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| 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                                                                                                                                                |
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clinical study protocol 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 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+/HER2unresectable 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 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  
| 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 50Confidential Page 6 of 115 Version 1.1 Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol |  
| IND FWD1802                                                                                                                                                      |          |             |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|-------------|
| Clinical Protocol                                                                                                                                                |          |             |
| 4.2.3 Part C - Dose Expansion Study                                                                                                                              |          |             |
| 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)                                                                                                                  |          |             |
| 4.7 Dose modifications                                                                                                                                           |          |             |
| 4.7.1 Dose Reductions ...............................................................................................................54                          |          |             |
| 4.7.2 Dose Escalations .                                                                                                                                         |          |             |
| 4.7.3 Temporary Withdrawal                                                                                                                                       |          |             |
| 5 Study Population                                                                                                                                               |          |             |
| 5.1 Number of Subjects                                                                                                                                           |          |             |
| 5.2 Inclusion Criteria                                                                                                                                           |          |             |
| 5.3 Exclusion Criteria                                                                                                                                           |          |             |
| 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                                                                                                                                    |          |             |
| 5.5.2 Investigator's Request ...........................................................................................61                                       |          |             |
| 5.5.3 Sponsor's Request .................................................................................................61                                      |          |             |
| 5.5.4 IRB and/or FDA's Request                                                                                                                                   |          |             |
| 6 Description of Study Treatment ..................................................................................................62                            |          |             |
| 6.1 Study Treatment ...................................................................................................................62                        |          |             |
| 6.2 Administration                                                                                                                                               |          |             |
| 6.3 Study Drug Packaging and Labeling                                                                                                                            |          |             |
| 6.4 Study Drug Storage ..............................................................................................................63                          |          |             |
| 6.5 Study Drug Accountability................................................................................................63                                  |          |             |
| 6.6 Study Drug Handling and Disposal                                                                                                                             |          |             |
| 6.7 Concomitant Medications ............................................................................................64                                       |          |             |
| 6.8 Assessment of Compliance ............................................................................................64                                      |          |             |
| 7 Study Procedures ...........................................................................................................................65                 |          |             |
| 7.1 Subject Identification ......................................................................................................65                              |          |             |
|                                                                                                                                                                  |          |             |
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| Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol                                                                                                  |          |             |  
| IND FWD1802                                                                                                                                      |                                                                                                                                                                                |             |
|--------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|
| Clinical Protocol                                                                                                                                | Copyright 2017 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may b |             |
| 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                                                                                                                             |                                                                                                                                                                                |             |
| 7.3.7 18 F-FES PET/CT ........................................................................................................66                 |                                                                                                                                                                                |             |
| 7.4 Study Procedures ........................................................................................................................67  |                                                                                                                                                                                |             |
| 7.4.1 Screening Period (Day -28~Day -1) for All Subjects                                                                                         |                                                                                                                                                                                |             |
| 7.4.2 Treatment Period ..................................................................................................68                      |                                                                                                                                                                                |             |
| 7.4.3 Post Treatment Follow-up Visit ..........................................................................69                                |                                                                                                                                                                                |             |
| 7.5 Biological Samples                                                                                                                           |                                                                                                                                                                                |             |
| 70                                                                                                                                               |                                                                                                                                                                                |             |
| 7.5.2 Sample Preparation                                                                                                                         |                                                                                                                                                                                |             |
| 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                                                                                                                                        |                                                                                                                                                                                |             |
| 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                                                                                                                  |                                                                                                                                                                                |             |
| 9.1 Adverse Events                                                                                                                               |                                                                                                                                                                                |             |
| 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                                                                                                             |                                                                                                                                                                                |             |
| 9.4 Recording AEs and SAEs .........................................................................................................77           |                                                                                                                                                                                |             |
| 9.4.1 All Adverse Events Regardless of Seriousness ..................................................77                                          |                                                                                                                                                                                |             |
| Confidential Page                                                                                                                                | 8 of 115                                                                                                                                                                       | Version l.l |
| Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol                                                                                  |                                                                                                                                                                                |             |  
| IND FWD1802                                                                                                                                                          |          |             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|-------------|
| Clinical Protocol                                                                                                                                                    |          |             |
| 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                                                                                                                                      |          |             |
| 9.5 Reporting Adverse Events                                                                                                                                         |          |             |
| 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)                                                                                                                                       |          |             |
| 10.2.2 Safety Analysis Set (SS)                                                                                                                                      |          |             |
| 10.2.3 Pharmacokinetic Concentration Set (PKCS)                                                                                                                      |          |             |
| 10.2.4 Pharmacokinetic Parameter Set (PKPS)                                                                                                                          |          |             |
| 10.2.5 Pharmacodynamics Analysis Set (PDS)                                                                                                                           |          |             |
| 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                                                                                                                                                 |          |             |
| 10.5.1 Adverse Events .......................................................................................................83                                      |          |             |
| 10.5.2 Laboratory Evaluations                                                                                                                                        |          |             |
| 10.5.3 Other Safety Evaluations ......................................................................................83                                             |          |             |
| 10.5.4 Pharmacokinetic Analysis ...................................................................................83                                                |          |             |
| 10.6 Pharmacodynamics Analysis                                                                                                                                       |          |             |
| 10.7 C-QT Analysis                                                                                                                                                   |          |             |
| 10.8 Preliminary Efficacy Analysis ....................................................................................84                                            |          |             |
| 1 Study Conduct Considerations                                                                                                                                       |          |             |
| 1.1 Quality Check (Study Monitoring) ...............................................................................84                                               |          |             |
| 1.2 Quality Assurance .................................................................................................................85                            |          |             |
| 1.3 Study and Site Closure ............................................................................................................85                            |          |             |
| 1.4 Record Retention                                                                                                                                                 |          |             |
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| Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol                                                                                                      |          |             |  
| Clinical Protocol                                                                                                                                       |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.5 Provision of Study Results and Information to Investigator ................................86                                                       |
| 1.6 Data Management .............................................................................................................86                     |
| 12 Ethics                                                                                                                                               |
| 12.1 Regulatory and Ethical Considerations ...........................................................................88                                |
| 12.2 Ethics Review                                                                                                                                      |
| 12.3 Written Informed Consent                                                                                                                           |
| 12.4 Confidentiality                                                                                                                                    |
| 13 Data recordkeeping ...................................................................................................................90             |
| 13.1 Inspection of Records                                                                                                                              |
| 13.2 Retention of Records                                                                                                                               |
| 14 Financing and Insurance ..............................................................................................................91             |
| 15 Publishing .......................................................................................................................................92 |
| 16 References and Appendices .....................................................................................................93                    |
| Appendix 1 ........................................................................................................................................95   |
| Appendix 2                                                                                                                                              |
| Appendix 3                                                                                                                                              |
| Appendix 4                                                                                                                                              |
| Appendix 5                                                                                                                                              |
| Appendix 6                                                                                                                                              |
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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   |
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list of figures

Figure 1 Clinical Design of FWD1802 in Phase I Trial.....................................................49 Figure 2. An example of FWD1802 label..........................................................................62  
| Synopsis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                       |                                                                                                                                                                                                                                             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Investigational                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | FWD1802                                                                                                               |                                                                                                                                                                                                                                             |
| Product Protocol                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | FWD1802-001C                                                                                                          |                                                                                                                                                                                                                                             |
| Number Version/Date                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 1.1 / Jul 13 2023                                                                                                     |                                                                                                                                                                                                                                             |
| Sponsor                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Shenzhen Forward Pharmaceuticals Co. Lt                                                                               |                                                                                                                                                                                                                                             |
| Number                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | of                                                                                                                    | Approximately 99 patients                                                                                                                                                                                                                   |
| Subjects Study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | A/B: ER+ /HER2- unresectable locally advanced or metastatic breast                                                    |                                                                                                                                                                                                                                             |
| Population                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | cancer. C: ER+/HER2- unresectable locally advanced or metastatic breast cancer  with ESR1 mutation Primary Objective: |                                                                                                                                                                                                                                             |
| Study  Objectives                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | -                                                                                                                     | 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. 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 |                                                                                                                       |                                                                                                                                                                                                                                             |
| Starting                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Dose                                                                                                                  |                                                                                                                                                                                                                                             |
| Selection Confidential Page                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 12 of 115                                                                                                             | Version 1.1                                                                                                                                                                                                                                 |
| Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                       |                                                                                                                                                                                                                                             |  
| IND FWD1802 Clinical Protocol 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. FWD1802   |                              |
|-----------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|
| Investigational Product and  Administration                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | 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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                              |
| 1.                                                              | Patients must understand and voluntarily sign the Informed Consent  Form (ICF).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                              |
| Inclusion  Criteria                                             | 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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| Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                              |  
| Clinical Protocol   | 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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |  
| IND FWD1802 Clinical Protocol                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | 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). 1. Documented medical history or ongoing gastrointestinal disease  (Including difficulty in swallowing capsules, Crohn's disease, |                                                                  |                                                                                            |
| Exclusion  Criteria                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                  |                                                                                            |  
| IND FWD1802 Clinical Protocol   | 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.                                                                                                                                                                                                                                                                                                                   |  
| IND FWD1802 Clinical Protocol   | 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 HCVRNA 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).   |
|---------------------------------|---|  
| IND FWD1802 Clinical Protocol                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | 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. 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.   |         |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|
| Study  Procedure 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 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |         |  
| IND FWD1802 Clinical Protocol                                   | 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. Oral (P.O)   |             |
|-----------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|
| Mode                                                            | of                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |             |
| administration Test product(s)                                  | FWD1802 Palbociclib                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |             |
| Combination  product(s)                                         | DLT Definition:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |             |
| DLT Definition  / MTD  evaluation  period                       | 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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| Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |             |  
| IND FWD1802 Clinical Protocol                                                                                                                                                                                                                                             | 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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| Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                            |             |    |                  |    |    |            |     |  
| IND FWD1802 Clinical Protocol   | Reiterated treatment cycles of 4 weeks until progression disease based on  radiological evaluation, undue drug toxicity, withdrawal of consent or  death, whichever occurs first.   |
|---------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Duration                        | of                                                                                                                                                                                  |
| treatment PK/PD Sample          | Please see Section7.5.1 PK Samples and Section 7.3.7 18F-FES PET/CT. Descriptive analysis (summary statistics) will be used to describe the  safety and efficacy endpoints.         |
| Statistical  Methods            | Safety Analysis:  Incidence and severity of adverse events according to the NCICTCAE (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.                                                                                                                                                                                     |  
| Single dose                                                                                                                                                                      | Multiple dose   | Follow-up   |                 |         |         |     |        |       |    |    |    |    |    |    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|-------------|-----------------|---------|---------|-----|--------|-------|----|----|----|----|----|----|
| Items                                                                                                                                                                            | Scree ning1     | 4 days      | Cycle 1 28days  | Cycle 2 | ≥Cycle3 | EOT | SFU  3 | LTFU4 |    |    |    |    |    |    |
| 2                                                                                                                                                                                |                 |             |                 |         |         |     |        |       |    |    |    |    |    |    |
| D28~                                                                                                                                                                                  | D 1             | D2~ D4      | D1              | D8      | D1      | D2  |        |       |    |    |    |    |    |    |
| Visit Day                                                                                                                                                                        | 2               | D1          |                 |         |         |     |        |       |    |    |    |    |    |    |
| 5                                                                                                                                                                                |                 |             |                 |         |         |     |        |       |    |    |    |    |    |    |
| D-1                                                                                                                                                                              | 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  X Criteria 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  |    |    |    |    |
| X                                                                                                                                                                                |                 |             |                 |         |         |     |        |       |    |    |    |    |    |    |
| Echocardiogram                                                                                                                                                                   | 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               |             |                 |         |         |     |        |       |    |    |    |    |    |    |
| Confidential Page                                                                                                                                                                | 22 of 115       | Version 1.1 |                 |         |         |     |        |       |    |    |    |    |    |    |
| Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol                                                                                                                  |                 |             |                 |         |         |     |        |       |    |    |    |    |    |    |  
| Clinical Protocol                                                                                                             | Single dose   | Multiple dose                                                              | Follow-up      |         |         |     |        |       |    |    |    |    |    |    |
|-------------------------------------------------------------------------------------------------------------------------------|---------------|----------------------------------------------------------------------------|----------------|---------|---------|-----|--------|-------|----|----|----|----|----|----|
| Items                                                                                                                         | Scree ning1   | 4 days                                                                     | Cycle 1 28days | Cycle 2 | ≥Cycle3 | EOT | SFU  3 | LTFU4 |    |    |    |    |    |    |
| 2                                                                                                                             |               |                                                                            |                |         |         |     |        |       |    |    |    |    |    |    |
| D28~                                                                                                                               | D 1           | D2~ D4                                                                     | D1             | D8      | D1      | D2  |        |       |    |    |    |    |    |    |
| Visit Day                                                                                                                     | 2             | D1                                                                         |                |         |         |     |        |       |    |    |    |    |    |    |
| 5                                                                                                                             |               |                                                                            |                |         |         |     |        |       |    |    |    |    |    |    |
| D-1                                                                                                                           | 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 NonDrug Supportive  Interventions                                                                                                                               | X             |                                                                            |                |         |         |     |        |       |    |    |    |    |    |    |
| Note: * The tests of hematology, urinalysis, blood biochemistry and coagulation before the first dose administration could be |               |                                                                            |                |         |         |     |        |       |    |    |    |    |    |    |  
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.  
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
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.  
| Table 2 Schedule of Events in Part B Dose Escalation Escalation                                                                                                              | Follow-up   |                                                                           |         |         |        |       |       |    |    |    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|---------------------------------------------------------------------------|---------|---------|--------|-------|-------|----|----|----|
| Items                                                                                                                                                                        | Screening1  | 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           |                                                                           |         |         |        |       |       |    |    |    |
| Confidential Page                                                                                                                                                            | 26 of 115   | Version 1.1                                                               |         |         |        |       |       |    |    |    |
| Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol                                                                                                              |             |                                                                           |         |         |        |       |       |    |    |    |  
| Escalation                                                                                                                    | Follow-up                                                              |         |         |         |        |       |       |    |    |    |
|-------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|---------|---------|---------|--------|-------|-------|----|----|----|
| Items                                                                                                                         | Screening1                                                             | 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 NonDrug Supportive  Interventions                                                                                                                               | X                                                                      |         |         |         |        |       |       |    |    |    |
| Note: * The tests of hematology, urinalysis, blood biochemistry and coagulation before the first dose administration could be |                                                                        |         |         |         |        |       |       |    |    |    |  
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).  
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.  
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.  
| Table 3 Schedule of Events in Part C Dose Expansion Expansion                                                                                                                | Follow-up   |                                                                            |         |         |        |       |       |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|----------------------------------------------------------------------------|---------|---------|--------|-------|-------|
| Items                                                                                                                                                                        | Screening1  | 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 ExplorationConfidential Page                                                                                                                                       | 30 of 115   | Version 1.1                                                                |         |         |        |       |       |
| Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol                                                                                                              |             |                                                                            |         |         |        |       |       |  
| Clinical Protocol                                                                                                             | Expansion   | Follow-up         |         |         |        |       |       |
|-------------------------------------------------------------------------------------------------------------------------------|-------------|-------------------|---------|---------|--------|-------|-------|
| Items                                                                                                                         | Screening1  | 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 NonDrug Supportive  Interventions                                                                                                                               | X           |                   |         |         |        |       |       |
| Note: * The tests of hematology, urinalysis, blood biochemistry and coagulation before the first dose administration could be |             |                   |         |         |        |       |       |  
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).  
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 premorning 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.  
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/                                    | Definition                                                                                                  |
| Specialist Term AE                               | Adverse event                                                                                               |
| AUC 0-t                                          | Area under the plasma concentration time curve The area under the plasma concentration-time curve from time |
| AUC0-inf                                         | 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                                                                             |  
| IND FWD1802 Clinical Protocol Abbreviation/                     | Definition                                            |             |
|-----------------------------------------------------------------|-------------------------------------------------------|-------------|
| Specialist Term                                                 | Ineternational Council for Harmonization of Techincal |             |
| ICH                                                             | 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                                |             |
| Confidential Page                                               | 35 of 115                                             | Version 1.1 |
| Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol |                                                       |             |  
| IND FWD1802 Clinical Protocol Abbreviation/   | Definition                          |
|-----------------------------------------------|-------------------------------------|
| Specialist Term 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 receptorpositive 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 ESR1mutant cancers show selective sensitivity to fulvestrant, the only approved SERD. 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 endocrineresistant 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.
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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 ERpositive 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. 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.
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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, Confidential Page 39 of 115 Version 1.1 Shenzhen Forward Pharmaceuticals Co. Lt Clinical Study Protocol 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.
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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 articlerelated 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 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.
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1.3 study rationale 1.3.1 rational

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.  
| 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).
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1.4 benefits and risks 1.4.1

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 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 12.0315.13% 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..