be provided to support later stages of clinical development for FWD1802 to be 
conducted in selected populations. 
1.5 Clinical Study Compliance 
This study will be conducted in compliance with this protocol, Good Clinical Practice 
(GCP), and all applicable regulatory requirements in United States  
 

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2 Objectives 
Primary Objective: 
• 
Establish the recommended phase II dose (RP2D) and/or the maximum tolerated dose 
(MTD) of FWD1802 as monotherapy and in combination with palbociclib in patients 
with ER+/HER2- unresectable locally advanced or metastatic breast cancer 
• 
Explore the safety and tolerability of FWD1802 as monotherapy and in combination 
with Palbociclib 
Secondary Objective: 
• 
Characterise Pharmacokinetics of FWD1802 as monotherapy and in combination 
with palbociclib  
• 
Explore preliminary efficacy signals 
Exploratory Objective: 
 
Biomarker of FWD1802 as monotherapy and in combination with palbociclib 

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3 Endpoints 
Safety should be evaluated at follow-up visits and throughout the study. Adverse events 
will be assessed for their severity (based on the NCI-CTCAE 5.0 rating), duration, and 
association with study treatment. 
The following safety indicators will be measured and evaluated at designated intervals 
throughout the study. Patient history was taken at baseline to understand underlying 
conditions. 
3.1 Safety and Tolerability 
 
Incidence of DLT in the MTD evaluation period, adverse events, treatment emergent 
adverse event (TEAE), serious adverse event (SAE), their relationship with the 
investigational product and respective severity. 
 
Changes in vital signs, ECOG score, ECG, physical examination, and laboratory tests 
before and after treatment, and the use of concomitant medication. 
3.2 PK Assessment 
 
Maximum plasma concentration (Cmax), Time to Cmax (Tmax), Area under the 
concentration versus time curve from time 0 to the last measurable concentration 
(AUC0-t), The area under the plasma concentration-time curve from time 0 
extrapolated to infinity (AUC0-inf); if data permitted, elimination half-life time (t1/2), 
apparent clearance (CL/F), apparent volume of distribution (Vz/F), and elimination rate 
constant (λz); 
 
Minimum concentration at steady state (Cmin_ss), Maximum concentration at steady 
state (Cmax_ss), Average concentration at steady state (Cave_ss), t1/2, CL/F, AUCtau_ss, 
Volume at steady state (Vss), elimination rate Constant (λz), accumulation ratio (AR) 
based on Cmax and AUCtau_ss; 
3.3 Efficacy Assessment 
 
Tumor response assessments by the corresponding criteria by RECIST v1.1 to assess 
Objective response rate (ORR), Clinical benefit rate (CBR), Duration of response 
(DoR), and Disease control rate (DCR) after the study treatment. 
3.4 Exploratory endpoints 
 
The correlation between ER target inhibition by using [18F]-fluorestradiol (FES) 
PET/CT and efficacy. 
 
Progression free survival (PFS) and Overall survival (OS). 
 
Other potential biomarker as needed. 

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4 Investigational Plan 
4.1 Overall Study Design 
This study is a multicenter, open-label, first-in-human study evaluating FWD1802 in 
patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer . It 
includes three parts: the dose escalation of FWD1802 as a monotherapy study (Part A), the 
dose escalation of FWD1802 in combination with palbocilib study (Part B) and the dose 
expansion of FWD1802 as a monotherapy study in ESR1 mutation patients. (Part C).Part 
A: Dose Escalation: It aims to investigate the safety, tolerability, PK, PD, and preliminary 
efficacy in patients with ER+ /HER2- unresectable locally advanced or metastatic breast 
cancer who have failed or are intolerant of standard treatment, or have no standard therapy. 
Part B: Dose Escalation: It aims to investigate the safety, tolerability, PK, PD, and 
preliminary efficacy in patients with ER+ /HER2- unresectable locally advanced or 
metastatic breast cancer who have failed or are intolerant of standard treatment, or have no 
standard therapy. 
Part C: Dose Expansion: It aims to further evaluate the safety, tolerability, PK, PD, and 
preliminary efficacy of FWD1802 in approximately 60 eligible subjects with ER+ /HER2- 
unresectable locally advanced or metastatic breast cancer with ESR1 mutation under the 
dose level of the recommended dose for expansion(s) identified in part A study. 
The overall study design is presented graphically in Figure 1. The detailed study procedures 
are provided in Section 7 
 
  
Figure 1 Clinical Design of FWD1802 in Phase I Trial 
 
4.2 Methodology 
4.2.1 Part A – Dose Escalation of FWD1802 as a Monotherapy 

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Part A study will be conducted in subjects diagnosed with ER+/HER2- unresectable locally 
advanced or metastatic breast cancer, to evaluate the safety and tolerability, PK, PD and 
preliminary anti-tumor activity of FWD1802 Tablet, and to determine RDEs. A maximum 
of 27 subjects will be enrolled. They will be sequentially allocated to 5 planned dose 
cohorts: 25 mg, 75 mg, 150 mg, 300 mg and 450 mg. 
Subjects enrolled will be orally administered a single dose of FWD1802 Tablet on Cycle 0 
Day 1 (C0D1), followed by a 5-day observation period to evaluate the PK and safety of the 
drug product. Starting on Cycle 1 Day 1 (C1D1), FWD1802 Tablet will be orally 
administered continuously once or quaque die (QD) for 28 consecutive days of each cycle. 
The DLT observation period is set as 34 days after the initial administration (1 cycle) 
(single-dose period and the first 28-day cycle). The second cycle and subsequent cycles 
will last for 28 days per cycle. The patients will continue to receive the study treatment 
until disease progression, death, unacceptable toxicity, withdrawal of informed consent, or 
other reasons to discontinue study treatment occurs, whichever comes first. 
Part A will utilize an accelerated dose escalation design to enroll one patient to dose levels 
1, which will be converted to a traditional ‘3+3’ design when a grade 2 or higher toxicity 
occurs during cycle 1 therapy at these dose levels unless it is clearly related to disease 
progression or extraneous cause, whichever comes first.  
Before starting the next dose level, all subjects (n=1, 3, or 6) at the current dose level must 
complete the DLT observation period. The Safety Monitoring Committee (SMC) will 
decide whether the study will proceed to the next dose level. Please refer to Section 4.7 
Dose modifications.  
Based on the safety data, a higher dose level beyond dose level 5 or an intermediate dose 
level can be explored as determined by the SMC. 
The planned escalation dose levels are shown below: 
Table 8. The Planned Dose Escalation Levels of FWD1802 in Phase Ia Study 
Groups 
Dose (mg) * 
Percentage of 
escalation (%) 
Number of 
subjects 
1(Starting dose) 
25 
/ 
1~3 
2** 
75 
200% 
3~6 
3** 
150 
100% 
3~6 
4** 
300 
100% 
3~6 
5** 
450 
50% 
3~6 
**Dose levels will be determined based on the results of lower doses, at the discretion of SMC. 
4.2.2 Part B- Dose Escalation of FWD1802 in combination with palbocilib 
The dose expansion study will be conducted in approximately 24 eligible subjects 
diagnosed with ER+/HER2- unresectable locally advanced or metastatic breast cancer, to 

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evaluate the safety, tolerability, PK, PD, and preliminary efficacy of FWD1802 in 
combination with palbocilib.  
The starting dose level for Part B study will be determined by SMC based on safety data 
(including the AE rate of non-DLT), PK, PD and preliminary efficacy in Part A. Every 
treatment cycle consists of 28 days. 
In brief, based on the available data obtained from Part A, 1 to 2 dose levels may be selected 
as the recommended dose levels (RDs) to evaluate FWD1802 in combination with 
palbocilib in these patients. 
4.2.3 Part C – Dose Expansion Study 
Part C (Dose Expansion of FWD1802 as a Monotherapy) can be conducted in parallel with 
Part A (Dose Escalation of FWD1802 as a Monotherapy) provided that the following two 
conditions are met: 
a) The starting dose of Part C study should be lower than the dose of monotherapy RP2D 
or the dose that has been explored and confirmed as safe for monotherapy. 
b) The SMC will review all available PK, PD, safety, tolerability and efficacy data for 
Part A study and decide whether the study may proceed to Part C portions. 
The dose expansion study will be conducted in approximately 60 eligible subjects 
diagnosed with ER+/HER2-/ESR1 mutation unresectable locally advanced or metastatic 
breast cancer, to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of 
FWD1802 Tablet at the recommended 1~2 dose level(s) for expansion. 
The specific number of subjects, administration dose and dosing regimen in dose expansion 
study will be determined by SMC based on the results of Part A study. 
4.3 Treatment Plan 
Subjects will receive FWD1802 tablets orally according to the overall study design; the 
administration scheme is shown above. Subjects will continue to receive FWD1802 until 
any of the criteria specified in Section 5.4 Subjects Withdrawal Criteria are met. 
Study drugs will be orally administered at the investigational site by site staff at 8 AM on 
the morning of the dosing days.  
Note:the first group of FWD1802 in phase A study (25 mg) will be conducted on the preset 
conditions, while the dose levels, dosing schedule and biological sample collection time 
points for other groups might be modified upon emerging data in this study. 
4.4 Dose Escalation/Stopping Criteria 
The combination of ‘accelerated escalation’ and the traditional ‘3+3’ was used for Part A 
study. It’s planned that one eligible subject will be enrolled for the evaluation of the first 

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dose levels (25 mg) using intra-individual dose escalation, when it is approved by sponsor 
and investigator. If no ≥ grade 2 adverse event (defined as any ≥ grade 2 adverse event 
occurs during the DLT observation period unless it is clearly related to disease progression 
or extraneous cause) occurs during the DLT observation period, dose escalation enters the 
2nd dose group with the traditional ‘3+3’ mode. Otherwise, additional 2 subjects will be 
added to the current dose group, and the dose group and subsequent dose groups will switch 
to a ‘3+3’ dose escalation design. Before starting the next dose level, all subjects (n=1, 3, 
or 6) at the current dose level must complete the DLT observation period and be determined 
by the Safety Monitoring Committee (SMC) to proceed to the next dose level. If no DLT 
has occurred at the end of the DLT observation period, subjects may adjust its dose level 
to any higher dose level that no DLT events have occurred during the DLT observation 
period, as assessed by the investigator and determined by the SMC, and on the condition 
that the investigator considers safe for the subjects. 
If MTD cannot be determined at this part due to too few DLT events, a higher dose or an 
intermediate dose can be explored as needed, after the dose escalation reaches the highest 
predicted dose or is determined by the SMC. 
The traditional ’3+3’ increment rule for dose escalation is as follows: 
 
The dose will be escalated if no DLT has been reported in the first 3 subjects of this 
dose group after DLT observation period.  
 
If 1 of the first 3 subjects enrolled has DLT occurred, then 3 additional subjects will be 
enrolled, with totally 6 subjects in this dose group. 
-If only 1 DLT event occurs in these 6 subjects, then the dose will be escalated. 
-If ≥ 2 DLT events occur in these 6 subjects, then no more subjects will be enrolled in 
this dose group and the dose escalation will be stopped. The SMC will decide whether 
to use the intermediate dose as the next dose level for the study or to terminate the dose 
escalation. 
 
If ≥ 2 DLT events occur in the first 3 subjects, then the dose escalation will be stopped, 
an intermediate dose or a lower dose level determined by the SMC will be selected as 
the next dose level for the study; or the dose escalation is terminated, according to the 
safety results of the enrolled subjects. 
4.5 Definition of MTD 
 
The maximum tolerable dose (MTD) is defined as the highest dose level while the 
incidence of DLT is less than 33% in the dose escalation study during the DLT 
evaluation period. 
 
Six patients are required to establish the MTD. If only 3 patients have been evaluated 
in the previous dose level below the non-tolerated dose, the cohort should be expanded 
to 6 patients at the previous dose level below the non-tolerated dose. If DLT is not 
observed in the additional 3 patients, or 6 patients have been evaluated at the previous 

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dose level, the MTD will be confirmed at the previous dose level below the non-
tolerated dose. 
 
If MTD is not established at the end of escalation, the maximum safety dose will be 
defined as the maximum administrated dose (MAD).  
 
The recommended dose for expansion(s) will be confirmed comprehensively based on 
the results of safety, tolerability, PK and PD. The RP2D should be a pharmacologically 
active dose and the dose should be selected by pooling and evaluating all available PK, 
PD, target engagement, efficacy, safety, and tolerability data to select the appropriate 
dose. There will need to be at least 6 patients at the recommended dose for expansion 
level(s) to evaluate the safety, PK, PD and tolerability. If the DLT does not occur during 
the DLT assessment period, the current highest dose level will not be considered as the 
basis of dose escalation and may be used as a reference to dose design and safety 
evaluation of the recommend dose. 
Based on the safety data, a higher dose level beyond dose level 9 or an intermediate dose 
level can be explored as determined by the SMC. 
4.6 Definitions of Dose-Limiting Toxicity (DLT) 
All AEs of the specified grades should count as DLTs except those that are clearly and 
incontrovertibly due to disease progression or extraneous causes. 
1. Hematological toxicity: 
 
CTCAE Grade ≥4 thrombocytopenia; 
 
CTCAE Grade 4 neutropenia lasting ˃7 days; 
 
CTCAE Grade ≥3 febrile neutropenia, where Grade 3 febrile neutropenia is defined 
as ANC <1000/mm3 and a single temperature of >38.3°C (101°F) or a sustained 
temperature of ≥38°C (100°F) for more than one hour; 
 
CTCAE Grade 3 thrombocytopenia (≥25,000/mm3 and <50,000/mm3) associated 
with bleeding; 
 
CTCAE Grade 4 (<25,000/m3) thrombocytopenia lasting>5days; 
2. Non-hematological toxicity: 
 
Hy’s law, defined as: 
 AST or ALT > 3 x the upper limit of normal (ULN) AND 
 Total bilirubin > 2 x ULN AND 
 Alkaline phosphatase < 2 x ULN AND 

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 No other reason for liver injury 
 
ALT or AST >8x ULN, ALT or AST >5x ULN for more than 2 weeks, ALT or AST >3x 
ULN and (TBL >2x ULN or INR >1.5) 
 For patients with hepatic metastases, AST or ALT > 8 x ULN or AST or ALT > 5 
x ULN for ≥ 14 days 
 
Grade > 3 non-hematologic toxicity with the exception of the following 
 Grade 3+ fatigue ≥7 days regardless of baseline Grade； 
 Grade 3 nausea and vomiting, lasting ≤ 2 days with optimal medical 
management； 
 Grade 3 diarrhea lasting ≤ 3 days with optimal medical management 
 ≥3+ non-hematologic abnormalities should also include laboratory values that 
cause symptoms. 
. 
4.7 Dose modifications 
4.7.1 Dose Reductions 
Dose reductions will be only allowed beyond DLT evaluation period in the dose escalation 
and expansion studies. Subjects who experience the unacceptable adverse events may 
continue treatment at the next lower dose level until disease progression or unacceptable 
toxicity. Adverse events considered for dose reduction should not include the events 
assessed by the investigator as exclusively related to underlying disease or other medical 
condition or concomitant treatment. The dose reduction guideline for general adverse 
events are outlined in Table 9. Provisions are not made for dose levels below 25 mg. If 25 
mg once daily is determined to be unsuitable based on DLT as defined above, 
FWD1802will be permanently discontinued. 
Table 9 Dose reductions guideline for general adverse events 
CTCAE grade 
Follow-up procedures and dose reductions 
CTCAE grade 1 
Continue to receive study treatment at same dose level 
Monitor closely. 
Provide supportive therapy. 
CTCAE grade 2 
Discontinue study treatment if there are clinical symptoms. 
Monitor closely. 
Provide supportive therapy. 
Restart study treatment at the same dose level if resolved to CTCAE grade 1 or 
baseline within 14 days. 
CTCAE grade 3 
Discontinue study treatment if there are clinical symptoms. 
Monitor closely. 

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CTCAE grade 
Follow-up procedures and dose reductions 
Provide supportive therapy. 
Restart to study treatment at one dose level lower (except dose group 1) if 
resolved to CTCAE grade 1 or baseline. 
Discontinue treatment if CTCAE grade 3 AE occurs again. 
Restart to study treatment at one dose level lower if resolved to CTCAE grade 1 
orbaseline within 21 days. 
CTCAE grade 4 
Discontinue study treatment if there are clinical symptoms. 
Monitor closely. 
Provide supportive therapy. 
Restart to study treatment at one dose level lower (except dose group 1) if 
resolved to CTCAE grade 1 or baseline within 21 days. 
If CTCAE grade 4 AE occurs again, discontinue permanently based on 
investigator and sponsor’s judgement. 
 
4.7.2 Dose Escalations 
Part A will utilize an accelerated dose escalation design to enroll one patient to dose levels 
1, which will be converted to a traditional 3+3 design when a grade 2 or higher toxicity 
occurs during cycle 1 therapy at these dose levels unless it is clearly related to disease 
progression or extraneous cause, whichever comes first. Intra-individual dose escalation 
will be allowed in this part A study when it is approved by sponsor and investigator. 
Upon completion of the DLT evaluation in patients in the high-dose level cohorts and 
confirmation that the dose is safe, patients in the low-dose level cohorts may be adjusted 
to the high-dose level study treatment that has completed the evaluation, with the consent 
of the principal investigator and the sponsor.  
Subjects in the dose expansion study may be allowed to transfer to a higher dose level if 
the benefits outweigh the risks, as assessed by the investigator, and determined by the SMC. 
The higher dose level should be safe and confirmed by the phase Ia dose escalation study, 
as assessed by the investigator and determined by the SMC. 
4.7.3 Temporary Withdrawal 
Study treatment may be suspended (not more than 28 days) for any of the following 
treatment-related adverse events: Grade 2 or higher adverse events, if clinically indicated, 
study treatment should be suspended until the event returns to grade 1 or baseline levels 
(see Table 9) 
The study drug may be discontinued for no more than 28 days until toxicity is relieved, or 
based on the investigator's judgment. If > 28 days, the patient continues to benefit from the 
treatment as assessed by the investigator, the patient may continue to receive the study 
treatment. 
 

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5 Study Population 
5.1 Number of Subjects 
 
Part A: approxiamately 27 patients 
 
Part B: approxiamately 12 patients in no more than 2 dose levels  
 
Part C: approxiamatetly 60 patients in no more than 2 dose cohorts, with 30 patients at 
the most in one dose cohort 
5.2 Inclusion Criteria 
1. Patients must understand and voluntarily sign the Informed Consent Form (ICF). 
2. Patients ≥ 18 years. 
3. Provision of blood sample to test ESR1 mutation status and for other biomarker 
assessment. In part A/B, the ESR1 mutation status will be tested retrospectively; In 
part C, only the patients with ESR1 mutation positive is eligible (See Appendix 6). 
4. Documented positive oestrogen receptor status of primary or metastatic tumour tissue, 
according to the local laboratory parameters. HER-2 negative. These laboratory 
parameters are consistent with accepted diagnostic guidelines such as the American 
Society of Clinical Oncology (ASCO) / College of American Pathologists (CAP) 
Clinical Practice Guideline for Pathologists estrogen (ER) and progesterone receptor 
(PgR) testing in breast cancer (Allison et al., 2020).  
5. Menopausal women according to one of the following criteria: 
 
Prior bilateral ovariectomy; 
 
Patients ≥ 60 years of age; 
 
Patients < 60 years of age presenting an amenorrhea of more than 12 months and 
follicle stimulating hormone (FSH) and plasma estradiol levels within the 
postmenopausal range as assessed by the local laboratory in the absence of 
chemotherapy, tamoxifen, tolimifene, or ovarian castration in the past 1 year, and 
no oral contraceptives, hormone replacement therapy, or gonadotropin-releasing 
hormone agonist or antagonist; 
 
Patients < 60 years of age who are taking either tamoxifen or tolomifene with two 
consecutive FSH and estradiol levels in the postmenopausal range. 
 
Or premenopausal or perimenopausal female subjects but must be willing to 
receive and maintain an approved luteinizing hormone-releasing hormone(LHRH) 
agonist during the study treatment period (LHRH agonist treatment initiated 28 
days prior to the first study drug treatment); or for males: willing to receive and 

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maintain an approved LHRH agonist during the study treatment period (LHRH 
agonist treatment initiated 28 days prior to the first study drug treatment). 
6. Previous therapy failed or intolerable, or standard therapy not available:  
Part A/C: Previous therapy failed or intolerable, or standard therapy not available. 
Part B/C: Patients should have received at least 1 line ET, or received no more than 1-
line systematic chemotherapy for advanced/metastatic disease, no more than 1 target 
therapy. 
7. Patients who are HIV positive with CD4+ T-cell counts ≥ 350 cells/uL may be 
eligible. 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
9. At least one measurable lesion according to RECISTv1.1 criteria. 
10. Life expectancy ≥ 12 weeks. 
11. Adequate organ and bone marrow function (no use of hematopoietic stimulating factor, 
no blood transfusion or human albumin within 7 days prior to screening): 
 
Blood routine: Absolute neutrophil count (ANC) ≥ 1.5×109/L; Platelet count 
(PLT) ≥100×109/L; Hemoglobin (HGB) ≥ 90 g/L; 
 
Liver function: Serum Total bilirubin (TBIL) ≤ 1.5 Upper limit of normal value 
(ULN); Alanine aminotransferase (ALT) and Aspartate transferase (AST) ≤ 
3×ULN in subjects without liver metastasis; ALT or AST≤ 5×ULN with liver 
metastasis; 
 
Renal function: Serum creatinine ≤ 1.5×ULN or estimated creatinine clearance 
(CLcr) ≥ 60 mL/min as calculated using Cockcroft-Gault formula; 
 
Coagulation function: Activated Partial thromboplastin Time (APTT) and 
international normalized ratio (INR) ≤ 1.5×ULN (or within target range if on 
anticoagulation therapy); 
 
Cardiac function: Echocardiography (ECHO) shows left ventricular ejection 
fraction (LVEF) > 50%. 
12. Women of childbearing potential must have a negative serum pregnancy test within 7 
days prior to the first dose. Female patients of childbearing potential must agree to use 
effective methods of contraception from the time of signature of informed consent, 
throughout the study and for 6 months after the last dose of the investigational product, 
like double barrier methods, condoms, oral or injectable contraceptives, intrauterine 
devices, etc. All female subjects will be considered to be of childbearing potential 

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unless they are postmenopausal, postmenopausal, or sterilized (hysterectomy, tubal 
resection). 
5.3 Exclusion Criteria 
1. Documented medical history or ongoing gastrointestinal disease (Including difficulty 
in swallowing capsules, Crohn's disease, ulcerative colitis, or short bowel syndrome) 
or other malabsorption that may affect the absorption of oral study drug. 
2. Participated in other clinical trials of investigational drugs or investigational devices 
within 4 weeks before the first medication; or received chemotherapy, targeted therapy, 
immunotherapy and clinical trial medication and other anti-tumor treatment within 4 
weeks, or received radiotherapy, endocrine drugs or Chinese traditional medicines with 
anti-tumor indications 2 weeks prior to the first dose. Or receive mitomycin and 
nitrosourea within 6 weeks prior to the first dose. 
3. The toxicity of previous anti-tumor treatment has not recovered to grade 0 or 1 (except 
for alopecia, chemotherapy-induced peripheral neurotoxicity ≤ grade 2). 
4. Major surgical surgery (except biopsy) or incomplete healing of the surgical incision 
within 4 weeks prior to the first study drug treatment. 
5. Known other malignant tumors within 2 years before enrollment (except for cervical 
carcinoma insitu, superficial noninvasive bladder tumors, breast ductal carcinoma in 
situ, prostatic intraepithelial neoplasia without evidence of prostate cancer, or 
curatively treated Stage I nonmelanoma skin cancer); 
6. Subjects with unstable or symptomatic or progressive Central nervous system (CNS) 
metastasis. Subjects with a history of brain metastases who were clinically stable and 
who underwent Magnetic resonance imaging (MRI) or Computed tomography (CT) 
Subjects with CT (if not suitable for MRI) who confirm no CNS disease progression 
can be enrolled (MRI or CT must be performed at least 4 weeks after the last brain 
radiotherapy).; 
7. Previous history of interstitial lung disease, drug-induced interstitial lung disease, 
symptomatic interstitial lung disease or any evidence of active pneumonia on chest CT 
scan within 4 weeks prior to the first study drug treatment; 
8. Known to interfere with the test requirements of mental illness or drug abuse disease; 
9. History of human immunodeficiency virus HIV infection, or active bacterial or fungal 
infection requiring systemic treatment within 14 days prior to the first study drug 
treatment. 
10. Presence of active syphilis infection. 

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11. Subjects with known active hepatitis B virus (HBV) or hepatitis C virus (HCV) 
infection with abnormal liver function (Absence of infection was defined as HBsAg 
negative, HBV DNA negative and HCV antibody negative), except to: 
 
Subjects who test positive for HBsAg or HBsAb during the screening period may 
be enrolled if the PCR test result for HCV-RNA is < 500 IU/ml (2000 copies/mL), 
but receive antiviral treatment according to the investigator's assessment and 
undergo PCR for HBV-DNA during the study treatment period; 
 
Subject has a positive test for HCV antibody at screening and can be enrolled if 
the PCR test result for HCV-RNA is negative. 
12. History of clinically significant cardiovascular disease, such as: 
 
Symptomatic congestive heart failure according to New York Heart Association 
Grades (NYHA > Grade 2); 
 
Severe/unstable angina, new angina within last 3 months; 
 
Myocardial ischemia and long-term use of drugs for control; according to NYHA, 
grade Ⅲ-Ⅳ cardiac insufficiency; 
 
Any event of acute myocardial infarction within 6 months before screening; 
 
Any grade ≥ 2 supraventricular arrhythmia or ventricular arrhythmia requiring 
treatment or intervention; 
 
Any grade atrial fibrillation, coronary/peripheral artery bypass graft, or 
cerebrovascular symptoms including transient ischemic attack; 
 
QTcF (Fridericia's correction formula used) > 470 ms; 
 
ECG < 50 bpm. 
13. History of serious allergic reactions to the study drugs or excipients used in the 
protocol. 
14. Women who are pregnant or lactating. 
15. Prior use of an oral selective estrogen receptor degrader (SERD). 
16. Subjects who use drugs or herbal supplements known to be moderate/strong inhibitors 
of CYP3A2 weeks prior to the first study drug treatment. Subjects who use drugs or 
herbal supplements known to be moderate/strong inducers of CYP3A4 weeks prior to 
the first study drug treatment. 
17. Received medications which inhibits the production of stomoch acid within 2 weeks 
or 5 drug half-lives (whichever is longer) prior to the first dose of study drugs. 

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18. Received medications which inhibits P-gp within 2 weeks or 5 drug half-lives 
(whichever is longer) prior to the first dose of study drugs. 
19. Patients with active or chronic corneal disease, other active eye disease requiring 
ongoing treatment, or any clinically significant corneal disease for which drug-induced 
keratopathy cannot be adequately monitored. 
20. Other conditions that the investigator considers inappropriately for this study. 
5.4 Subjects Withdrawal Criteria 
During the study, the subject may withdrawal due to the following reasons. 
5.4.1 Investigator’s Decision 
1. The investigator considers it necessary to stop the trial due to medical ethics; 
2. Unacceptable adverse event (AE) occurred and the investigator judged that it was not 
appropriate for the best interest of the subjects to continue the study treatment; 
3. Subjects significantly violate the study protocol, and the investigator determines that 
the study treatment needs to be terminated; 
4. Disease progression is confirmed according to efficacy evaluation criteria (unless the 
investigator determines that the subject would clinically benefit from continued 
treatment); 
5. Prior to the last biological samples, subjects use other medications that might influence 
the evaluation of the study drug; 
6. Other conditions that the investigator determines requiring withdrawal from the study 
treatment. 
5.4.2 Subjects Withdrawing on Their Own 
Subjects who are not willing to continue the study have the right to withdraw from the 
study at any time. If subjects do not explicitly request to withdraw the study, but they are 
no long receive doses or assessments, these subjects are also considered to have 
“withdrawn” or “dropped out”. 
The primary reasons for discontinuation of treatment of a subject with the study drug will 
be clearly documented in the subject's medical record and recorded on the appropriate case 
report form (CRF). Once a treatment is permanently discontinued, the subject will not be 
allowed to be retreated. In the case of subjects lost to follow-up, the last-know-alive date 
as determined by the investigator should be reported and documented in the subject’s 
medical records. 

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If a subject discontinues study drug temporarily, for example, as a result of an AE or serious 
adverse event (SAE), every attempt should be made to perform the required study-related 
follow-up and procedures. If this is not possible or acceptable to the subject or investigator, 
the subject may be withdrawn from the study and the circumstances clearly noted in the 
source documents. The reasons for withdrawal or lost to follow-up must be documented in 
the CRF. All data should be collected up until the point of withdrawal included in the study. 
This data will be documented on CRF and included in the analysis of the study. 
5.5 Criteria for Trial Termination 
5.5.1 Serious Safety Concerns 
1. the dose stopping criteria (see 4.4 Dose Escalation/Stopping Criteria) has been reached, 
in the judgement of the investigator, the trial should be stopped; 
2. During the trial, a significant mistake of the trial protocol is identified, which makes it 
difficult to evaluate the effect of study drug, or cause significant safety concerns; 
3. A significant deviation of study protocol occurs, and the investigator decide that it is 
difficult to evaluate the study drug with further continuation. 
5.5.2 Investigator’s Request 
During the trial, there may be some circumstances that the investigator cannot continue a 
trial. It is required that the investigator must notify subjects, sponsors, and IRB or the early 
termination and state reasons. 
5.5.3 Sponsor’s Request 
Sponsor may request to early terminate the trial due to following reasons: 
 
Financial difficulties; 
 
Management; 
 
Investigator cannot obey the protocol, and all other required laws and rules; 
 
The study site cannot enrol enough subjects; 
 
Other concerns. 
If deciding to early terminate the trial, the sponsor must notify the investigator, and IRB in 
writing with reasons, prior to the early termination. 
5.5.4 IRB and/or FDA’s Request 
IRB and FDA has the right to early terminate the trial.  
 
 

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6 Description of Study Treatment 
6.1 Study Treatment 
FWD1802 is an oral solid dosage form manufactured in strengths of 5mg, 25mg and 150 
mg, containing the following inactive ingredients: mannitol 160C, microcrystalline 
cellulose PH-101, hydroxypropyl methylcellulose (LV) E5 LV, sodium starch glycolate 
DST, magnesium stearate LIGAMED MF-2-V-MB, silicon dioxide SYLOID 244 FP, Film 
Coating System Opadry®321A620006-CN Yellow, and purified water. 
6.2 Administration 
FWD1802 will be orally administered under fed conditions. The dose will depend on the 
cohort the subject is assigned to. 
6.3  Study Drug Packaging and Labeling 
FWD1802 tablets are packaged in the HDPE (high density polyethylene) bottles for oral 
solid dosage form and sealed with polypropylene (PP)/low density polyethylene (LDPE) 
child-resistant caps (CRC) including desiccant . 5 mg tablets are available in 30 mL HDPE 
bottles/CRC of 30 film coated tablets, 25 mg and 150 mg tablets are available in 60 mL 
HDPE bottles/ CRC of 35 film coated tablets. The contents of the label will be in 
accordance with all applicable regulatory requirements. An example of a study drug label 
for FWD1802 is shown in  
 
Figure 2. 
IND Study No.: XX  
Protocol Number: FWD1802-001 
FWD1802 Tablet 5 mg, 25 mg, 150 mg 
For oral use, Administer as per protocol 
Lot No.: XXXX 
Expiry Date: XXXX 
Subject Number: XXXX 
Dosage Units: XX tablets per bottle 
Storage condition:  Stored at ≤25℃, 
sealed and dried, protected from light. 
For Clinical Trial Use Only 
 
Study Sponsor: Shenzhen Forward Pharmaceuticals Co., Ltd. 
Caution: New drug limited by United States law to investigational use 
IND Study No.: XX  
Protocol Number: FWD1802-001 
FWD1802 Tablet 5 mg, 25 mg, 150 mg 
For oral use, Administer as per protocol 
Lot No.: XXXX 
Expiry Date: XXXX 
Subject Number: XXXX 

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Figure 2. An example of FWD1802 label 
 
6.4 Study Drug Storage 
The study drug should be stored in sealed and dry containers, 2~8℃, keep out of light, as 
per the requirements on the label. 
Study drugs must be dispensed or administered according to procedures described herein. 
Only subjects enrolled in the study may receive the study drugs. Only authorized site staff 
may supply or administer the study drugs. All study drugs must be stored in a secure area 
with access limited to the investigator and authorized site staff. Investigational sites should 
use appropriate labeling, which addresses storage conditions and expiration post dispensing, 
per institutional and regulatory guidelines. Shenzhen Forward Pharmaceuticals Co. Lt will 
assure that the stability of the study drug is monitored to ensure suitability for continued 
use at the investigational site. 
The details information of study drug please refer to 3.2 P Drug Product. 
 
6.5 Study Drug Accountability 
The investigator is responsible for ensuring adequate accountability of all used and unused 
study drug. This includes acknowledgment of receipt of each shipment of study drug 
(quantity and condition) and maintaining dispensing records. Any study drug that is not 
used must be recorded in the source and/or dispensing records. Missed doses should be 
clearly documented along with the reason. All study drug supplies and associated 
documentation will be reviewed and verified by the study monitor. Study drug should be 
retained by the site; the site will follow the pharmacy instructions on disposal and/or 
destruction of all unused supplies. Copies of all forms, and documentation regarding drug 
receipt and drug accountability records, will be retained according to the regulations 
governing record retention. 
6.6  Study Drug Handling and Disposal 
When preparing FWD1802 appropriate precautions for handling chemicals should be taken 
by the investigational staff, according to institutional policy, although no special 
precautions need to be taken. After completion of the study, all unused FWD1802 will be 
inventoried and packaged for shipment by the site to a designated destruction facility or 
Dosage Units: XX tablets per bottle 
Storage condition:  Stored at ≤25℃, 
sealed and dried, protected from light. 
For Clinical Trial Use Only 
 
Study Sponsor: Shenzhen Forward Pharmaceuticals Co., Ltd. 
Caution: New drug limited by United States law to investigational use 

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will be destroyed locally at the investigational site.  The study monitor will instruct the 
site in the disposal and/or destruction of all unused FWD1802 supplies. 
6.7 Concomitant Medications 
Concomitant Medications means any drug other than the study drug used during the study 
period (including the screening period and all study visits). 
If the use of the combination medications is due to an adverse event, it must be documented 
and reported in accordance with the relevant regulations and the adverse events and serious 
adverse events requirements of Section 9 of this protocol. 
The supervisor must be notified if the use of the combination medications affects the 
subject's participation in the study. 
Details of all drug combinations must be recorded, including drug name, reason for use, 
start date, end date or continuation date, indication, and dosage. 
The use of other antitumor treatments or experimental drugs is prohibited during the study 
period. Palliative radiotherapy and bisphosphonate therapy for bone lesions are permitted. 
Herbal preparations or related over-the-counter preparations containing herbal ingredients 
are prohibited during the study and treatment period (For details please see Appendix 5). 
6.8 Assessment of Compliance 
When subjects are dosed at the study site, they will receive study drugs directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study drug 
will be confirmed prior to dosing by a member of study site staff other than the person 
administering the study drug. Study site personnel will examine each subject’s mouth to 
ensure that the study drug was swallowed. 
 
 

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7 Study Procedures 
The study procedures to be conducted for each subject enrolled in the study are described 
in the text that follows and presented in Table 1, Table 2 and Table 3. The investigator must 
document any deviation from protocol procedures and notify the sponsor or contract 
research organization.  
7.1 Subject Identification 
Subjects appropriate for this trial will be identified by the investigator (or designee) who 
will make a preliminary determination of the subject’s eligibility for the trial in accordance 
with the provisions of the study protocol. 
Documentation of the personally signed and dated Informed Consent Form (ICF) for each 
subject is required before initiating the screening process. After written ICF has been 
obtained and eligibility to participate established, investigative site personnel will obtain 
the subject’s identification number and study drug assignment as appropriate. 
7.2 Study Start and End of Study Definitions 
The start of the study is defined as the date the first subject, who is subsequently enrolled, 
signs an ICF. The point of enrolment occurs at the time of subject number allocation. The 
end of study is defined as the date of the last subject’s last assessment. 
7.3 Description of Assessments 
7.3.1 Laboratory Assessments 
All protocol required clinical laboratory assessments should be performed at the 
investigational site’s local laboratory. All clinical laboratory results must be documented 
on the CRF and reference ranges and safety parameters must be provided for each 
laboratory used. The following assessments will be performed and evaluated during the 
study. 
Table 10 Laboratory Assessments 
Hematology 
red blood cell counts (RBC), white blood cell counts (WBC), and differential 
counts (neutrophils (NE), lymphocytes (LY#), monocytes (MO#), eosinophils 
(EO#), and basophils (BA)), platelet count (PLT), hemoglobin (HGB), and 
hematocrit (HCT) 
Coagulation 
Function 
PT (Prothrombin Time), APTT (Partial Thromboplastin Time), INR 
(International Normalized Ratio), Thrombin time (TT) and fibrinogen (FIB) 
Fasting Serum 
Biochemistry 
ALT, AST (Aspartate Transaminase), GGT (Gamma-glutamyl Transpeptidase), 
TBIL (total bilirubin), DBIL (direct bilirubin), BUN (Urea Nitrogen) or urea, Cr 
(Creatinine), UA (uric acid), GLU (blood glucose), potassium, sodium, chlorine, 
calcium, phosphate, magnesium, TP (total protein), ALB (albumin), 
albumin/globulin ratio, LDH (Lactate Dehydrogenase), TBA (Total Bile Acid), 
TG (Triglyceride), CK (Creatine kinase), CK-MB (creatine kinase 
isoenzyme)and ALP  (Alkaline Phosphatase). 

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Pregnancy Test 
serum β-Human Chorionic Gonadotropin (β-HCG). Lack of childbearing 
potential must be noted in the source documents, if applicable. 
Urinalysis 
specific gravity, pH, white blood cells, red blood cells, α1 microglobulin,  β 
macroglobulin, occult blood, proteins and glucose. 
Infectious 
Disease 
Screening 
HCV, HBV, HIV, syphilis, etc., but if the subject can present the test results done 
within 4 weeks prior to the administration, the screening can be exempted. 
 
7.3.2 Medical History 
Medical history, including details of illnesses and allergies, date(s) of onset, whether 
condition(s) is currently ongoing, and medication history (anti-tumor therapies), including 
nicotine and alcohol use, will be collected for all subjects during screening. 
7.3.3 Physical Examination 
A complete physical examination should include source documentation of general 
appearance, and following body systems: head, neck and thyroid; eyes, ears, nose, throat, 
mouth and tongue; chest; respiratory, cardiovascular; lymph nodes; abdomen; skin, hair, 
nails, musculoskeletal; neurological and mental status.  
Height, and body weight will be collected at specified time points. 
7.3.4 Vital Signs 
Vital signs measurement includes respiratory rate, heart rate, body temperature and blood 
pressure. Heart rate and blood pressure will be first checked in the seat position and then 
in the standing position at every time point of the scheduled plan. 
7.3.5 Electrocardiogram 
Standard 12-lead ECG assessments will be performed, after resting in supine position for 
at least 5 min to assess heart rate, rhythm, and interval information such as PR, QRS, QT, 
QTc and so on. The Investigator will review the ECGs for any clinically significant 
abnormalities to ensure subject safety. 
If a subject has possible cardiac-related symptoms, repeat ECGs will be obtained every 30 
min±3 min until the waveform reverts to its baseline appearance, or symptoms resolve, or 
are determined not to be cardiac-related. Participants with cardiac-related symptoms that 
are associated with ECG changes will be transferred to appropriate emergency department 
for further evaluation and treatment at the discretion of the Investigator. 
7.3.6 Echocardiogram 
Echocardiogram will be performed during the study and left ventricular ejection fraction 
(LVEF) was recorded. 
7.3.7 18F-FES PET/CT 

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The patients underwent both 18F-FES and 18F-FDG PET/CT at screening period and C2D8 
to monitor the detect in ER target occupation and inhibition. The detection iterval between 
18F-FES and 18F-FDG PET/CT was within 7 days. 
All of the patients were requested to fast for more than 4 h prior to 18F-FES PET/CT scans 
to eliminate the excretion of 18F-FES from the hepatobiliary system and the gastrointestinal 
tract, which might interfere with image interpretation in the pelvic cavity. 
7.4 Study Procedures 
After signing the informed consent form, the subjects will complete the screening and 
baseline assessment during the screening period and be enrolled in the study after 
confirming that they meet the inclusion criteria.The investigator selects subjects who will 
understand the study and comply with the instructions. At each visit, the investigator shall 
remind subjects to follow the study protocol procedures. If the subjects withdraw from the 
study or terminate the treatment for any reason, they should return to the hospital for EOT 
visit and follow-up visits during the follow-up period. Blood samples should be collected 
after discontinuing the drugs and safety-related follow-up should be conducted (SFU visit).  
7.4.1 Screening Period (Day -28~Day -1) for All Subjects 
After signing the ICF, a subject should undergo medical screening to assess whether he/she 
is eligible to participate in the study according to the inclusion criteria. The screening 
evaluation will be completed within 28 days prior to the first administration of the 
investigational drug. 
Administrative Procedures: 
• 
Informed Consent 
• 
Inclusion/Exclusion Criteria 
• 
Demographics 
• 
Medical history 
• 
Concurrent diseases 
Clinical Procedures/Assessments: 
• 
Weight 
• 
Body height 
• 
Physical examination 
• 
vital signs 

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• 
ECOG Score 
• 
12-lead ECG 
• 
Echocardiogram 
Laboratory tests: 
• 
Blood Chemistry 
• 
Hematology 
• 
Coagulation 
• 
Urinalysis 
• 
Virology: HBV, HCV, and HIV 
• 
Pregnancy 
• 
COVID-19 
Efficacy Assessments: 
• 
Tumor Assessmen 
Biomarker Exploration: 
• 
18F-FES PET/CT15 
Other: 
• 
Adverse events and concomitant medication; 
The information above should be obtained from the source file. For test values outside the 
normal range (outliers), the investigator will assess whether to repeat the test. 
The investigator will review patient’s medical history at the time of screening period. The 
history includes all current active diseases and any other conditions deemed clinically 
significant by the investigator. The date of last prior anticancer therapy(s) and treatment 
response must be recorded. Pre-enrollment imaging data can be collected for the 
investigator's reference. A complete medication history within 28 days prior to the first 
administration of the study drug should be reported. 
7.4.2 Treatment Period 
7.4.2.1 Part A study 

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See Table 1 for details. 
7.4.2.2 Part B study  
See Table 2 for details. 
7.4.2.3 Part C study  
See Table 3 for details. 
7.4.3 Post Treatment Follow-up Visit 
7.4.3.1 End of treatment (EOT) visit  
The end-of-treatment (EOT) will occur at the earliest day possible within 7 days after the 
last dose of FWD1802 or the subject decides to withdraw from study treatment for any 
reason. 
Clinical Procedures/Assessments: 
• 
Weight 
• 
Body height 
• 
Physical examination  
• 
vital signs 
• 
ECOG Score 
• 
12-lead ECG 
• 
Echocardiogram; 
Laboratory tests: 
• 
Blood Chemistry 
• 
Hematology 
• 
Coagulation 
• 
Urinalysis 
Other: 
• 
Adverse events and concomitant medication; 
7.4.3.2 Safety follow-up (SFU)  
Mandatory safety follow-up (SFU) should be performed at 28 ±7 days after the last 
administration and prior to the initiation of a new anti-tumor therapy. Subjects who 

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discontinue the study due to an unacceptable adverse event should be followed until AE 
relieves to grade 0-1 or AE is stable. If EOT visit is within the safety follow-up window, 
no further safety follow-up is required. 
Adverse events and concomitant medication; 
7.4.3.3 Long term follow-up (LTFU)  
LTFU is survival follow up. After completion of the treatment and safety follow-up period, 
all the subjects will be followed for survival status. Subjects will be contacted by phone or 
in person every 12 weeks ±7 days after discontinuation to assess survival status until 
subject death or study termination. Survival and subsequent antitumor therapy will be 
collected during these calls/interviews. 
7.5 Biological Samples 
7.5.1 PK Samples 
Blood samples will be collected from all the subjects for PK analysis. 
 
Part A study: 
Table 11 PK Sample Time Points and Time Windows  
Time for 
Blood 
Collection 
Single Dosing Study 
Multiple Dosing Study 
Cycle 0 (4 Days) 
Cycle 1 (28 Days) 
Cycle 2 (28 
days) 
≥Cycle 3 
(28 days) 
D1 
D2 
D3 
D1 
D8 
D15 
D1 
D1 
-1h (prior 
to dosing) 
X 
 
 
X 
X 
X 
X 
X 
0.5 h 
X 
 
 
 
 
X 
 
 
1 h 
X 
 
 
 
 
X 
 
 
2 h 
X 
 
 
 
 
X 
 
 
3 h 
X 
 
 
 
 
X 
 
 
4 h 
X 
 
 
 
 
X 
X 
X (±2h) 
6 h 
X 
 
 
 
 
X 
 
 
8 h 
X 
 
 
 
 
X 
 
 
10 h 
X 
 
 
 
 
X 
 
 
24 h 
X  
X 
X 
 
 
 
X 
(C1D16 
pre-
dose) 
 
 
 
Part B study: 
Time for 
Blood 
Collection 
Multiple Dosing Study 
Cycle 1 (28 Days) 
Cycle 2 (28 days) 
≥Cycle 3 (28 
days) 
C1D1 
C1D8 
C1D15 
 
C2D1 
C3D1 
-1h (prior 
to dosing) 
X 
 
X 
X 
X 
X 
0.5 h 
X 
 
X 
 
 

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1 h 
X 
 
X 
 
 
2 h 
X 
 
X 
X 
 
3 h 
X 
 
X 
X 
 
4 h 
X 
 
X 
X 
 
6 h 
X 
 
X 
X 
 
8 h 
X 
 
X 
 
 
10 h 
X 
 
X 
 
 
24 h 
X（C1D2 
pre-dose） 
 
X（C1D16 
pre-dose） 
 
 
 
Part C study： 
Time for 
Blood 
Collection 
Multiple Dosing Study 
Cycle 1 (28 Days) 
Cycle 2 (28 days) 
≥Cycle 3 (28 days) 
C1D1 
C2D1 
C3D1 
-1h (prior 
to dosing) 
X 
X 
X 
0.5 h 
 
 
 
1 h 
 
 
 
2 h 
X 
X 
 
3 h 
X 
X 
 
4 h 
X 
X 
X (±2h) 
6 h 
X 
X 
 
8 h 
X 
X 
 
10 h 
X 
X 
 
24 h 
X（C1D2 pre-dose） 
X（C2D2 pre-dose） 
 
 
Table 12 PK Samples Time Windows 
Collection Time Point 
Time window 
D1 (prior to dosing) 
Within 60 min 
0~4 h after administration (4 h included) 
±3 min 
4~10 h after administration (10 h included) 
±5 min 
10~24 h after administration (24 h included) 
±10 min 
Greater than 24 after administration (24 h not included) 
±30 min 
 
7.5.2 Sample Preparation 
Details of sample collection, processing, shipping and storage will be described in the 
separately Laboratory Manual. 
Samples will be analyzed using a previously validated method, which will be described in 
the Laboratory Manual of the study site. 
 

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8 Lifestyle and/or Dietary Management 
8.1 Pregnancy Precautions 
8.1.1 Definition of Childbearing Potential 
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty until becoming post-menopausal, unless permanently 
sterile or ovarian failure with medical documentations.  
Post-menopausal defined as no menses for at least 12 months after stopping all hormone 
treatments and with follicle stimulating hormone (FSH) level in the post-menopausal range 
(confirmed by lab test). 
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age. 
A male born subject is considered fertile after the initiation of puberty unless permanently 
sterile by bilateral orchiectomy or medical documentation. 
8.1.2 Contraception Requirements for Female Subjects of Childbearing Potential 
Complete abstinence from intercourse of reproductive potential is an acceptable method of 
contraception only when it is in line with the subject’s preferred and usual lifestyle.  
Sexually active female subjects of childbearing potential must agree to use at least 1 highly 
effective contraception and 1 additional method at least 1 month prior to initiation of the 
study, during the study, and for 6 months after the last administration of the study drug.  
Female subjects must also refrain from egg donation and in vitro fertilization during the 
study and until at least 30 days after the last of study drug.  
8.1.3 Acceptable Methods Considered Highly Effective 
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective. Such methods include: 
 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: oral; intravaginal; transdermal. OR  
 
Progestogen-only hormonal contraception associated with inhibition of ovulation: oral; 
injectable; implantable. Note: hormonal contraception may be susceptible to 
interaction with the ER+/HER2- unresectable locally advanced or metastatic breast 
cancer with or without ESR1 mutation, which may reduce the efficacy of the 
contraception method. 
 
Intrauterine device 
 
Tubal sterilization 

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 
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure) 
8.1.3.1 Methods that are Considered Less Highly Effective 
 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action. 
 
Male condom with or without spermicide 
 
Cap, diaphragm, or sponge with spermicide 
Note: a combination of male condom with either cap, diaphragm or sponge with spermicide 
(double-barrier methods) are also considered acceptable, but not highly effective, birth 
control methods. 
8.1.4 Unacceptable Birth Control Methods 
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, 
ovulation, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method. Female condom and male condom 
should not be used together. 
Counseling about contraception and behaviors associated with an increased risk of 
pregnancy must be repeated, and pregnancy testing will be conducted at specified times 
8.2 Meals and Dietary Restrictions 
FWD1802 (and palbociclib) is administrated after meal (within 30 minutes) with 
approximately 240 ml water. The subjects should start the recommended meal 30 minutes 
before administration of the drug product. Other dietary restrictions are as follows: 
 
During each dosing session, subjects will abstain from ingesting caffeine or xanthine 
containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hours prior to 
the start of dosing until collection of the final PK samples during each session. 
 
During each dosing session, subjects will abstain from alcohol for 24 hours prior to 
the start of dosing and during each session. 
 
Use of tobacco products is not allowed 3 months prior to the screening visit. 
 
Use of traditional Chinese medicines or herbal products is not allowed 2 weeks prior 
to and during the study. 
8.3 Physical Activity 

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 
Subjects will abstain from strenuous exercise for 48 hours prior to each blood 
collection for clinical laboratory tests. Subjects may participate in light recreational 
activities during studies (e.g., watching television, reading). 
 
Subjects will be advised to stay indoors to avoid ≥ 15 min extreme exposure to the sun 
or sunbathing. 
 
 

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9 Assessments of Adverse Events 
9.1 Adverse Events 
The investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an AE or SAE as provided in this clinical study protocol. During 
the study, when there is a safety evaluation, the investigator or site staff will be responsible 
for detecting AEs and SAEs, as detailed in this section of the protocol. 
The following definitions of terms are guided by the International Conference on 
Harmonization and the US Code of Federal Regulations and are included here verbatim. 
The terms “serious adverse event” and “adverse event” are commonly used by the Sponsor. 
9.1.1 Adverse Event Definition 
An AE is any untoward medical occurrence in a subject or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
Examples of an AE include: 
 
Significant or unexpected worsening or exacerbation of the condition/indication under 
study.   
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity (grade) of the condition. 
 
New conditions detected or diagnosed after investigational product administration 
even though may have been present prior to the start of the study. 
 
Signs, symptoms, or the clinical sequelae associated with a suspected interaction of 
the investigational product with a concomitant medication. 
9.1.2 Serious Adverse Event Definition 
Any untoward medical occurrence that at any dose: 
 
Results in death, 
 
Is life-threatening-  
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to any adverse 
drug experience (AE) that places the subject or participant, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death.   

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 
Requires in subject hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the subject or participant has been 
detained (usually involving at least an overnight stay) at the hospital or emergency 
ward for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.  Hospitalization for 
elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
 
Results in persistent or significant disability/incapacity 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
 
Is a congenital abnormality/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the subject or participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
above definition. 
9.2 Relationship of Adverse Event to Study Drug 
The investigator or designated physician-sub investigator responsible for the care of the 
subjects in the study will assess the relationship of each AE or laboratory abnormality to 
FWD1802 using clinical judgement and the following considerations: 
 
No: Evidence exists that the AE has an etiology other than the FWD1802. For SAEs, 
an alternative causality must be provided (eg, pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication). 
 
Yes: There is reasonable possibility that the event may have been caused by the study 
drug.  
It should be emphasized that ineffective treatment should not be considered as causally 
related in the context of AE reporting.  
The relationship to study procedures (eg, blood draw) should be assessed using the 
following considerations: 
 
No: Evidence exists that the adverse event has an etiology other than the study 
procedure. 

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 
Yes: There is reasonable possibility that the adverse event occurred as a result of 
protocol procedures. 
9.3  Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrence.  Subjects are also required to report any AEs and/SAEs, including but not 
limited to loose stools or diarrhea.  
9.4 Recording AEs and SAEs 
9.4.1 All Adverse Events Regardless of Seriousness 
Any adverse medical condition or laboratory abnormality with an onset date before initial 
dose of study drug administration is considered to be pre-existing in nature.  Any known 
pre-existing conditions that are ongoing at time of study entry, and any events of Grade 3 
or 4 severity that occur up to 14 days before study entry (even if resolved prior to study 
entry) should be recorded in the appropriate section of the CRF.  
All AEs occurring from initial FWD1802 administration up to 30 days following the last 
dose of FWD1802 must be recorded as an AE in the subject’s source documents and on the 
CRF regardless of frequency, severity (grade) or assessed relationship to the study drug.  
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of 
a pre-existing condition that occurs after the subject begins taking FWD1802 is also 
considered an AE. 
9.4.2 Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events and Serious Adverse Events 
Abnormal laboratory findings (e.g., clinical chemistry and hematology) or other abnormal 
assessments (e.g., ECGs) that are judged by the investigator as clinically significant will 
be recorded as AEs or SAEs if they meet the definitions as defined in Section 9 Assessments 
of Adverse Events. Clinically significant abnormal laboratory findings or other abnormal 
assessments that are detected during the study or are present at baseline and significantly 
worsen following the start of the study will be reported as AEs or SAEs. However, 
clinically significant abnormal laboratory findings or other abnormal assessments that are 
associated with the disease being studied, unless judged by the investigator as more severe 
than expected for the subject’s condition, or that are present or detected at the start of the 
study and do not worsen, will not be reported as AEs or SAEs.  The investigator will 
exercise his or her medical and scientific judgment in deciding whether an abnormal 
laboratory finding or other abnormal assessment is clinically significant. 
9.4.3 Grading of Adverse Events 
AE will be graded according to CTCAE v5.0. 

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9.5  Reporting Adverse Events 
9.5.1 All AEs 
All events meeting the criteria for AE that occur after the initial dose of FWD1802 during 
treatment, or within 30 days of the last dose of FWD1802 (including all deaths) must be 
reported to the Sponsor regardless of cause or assessed relationship to therapy. SAEs will 
be collected from the time of signed ICF, throughout the entire study, till the follow-up 
period. SAEs occurring at any time, even after the reporting timeline, must also be reported 
immediately if suspected to be associated with the study drug.  
 
The Investigator should instruct the subject to be truthful about changes following the 
administration. Inducted questions should be avoided; 
 
Closely monitor AEs or unexpected toxicities (including symptoms, signs, and 
laboratory tests), analyse reasons and follow-up; 
 
For AE report, include/attach detailed descriptions about symptions, severity, time, 
duration, measurement, the association with study drug, etc. Record should be signed 
and dated by the Investigator; 
 
All AEs should be followed-up until resolve, stable or loss of follow-up.  
9.5.1.1 SAE 
Unless stated by the protocol or other profiles (i.e. investigator’s brochure), SAE should be 
reported to the Sponsor or sponsor assigned safety representative within 24 h of knowledge. 
The written report should include/attach detailed descriptions including copies of hospital 
case reports, autopsy reports (if any), and other documents when requested and applicable 
to the SAE Report. If these items are not immediately available, they are to be provided as 
soon as possible as a follow-up to the initial SAE Report. For all fatal or life-threatening 
SAEs contact the Sponsor immediately (as listed on title page of the protocol) and then fax 
or email the initial report as soon as possible. 
Follow-up will be conducted by the Sponsor or sponsor assigned safety representatives and 
as needed with investigational site personnel to obtain any additional information needed 
to complete the reporting of the event. 
9.5.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)  
Unexpected adverse event or suspected adverse reaction refers to an event or reaction that 
is not listed in the investigator’s brochure or is not listed at the specificity or severity that 
has been observed; or, if an investigator’s brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current IND application. 
Initial reporting: IND application sponsor must report any suspected adverse reaction or 
adverse reaction to study treatment that is both serious and unexpected. 

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SUSAR must be reported to FDA as soon as possible but no later than within 15 calendar 
days following the sponsor’s initial receipt of the information. 
Unexpected fatal or life-threatening suspected adverse reactions represent especially 
important safety information and must be reported to FDA as soon as possible but no later 
than 7 calendar days following the sponsor’s initial receipt of the information. 
Follow-up reporting: Any relevant additional information obtained by the sponsor that 
pertains to a previously submitted IND safety report must be submitted as a Follow-up IND 
Safety Report. Such report should be submitted without delay, as soon as the information 
is available but no later than 15 calendar days after the sponsor receives the information. 
9.5.2 Follow-Up of AE/SAE 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide further information to Sponsor on the subject’s condition.   
AEs that are ongoing with a toxicity of Grade 3 or 4, or have a relationship to 
investigational drug that is suspected, will be queried for resolution at study conclusion and 
until resolved or stable and not clinically significant. All SAE’s will be followed until they 
completely resolve, or are otherwise stable. Subjects who discontinue the study due to 
disease progression should also be followed until adverse event resolves to grade 0-1 or is 
stable. Once resolved/stabilized, the appropriate AE CRF page(s) or SAE form(s) will be 
updated. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
As reasonably requested by the Sponsor, the investigator will perform or arrange for the 
conduct of supplemental measurements and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. If a subject dies during participation in the 
study or during a recognized follow-up period, Sponsor will be provided with a copy of 
any post-mortem findings, including histopathology, if possible. 
9.5.3 Post-Study Reporting Requirements 
Although such information may not be routinely sought or collected by Sponsor, SAEs that 
occur after the subject has completed the clinical study may be reported. Such cases will 
be evaluated for expedited reporting. 
9.5.4 Pregnancy 
The risks of treatment with FWD1802 during pregnancy have not been evaluated. To 
ensure participant’s safety, each pregnancy in a subject on drug must be reported to the 
sponsor within 24 h of learning of its occurrence. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of the birth, 
and presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. Pregnancy and follow-up will be documented, and should include 

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an assessment of the possible relationship to the IND drug of any pregnancy outcome. 
Pregnant women who are abortive or need induction of labor should be reported as an SAE. 
Pregnancy outcomes must also be collected for the female partners of any males who takes 
study treatment in the trial, pending consent from the mother. 
 
 

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10 Statistics 
A Statistical Analysis Plan (SAP) will be written prior to database lock. The SAP will detail 
the planned statistical analysis methods to be conducted. A summary of the proposed 
statistical analysis plan to be conducted is provided in the following sections. 
10.1 Sample Size Estimate 
The sample size estimate of a total of 99 subjects in this trial is based on the enrollment of 
all parts of the study. This number is considered adequate to determine the safety, 
tolerability, PK, PD and preliminary efficacy in patients with ER+/HER2- unresectable 
locally advanced or metastatic breast cancer. The study is summarized below. 
Table 13 Sample Size Estimate for the Study 
Design 
Name of Study 
Number of Subjects 
Groups 
open-label, single 
arm 
Part A: Dose 
Escalation  
27 subjects  
5 cohorts 
(1~6 subjects for each dose 
level) 
open-label, single 
arm 
Part B: Dose 
Escalation 
12 patients 
no more than 2 dose levels 
open-lable, single 
arm 
Part C: Dose 
Expansion  
60 subjects in total 
no more than 2 dose cohorts, 
with 30 patients at the most in 
one dose cohort 
 
10.2 Analysis Sets 
10.2.1 Full Analysis Set (FAS) 
All patients who received at least 1 dose of FWD1802. 
10.2.2 Safety Analysis Set (SS) 
All enrolled subjects who have received the investigational product at least once and have 
at least 1 valid safety assessment data. They will be used for listings and summaries of 
safety analysi. 
10.2.3 Pharmacokinetic Concentration Set (PKCS) 
All enrolled subjects who have received the investigational product at least once and have 
at least 1 valid concentration data of FWD1802. They will be used for listings and 
summaries of PK concentrations. 
10.2.4 Pharmacokinetic Parameter Set (PKPS) 
All enrolled subjects who have received the investigational product at least once and have 
at least 1 valid PK parameter data of FWD1802. They will be used for listings and 
summaries of PK parameters. 
10.2.5 Pharmacodynamics Analysis Set (PDS) 

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All enrolled subjects who have received the investigational product at least once and have 
at least 1 valid (non-baseline) PD data.   
10.2.6 Efficacy Analysis Set (EAS) 
All enrolled subjects who have used the investigational product and have at least one 
efficacy observation value. 
Upon completion of the dose expansion study, an integrated dose response and exposure-
response analyses for the recommended phase 2 dose (RP2D) will be determined. 
10.2.7 Interim Analysis 
No formal interim analysis is planned for this study. But prior to the dose-expansion part, 
the investigator, sponsor and medical monitor will review the safety and PK data 
accumulated in dose-escalation part, and make the decision.   
10.3 Data Handling Conventions 
Missing data can have an impact on the interpretation of the study data. In general, values 
for missing data will not be imputed. 
Where appropriate, safety data for subjects that do not complete the study will be included 
in summary statistics. For example, if a subject receive study drug, the subject will be 
included in a summary of adverse events according to the treatment received; otherwise, if 
the subject is not dosed then they will be excluded from the summary. If safety laboratory 
results for a subject are missing for any reason at a time point, the subject will be excluded 
from the calculation of summary statistics for that time point. If the subject is missing a 
pre-dose value, then the subject will be excluded from the calculation of summary statistics 
for the pre-dose value and the change from pre-dose values.  
Values for missing safety laboratory data will not be imputed; however, a missing baseline 
result may be replaced with a screening result, if available. If no pre-study laboratory value 
is available, the baseline value will be assumed to be normal for the summary of graded 
laboratory abnormalities.  
10.4  Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods, including age, gender, race, weight, past medical and surgical history, vital signs, 
concomitant medications, and clinical laboratory parameters. 
10.5  Safety Analysis 
Incidence and severity of adverse events according to the NCI-CTCAE (V 5.0) will be 
summarized and displayed in number/percentage. The exposure extent to the study drug 
will be displayed. 

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10.5.1 Adverse Events 
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), Preferred Terminology (PT), 
will be attached to the clinical database. See Section 9 for the definition and the severity of 
AE. 
Events will be summarized on the basis of the date of onset for the event. A treatment-
emergent adverse event (TEAE) will be defined as following: 
 
Any AEs with an onset date on or after the study drug start date and no later than 30 
days after permanent discontinuation of study drug. 
 
Any AEs leading to premature discontinuation of study drug. 
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be 
provided. TEAEs will also be summarized by relationship to study drug and severity. In 
addition. TEAEs leading to premature discontinuation of study drug and study will be 
summarized and listed. 
All AEs collected during the course of the study will be presented in data listing with a 
field for treatment-emergent event (yes/no). 
10.5.2 Laboratory Evaluations 
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum and 
maximum) by treatment cohorts and time along with the corresponding change from 
baseline values.  
10.5.3 Other Safety Evaluations 
The results of scheduled assessments of DLTs, pregnancy tests, physical examination, 
ECGs, vital signs laboratory tests will be listed for each subject and summarized by dose 
level and scheduled time point using appropriate descriptive and graphic statistics. The 
change from baseline data will also be listed. 
10.5.4 Pharmacokinetic Analysis 
A descriptive analysis of the plasma concentration and derived PK parameters of FWD1802 
and its metabolite (if possible) will be conducted by dose level. Plasma concentration 
patient profiles versus time and mean concentration versus time will be displayed. 
10.6 Pharmacodynamics Analysis 
Pharmacodynamic analysis will be performed based on PD analysis set. Explore the 
relationship between exposure or dose of FWD1802 and biomarkers, safety, and clinical 
efficacy where possible. 

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10.7 C-QT Analysis 
Based on the changes of PK and QT interval, an exploratory statistical analysis of C-QT 
will be performed.  
The QT/QTc interval at each time point and its change from baseline will be analyzed 
descriptively, and the line chart will be used to describe the change at each time point and 
between each cohorts.  
Baseline correction (ΔQTc) and placebo correction (ΔΔQTc) will be applied to the obtained 
QT/QTc interval, and ΔQTc will be used as the dependent variable to measure the degree 
of drug effect on QT/QTc, such as a linear mixed effects model. 
If possible, combined with the changes of investigational product concentration and 
QT/QTc interval, model exploration analysis will be performed. 
10.8 Preliminary Efficacy Analysis 
 
Objective Response Rate (ORR): The proportion of subjects with tumors shrinking to 
a certain amount or volume and maintaining a certain period, including the complete 
response (CR) and partial response (PR) cases. The objective response rate and 95% 
confidence interval will be calculated. 
 
Duration of response (DoR): The time from the first assessment of CR or PR to the 
first assessment of disease progression or death of any cause. For subjects who 
continue to survive without progression after meeting response criteria, the duration of 
response will be deleted on the last assessable tumor assessment date or the last disease 
progression follow-up date. 
 
Disease control rate (DCR): The proportion of patients with tumors shrinking or 
stabilizing and remaining for a certain period includes cases of CR and PR and stable 
disease (SD). 
The ORR and its exact 95% Clopper-Pearson confidence interval will be calculated. The 
CBR, DCR will also be calculated similarly. All of the time-to-event data (PFS, DOR,OS ) 
will be estimated using Kaplan-Meier method, and the median along with two-sided 95% 
CI will be displayed(use the Greenwood’s formula for estimation of standard errors). 
11 Study Conduct Considerations 
11.1 Quality Check (Study Monitoring) 
In accordance with applicable regulations including GCP, and rocedures, Shenzhen 
Forward Pharmaceuticals Co. Lt monitors will contact the site prior to the start of the study 
to review with the site staff the protocol, study requirements, and their responsibilities to 
satisfy regulatory, ethical and Shenzhen Forward Pharmaceuticals Co. Lt requirements. 
When reviewing data collection procedures, the discussion will also include identification, 
agreement and documentation of data items for which the source records will be identified. 

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Shenzhen Forward Pharmaceuticals Co. Lt will monitor the study and site activity to verify 
that the: 
 
Data are authentic, accurate and complete. 
 
Safety and rights of subjects are being protected. 
 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to allow 
the monitor direct access to all relevant documents. 
11.2 Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, Shenzhen 
Forward Pharmaceuticals Co. Lt may conduct a quality assurance audit. Regulatory 
agencies may also conduct regulatory inspections of this study. Such audits/inspections can 
occur at any time during or after completion of the study. If an audit or inspection occurs, 
the investigator and institution agree to allow the auditor/inspector direct access to all 
relevant documents and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues. 
11.3 Study and Site Closure 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations including GCP and Shenzhen Forward Pharmaceuticals Co. Lt 
procedures. 
In addition, Shenzhen Forward Pharmaceuticals Co. Lt reserves the right to temporarily 
suspend or prematurely discontinue this study at any time for reasons including, but not 
limited to, safety or ethical issues or severe non-compliance. Shenzhen Forward 
Pharmaceuticals Co. Lt will discuss with this with the investigator or the head of the 
medical institution (where applicable), including the reasons for taking such action. When 
feasible, Shenzhen Forward Pharmaceuticals Co. Lt will provide advance notification to 
the investigator or the head of the medical institution, where applicable, of the impending 
action prior to it taking effect. 
If the study is suspended or prematurely discontinued for safety reasons, Shenzhen Forward 
Pharmaceuticals Co. Lt ill promptly inform the investigator or the head of the medical 
institution (where applicable) and the regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action. If required by the applicable 
regulations, the investigator or the head of the medical institution (where applicable) must 
inform the IRB/IEC promptly and provide the reason(s) for the suspension or premature 
discontinuation. 
11.4 Record Retention 

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Following closure of the study, the investigator or the head of the medical institution (where 
applicable) must maintain all site study records, except for those required by local 
regulations to be maintained by someone else, in a safe and secure location. The records 
must be maintained to allow easy and timely retrieval, when needed (e.g., audit or 
inspection), and, whenever feasible, to allow any subsequent review of data in conjunction 
with assessment of the facility, supporting systems, and staffs. Where permitted by local 
laws/regulations or institutional policy, some or all of these records can be maintained in a 
format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs 
to be exercised before such action is taken. The investigator must assure that all 
reproductions are legible and are a true and accurate copy of the original, and meet 
accessibility and retrieval standards, including the ability to re-generate a hard copy, if 
required. Furthermore, the investigator must ensure that there is an acceptable back-up of 
these reproductions and that an acceptable quality control process exists for making these 
reproductions.  
Shenzhen Forward Pharmaceuticals Co. Lt will inform the investigator of the time period 
for retaining these records to comply with all applicable regulatory requirements. The 
minimum retention time will meet the strictest standard applicable to that site for the study, 
as dictated by any institutional requirements or local laws or regulations, or Shenzhen 
Forward Pharmaceuticals Co. Lt standards/procedures; otherwise, the retention period will 
default to 5 years. 
The investigator must notify Shenzhen Forward Pharmaceuticals Co. Lt of any changes in 
the archival arrangements, including, but not limited to, archival at an off-site facility or 
transfer of ownership of the records in the event the investigator leaves the site. 
11.5 Provision of Study Results and Information to Investigator 
When required by applicable regulations, the investigator signatory for the clinical study 
report will be determined at the time the report is written. When the clinical study report is 
completed, Shenzhen Forward Pharmaceuticals Co. Lt will provide the investigator with a 
full summary of the study results. In addition, the investigator will be given reasonable 
access to review the relevant statistical tables, figures, and reports and will be able to review 
the results for the entire study at any Shenzhen Forward Pharmaceuticals Co. Lt’s site or 
other mutually agreeable location. 
11.6 Data Management 
Shenzhen Forward Pharmaceuticals Co. Lt’s or an appointed third party’s data management 
will identify and implement the most effective data acquisition and management strategy 
for each clinical trial protocol and deliver datasets which support the protocol objectives. 
Subject data will be entered into Shenzhen Forward Pharmaceuticals Co. Lt released CRFs 
and combined with data provided from other sources (e.g., diary data, laboratory data) in a 
validated data system. Clinical data management will be performed in accordance with the 
applicable Shenzhen Forward Pharmaceuticals Co. Lt’s or third party’s standards and will 
include data cleaning procedures with the objective of removing errors and inconsistencies 
in the data which could otherwise impact on the analysis and reporting objectives, or the 

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credibility of the clinical study report. Adverse events and concomitant medications terms 
will be coded using the standards of MedDRA. Original CRFs will be retained by Shenzhen 
Forward Pharmaceuticals Co. Lt, while the investigator will retain a copy. In all cases, 
subject initials will not be collected nor transmitted to Shenzhen Forward Pharmaceuticals 
Co. Lt.   
 
 

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12 Ethics 
12.1 Regulatory and Ethical Considerations 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance 
with the following: 
 
International Conference on Harmonization E6 Good Clinical Practice (GCP) 
Consolidated Guideline. 
 
All applicable laws and regulations, including, without limitation, data privacy laws, 
clinical trial disclosure laws and regulations. 
12.2 Ethics Review 
Prior to initiation of the study, the investigator must provide the sponsor with a copy of the 
written institutional review board (IRB) approval of the protocol and study participant 
information and consent form (PICF). This approval letter will identify the study informed 
consent form (ICF) by date and the study protocol by protocol number, title and date. The 
investigators will receive all the documentation needed for submitting the current protocol 
to the IRB. The composition of the IRB will also be provided to the sponsor. If approval is 
suspended or terminated by the IRB, the investigator will notify the sponsor immediately. 
It is the responsibility of the investigator to report study progress to the IRB as required or 
at intervals not greater than one year. 
The principal investigator at each study site or his/her nominee, will be responsible for 
reporting any SAEs to the IRB as soon as possible, and in accordance with the guidelines 
of the IRB. 
A copy of the approval letter from the IRB must be received by Shenzhen Forward 
Pharmaceuticals Co. Lt prior to shipment of drug supplies to the investigator. The approval 
letter must contain, at a minimum, the protocol title and/or number, the investigator’s name, 
and the date of approval. 
Changes to the protocol and ICF must also be submitted to the IRB for review and approval. 
Any new or revised IRB approval letters must be forwarded to Shenzhen Forward 
Pharmaceuticals Co. Lt promptly.  The investigator must follow all applicable regulatory 
requirements pertaining to the use of an amended PICF before obtaining any new subjects’ 
consent to participate in the study. Records of the IRB annual review, and if applicable, 
approval of all documents pertaining to this study must be sent to Shenzhen Forward 
Pharmaceuticals Co. Lt and kept on file with the investigator. These documents are subject 
to regulatory authority or Shenzhen Forward Pharmaceuticals Co. Lt inspection at any time 
during the study and for 2 years following the last marketing application for the drug. The 
Sponsor will be responsible for reporting all serious, life threatening or fatal AEs with a 
causal relationship to the investigational product to appropriate regulatory agencies within 
their required time lines.  

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12.3 Written Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from each 
individual participating in this phase 1/2 clinical trial after adequate explanation of the aims, 
methods, objectives, and potential hazards (including insurance and other procedures for 
compensation in case of injury) of the study and prior to undertaking any study-related 
procedures. All prospective subjects will be given a copy of the approved (in writing) study 
ICF to read.   
The investigator must utilize an IRB-approved consent form for documenting written 
informed consent. Each informed consent will be appropriately signed and dated by the 
subject and the person obtaining consent. Source documentation of the informed consent 
process must indicate whether informed consent was obtained prior to participation in the 
study.   
It will be pointed out that subjects can refuse to participate in the study, or withdraw from 
the study without prejudice to further care and treatment. Ample time and opportunity will 
be allowed for each subject to enquire about details of the study and to decide whether or 
not to participate in the study.   
Subjects will be informed of any significant new finding, which arises during the course of 
the research that may affect their decision to continue participation. 
12.4 Confidentiality 
The investigator must assure that subjects’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only subject initials, date of birth, 
and an identification code will be recorded on any form or biological sample submitted to 
the sponsor, IRB or laboratory. Laboratory specimens must be labeled in such a way as to 
protect subject identity while allowing the results to be recorded to the proper subject. 
Subject data will be processed in accordance with all applicable regulations. 
The investigator agrees that all information received from Sponsor, including but not 
limited to the investigator brochure, this protocol, eCRF, the study drug, and any other 
study information, remain the sole and exclusive property of Sponsor during the conduct 
of the study and thereafter. This information is not to be disclosed to any third party (except 
employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Sponsor. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site 
to any third party or otherwise into the public domain. 
 
 

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13 Data recordkeeping 
13.1  Inspection of Records 
The investigator should understand that all records including source documents for this 
clinical trial should be made available to appropriately qualified personnel from Sponsor 
or its representatives, or to regulatory authority or health authority inspectors. 
13.2  Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. 
Source documents are original documents, data, and records from which the subject’s CRF 
data are obtained. These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and 
correspondence. CRF entries may be considered source data if the CRF is the site of the 
original recording (i.e., there is no other written or electronic record of data).  
All source documents, CRFs and study documentation will be kept by the investigator for 
the appropriate retention period as stipulated by local regulations and ICH-GCP. 
No trial document should be destroyed without prior written agreement between the 
sponsor and the investigator. Study data is always moved to an offsite location after study 
conduct is complete, the investigator must notify the sponsor in writing of the new 
responsible person and/or the new location.  
 
 

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14 Financing and Insurance 
Subjects may be compensated for the time that they spend participating in the study using 
a formula determined by the study site. 
Insurance will be provided in conformity with the ICH-GCP for all subjects involved in the 
study. The subject should not take part in any other clinical study whilst enrolled in this 
study. The subject should report any health injury that could have occurred as a result of 
the clinical study to the investigator without delay. 
 
 

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15 Publishing 
Following completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigator to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which 
it will be submitted, and other related issues. Data is the property of the Sponsor and cannot 
be published without prior authorization granted by the Sponsor, but data and publication 
thereof will not be unduly withheld.

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16 References and Appendices 
Ahmad, I., & Shagufta. (2015). Recent developments in steroidal and nonsteroidal 
aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer. Eur J 
Med Chem, 102, 375-386. doi:10.1016/j.ejmech.2015.08.010 
 
Allison, K. H., Hammond, M. E. H., Dowsett, M., McKernin, S. E., Carey, L. A., 
Fitzgibbons, P. L., Perlmutter, J. (2020). Estrogen and progesterone receptor testing in 
breast cancer: ASCO/CAP guideline update. JOURNAL OF CLINICAL ONCOLOGY, 
38(12), 1346-1366. 
 
Cockcroft DW, G. M. (1976). Prediction of creatinine clearance from serum creatinine. 
Nephron., 16(1), 31-42.  
 
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Verweij, 
J. (2009). New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer, 45(2), 228-247. doi:10.1016/j.ejca.2008.10.026 
 
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Fribbens, C., O'Leary, B., Kilburn, L., Hrebien, S., Garcia-Murillas, I., Beaney, M., Turner, 
N. C. (2016). Plasma ESR1 Mutations and the Treatment of Estrogen Receptor-Positive 
Advanced Breast Cancer. J Clin Oncol, 34(25), 2961-2968. doi:10.1200/jco.2016.67.3061 
Harbeck, N., Penault-Llorca, F., Cortes, J., Gnant, M., Houssami, N., Poortmans, P.,  
 
Cardoso, F. (2019). Breast cancer. Nat Rev Dis Primers, 5(1), 66. doi:10.1038/s41572-019-
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Dustin, D., Gu, G., & Fuqua, S. A. W. (2019). ESR1 mutations in breast cancer. Cancer, 
125(21), 3714-3728. doi:10.1002/cncr.32345 
 
Hernando, C., Ortega-Morillo, B., Tapia, M., Moragon, S., Martinez, M. T., Eroles, P., 
Cejalvo, J. M. (2021). Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel 
Breast Cancer Therapy: Present and Future from a Clinical Perspective. Int J Mol Sci, 
22(15). doi:10.3390/ijms22157812 
 
Liu, S., Han, S. J., & Smith, C. L. (2013). Cooperative activation of gene expression by 
agonists and antagonists mediated by estrogen receptor heteroligand dimer complexes. Mol 
Pharmacol, 83(5), 1066-1077. doi:10.1124/mol.112.084228 
 
Lu, Y., & Liu, W. (2020). Selective Estrogen Receptor Degraders (SERDs): A Promising 
Strategy for Estrogen Receptor Positive Endocrine-Resistant Breast Cancer. J Med Chem, 
63(24), 15094-15114. doi:10.1021/acs.jmedchem.0c00913 
 
Maughan, K. L., Lutterbie, M. A., & Ham, P. S. (2010). Treatment of breast cancer. Am 

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Fam Physician, 81(11), 1339-1346.  
 
Nevens, F., Andreone, P., Mazzella, G., Strasser, S. I., Bowlus, C., Invernizzi, P., Shapiro, 
D. (2016). A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. 
New England Journal of Medicine, 375(7), 631-643. doi:10.1056/NEJMoa1509840 
 
Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. T., & 
Carbone, P. P. (1982). Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol, 5(6), 649-655.  
 
Organization. 
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https://www.iarc.who.int/cancer-type/breast-cancer 
 
Osborne, C. K. (1998). Tamoxifen in the treatment of breast cancer. N Engl J Med, 339(22), 
1609-1618. doi:10.1056/nejm199811263392207 
 
Ravisekar, J. R. B. a. O. (2007). Aromatize Inhibitors for Treatment of Breast Cancer. 
Current Cancer Therapy Reviews, 3(1, 2007), 67-79.  
 
Reinert, T., Saad, E. D., Barrios, C. H., & Bines, J. (2017). Clinical Implications of ESR1 
Mutations in Hormone Receptor-Positive Advanced Breast Cancer. Front Oncol, 7, 26. 
doi:10.3389/fonc.2017.00026 
 
Shagufta, Ahmad, I., Mathew, S., & Rahman, S. (2020). Recent progress in selective 
estrogen receptor downregulators (SERDs) for the treatment of breast cancer. RSC Med 
Chem, 11(4), 438-454. doi:10.1039/c9md00570f 
 
Wolff, A. C., Hammond, M. E. H., Allison, K. H., Harvey, B. E., Mangu, P. B., Bartlett, J. 
M., Hanna, W. (2018). Human epidermal growth factor receptor 2 testing in breast cancer: 
American Society of Clinical Oncology/College of American Pathologists clinical practice 
guideline focused update. Archives of pathology & laboratory medicine, 142(11), 1364-
1382 
 
 
  
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Appendix 1 
Guidelines for Evaluation of Objective Tumor Response Using RECIST 1.1 (Response 
Evaluation Criteria in Solid Tumors) 
1. Introduction 
This appendix details the implementation of RECIST (Response Evaluation Criteria in 
Solid Tumors) 1.1 guidelines (Eisenhauer et al., 2009) for the study with regards to 
investigator assessment of tumor burden including protocol-specific requirements for this 
study. 
2. Measurability of tumor at baseline  
2.1 Definitions  
At baseline, tumor lesions/lymph nodes will be categorised measurable or non-measurable 
as follows:  
2.1.1 Measurable  
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 P15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. See also notes below on ‘Baseline 
documentation of target and non-target lesions’ for information on lymph node 
measurement.  
2.1.2 Non-measurable  
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with P10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, and 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. 
2.1.3. Special considerations regarding lesion measurability 

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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: 
 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
2.2 pecifications by methods of measurements 
2.2.1 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. 
2.2.2. Method of assessment  
The same method of assessment and the same technique should be used to characterise 
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.  

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Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and P10 mm diameter as assessed using calipers (e.g. skin nodules). For the 
case of skin lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is suggested. As noted above, when lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken since it is more 
objective and may also be reviewed at the end of the study.  
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. As is described 
in Appendix II, when CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (e.g. for body scans). 
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 that the same technique and measurements will be taken from one 
assessment to the next (described in greater detail in Appendix II). If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. 
If there is concern about radiation exposure at CT, MRI may be used instead of CT in 
selected instances.  
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. However, they can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response or surgical resection is an endpoint.  
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
If markers are initially above EUROPEAN JOURNAL OF CANCER 45 (2009) 228 – 247 
231 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. 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 effects of treatment (e.g., with certain taxane compounds or 

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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. 
3. Tumor response evaluation 
3.1Assessment of overall tumor burden and measurable disease  
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. Only 
patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint. Measurable disease is defined by the 
presence of at least one measurable lesion. In studies where the primary endpoint is tumor 
progression (either time to progression or proportion with progression at a fixed date), the 
protocol must specify if entry is restricted to those with measurable disease or whether 
patients having non-measurable disease only are also eligible. 
3.2. Baseline documentation of ‘target’ and ‘non-target’ lesions  
When more than one measurable lesion is present at baseline all lesions up to a maximum 
of five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline 
(this means in instances where patients have only one or two organ sites involved a 
maximum of two and four lesions respectively will be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumor. Pathological nodes which are defined 
as measurable and may be identified as target lesions must meet the criterion of a short axis 
of P15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge if a 
node is involved by solid tumor. Nodal size is normally reported as two dimensions in the 
plane in which the image is obtained (for CT scan this is almost always the axial plane; for 
MRI the plane of acquisition may be axial, saggital or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as being 20 
mm · 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In 
this example, 20 mm should be recorded as the node measurement. All other pathological 
nodes (those with short axis P10 mm but <15 mm) should be considered non-target lesions. 
Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed. 

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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterise any objective 
tumor regression in the measurable dimension of the disease.  
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are 
not required and these lesions should be followed as ‘present’, ‘absent’, or in rare cases 
‘unequivocal progression’ (more details to follow). In addition, it is possible to record 
multiple nontarget lesions involving the same organ as a single item on the case record 
form (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
3.3. Response criteria  
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
3.3.1. 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 more 
new lesions is also considered progression).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study 
3.3.2. Special notes on the assessment of target lesions 
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 
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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 
subsequent evaluation, even when very small (e.g. 2 mm). However, 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 default 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 is able 
to provide an actual measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. As noted in Appendix II, when non-nodal 
lesions ‘fragment’, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of 
each individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal longest 
diameter for the ‘coalesced lesion’. 
3.3.3. Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine 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). 
3.3.4. Special notes on assessment of progression of non-target disease 
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When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy (see further details below). A modest ‘increase’ in the size of one or more non-
target 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 circumstance arises in some phase 
III trials when it is not a criterion of study entry to have measurable disease. The same 
general concepts apply here as noted above, however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in non-
measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are truly non-measurable) a useful test that can be applied when assessing patients 
for unequivocal progression is to consider if the increase in overall disease burden based 
on the change in non-measurable disease is comparable in magnitude to the increase that 
would be required to declare PD for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase 
diameter in a measurable lesion). Examples include an increase in a pleural effusion from 
‘trace’ to ‘large’, an increase in lymphangitic disease from localised 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 disease, the 
very nature of that disease makes it impossible to do so; therefore, the increase must be 
substantial. 
3.3.5. 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. 

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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
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. 
3.4. Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. On 
occasion, a response may not be documented until after the end of therapy so protocols 
should be clear if post-treatment assessments are to be considered in determination of best 
overall response. Protocols must specify how any new therapy introduced before 
progression will affect best response designation. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also 
take into consideration the appearance of new lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory 
measurement. Specifically, in non-randomized trials where response is the primary 
endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall response’. 
This is described further below. 
3.4.1. Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 
1 the next page provides a summary of the overall response status calculation at each time 
point for patients at baseline. 
3.4.2. Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 

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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. 
3.4.3. Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response 
IS NOT required: Best response in these trials is defined as the best response across all 
time points (for example, a patient who has SD at first assessment, PR at second assessment, 
and PD on last assessment has a best overall response of PR). When SD is believed to be 
best response, it must also meet the protocol specified minimum time from baseline. If the 
minimum time is not met when SD is otherwise the best time point response, the patient’s 
best response depends on the subsequent assessments. For example, a patient who has SD 
at first assessment, PD at second and does not meet minimum duration for SD, will have a 
best response of PD. The same patient lost to follow-up after the first SD assessment would 
be considered inevaluable. 
Table 14 Time Point Response 
Target lesions 
Non-Target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
CR 
Non-CR/Non PD 
No 
PR 
CR 
NE 
No 
PR 
RR 
Non PD or NE 
No 
PR 
SD 
Non PD or NE 
No 
SD 
NA 
Non CR/Non PD 
No 
SD (Non CR/non PD) 
NE 
Non-PD or NE 
No 
NE 
NA 
NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease 
IR = incomplete response, NE = not evaluable, NA = not applicable (relevant when no NTLs at baseline) 
Best response determination in trials where confirmation of complete or partial response 
IS required: Complete or partial responses may be claimed only if the criteria for each are 
met at a subsequent time point as specified in the protocol (generally 4 weeks later).  
4.4.4. Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes. As noted earlier, this means 
that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF). 

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In trials where confirmation of response is required, repeated ‘NE’ time point assessments 
may complicate best response determination. The analysis plan for the trial must address 
how missing data/assessments will be addressed in determination of response and 
progression. For example, in most trials it is reasonable to consider a patient with time 
point responses of PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective 
progression even after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy. The objective 
response status of such patients is to be determined by evaluation of target and non-target 
disease as shown in Table 1. 
Conditions that define ‘early progression, early death and inevaluability’ are study specific 
and should be clearly described in each protocol (depending on treatment duration, 
treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
assigning a status of complete response. FDG-PET may be used to upgrade a response to a 
CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is 
thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should 
be prospectively described in the protocol and supported by disease 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.  
3.5. Frequency of tumor re-evaluation  
Frequency of tumor re-evaluation while on treatment should be protocol specific and 
adapted to the type and schedule of treatment. However, in the context of phase II studies 
where the beneficial effect of therapy is not known, follow-up every 6–8 weeks (timed to 
coincide with the end of a cycle) is reasonable. Smaller or greater time intervals than these 
could be justified in specific regimens or circumstances. The protocol should specify which 
organ sites are to be evaluated at baseline (usually those most likely to be involved with 
metastatic disease for the tumor type under study) and how often evaluations are repeated. 
Normally, all target and non-target sites are evaluated at each assessment. In selected 
circumstances certain non-target organs may be evaluated less frequently. For example, 
bone scans may need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 

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After the end of the treatment, the need for repetitive tumor evaluations depends on whether 
the trial has as a goal the response rate or the time to an event (progression/death). If ‘time 
to an event’ (e.g. time to progression, disease-free survival, progression-free survival) is 
the main endpoint of the study, then routine scheduled re-evaluation of protocol specified 
sites of disease is warranted. In randomized comparative trials in particular, the scheduled 
assessments should be performed as identified on a calendar schedule (for example: every 
6–8 weeks on treatment or every 3–4 months after treatment) and should not be affected 
by delays in therapy, drug holidays or any other events that might lead to imbalance in a 
treatment arm in the timing of disease assessment. 
3.6. Confirmatory measurement/duration of response 
3.6.1. Confirmation 
In non-randomized trials where response is the primary endpoint, 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. 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. 
3.6.2. 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 
disease 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. 
3.6.3. Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date 
of randomization) until the criteria for progression are met, taking as reference the smallest 
sum on study (if the baseline sum is the smallest, this is the reference for calculation of 
PD). 
The clinical relevance of the duration of stable disease varies in different studies and 
diseases. If the proportion of patients achieving stable disease for a minimum period of 
time is an endpoint of importance in a particular trial, the protocol should specify the 

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minimal time interval required between two measurements for determination of stable 
disease. 
Note: The duration of response and stable disease as well as the progression-free survival 
are influenced by the frequency of follow-up after baseline evaluation. It is not in the scope 
of this guideline to define a standard follow-up frequency. The frequency should take into 
account many parameters including disease types and stages, treatment periodicity and 
standard practice. However, these limitations of the precision of the measured endpoint 
should be taken into account if comparisons between trials are to be made. 
3.7. Progression-free survival/proportion progression-free 
This guideline is focused primarily on the use of objective response endpoints for phase II 
trials. In some circumstances, ‘response rate’ may not be the optimal method to assess the 
potential anticancer activity of new agents/regimens. In such cases ‘progression-free 
survival’ (PFS) or the ‘proportion progression-free’ at landmark time points, might be 
considered appropriate alternatives to provide an initial signal of biologic effect of new 
agents. It is clear, however, that in an uncontrolled trial, these measures are subject to 
criticism since an apparently promising observation may be related to biological factors 
such as patient selection and not the impact of the intervention. Thus, phase II screening 
trials utilizing these endpoints are best designed with a randomized control. Exceptions 
may exist where the behavior patterns of certain cancers are so consistent (and usually 
consistently poor), that a non-randomized trial is justifiable. However, in these cases it will 
be essential to document with care the basis for estimating the expected PFS or proportion 
progression-free in the absence of a treatment effect. 
3.8. Independent review of response and progression 
For trials where objective response (CR + PR) is the primary endpoint, and in particular 
where key drug development decisions are based on the observation of a minimum number 
of responders, it is recommended that all claimed responses be reviewed by an expert(s) 
independent of the study. If the study is a randomized trial, ideally reviewers should be 
blinded to treatment assignment. Simultaneous review of the patients’ files and radiological 
images is the best approach.  
Independent review of progression presents some more complex issues: for example, there 
are statistical problems with the use of central-review-based progression time in place of 
investigator-based progression time due to the potential introduction of informative 
censoring when the former precedes the latter.  
3.9. Reporting best response results 
When response is the primary endpoint, and thus all patients must have measurable disease 
to enter the trial, all patients included in the study must be accounted for in the report of 
the results, even if there are major protocol treatment deviations or if they are not evaluable. 
Each patient will be assigned one of the following categories: 

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1. Complete response 
2. Partial response 
3. Stable disease 
4. Progression 
5. Inevaluable for response: specify reasons (for example: early death, malignant disease; 
early death, toxicity; tumor assessments not repeated/incomplete; other (specify)). 
Normally, all eligible patients should be included in the denominator for the calculation of 
the response rate for phase II trials (in some protocols it will be appropriate to include all 
treated patients). It is generally preferred that 95% two-sided confidence limits are given 
for the calculated response rate. Trial conclusions should be based on the response rate for 
all eligible (or all treated) patients and should not be based on a selected ‘evaluable’ subset. 

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Appendix 2 
ECOG Performance Status*(Oken et al., 1982) 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 

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Appendix 3 
A formula(Cockcroft DW, 1976) has been developed to predict creatinine clearance (Ccr) 
from serum creatinine (Scr) in adult males: 
𝐶𝑐𝑟= (140 −𝑎𝑔𝑒)(𝑤𝑡 𝑘𝑔)
72 × 𝑆𝑐𝑟(𝑚𝑔/100 𝑚𝑙) 
(15% less in females). 
 
 

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Appendix 4  
SOP for Emergency 
 
Special treatment 
1. Stop administration; 
2. Monitoring vital signs: ECG, blood pressure, respiration, temperature; 
3. Gastric lavage: 1%~2% sodium chloride solution or 1:5000 potassium permanganate 
solution; 
4. Catharsis: Sodium sulfate 15~30 g, add water 200 mL; 
5. Enema: Wash with 1% lukewarm soapy water (about 5000 mL) at high level 
continuously. 
 
 
Supportive therapy 
1. Sedation and oxygen administration; 
2. Establish intravenous infusion channels, open respiratory channels, and give 
endotracheal intubation, cardiac massage and ventilator assisted breathing support 
when necessary; 
3. Adequate fluid replacement to maintain circulating blood volume: intravenous 
injection of normal saline or glucose sodium chloride, according to the condition of 
colloid supplement to ensure circulation osmotic pressure; 
4. Strengthen the heart, improve the pressure, maintain the stability of blood pressure, 
and ensure the blood supply of important organs: 20-60mg adrenal corticosteroid plus 
5% glucose 50-250ml intravenous infusion can be given first, and dopamine can be 
pumped for maintenance after the blood pressure is stabilized; 
5. Diuretic, diuretic drugs such as furosemide were given according to the volume of 
urine, sodium bicarbonate was given in appropriate amount, and the urine was 
alkalized; 
6. Maintain the balance of water, electrolyte, acid and base; 
7. Anti-arrhythmia; 
8. Symptomatic treatment to maintain nitrogen balance. 
 
 
Anti-allergy treatment 

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1. Promethamine 10 mg or promethazine 25-50mg, supine, oxygen inhalation, ensure the 
airway patently; 
2. 0.1% epinephrine 0.1-0.2ml plus 5% glucose by intravenous drip; 
3. Use glucocorticoids such as dexamethasone; 
 
 
Correct respiratory and circulatory failure 
Give oxygen or artificial respiration, with kelamine 0.375 g, lobelin 3~6mg injection 
alternately, every 15~30 minutes. If necessary, intravenous injection 1~2 times strong heart 
glycoside drug digitalis preparation. 
 
 
 

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Appendix 5 
CYP3A and P-gp Inducers and Inhibitors 
 
Strong Inhibitors 
Strong Inducers 
CYP3A4 
 
cobicistat, danoprevir and ritonavir, elvitegravir and 
ritonavir, grapefruit juice, indinavir and ritonavir, 
itraconazole, ketoconazole, lopinavir and ritonavir, 
paritaprevir and ritonavir and ombitasvir (and/or 
dasabuvir), posaconazolee, ritonavir, saquinavir and 
ritonavir, tipranavir and ritonavir, telithromycin, 
troleandomycin, voriconazole, ceritinib, clarithromycin, 
idelalisib, nefazodone, nelfinavir 
apalutamide, 
carbamazepine, 
enzalutamide, ivosidenib, 
lumacaftor, mitotane, 
phenytoin, rifampin 
Moderate Inhibitors 
Moderate Inducers 
aprepitant, ciprofloxacin, conivaptan, crizotinib, 
cyclosporine, diltiazem, dronedarone, erythromycin, 
fluconazole, fluvoxamine, grapefruit juice, imatinib, 
isavuconazole, tofisopam, verapamil 
bosentan, cenobamate, 
dabrafenib, efavirenz, 
etravirine, lorlatinib, 
pexidartinib, 
phenobarbital, primidone, 
sotorasib 
P-gp 
Strong/Moderate Inhibitors 
Strong/Moderate 
Inducers 
amiodarone, clarithromycin, cobicistat, cyclosporine, 
dronedarone, erythromycin, itraconazole, ketoconazole, 
lapatinib, lopinavir and ritonavir, quinidine, ranolazine, 
saquinavir and ritonavir, verapamil 
-- 
Reference:https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 
 
Proton pump inhibitors (PPIs) 
PPIs 
lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), rabeprazole 
(AcipHex), and esomeprazole (Nexium) 
Reference: https://www.fda.gov/media/144026/download 
 
 
 

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Appendix 6 
ESR1 Mutations in Breast Cancer 
Nuclear receptor location 
Mutation 
AF1 
S47T 
A65V 
N69K 
P147Q 
G160D 
DBD 
P222S 
R233G 
Hinge 
K252N 
R271K 
E279V 
S282C 
A293V 
K303R 
S329Y 
G344D 
AF2/LBD 
L370F 
E380Q 
V392I 
M396V 
N407I 
V418E 
G420D 
M421V 
S432L 
M437I 
G442R 
F461V 
S463P 
L466Q 
E471D 
V478L 
R503W 
E523Q 
H524L 
K531E 
N532K 
V533M 
V534E 
P535H/T 
L536H/Q/P/R 
Y537C/D/H/N/S 
D538G/N 
L540Q 
E542G 
A546D/T 
L549P 

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R555C/H 
G557R 
T570I 
S576L 
A593D 
Note: Location of ESR1 missense mutations found in clinical samples. 47/62 identified mutations occur 
in the LBD, and several are associated with ligand-independent activation of ER. AF1, activation 
function 1; DBD, DNA binding domain; AF2, activation function 2; LBD, ligand binding 
domain(Dustin, Gu, & Fuqua, 2019). 
 

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