Clinical trial NCT04198818
Conditions: Advanced Tumors Melanoma Non-Small-Cell Lung Cancer Erdheim-Chester Disease Other RAS/RAF/MEK/ERK Mutated Tumors
Keywords: Melanoma Non-Small-Cell Lung Cancer Erdheim-Chester Disease MAPK pathway ERK1 ERK2
Sponsor: Haihe Biopharma Co., Ltd.
Start date: 2020-01-07; Completion date: 2023-03-31
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, Tolerability and Pharmacokinetics of HH2710 in Patients with Advanced Tumors, composed of a Phase I dose escalation and dose expansion stage and a Phase II dose extension stage.

Detailed description:
HH2710 is developed by Shanghai Haihe Pharmaceutical Co., Ltd. HH2710 is a highly potent, selective, reversible, ATP-competitive ERK1/2 inhibitor. This is a first-in-human study of HH2710 and is designed as an open-label, multicenter, Phase I/II study which is composed of a Phase I dose escalation and dose expansion stage and a Phase II dose extension stage.

Arms: arm 1: to determine the MTD of HH2710 and/or Recommended Phase II dose (RP2D).
Interventions: intervention 1: HH2710
Intervention descriptions: intervention 1: HH2710 is a small molecule that potently inhibits both ERK1 and ERK2 protein kinases in the nanomolar range. The kinase selectivity assessment towards a panel of over 400 protein kinases showed that HH2710 barely inhibited other kinases at a concentration up to 1 μM, except the substantial inhibition against ERK1 (MAPK1), ERK2 (MAPK2) and the MAPK pathway upstream kinases MEK and RAF proteins.

Protocol documents:
ICF_002.pdf: 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
Master ICF Version Number: 3.0 
Date: 22-Mar-2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 1 of 19 
[Investigator name] 
[Investigator address or affiliation] 
[Investigator telephone number] 
[IRB/IEC name] 
Important 
This informed consent (“permission”) form may contain words that you do not 
understand. Please ask the study doctor or the study staff to explain any words or 
information that is not clear to you. 
Joining a study is an important decision. You should ask the study team any 
questions you may have about the study and this informed consent form before 
making a decision to participate. 
Also, you may have your primary doctor call the study doctor to ask any 
questions he/she feels are necessary to evaluate the study and your possible 
participation in it. 
You may take home an unsigned copy of this informed consent form to think 
about it or discuss it with family or friends before making your decision to take 
part in the study. 
Master Informed Consent Form 
Study Title: 
A First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, 
Tolerability and Pharmacokinetics of HH2710 in Patients with 
Advanced Tumors 
Protocol Number:   HH2710-G101 
Sponsor: 
Haihe Biopharma Co., Ltd. 
Name of Investigator or Other Person Administering Consent: [Name of Investigator or 
other person] 
ClinicalTrials.gov ID: NCT04198818


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 2 of 18 
 
 
Why is this study being done? 
Haihe Biopharma has begun a study of an investigational drug (also known as the “study drug”) 
called HH2710 as a possible treatment for advanced tumors. An investigational drug is one that 
has not been approved by the United States (US) Food and Drug Administration (FDA). You are 
being asked to take part in this study because you have been diagnosed with advanced tumors. If 
you do not want to take part in the study, your decision will be respected. This study involves 
research. 
Your participation in this study is voluntary. If you decide not to take part in this study, you can 
continue with your current medical care. 
The main purpose of this study is to learn how well the study drug works and how safe the study 
drug is. 
How many people will take part in this study? 
This study will be conducted in 2 Phases: Phase I (also known as a “first-in-humans” study) and 
Phase II (the next phase of the study to determine whether the drug has any biological activity or 
effect). This study has 3 parts including Phase I dose escalation (to establish the maximum 
tolerated dose [the highest dose that does not cause unwanted side effects]), Phase I dose 
expansion (additional people are enrolled to collect more information), and Phase II dose 
extension (further effect of study drug will be studied in this phase). 
A total of approximately 58 people will be enrolled in Phase I dose escalation part, an additional 
10 people per dose cohort will be enrolled in Phase I dose expansion part; the total number of 
people in this part will depend upon number of doses to be studied. Approximately 108 people 
will be enrolled in Phase II dose extension part of the study. You will participate in only one 
phase of the study. 
How long will my participation in this study last? 
Your participation in this study will last until you or your doctor decides your participation 
should end, or progression of your disease (your tumor gets worse), or the Sponsor stops the 
study, whichever comes first. You will need to visit the research site for the screening visit, 
3 times each during Cycle 1 and Cycle 2, and then whenever dictated by your health or the study 
doctor, but at least once every 2 cycles of a 21-day cycle from Cycle 3, then at the end of 
treatment visit, safety follow-up visit, and disease progress follow-up visit. You will be contacted 
by telephone for survival follow-up visit. 
What will happen during this study? 
The study is divided into 2 phases. During this study (both the phases), there is a screening visit, 
a baseline visit, 1 or more treatment cycles, an end of treatment visit, a safety follow-up visit, a 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 3 of 18 
 
 
disease progress follow-up visit, and a survival follow-up visit. You might have only 1 treatment 
cycle during this study, or you might have 2 or more treatment cycles if the study doctor 
determines that you meet the requirements for additional treatment cycles. 
During each study period, you will have 1 or more visits with the study doctor at the center. The 
screening visit and the treatment period visits will last about 3 to 4 hours, and all other visits will 
last about 1 to 2 hours. 
Before any study-related tests and procedures can be done, you will be asked to read and sign 
this informed consent form. After you sign this informed consent form, the study will begin with 
a screening visit. The purpose of the screening visit is to determine if you meet the requirements 
to take part in this study. If you do not meet the requirements, the study doctor will explain why 
and will discuss with you other treatment options. 
Phase I: The first 3 patients will receive an HH2710 capsule 1 time on the first day, followed by 
twice every day orally (by mouth) during a 21-day cycle from the second day. The fourth and 
later patients will take study drug orally every day during a 21-day cycle from the first day 
following the dosing schedule and instructions, which is very important. You are required to fast 
for about 2 hours before and after taking the study drug. All the patients who will take part in this 
phase will receive 1 of the doses as described in the table below. The dose level and frequency 
will be assigned to you by your study doctor, depending upon when you will enter the study. 
The dosing and treatment schedule: 
 
Dose 
Level 
Dose of HH2710 
Patient 
Study Drug form and 
route of administration 
Dosing Frequency 
Level 1 
25 mg 
3 
Capsules for oral use 
QD at C1D1, then BID from C1D2 
(21 days/cycle) 
Level 2 
50 mg 
3 
Capsules for oral use 
BID (21 days/cycle) 
Level 3 
100 mg 
3+N# 
Capsules for oral use 
BID (21 days/cycle) 
Level 4 
300 mg 
3+N# 
Capsules for oral use 
QD (21 days/cycle) 
Level 5 
400 mg 
(Total daily dose*) 
3+N 
Capsules for oral use 
QD/BID (21 days/cycle) 
Level 6 
600 mg 
(Total daily dose*) 
3+N 
Capsules for oral use 
QD/BID (21 days/cycle) 
Level 7 
800 mg 
(Total daily dose*) 
3+N 
Capsules for oral use 
QD/BID (21 days/cycle) 
Abbreviations: QD = once daily; BID = twice daily; C1D1 = Cycle 1 Day 1; C1D2 = Cycle 2 Day 2. 
#: The number of subjects enrolled in each dose is specified by the Bayesian optimal interval rules; 
*: Proposed daily dose is the total dose each day with QD or BID dose frequency. 
Dosing frequency and dose level may be adjusted on the basis of available pharmacokinetic data and safety. 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 4 of 18 
 
 
Phase II: The recommended dose level and frequency for Phase II will be decided based on 
Phase I results. All patients enrolled in this phase will take the study drug orally once daily 
(QD)/twice daily (BID) during a 21-day cycle. You will be enrolled in one of the 4 cohorts 
depending upon your disease type. It is very important that you follow the dosing schedule and 
instructions. You are required to fast for about 2 hours before and after taking the study drug. 
Study Procedures and Assessments 
This is a description of the procedures and assessments that will be performed during the study, 
including the prescreening and screening visits, is shown below. In addition to the visits 
described below, the study doctor may ask you to come in for extra visits, if necessary, for your 
safety. 
Molecular Screening Visit 
You will be asked to provide molecular screening consent before any other study-related 
procedures and assessments. Please read the information below for more details. 
Consent for Genetic Analysis: An archived tumor tissue or slices (means previously collected 
and stored) or fresh tumor biopsy sample will be collected for molecular screening. You will be 
asked to provide your consent on the “Molecular Screening Informed Consent (Biomarker ICF)” 
to take part in this study. The biomarker samples (samples of substances in your body that can 
measure the presence of disease or the effects of treatment) will be used to study the biology (eg, 
DNA, RNA, proteins, and metabolites) to understand how HH2710 works and to learn about 
advanced tumors. 
Participation in this testing is mandatory in Phase II stage. If you do not want your genotyping 
sample to be used in this molecular screening, you cannot take part in the main study. If you 
agree to the genotyping testing, you will be provided with separate informed consent document 
(Biomarker ICF) to sign. As for Phase I dose expansion stage, you are required to provide the 
local laboratory test results of MAPK pathway gene alteration status to determine the eligibility 
of patient participating in clinical screening procedure. Your study doctor will tell you which 
phase you will be in if you are willing to join the study. 
Screening Visit 
The study doctor will perform the following examinations and tests to determine if you should 
take part in the study: 
1. You will be asked about your health and the medicines that you have taken or are 
currently taking, and the medical procedures that you have had. 
2. You will be asked about your cancer diagnosis and treatment history. 
3. Your birth date, sex, and race, per national regulations, will be recorded. 
4. You will be assessed for your disease-related signs and symptoms. 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 5 of 18 
 
 
5. The study doctor will perform a physical examination to check your overall health, 
including height and weight. 
6. Your blood pressure, heart rate, respiratory rate, and body temperature will be measured. 
7. An electrocardiogram (ECG) will be done. This is a test that measures the electrical 
activity of the heart. A technician will place patches on your chest that will be connected 
by wires to a machine. The machine will record the electrical activity of your heart. 
8. The study doctor will examine you and will also assess how your cancer affects your 
daily activities (Eastern Cooperative Oncology Group [ECOG] performance status). 
9. The study doctor will examine your eyes. 
10. A urine sample (about ½ cup) will be taken to check your overall health. 
11. Echocardiogram (ECHO; a soundwave test of your heart) or multigated acquisition 
(MUGA; video test of your heart) scan will be done 
12. Tumor measurements including computed tomography (CT) or magnetic resonance 
imaging (MRI) scans. 
13. Tumor tissue may be collected by biopsy for central histological review (ie, by 
microscopy) of your disease and biomarker analyses, which depends on the study phase 
you participate in. 
14. Blood samples will be collected for the following laboratory tests. Approximately 7 ½ 
teaspoons or 37 mL of blood will be taken from your arm using a needle. 
• Safety laboratory tests will be done to check your overall health. 
• Cardiac function tests will be done to measure troponin (a protein that controls 
muscle contraction) levels in your blood. 
• If you are a woman who is able to have children, your blood will be tested to see if 
you are pregnant. The results of the pregnancy test must be negative in order for you 
to participate in this study. 
• Tests will be done to screen for certain viruses (including human immunodeficiency 
virus and hepatitis B and C viruses). If your test result is positive and you have given 
or received blood, blood products, organs, or tissues, the Public Health Department 
will be notified as required by law. These tests are mandatory. If you decline these 
tests, you will not be allowed to participate in the study. 
15. The study doctor will review any side effects experienced after signing this informed 
consent form. 
Treatment Period 
The study doctor or the study doctor’s staff will perform the following tests and procedures. You 
will be asked to visit the study site 3 times each during Cycle 1 (baseline [Day 1], Day 8, and 
Day 15) and Cycle 2 (Day 22, Day 29, and Day 36) and then on the 1st day of every 2 cycles 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 6 of 18 
 
 
starting from Cycle 3 (Day 43). The study staff will explain to you in detail about study site visits. 
1. You will be asked about your cancer diagnosis and treatment history. 
2. You will be assessed for your disease-related signs and symptoms. 
3. You will be asked about your health and the medicines that you have taken or are 
currently taking, and the medical procedures that you have had. 
4. The study doctor will perform a physical examination to check your overall health and 
weight; after the screening visit, the physical examination will be performed if the study 
doctor believes you need it. Also, the study doctor will examine your eyes, if needed. 
5. Your blood pressure, heart rate, respiratory rate, and body temperature will be measured. 
6. The study doctor will examine you and will assess how your cancer affects your daily 
activities (ECOG performance status). 
7. The study doctor will examine your eyes. 
8. If you are a woman who is able to have children, your blood will be collected and tested 
to see if you are pregnant at the baseline. After the baseline, your urine pregnant result is 
also accepted during the treatment period. 
9. Study drug will be provided at each study visit. 
10. Study drug should be administered continuously, according to dose schedule. 
11. Tumor measurements including CT or MRI scans (every 2 cycles, approximately every 
6 weeks ±7 days). 
12. An ECG will be done at each study visit. (Note: ECGs will be obtained prior to dosing 
and 1, 3, 4, and 8 hours after dosing on Cycle 1 Day 1 and Cycle 2 Day 1). 
13. An ECHO or MUGA scan should be measured at your study doctor’s discretion if there 
are signs or symptoms of cardiotoxicity (damage to your heart) during the study. 
14. A urine sample (about 1/2 cup) will be taken to check your overall health (may not be 
performed at the Baseline visit, based on your doctor’s decision). 
15. Blood samples will be collected for the laboratory tests listed below. Approximately 
7 ½ teaspoons or 37 mL of blood will be taken from your arm using a needle. 
• Safety laboratory tests will be done to check your overall health (may not be 
performed at Baseline visit based on your doctor’s decision). 
• If you are a woman who is able to have children, your blood will be tested to confirm 
if you are pregnant when the urine pregnancy test is positive. 
16. The following blood tests will be performed during Phase I dose escalation stage only on 
Day 1, Day 2, Day 7, Day 10, Day 15, and Day 16 of Cycle 1; on Day 1 of Cycles 2, 3, 5, 
7, and 9; and during Phase I dose expansion stage and Phase II dose extension on Day 1, 
Day 2, Day 15 and Day 16 of Cycle 1 (only pharmacokinetic samples): 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 7 of 18 
 
 
• Pharmacokinetic (PK) tests will be done to look at how your body metabolizes 
(breaks down) the study drug. The blood samples will be taken before and after 
the study drug administration. 
17. The following blood tests will be performed during Phase I only at Day 1 and Day 15 of 
Cycle 1 (only conducted in sites that are capable of sample collection and processing for 
Pharmacodynamic samples): 
• Pharmacodynamic (PD) tests for certain blood components called biomarkers 
(markers of drug response including phosphorylation of ribosomal S6 kinase 
[pRSK and total RSK]) will be done to learn more about how the study drug 
affects your body and to better understand how the study drug works. 
18. You will be asked to return all the unused study drug at each study site visit. 
19. Study drug compliance will be assessed by capsule count at each visit. 
20. Review of side effects experienced since your previous study visit. 
End of Treatment/Early Discontinuation Visit 
For all patients who leave the study before study completion, the study doctor’s staff will 
perform the following tests and procedures within 7 days of the last dose: 
1. You will be asked about your cancer diagnosis and treatment history. 
2. You will be assessed for your disease-related signs and symptoms. 
3. You will be asked about your health and the medicines that you have taken or are 
currently taking, and the medical procedures that you have had. 
4. The study doctor will perform a physical examination to check your overall health, 
including weight. 
5. Your blood pressure, heart rate, respiratory rate, and body temperature will be measured. 
6. The study doctor will examine you and will also assess how your cancer affects your 
daily activities (ECOG performance status). 
7. The study doctor will examine your eyes. 
8. A urine sample (about 1/2 cup) will be taken to check your overall health based on your 
doctor’s decision. 
9. If you are a woman who is able to have children, your urine or blood will be tested to see 
if you are pregnant. 
10. Tumor measurements including CT or MRI scans. 
11. An ECG will be done. 
12. Blood samples will be collected for the following laboratory tests. Approximately 7 ½ 
teaspoons or 37 mL of blood will be taken from your arm using a needle. 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 8 of 18 
 
 
• Safety laboratory tests will be done to check your overall health. 
13. You will be asked to return all the unused study drug. 
14. Study drug compliance will be assessed by capsule count. 
15. Review of side effects experienced since your previous study visit. 
Follow-Up Period 
Safety Follow-Up Visit 
A safety follow-up visit will be scheduled within 30 days (+ 7 days) after the last dose of study 
drug. At this visit, the study doctor or the study doctor’s staff will perform the following tests 
and procedures: 
1. You will be asked about the medicines that you have taken or are currently taking. 
2. An ECG will be done. 
3. A urine sample (about ½ cup) will be taken to check your overall health. 
4. Blood samples will be collected for the following laboratory tests. Approximately 7 ½ 
teaspoons or 37 mL of blood will be taken from your arm using a needle. 
Safety laboratory tests will be done to check your overall health, which including blood 
routine, blood biochemistry, thyroid function, and coagulation as protocol required. 
5. Echocardiogram (ECHO; a soundwave test of your heart) or multigated acquisition 
(MUGA; video test of your heart) scan will be done. 
6. Review of side effects experienced since your previous study visit. 
7. You will be asked about the new treatment for your disease and survival condition i.e. 
your present health. 
Follow-Up of Progressive Disease 
A follow-up visit to check progression of your disease will be scheduled once every 6 weeks 
after the last dose of study drug. At this visit, the study doctor or the study doctor’s staff will 
perform the following tests and procedures: 
1. Tumor measurements including CT or MRI scans. 
2. You will be asked about the new treatment for your disease and survival condition i.e. 
your present health. 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 9 of 18 
 
 
Survival Follow-Up 
All patients who discontinued from study drug for any reason will be contacted every 3 months 
by telephone from the time of worsening of their disease or starting a new treatment to 1 year in 
order to inquire about their status. 
What do I have to do? 
During the study, you will have the following responsibilities: 
• Tell your study doctor if you have any allergies, including drug allergies. If you are 
unsure, ask your primary doctor. 
• Attend all scheduled visits. 
• Take the study drug as directed. 
• Return any unused study drug and containers as instructed by the study staff. 
• Follow the study doctor’s instructions about whether you may continue to take your 
regular prescribed medications or over-the-counter medicines during the study period. 
• Tell the study doctor of any changes to your current medications, illnesses or injuries, 
unexpected or troublesome side effects, or problems that occur during the study. 
• Tell the study doctor if you plan to have an elective surgery or any other medical 
treatment or procedure. 
• You should not perform activities requiring mental alertness, judgment, or physical 
coordination such as driving or operating machinery, or doing anything that requires you 
to be alert, unless you feel secure and safe to do so. 
• You should continue to make regular visits to your primary doctor or any other special 
doctors whom you were seeing before starting the study, because being in the study does 
not replace regular medical care. 
• Make sure that the study drug is kept out of the reach of children and people who have a 
limited capacity to read or understand. You are the only person who should take the study 
drug. 
• Contact the study doctor if you find you have any questions about the study after you sign 
this form. 
• You and/or your partner must use a reliable form of contraception during the study. If 
you or your partner becomes pregnant while you are in the study, be sure to tell the study 
doctor as soon as possible. 
What are the benefits of being in this study? 
There is no guarantee that you will receive any benefits. However, you will be helping others by 
contributing to medical research. Additionally, you may experience some benefits, for example, 
your symptoms can improve and your tumor might shrink. 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 10 of 18 
 
 
What are the risks and possible discomforts? 
If you choose to take part in this study, there are risks that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual. 
• You may be asked sensitive or private questions which you normally do not discuss. 
The drug used in this study may affect the function of other organs, such as your liver, kidneys, 
heart, and blood. The study doctor will be testing your blood and will inform you if changes 
occur that may affect your health. 
There is also a risk that you could have side effects from the study drug and the study approach. 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
The study drug has not been used in humans before, so the side effects are unknown at this time. 
However, based on its mode of action (the way the drug affects the body) and studies in animals, 
its side effects are thought to be similar to other drugs of same target class described below. 
There might be other side effects that researchers do not yet know. The common and possible 
side effects are listed in the following tables. 
 
Common Side Effects 
diarrhea, nausea, vomiting, decreased appetite, abdominal 
(belly) pain, impaired gastric emptying (stomach doesn’t 
empty food as quickly as it should), rash, pruritus (itchy 
skin), alopecia (hair loss), fatigue, chills, increased serum 
bilirubin (blood levels of a liver compound), increased 
blood urea nitrogen (a waste product from the liver), 
increased blood creatinine (a waste product from 
muscles), anemia (low level of red blood cells), and 
altered taste 
Potentially Severe Side Effects 
retinal vein occlusion (blockage of small veins that carry 
blood  away  from  the retina  [part  of  your eye]), 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 11 of 18 
 
 
 
retinoapathy (damage to the blood vessels in the eye 
which may cause vision problems), acute renal (kidney) 
failure, increased creatine phosphokinase (a protein that 
helps chemical changes happen in your body) 
 
Let your study doctor know of any questions you have about possible side effects. 
Pregnancy/Birth Control 
Because the effect of study drug on unborn babies is not known, you should not become pregnant, 
breastfeed, or father a baby while in this study. 
Women 
Taking the study drug may involve unknown risks to a pregnant woman, an embryo, fetus 
(unborn baby), or breastfeeding infant. Therefore, if you are pregnant, planning to become 
pregnant, or are breastfeeding a child, you cannot take part in this study. 
Before entering the study, a pregnancy test will be done for all women who are able to become 
pregnant. This test might not detect an early pregnancy. Pregnancy tests will be repeated during 
the study. 
The only certain way not to become pregnant is to not have sex. If you choose to have sex during 
the study, you must use an effective method of birth control while you are taking part in this 
study and for 6 months after you finish the study treatment. If you are already using a method of 
birth control, the study doctor or study staff will discuss with you whether your current method 
of birth control is acceptable for use during this study. Methods of effective birth control include 
surgery, hormonal contraceptive, patch, vaginal ring, intrauterine device, or double physical 
barrier such as condoms plus diaphragm. 
If during the study you become pregnant, you should tell the study doctor as soon as possible. 
The study drug will be stopped, and your involvement in this study will end. 
Men 
Male subjects should be surgically sterile or compliant with a highly effective contraceptive 
method during the study and for a minimum of 6 months after you finish the study treatment. 
These may include surgery or a physical barrier such as a condom. 
The Sponsor may like to receive updates on the progress of the pregnancy and its outcome. If 
you agree to this, you will be asked to sign a separate informed consent. 
What if there are new findings? 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 12 of 18 
 
 
If new findings that would affect your safety and willingness to participate in the study are 
identified while you are in the study, you will be told as soon as possible, so you can decide 
whether to leave the study or continue. If you continue, you will be required to sign a new 
informed consent form. 
What other options are available if I do not take part in this study? 
You do not have to take part in the study to treat your advanced tumor. By participating in this 
study, you may be foregoing effective therapies that may include FDA-approved therapies which 
may shrink tumor, delay progression of cancer, or provide symptom relief, if those therapies are 
available in your country. There are other options of therapies, such as immunotherapy, 
chemotherapy, dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, and binimetinib. 
Your primary doctor or the study doctor can answer any questions that you have about other 
treatments. 
You should also contact your primary doctor to ask about other research currently being done in 
the treatment of advanced tumor. 
Who is paying for this study? 
Haihe Biopharma is funding this study. The study doctor will be paid for his/her work in this 
study. 
What are the costs? 
The study drug will be given at no cost to you, and you will not be charged for any study doctor 
visits, laboratory work, tests, or procedures that are needed for the study. 
Will I be paid for being in the study? 
You will receive no payment for taking part in this study. However you may be reimbursed for 
any reasonable travel, parking, meals, and other expenses associated with the research project 
visit, upon approval from the Sponsor, Haihe Biopharma. 
What if I get sick or hurt? 
If you require medical treatment for an illness or injury that is a direct result of taking the study 
drug, Haihe Biopharma will pay for reasonable and routine costs of such treatments if the 
following conditions are met: 
• The illness or injury was a result of taking part in the study. 
• The cost of treatment or any part of the costs is not covered by any other health insurance, 
government health program, or other institutions providing coverage for health care. 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 13 of 18 
 
 
Can I leave the study after it has begun? 
Yes. Taking part in this study is voluntary, and you can leave the study at any time for any 
reason. There will also not be any penalty or loss of benefits to which you are entitled at this site 
if you decide not to take part or if you decide to leave the study. 
If you decide to leave the study, you should contact the study doctor who will explain the safest 
way to end participation, which may involve the completion of some final tests and examinations. 
You should also contact your primary doctor so he or she can provide you with the best course of 
continuing care. 
The study doctor or Haihe Biopharma can remove you from the study, without your permission, 
for some reasons. Possible reasons for doing so include the following: 
• Any change in your medical condition that might make continuation in the study harmful 
to you 
• Your failure to follow the study doctor’s instructions 
• Discovery that you do not meet the study requirements 
• Cancellation of the study 
• Administrative purposes: For example, insufficient drug supply or site closing etc. 
What will happen to the samples that I provide? 
The blood samples that you give will be used only for specific tests that are needed for this study. 
Your samples will be destroyed as soon as possible after those specific tests are completed. Your 
samples will be tested and destroyed according to the standard procedures of the laboratory. 
What happens when this study stops? 
When the study stops, you will be under the care of your primary doctor who will decide the best 
way to treat your disease. The study drug will no longer be available to you. 
You have the right to be informed of the overall results of the study. 
Will my records be kept private? 
To participate in this study, you must read and sign the Privacy Notice at the end of this form 
(see Appendix 1). 
What if I have a question or concern? 
You should feel free to ask questions about the study and your rights as a subject before, during, 
and after the study. 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 14 of 18 
 
 
Important 
Do not sign this informed consent form unless you have had a chance to ask 
questions and have received satisfactory answers to all of your questions. 
Signing your name to this informed consent form means that you voluntarily 
agree to take part in this study. 
This agreement can be withdrawn at any time; although, data collected up to that 
point is legally allowed to be used. 
 
 
 
 
 
 
Whom can I call? 
If you have any questions about this study or if at any time you believe that you 
have a research-related injury or a reaction to the study drug, you should contact 
<insert study doctor’s name> by telephone at <insert his/her telephone number>. 
If you have any questions regarding your rights as a research subject, you may 
contact <insert IRB/IEC name> by telephone at <insert IRB/IEC telephone 
number>. 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 15 of 18 
 
 
Consent to Participate 
By signing this informed consent form, I agree to the following: 
• I have read, and I understand this informed consent form. 
• I have been given the chance to ask any questions that I had about the study, and all 
questions that I asked were answered to my satisfaction. 
• I understand the risks of taking part in this study as described in this informed consent 
form. 
• I understand that there is no guarantee that I will receive any benefits from taking part in 
this study. 
• I freely consent to be treated with drug under the study doctor’s care. 
• I confirm that all information that I have given about my medical history is correct to the 
best of my knowledge. 
• I understand that I am free to withdraw from the study at any time for any reason. I will 
tell the study doctor if I decide to withdraw so that my participation may end in an 
orderly manner, and my future care can be discussed. 
• I understand that I will be told of any new information that might relate to my willingness 
to continue in the study. 
• I will tell the study doctor if I have any physical or psychiatric (“mental health”) 
symptoms or problems. 
• I understand that I will receive a signed and dated copy of this informed consent form for 
my records. 
My consent to participate in this study does not take away any legal rights in the case of 
negligence (carelessness) or other legal fault of anyone who is involved with this study. 
 
 
Name of participant (print) 
 
 
Signature of participant 
Date (dd/Mmm/yyyy) 
 
 
Signature of study doctor or person administering consent 
Date (dd/Mmm/yyyy) 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 16 of 18 
 
 
 
Appendix 1: Privacy Notice 
Identification of Data Controller: During the study, the Sponsor will direct the collection and 
use of your personal information (data) needed for the study. The Sponsor is the data controller 
of your personal data under applicable data protection laws. You can contact the Sponsor at: 
Ms. Xianqing Hu 
Haihe Biopharma Co., Ltd. 
No. 865 Zuchongzhi road, Pudong New Area, Shanghai, China 
Tel: +86 21 20568888 
 
The study center may also be considered as a data controller of your personal data under 
applicable data protection laws. You may contact the study doctor using the contact information 
for the study doctor on the first page of this informed consent form. 
If you have any questions or would like to see the data collected about you for this study, you 
should contact the study doctor. 
Data to be Collected and Processed: The study staff will collect data about you for the study. 
This data may include your name or initials, date of birth, gender, contact details, and 
information needed for payment processing. In addition, the following sensitive personal data 
about you may be collected: health, race, genetic information. 
How Your Personal Data Will be Used: The personal data collected about you will be recorded 
in your study file by the study staff to run the study and to monitor your safety as a participant. 
Your personal data may be processed on a computer and/or on paper. The collection of this data 
is necessary to conduct the study and comply with applicable laws. You will not be able to 
participate in the study if you fail or refuse to provide your information. 
There are laws about the recording, forwarding, storage, and analysis of your personal data, 
including sensitive personal data. These laws require your voluntary and explicit consent before 
you participate in the study. If you do not consent to the collection and use of your personal 
information, you will not be able to be in the study. 
Results of this study may be presented at meetings or in publications; however, your identity will 
never be shared. Your personal data will not be used for any direct marketing purposes. 
If information regarding a communicable disease is collected, the information may be shared 
with a public health authority that is authorized by law to collect or receive such information for 
the purpose of preventing or controlling disease, injury, or disability, and conducting public 
health surveillance, investigations, or interventions. 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 17 of 18 
 
 
Storage of Your Personal Data: According to legal requirements, your personal data will be 
stored in the study databases and/or paper files for at least 15 years after the study ends, as 
required by applicable laws. 
Transferring the Personal Data to a Third Party: To keep your identity private, all data that is 
sent or provided outside of the study center will show only a coded identification number instead 
of your name. Only the study doctor and authorized personnel will be able to connect this code to 
your name. They will use a list that will be kept in a secure place to link this code to your name 
in case of an emergency. The coded data from the study showing your involvement (including 
uncoded personal information) will be provided to the Sponsor and other individuals and/or 
companies that act on the Sponsor’s behalf, including Syneos Health. Also, your medical records 
(including uncoded personal data) may be reviewed by the Sponsor and other individuals and/or 
companies that act on the Sponsor’s behalf, including Syneos Health; government agencies in 
countries where the study drug may be considered for approval (such as the US FDA); [IRB/IEC 
name], a group that reviews and approves studies; and independent auditors for the purposes of 
confirming your participation in the study, monitoring your safety during the study, and 
monitoring the conduct of the study. Further, your personal information may be disclosed in 
response to lawful requests by public authorities, including those to meet national security or law 
enforcement requirements. 
If your personal data is shared with other companies that are located outside of the country where 
you live, the Sponsor will make sure your data is protected as required by your country’s data 
protection laws. Some of these other companies may be located in countries whose data 
protection and privacy laws may be less strict than in your own country, including the United 
States and  
. You may contact the study doctor to get more information about 
the precautions used to protect your personal data outside of your country. You may also ask the 
study doctor for a copy of those precautions. 
With your permission, the study doctor will tell your primary doctor about your role in this study. 
A description of this clinical trial will be available on http://www.clinicaltrials.gov as required 
by US law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
Your Rights as a Data Subject: You have the right to access and correct the data collected 
about you during the study and submit any questions or concerns about the collection or 
processing of your personal data; however, this access is suspended until after the study has 
ended. Your rights will be reinstated at the conclusion of the study. 
You have the right to withdraw your consent for the processing of your personal data at any time. 
You must withdraw your consent by writing to the study doctor. However, data collected before 


Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inventive Health group of companies” 
This document is confidential. 
Subject Initials:  
Date:  
 
 
Master ICF Version Number: 2.2 
Date: 17-Jul-2021 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 18 of 18 
 
 
you remove your consent is still legally allowed to be used. If you withdraw your consent, you 
will no longer be able to take part in the study. 
Consent Language 
Consent to the Collection, Processing, and Use of Personal Data 
By signing below, I agree that: 
(1) My personal data, including sensitive personal data, can be collected, used, and archived for 
purposes of carrying out the study as described in this Privacy Notice; 
(2) My personal data, including sensitive personal data, can be transferred to and shared with 
other companies both within and outside of the European Economic Area (EEA), including 
to countries that may not have the same level of data protection as the EEA, as described in 
the Privacy Notice; 
This consent is valid unless you change your mind and provide a written notice to the study 
doctor. You will receive a signed and dated copy of this Privacy Notice. 
 
 
Name of participant (print) 
 
 
Signature of participant 
Date (dd/Mmm/yyyy) 


“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Biomarker ICF Version Number: 2.1        Date: 18-Feb-2021 
Controlled Document ID: 4106C.00, Effective Date: 30-APR-2018 
Page 1 of 5 
Biomarker Informed Consent Form 
[Investigator name] 
[Investigator address or affiliation] 
[Investigator telephone number] 
[IRB/IEC name] 
Study Title: A First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, 
Tolerability and Pharmacokinetics of HH2710 in Patients with Advanced Tumors 
Protocol No.: HH2710-G101 
Sponsor: 
Haihe Biopharma Co., Ltd. 
Name of Doctor or Other Person Administering Consent: [Name of doctor or other person] 
Introduction and Purpose of Genetic Analysis 
You are a participant in a clinical study with HH2710 being investigated for the treatment of 
advanced tumors, and you are being asked if you would like to take part in a genetic analysis 
called as molecular screening. Before you decide, we would like you to understand why the 
research is being done and what it would involve for you. One of the study staff will go through 
this informed consent with you and answer any questions you may have. Talk to others about the 
study if you wish.  
Your participation in the molecular screening is mandatory in Phase II stage. In case you refuse 
to participate in this analysis, you cannot participate in the main study.   
If you agree to participate, you will be asked to sign the molecular screening informed consent 
form at the end of this document before your tumor biopsy or tissue samples are collected.  
Purpose and background 
Your genetic data consist of genes and other biological and chemical processes, structures, and 
sequences (for example, DNA, RNA, chromosomes, genes, proteins, and metabolites), all of 
which are in your blood and body tissues. These genetic data make you different from anyone 
else. Some genetic data control things like the color of your hair or eyes. Other genetic data 
might make you more likely to get certain diseases or affect whether a drug helps you and/or 
gives you side effects. Genetic tests might be used to sequence your DNA, RNA, chromosomes, 
ClinicalTrials.gov ID: NCT04198818


Biomarker Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Biomarker ICF Version Number: 3.0        Date: 22-Mar-2022 
Controlled Document ID: 4106C.00, Effective Date: 30-Apr-2018 
Page 2 of 5 
and genes, but analyses of genetic tests will be limited only to results that might relate to the 
study drug, the disease, and your medical conditions.   
Mitogen-activated protein kinase (MAPK) is a type of protein kinase that is specific to the amino 
acids serine and threonine, which are important molecules in transmitting signals from the 
surface of a cell to its nucleus (center). They regulate cell functions including proliferation 
(growth and increase), gene expression (the process of gene information becoming a useful 
product), differentiation (changing from one cell type to another), mitosis (division of cells), cell 
survival, and apoptosis (cell death).   
For the Phase I does escalation, determination of the MAPK pathway gene alteration status is not 
required, but information will be collected and documented if available. For the Phase I 
expansion stage, local laboratory test results of MAPK pathway gene alteration status are 
required to be collected and documented to determine the eligibility of the study. For the Phase II 
stage, besides the local laboratory test results of MAPK pathway gene alteration status, a 
molecular screening assessing archival and/or fresh FFPE tumor samples is mandatory for a 
confirmatory detection of MAPK pathway gene status by a Sponsor designated central laboratory.  
MAPK pathway genetic alteration status information collected before taking part in study might 
be acceptable, if already documented in your medical records. 
Potential biomarkers for HH2710 response or resistance in blood or tumor specimens, including 
but not limited to genetic alterations in the MAPK pathway, will also be studied.   
Molecular screening testing can be done while you are receiving standard treatment for your 
tumor or whenever possible.   
Procedures 
Tumor biopsy or tissue samples will be collected for molecular screening.  
Your samples will be coded before being shipped to a Sponsor designated central laboratory and 
will be stored there until they are analyzed. Staff members there are experienced in handling and 
testing samples from research studies.  
Your samples will only be used for study-related purposes. No other analyses will be performed 
without your approval and the approval of the Ethics Committee. You have the right to refuse 
permission for these additional tests to be done, and you may (at any time) request that your 
samples be destroyed. 
You may also request that all previously retained samples be destroyed. Your samples will not be 
used for any new tests, however, the information already gathered from your samples will be 
retained for the integrity of the study.   
Risks and discomforts 


Biomarker Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Biomarker ICF Version Number: 3.0        Date: 22-Mar-2022 
Controlled Document ID: 4106C.00, Effective Date: 30-Apr-2018 
Page 3 of 5 
The risks of a biopsy can include bleeding, pain, and infection. To reduce these risks, the site of 
the biopsy will be numbed and sterile techniques will be used.  
When your blood is drawn, you may feel light-headed. At the site where the blood was drawn, 
you may have inflammation of the vein (blood vessel), pain, bruising, or bleeding. There is also a 
low possibility of infection.   
Confidentiality and data protection 
Information provided in the main informed consent form in Appendix 1 (Privacy Notice) applies 
for this testing. Your identity will not be disclosed unless required by law. 
Insurance 
Information provided in the main subject information sheet and informed consent form in the 
“What if I get sick or hurt” section applies for this testing. 
Compensation 
You will not have to pay to take part in this testing, and you will not be paid for your 
participation in this testing. If the Sponsor is able to create or design new tests or medications as 
a result of this study, you will not receive any money (reimbursement) because of your 
participation in this testing. 
Potential benefit 
Being in the sub-studies will not directly help you. Information from the sub-studies may help 
researchers understand advanced tumors, respond to treatment, and discover new tests or 
medications to help patients with this disease, possibly including you, in the future.   
Voluntary participation and withdrawal 
Your participation in this testing is voluntary. You do not have to take part in this testing if you 
do not want to take part. In case you refuse to participate in this analysis, you cannot participate 
in the main study in Phase II stage.   
If you do not want to take part in this sub-study, there will be no penalty to you. You will not 
lose any benefits to which you are otherwise entitled, and your regular medical care at this study 
site will not change. 
You can stop your participation in this testing at any time without giving any reason by 
informing your study doctor. Your samples will be destroyed, and no new data will be collected 
about you after you withdraw from this testing. 
Contact person 


Biomarker Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Biomarker ICF Version Number: 3.0        Date: 22-Mar-2022 
Controlled Document ID: 4106C.00, Effective Date: 30-Apr-2018 
Page 4 of 5 
If you have any questions about this testing, please contact the study doctor, Dr [name of 
principal investigator] at [phone number] or [name of sub-investigator, research nurse, etc] at 
[phone number]. 


Biomarker Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Biomarker ICF Version Number: 3.0        Date: 22-Mar-2022 
Controlled Document ID: 4106C.00, Effective Date: 30-Apr-2018 
Page 5 of 5 
Consent to Participate 
By signing this informed consent form, I agree to the following: 
• I have read and I understand this informed consent form.  
• I confirm that the substudy has been explained to me. 
• I have been given the chance to ask questions that I have had about this testing, and all 
questions that I have asked have been answered to my satisfaction. 
• I know who to contact if I have any further questions. 
• I confirm that I voluntarily agree to participate in this testing. 
 
An original copy of the information sheet and signed consent form will be given to you to 
keep. 
 
_______________________________________ 
Name of participant (print) 
 
_______________________________________ 
_________________ 
Signature of participant 
Date (dd/Mmm/yyyy) 
 
_______________________________________ 
_________________ 
Signature of study doctor or person administering consent 
Date (dd/Mmm/yyyy) 
 


Pregnant Partner Informed Consent Form 
Sponsor: HaiHe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
Pregnant Partner ICF Version Number: 2.1 
 Date: 18-Feb-2021 
Controlled Document ID: 4106B.00, Effective Date: 30-Apr-2018 
Pregnant Partner Informed Consent Form 
Study Title: 
A First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, 
Tolerability and Pharmacokinetics of HH2710 in Patients with Advanced 
Tumors 
Protocol Number:  HH2710-G101 
Sponsor:  
 
Haihe Biopharma Co., Ltd. 
Name of Doctor or Other Person Administering Consent: [Name of doctor/other person] 
Principal Investigator: 
[Insert name, affiliation, location] 
Telephone number: 
Daytime: 
[Phone number] 
After office hours: 
[After hours phone number] 
Introduction and Purpose of the Form 
Your partner, the biological father of your baby, is/was participating in the clinical trial listed 
above, whose primary purpose is/was to learn how well the study drug works and how safe the 
study drug (HH2710) is for treating patients with advanced tumors. 
You have become pregnant while your partner is/was taking part in this clinical study or in the 6 
months after he discontinued from the study drug.  
As the effect and risks of the study drug on sperm, ova, unborn children, and infants are not 
known, we kindly request that you sign this consent form to allow the collection of data related 
to your and your baby’s health conditions both during your pregnancy and after the outcome of 
your pregnancy.  
The data collected will only be processed to the extent necessary to monitor the health of you 
and your baby during your pregnancy and potentially after the outcome of your pregnancy. Data 
collected will help doctors monitor the potential risks to you or your baby as a result of your 
partner’s exposure to the study drug.  
The data will be collected by the study doctor for reporting of side effects. 
Please take time to read the following information. Your participation in this data collection 
research is voluntary. You do not have to agree to have information about your pregnancy 
collected, and you can change your mind at any time. If you do not agree to have information 
about your pregnancy collected, this will not affect your partner’s ability to participate in the 
ClinicalTrials.gov ID: NCT04198818


Pregnant Partner Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Pregnant Partner ICF Version Number: 3.0        Date: 22-Mar-2022 
Controlled Document ID: 4106B.00, Effective Date: 30-Apr-2018 
Page 2 of 8 
research study. Your decision will not affect you, your partner’s, or your baby’s regular medical 
care.  
Type of information requested 
With this form, we are asking for your permission to collect medical information about your 
pregnancy, its outcome, the date of conception, medications/medical treatments that you have 
taken/received or may take/receive during your pregnancy, and, if appropriate, information about 
the birth and health of your baby (including sex, birth weight, and size), as well as information 
about your personal health, now and in the past, including information on prior pregnancies, if 
any. The goal of this data collection is to determine if the study drug that your partner was given 
has an effect on your pregnancy and/or the health of your baby. Also, your demographic data and 
personal data on your physical or disease condition may be collected. Your identity and that of 
your baby, however, will be kept secret and will not be collected.  
This information will be collected, if appropriate, until your baby is born.  
Possible side effects, risks, or discomforts 
The study doctor will not perform any examinations, tests, or procedures on you.  
Your only involvement in the study will be to answer questions and provide information. 
Benefits 
There are no direct benefits to you or your baby for agreeing to share your data. However, we 
hope that the information we gather about your pregnancy will help future patients and their 
partners by helping us understand the potential risks of the study drug. 
Compensation 
You will not be paid for the collection of your and your baby’s personal and health data.  
Confidentiality and data protection 
For your data to be used, you must read and sign the Privacy Notice at the end of this form (see 
Appendix 1).  
Insurance 
You should contact your health insurance to understand your coverage. 
Contact person 
 
For safety reasons, it is recommended that your general practitioner, obstetrician or gynecologist, 
or other specialist is informed about your pregnancy and that your partner is taking part in a 
research study. 


Pregnant Partner Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Pregnant Partner ICF Version Number: 3.0        Date: 22-Mar-2022 
Controlled Document ID: 4106B.00, Effective Date: 30-Apr-2018 
Page 3 of 8 
If you have any questions about this form or how your information will be used, please contact 
your partner’s study doctor at the address and/or telephone number provided below. The study 
doctor is collecting only information related to the progress of your pregnancy and its outcome; 
you should contact your regular health care providers for any health concerns that you may have.  
<Insert address and contact information of study doctor.> 
 


Pregnant Partner Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Pregnant Partner ICF Version Number: 3.0        Date: 22-Mar-2022 
Controlled Document ID: 4106B.00, Effective Date: 30-Apr-2018 
Page 4 of 8 
Authorization for Release of Medical Information 
 
Study Title: A First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, Tolerability 
and Pharmacokinetics of HH2710 in Patients with Advanced Tumors 
Protocol Number: HH2710-G101 
Sponsor: Haihe Biopharma Co., Ltd. 
 
Principal Investigator: 
[Insert name, affiliation, location] 
Telephone number: 
Daytime: 
 
 
[Phone number] 
After office hours: 
 
[After hours office number] 
 
• I have read, and I understand the information provided in this form.  
• I have been given the chance to ask questions that I have had about the study, and all 
questions that I asked have been answered to my satisfaction.  
• I understand that I will not receive any benefits from providing my and my baby’s health 
information. 
• I freely consent to allow the use and disclosure of my and my baby’s health information 
in connection with this safety activity as described in this Authorization Form.  
• I understand that I am free to withdraw my consent at any time for any reason. I will tell 
the study doctor if I decide to withdraw my consent. 
• I consent to provide the contact data of my pregnancy healthcare provider to my partner’s 
study doctor. 
• I understand that I will receive a signed and dated copy of this Authorization Form for 
my records. 
My consent to participate in this study does not take away any legal rights in the case of 
negligence (carelessness) or other legal fault of anyone who is involved with this study.  
 


Pregnant Partner Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Pregnant Partner ICF Version Number: 3.0        Date: 22-Mar-2022 
Controlled Document ID: 4106B.00, Effective Date: 30-Apr-2018 
Page 5 of 8 
Read and understood 
 
_______________________________________ 
Pregnant Partner’s first and last name (Print) 
 
______________________________________ 
___________________ 
Signature of Pregnant Partner 
Date (dd/Mmm/yyyy) 
 
______________________________________________________________ 
Subject’s first and last name and study ID number (Print) 
 
______________________________________ 
___________________ 
Signature of study doctor or person administering consent 
Date (dd/Mmm/yyyy) 
 


Pregnant Partner Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Pregnant Partner ICF Version Number: 3.0        Date: 22-Mar-2022 
Controlled Document ID: 4106B.00, Effective Date: 30-Apr-2018 
Page 6 of 8 
Appendix 1: Privacy Notice 
Identification of Data Controller: During the study, the Sponsor will direct the collection and 
use of your personal information (data) needed for the outcome of your pregnancy. The Sponsor 
is the data controller of your and your baby’s personal data under applicable data protection laws. 
You can contact the Sponsor at:  
Ms. Xianqing Hu 
No. 865 Zuchongzhi Road, Pudong New Area, Shanghai, China 
Tel: +86 21 20568888 
The study center may also be considered as a data controller of your and your baby’s personal 
data under applicable data protection laws. You may contact the study doctor using the contact 
information for the study doctor on the first page of this informed consent form. <If 
relevant>You can contact the study center’s data protection officer at: <Study center to provide 
contact information>. 
If you have any questions or would like to see the data collected about you and your baby for this 
study, you should contact the study doctor. 
Data to be Collected and Processed: The study staff will collect health information about you 
and your baby. This data may include your name or initials, date of birth, gender, and contact 
details and information about the birth and health of your baby such as sex, birth weight, and size. 
In addition, the following sensitive personal data about you may be collected: health, ethnicity, 
race, sexual activity or orientation, genetic information, and fingerprints or eye scans (to help 
verify your identity). 
How Your and Your Baby’s Personal Data Will be Used: The personal data collected about 
you and your baby will be recorded in your partner’s study file by the study staff to monitor your 
and your baby’s safety. Your and your baby’s personal data may be processed on a computer 
and/or on paper. The collection of this data is necessary to determine if the study drug that your 
partner was given has an effect on your pregnancy and/or the health of your baby. 
There are laws about the recording, forwarding, storage, and analysis of your and your baby’s 
personal data, including sensitive personal data. These laws require your voluntary and explicit 
consent before any data are collected about you and your baby.  
Results of this study may be presented at meetings or in publications; however, your identity will 
never be shared. Your personal data will not be used for any direct marketing purposes.  
If information regarding a communicable disease is collected, the information may be shared 
with a public health authority that is authorized by law to collect or receive such information for 


Pregnant Partner Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Pregnant Partner ICF Version Number: 3.0        Date: 22-Mar-2022 
Controlled Document ID: 4106B.00, Effective Date: 30-Apr-2018 
Page 7 of 8 
the purpose of preventing or controlling disease, injury, or disability, and conducting public 
health surveillance, investigations, or interventions. 
Storage of Your and Your Baby’s Personal Data: According to legal requirements, your 
personal data will be stored in the study databases and/or paper files for at least 15 years after the 
study ends, as required by applicable laws.  
Transferring the Personal Data to a Third Party: To keep your and your baby’s identity 
private, all data that is sent or provided outside of the study center will show only a coded 
identification number instead of your name. Only the study doctor and authorized personnel will 
be able to connect this code to your name. They will use a list that will be kept in a secure place 
to link this code to your name in case of an emergency. The coded data from the study showing 
your and your baby’s involvement (including uncoded personal information) will be provided to 
the Sponsor and other individuals and/or companies that act on the Sponsor’s behalf, including 
Syneos Health. Also, your and your baby’s medical records (including uncoded personal data) 
may be reviewed by the Sponsor and other individuals and/or companies that act on the 
Sponsor’s behalf, including Syneos Health; government agencies in countries where the study 
drug may be considered for approval (such as the US FDA); [IRB/IEC name], a group that 
reviews and approves studies; and independent auditors for the purposes of monitoring your and 
your baby’s safety. Further, your and your baby’s personal information may be disclosed in 
response to lawful requests by public authorities, including those to meet national security or law 
enforcement requirements. 
If your and your baby’s personal data is shared with other companies that are located outside of 
the country where you live, the Sponsor will make sure that your and your baby’s data is 
protected as required by your country’s data protection laws. Some of these other companies 
may be located in countries whose data protection and privacy laws may be less strict than in 
your own country, including the United States and ________________. You may contact the 
study doctor to get more information about the precautions used to protect your and your baby’s 
personal data outside of your country. You may also ask the study doctor for a copy of those 
precautions. 
With your permission, the study doctor will tell your primary doctor about your role in this study.  
A description of this clinical trial will be available on http://www.clinicaltrials.gov as required 
by US law. This website will not include information that can identify you. At most, the website 
will include a summary of the results. You can search this website at any time.  
Your Rights as a Data Subject: You have the right to access and correct the data collected 
about you and your baby during the study and submit any questions or concerns about the 
collection or processing of your and your baby’s personal data, however this access is suspended 
until after the study has ended. Your rights will be reinstated at the conclusion of the study.  


Pregnant Partner Informed Consent Form 
Sponsor: Haihe Biopharma Co., Ltd.; Protocol No.: HH2710-G101 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
“Syneos Health” as used in this document includes Syneos Health, Inc. and its operating companies and subsidiaries which include 
but are not limited to the INC Research group of companies and the inVentiv Health group of companies” 
This document is confidential. 
Pregnant Partner ICF Version Number: 3.0        Date: 22-Mar-2022 
Controlled Document ID: 4106B.00, Effective Date: 30-Apr-2018 
Page 8 of 8 
You may make these requests by contacting the study doctor. You may also have the right to file 
a complaint regarding the handling of your and your baby’s personal information with your local 
data protection authority. 
You have the right to withdraw your consent for the processing of your and your baby’s personal 
data at any time. You must withdraw your consent by writing to the study doctor. However, data 
collected before you remove your consent is still legally allowed to be used. 
Consent Language 
Consent to the Collection, Processing, and Use of Personal Data 
By signing below, I agree that: 
(1) My and my baby’s personal data, including sensitive personal data, can be collected, used, 
and archived for purposes of determining if the study drug my partner was given has any 
effect on my pregnancy and/or the health of my baby as described in this Privacy Notice 
(2) My and my baby’s personal data, including sensitive personal data, can be transferred to and 
shared with other companies both within and outside of the European Economic Area 
(EEA), including to countries that may not have the same level of data protection as the 
EEA, as described in the Privacy Notice 
This consent is valid unless you change your mind and provide a written notice to the study 
doctor. You will receive a signed and dated copy of this Privacy Notice. 
_______________________________________ 
Pregnant Partner’s First and Last Name (print) 
______________________________________ 
___________________ 
Signature of Pregnant Partner 
 
Date (dd/Mmm/yyyy) 
______________________________________________________________ 
Subject’s First and Last Name and Study ID number (Print) 
 
 
 
 
 
 
 

Prot_000.pdf: 
Clinical Development 
HH2710 
Clinical Trial Protocol HH2710-G101 
A First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, 
Tolerability and Pharmacokinetics of HH2710 in Patients with Advanced 
Tumors 
File type 
Oncology Clinical Trial Protocol 
IND Number 
144684 
Version No. 
V2.0 
Development phase 
Phase I/II 
File status 
Final 
Release date 
Sponsor  
21-Mar.-2022
Haihe Biopharma Co., Ltd. 
No. 865 ZuChongzhi Road, Pudong New 
Area, Shanghai, China (201203) 
Property of Haihe Biopharma Co., Ltd. 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the consent of Haihe 
ClinicalTrials.gov ID: NCT04198818


Haihe 
Confidential 
Page 2 
Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
Signature Page of the Sponsor 
Protocol Title: 
A First-in-Human, Open Label, Phase I/II Study to Evaluate the 
Safety, Tolerability and Pharmacokinetics of HH2710 in Patients 
with Advanced Tumors 
Protocol Number: 
HH2710-G101 
Version Date: 
21-Mar-2022 
Version Number: 
V2.0 
 
 
 
 
I have read the study protocol including all appendices and current Investigator's Brochure (IB) 
and agree with all the details of completing the study and relevant confidentiality provisions 
contained in the protocol. I have fully understood the study protocol, will comply with the 
Declaration of Helsinki, International Council for Harmonization (ICH) E6 GCP (including filing 
of essential documents), regulations of the National Medical Products Administration and relevant 
regulations, and conscientiously perform my duties. 
 
 
Sponsor’s name: Haihe Biopharma Co., Ltd. 
Sponsor address: No. 865, ZuChongzhi Road, Pudong New Area, Shanghai, China. 
201203 
 
 
Approved by: 
Signature: 
 
Date: 
 


Haihe 
Confidential 
Page 3 
Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
Signature Page of the Investigator 
 
Protocol Title: 
A First-in-Human, Open Label, Phase I/II Study to Evaluate the 
Safety, Tolerability and Pharmacokinetics of HH2710 in Patients 
with Advanced Tumors 
Protocol Number: 
HH2710-G101 
Version Date:  
21-Mar-2022 
 
Version Number: 
V2.0 
 
 
I have read the study protocol including all appendices and current Investigator's Brochure (IB) 
and agree to carry out the study in compliance with it. I will provide data of the study protocol and 
corresponding guidance and assistance to all personnel taking part in the study under my 
management to ensure they are fully informed of matters associated with the drug and the study.  
I will comply with the Declaration of Helsinki, International Council for Harmonization (ICH) E6 
GCP (including filing of essential documents), and applicable requirements of the National 
Medical Products Administration, local health and regulatory authorities and Ethics Committee 
(EC) to carry out the trial. By accepting this document, I agree that I shall not publish or disclose 
any unpublished information contained in this document without the prior written permission of 
the sponsor. 
 
Principal Investigator’s Name: 
 
 
Clinical Study Site: 
 
 
Signature: 
 
Date: 
 
 
 


Haihe 
Confidential 
Page 4 
Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
Version History 
Version 1.2, [27-AUG-2019]  
Initial creation 
 
Version 1.3, [20-JAN-2021]  
1) Company name has been updated. 
2) In the protocol summary and the text, from the fourth dose group in the dose 
escalation phase, administration changed from "twice a day (BID)" to "once a 
day (QD)". 
3) In the protocol summary and the Section 5.2, The content of QT interval has 
been updated in the Inclusion Criteria 10. 
4) In the protocol summary and the Section 5.2, The content of hemoglobin has 
been updated in the Inclusion Criteria 11. 
5) Two exclusionary criteria, exclusionary criteria 2 and exclusionary criteria 3, 
are added to the protocol summary and Section 5.3. 
6) In the protocol summary and the Section 5.3, The content of Anticancer 
treatments has been updated in the Exclusion Criteria 9. 
7) In the protocol summary and the Section 5.3, The content of Antibiotic 
treatment required has been updated to systemic medication required in the 
Exclusion Criteria 13. 
8) In the protocol summary and the Section 5.3, The content of Contraception has 
been updated in the Exclusion Criteria 21. 
9) “Grade 2 toxicity” has been clarified to “grade 2 adverse event” in Section 
6.2.3. 
10) The content description of neutropenia in Table 6-8 has been updated. 
11)  The prohibition of combination therapy in Section 6.4.3 has been updated. 
12)  In Table 7-1, the audit of the inclusion/exclusion criteria and safety follow-up 
have been updated.The footnote description in Table 7-1 has been updated. 
13) The description of the replacement policy in Section 7.1.4.3 has been updated. 
14) The content of survival follow-up in Section 7.1.5.3 has been updated. 


Haihe 
Confidential 
Page 5 
Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
15) The Laboratory assessment and 12-lead ECG in Section 7.2.1 have been 
updated. 
16) The content of blood sample collection in Section 7.2.2.1 has been updated. 
17) The content of PD in Section 7.2.3 has been updated. 
18) The content of imaging assessment in Section 7.2.5 has been updated. 
19) The content of Adverse events in Section 8.1 have been updated. 
20) The description in the report in Section 8.2.2 has been updated. 
21) “Drug safety department” in Section 8 has been updated to “Pharmacovigilance 
Department” 
22) The description of biomarkers in the protocol summary, sections 1.2.1.3, 
section 4.1, section 5.1, section 7.1.1, section 7.2.4, and Tables 7-4 has been 
updated. 
23)  The content of the PK parameter description in Table 10-2 has been updated. 
24) In the appendix 6, The QTc Fridericia formula has been updated. 
 
Version 2.0, [21-Mar-2022]  
1) To update the company address. 
2) To update study design (dose level, frequency and patient number) based on 
emerging clinical data including safety, efficacy and PK data throughout the 
protocol. 
3) To remove phase Ⅱ exploratory objective and exploratory endpoint since it was 
not planned currently in protocol summary and section 3. 
4) To update eye related exclusion criteria in protocol summary and section 5.3 
exclusion criteria #17. 
5) To update eye related management in table 6-6, table 6-8, section 7.1.table 7-
1,section 7.2.1.1. 
6) To update the risk-benefit assessment and safety part based on emerging data in 
section 1.3 and section 8. 
7) To update LCH tumor assessment and management in table 6-6, table 6-8, 
section 7.2.5. 


Haihe 
Confidential 
Page 6 
Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
8) To change the sample collection plan since the central lab is not  available in 
America in table 7-1, section 7.1.1, section 7.2.3,section 7.2.4.1. 
9) In figure 4-1 update the flow chart. 
10) In protocol summary and section 5.2 update the inclusion criteria #11. 
11) In protocol summary and section 5.2 update the exclusion criteria #15. 
12) In protocol summary, section 5 removed patients with other MAPK pathway 
gene mutation description. 
13) In section 6.1.2 removed guideline for continuation of treatment. 
14) Add the Permitted concomitant therapy requiring caution and/or action in 
section 6.4.2 and section 1.2.1.1.1. 
15) In table 7-1 update the EOT visit within 
16) In table 7-1 and section 7.2.1.8 removed chest X ray check 
17) In table 7-1 and section 7.2.1.5 update the pregnancy test. 
18) In table 7-1 add vital sign time window. 
19) In table 7-1 and  section 7.2.1.5 add HCV RNA and HBV DNA check 
description. 
20) The EOT and EOS definition updated in section 7.1.4.1 
21) In section 7.1.4.2 update the criteria for patient premature withdrawal 
22) In section 7.2.1.5 removed urine protein check. 
23) In section 7.2.1.7 add the time window for ECG. 
24) Update the table 7-3 “PK blood sampling time for Phase I dose expansion stage 
and Phase II”. 
25) In section 7.2.5 update efficacy assessment description. 
26) In table 6-1 removed “level 7 1000mg” 
27) update the table 6-4 provisional dose level. 
 
 


Haihe 
Confidential 
Page 7 
Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
Table of contents 
Signature Page of the Sponsor .............................................................................................2 
Signature Page of the Investigator .......................................................................................3 
Table of contents ..................................................................................................................7 
List of figures .....................................................................................................................11 
List of tables .......................................................................................................................11 
List of abbreviations ..........................................................................................................13 
Glossary of terms ...............................................................................................................16 
Protocol summary ..............................................................................................................18 
1 
Background ........................................................................................................................28 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment ..............28 
1.2 
Introduction to investigational treatment(s) ...........................................................31 
1.2.1 
Overview of HH2710 ............................................................................31 
1.2.2 
Known potential risk .............................................................................36 
2 
Rationale ............................................................................................................................37 
2.1 
Study rationale and purpose ...................................................................................37 
2.2 
Rationale for the study design ................................................................................38 
2.3 
Rationale for dose and regimen selection ..............................................................39 
3 
Objectives and endpoints ...................................................................................................42 
4 
Study design .......................................................................................................................44 
4.1 
Description of study design....................................................................................44 
4.2 
Timing of interim analyses and design adaptations ...............................................47 
4.3 
Definition of end of the study ................................................................................48 
4.4 
Early study termination ..........................................................................................48 
5 
Population ..........................................................................................................................49 
5.1 
Patient population ..................................................................................................49 
5.2 
Inclusion criteria ....................................................................................................49 
5.3 
Exclusion criteria ...................................................................................................51 
6 
Treatment ...........................................................................................................................53 


Haihe 
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Page 8 
Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
6.1 
Study treatment ......................................................................................................53 
6.1.1 
Dosing regimen .....................................................................................53 
6.1.2 
Treatment duration ................................................................................55 
6.2 
Dose escalation guidelines .....................................................................................55 
6.2.1 
Starting dose ..........................................................................................55 
6.2.2 
Provisional dose levels ..........................................................................56 
6.2.3 
Guidelines for dose escalation and determination of (MTD/RP2D) .....57 
6.2.4 
Definitions of dose limiting toxicities (DLTs) ......................................61 
6.3 
Dose modifications ................................................................................................64 
6.3.1 
Dose modification and dose delay .........................................................64 
6.3.2 
Follow-up for toxicities .........................................................................75 
6.3.3 
Anticipated risks and safety concerns of the study drug .......................76 
6.4 
Concomitant medications .......................................................................................76 
6.4.1 
Permitted concomitant therapy ..............................................................76 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ...........76 
6.4.3 
Prohibited concomitant therapy .............................................................77 
6.5 
Patient numbering, treatment assignment or randomization ..................................77 
6.5.1 
Patient numbering ..................................................................................77 
6.5.2 
Treatment assignment or randomization ...............................................77 
6.5.3 
Treatment blinding ................................................................................78 
6.6 
Study drug preparation and dispensation ...............................................................78 
6.6.1 
Study drug packaging and labeling .......................................................78 
6.6.2 
Drug supply and storage ........................................................................79 
6.6.3 
Study drug compliance and accountability............................................79 
6.6.4 
Disposal and destruction........................................................................79 
7 
Visit schedule and assessments ..........................................................................................79 
7.1 
Study flow and visit schedule ................................................................................79 
7.1.1 
Molecular screening ..............................................................................86 
7.1.2 
Screening examination ..........................................................................87 
7.1.3 
Treatment period ...................................................................................90 


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Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
7.1.4 
End of treatment visit including study completion and premature 
withdrawal .............................................................................................90 
7.1.5 
Follow up period....................................................................................93 
7.2 
Assessment types ...................................................................................................94 
7.2.1 
Safety assessments.................................................................................94 
7.2.2 
Pharmacokinetics ...................................................................................99 
7.2.3 
Pharmacodynamics Biomarker Assessment ........................................101 
7.2.4 
Genetic Biomarkers Assessment .........................................................102 
7.2.5 
Efficacy assessments ...........................................................................103 
8 
Safety monitoring and reporting ......................................................................................104 
8.1 
Adverse events .....................................................................................................104 
8.1.1 
Definition of Adverse Event（AE） ..................................................104 
8.1.2 
Adverse Events Follow up and Reporting ...........................................104 
8.1.3 
Assessment of Adverse Events ............................................................105 
8.2 
Serious Adverse Event (SAE) ..............................................................................106 
8.2.1 
Definition of SAE ................................................................................106 
8.2.2 
Serious Adverse Event Reporting .......................................................107 
8.2.3 
SAE Follow-up ....................................................................................107 
8.2.4 
Serious and Unexpected Suspected Adverse Reaction .......................108 
8.3 
Reporting of Pregnancy .......................................................................................108 
8.4 
Emergency unblinding of treatment assignment ..................................................108 
8.5 
Warnings and precautions ....................................................................................108 
8.6 
Steering Committee..............................................................................................109 
9 
Data collection and management .....................................................................................109 
9.1 
Data confidentiality ..............................................................................................109 
9.2 
Data collection .....................................................................................................109 
9.3 
Data review ..........................................................................................................110 
9.4 
Database locking and archiving ...........................................................................110 
9.5 
Database management and quality control ..........................................................110 
10 Statistical methods and data analysis ...............................................................................111 


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Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
10.1 
Study Endpoints ...................................................................................................111 
10.2 
Analysis sets .........................................................................................................111 
10.2.1 
All-Treated Set ....................................................................................111 
10.2.2 
Safety Set .............................................................................................111 
10.2.3 
Pharmacokinetic analysis set ...............................................................111 
10.2.4 
Pharmacodynamics analysis set ..........................................................112 
10.3 
Covariates and Subgroups ....................................................................................112 
10.4 
Sample Size Considerations .................................................................................112 
10.5 
Planned Analyses .................................................................................................114 
10.5.1 
Interim Analyses ..................................................................................114 
10.5.2 
Primary Analysis .................................................................................114 
10.5.3 
Final Analysis ......................................................................................114 
10.6 
Planned Methods of Analysis ..............................................................................115 
10.6.1 
General Considerations .......................................................................115 
10.6.2 
Primary Efficacy Endpoint ..................................................................115 
10.6.3 
Secondary Efficacy Endpoint(s) ..........................................................115 
10.6.4 
Pharmacokinetic Analysis ...................................................................116 
10.6.5 
Pharmacodynamics Analysis ...............................................................117 
10.6.6 
Safety Endpoints ..................................................................................117 
10.6.7 
Handling of missing values/censoring/discontinuations .....................117 
10.6.8 
Censoring Rules for Duration of Response (DoR) ..............................118 
11 Ethical considerations and administrative procedures .....................................................118 
11.1 
Regulatory and ethical compliance ......................................................................118 
11.2 
Responsibilities of the investigator and IRB/IEC/REB .......................................118 
11.3 
Informed consent procedures ...............................................................................118 
11.4 
Discontinuation of the study ................................................................................119 
11.5 
Publication of study protocol and results .............................................................119 
11.6 
Study documentation, record keeping and retention of documents .....................119 
11.7 
Confidentiality of study documents and patient records ......................................120 
11.8 
Audits and inspections .........................................................................................120 


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Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
11.9 
Financial disclosures ............................................................................................121 
12 Protocol adherence ...........................................................................................................121 
12.1 
Amendments to the protocol ................................................................................121 
13 References (available upon request) ................................................................................121 
14 Appendices .......................................................................................................................125 
14.1 
Appendix 1 RECIST v1.1 ....................................................................................125 
14.2 
Appendix 2  ECOG performance status score .....................................................135 
14.3 
Appendix 3  Cockcroft-Gault formula and calculation formula of body surface 
area .......................................................................................................................136 
14.4 
Appendix 4  Women of child-bearing age and contraceptive measures ..............137 
14.5 
Appendix 5  New York Heart Association (NYHA) Functional Classification ..138 
14.6 
Appendix 6  QTc Fridericia's formula .................................................................139 
14.7 
Appendix 7 CYP3A4 inhibitor and inducer .........................................................140 
14.8 
Appendix 8 Examples of P-gp inhibitor ..............................................................142 
 
List of figures 
 
Figure 1-1. ERK regulates both cytosolic targets and nuclear transcription factors, thus 
promoting proliferation, survival and other malignant phenotypes. ............................................. 28 
Figure 4-1 Study Flow Chart ........................................................................................................ 46 
Figure 4-2 the proposed interim analysis sketch map for cohort 1 and 2 ..................................... 47 
Figure 6-1 Flowchart for study conduct using the BOIN design .................................................. 58 
 
List of tables 
Table 3-1 Objectives and related endpoints .................................................................................. 42 
Table 4-1 Optimized stopping boundaries for cohort 1 and cohort 2 in Phase II ......................... 46 
Table 6-1 Proposed Dose and treatment schedule of Phase I ....................................................... 53 
Table 6-2 Dose and treatment schedule of Phase II ...................................................................... 54 
Table 6-3 Calculation of the MRSD for HH2710 ......................................................................... 56 


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Table 6-4 Provisional dose levels ................................................................................................. 56 
Table 6-5 Dose escalation/de-escalation rule for the BOIN Design ............................................. 59 
Table 6-6 Criteria for defining dose-limiting toxicities ................................................................ 62 
Table 6-7 Dose adjustment of HH2710 ........................................................................................ 65 
Table 6-10 Preparation and dispensing ......................................................................................... 78 
Table 7-1 Visit evaluation Schedule of Assessments and Procedures .......................................... 81 
Table 10-1 Optimized stopping boundaries for cohort 1 and cohort 2 in Phase II ..................... 113 
Table 10-2 PK Parameters Description....................................................................................... 116 
 
 
 


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List of abbreviations 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APTT 
Activated partial prothrombin time 
AST 
Aspartate aminotransferase  
ATD 
Accelerated titration designs 
BED 
Biological effective dose 
BID 
Twice daily 
BOIN 
Bayesian optimal interval 
BOP2 
Bayesian optimal phase 2 
BP 
Blood pressure 
CLcr 
Creatinine clearance rate 
CNS 
Central nervous system 
CR 
Complete remission/complete response 
CRF 
Case report/record form 
CRM 
Continual reassessment method 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CTEP 
Cancer Therapy Evaluation program 
CYPs 
Cytochromes P450 
CYP3A4 
Cytochrome P450 isoform 3A4 
DBP 
Diastolic blood pressure 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DoR 
Duration of response 
ECD 
Erdheim-Chester disease  
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG 
Eastern cooperative oncology group 
eCRF  
Electronic case report/record form 
ECs 
Ethics committees 
EDC 
Electronic data collection 
EOT 
End of treatment 
ERK 
Extracellular signal-regulated kinase 
FFPE 
Formalin-fixed, paraffin-embedded 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 


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HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 
hERG 
Human ether-a-go-go-related gene 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severe toxic dose 
IB 
Investigator’s brochure 
IC50 
Half maximal inhibitory concentration 
ICH  
International Conference on Harmonization 
ICF 
Informed consent form 
INR 
International normalized ratio  
IEC 
Independent ethics committee 
IRB 
Institutional review board 
LC/MS-MS 
Liquid chromatography-tandem mass spectrometry  
LCH 
Langerhans cell histiocytosis syndrome 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction  
MAPK 
Mitogen-activated protein kinase 
MBP 
Mean blood pressure 
MEDDRA 
Medical Dictionary for Regulatory Activities 
MEK 
Mitogen-activated protein kinase/extracellular signal-related kinase 
MUGA 
Multi-gated acquisition 
NCI 
National cancer institute 
NGS 
Next generation sequencing 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate  
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Pharmacodynamics 
PD 
Progressive disease  
PFS 
Progression-free survival 
PHI 
Protected health information 
PI 
Principal investigator 
PI3K 
Phosphatidylinositol 3-kinase 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetic analysis set 
PT 
Prothrombin time 
QD 
Once daily 
QT 
A measure between Q and T waves in heart electrical system 
QTc 
Corrected QT interval 


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QTcF 
Fridericia-corrected QT interval 
RBC 
Red blood cell 
REB 
Research ethics board 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended phase two dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Steering committee  
SD 
Standard deviation 
SD 
Sprague Dawley 
SEC 
Study evaluation completion 
SFUV 
Safety Follow-up Visit 
SMC 
Safety monitoring committee  
SOC 
System organ class 
SS 
Safety set  
TEAEs 
Treatment-emergent adverse events 
TTP 
Time to progression 
TTR 
Time to response 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
 
 
 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient 
Cohort 
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g.: q21 days) 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.)  
Enrollment 
Point/time of patient entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.” 
Investigational 
treatment 
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are tested 
in a fixed combination. Investigational treatment generally does not include other 
study treatments administered as concomitant background therapy required or 
allowed by the protocol when used in within approved indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment 
Patient Number 
/Subject Number 
(Patient No.) 
A unique identifying number assigned to each patient/subject /healthy volunteer 
who enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature patient 
withdrawal 
Point/time when the patient exits from the study prior to the planned completion 
of all study treatment administration and/or assessments; at this time all study 
treatment administration is discontinued and no further assessments are planned, 
unless the patient will be followed for progression and/or survival 


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Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has spread 
from the original site to other parts of the body 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins. 
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for any reason; 
may or may not also be the point/time of premature patient withdrawal 
Treatment group 
A treatment group defines the dose and regimen or the combination and may 
consist of 1 or more cohorts. Cohorts are not expanded; new cohorts are enrolled. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points 
 
 
 


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Protocol summary 
Protocol number 
HH2710-G101 
Title 
A First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, 
Tolerability and Pharmacokinetics of HH2710 in Patients with Advanced 
Tumors 
Sponsor 
 Haihe Biopharma Co., Ltd. 
Phase 
Phase I/II  
Location and sites 
Multinational, Multicenter 
Purpose and rationale 
The purpose of this study is to characterize the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of 
HH2710 administered orally in adult patients with advanced tumors. 
Primary Objective(s) 
and Endpoints 
Phase I:  
Primary objective: 
- 
To evaluate the safety, tolerability of HH2710 administered orally in 
patients with advanced tumors. 
- 
To identify the Maximum Tolerated Dose (MTD) and/or 
Recommended Phase II dose (RP2D). 
Primary endpoints:  
- 
Safety and Tolerability: The incidence, type, and severity of adverse 
events (AEs) assessed according to the National Cancer Institute-
Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
V5.0, physical examination findings, clinical laboratory values, vital 
signs and Electrocardiograms (ECGs); 
- 
The MTD, if any, and RP2D for HH2710 will be determined based 
on safety, tolerability, PK, preliminary efficacy, and other available 
data. 
 
Phase II:  
Primary objective 
- 
To evaluate efficacy of HH2710 in patients with advanced tumors 
with alterations on the genes of the mitogen-activated protein kinase 
(MAPK) signaling pathway, at the recommended phase 2 dose 
(RP2D). 


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Primary endpoints: 
- 
Tumor objective response rate (ORR) based on RECIST version 1.1. 
Secondary Objective(s) 
and Endpoints 
Phase I: 
Secondary objectives: 
- 
To characterize the pharmacokinetic profile of HH2710 and selected 
metabolites when administered orally in patients with advanced 
tumors. 
Secondary endpoints:  
- 
Peak plasma concentration (Cmax), peak time (tmax), area under the 
plasma concentration-time curve from time 0 to time (t) (AUC0-t), 
plasma elimination half-life (t1/2), plasma clearance rate constant 
(λz), apparent clearance (CL/F), apparent volume of distribution 
(Vz/F) 
Phase II:  
Secondary objectives: 
- 
To evaluate the efficacy of HH2710 in advanced tumor patients with 
MAPK signaling pathway genetic alterations. 
- 
To evaluate the safety of HH2710. 
Secondary endpoints: 
- 
Efficacy: the duration of response (DoR), progression-free survival 
(PFS), disease control rate (DCR), time to response (TTR), time to 
progression (TTP), and 1-year overall survival (OS) rate. 
- 
Safety: The incidence, type, and severity of adverse events (AEs) 
assessed according to the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) V5.0, 
physical examination findings, clinical laboratory values, vital signs 
and Electrocardiograms (ECGs). 
Exploratory 
Objective(s) and 
Endpoints 
Phase I:  
Exploratory objectives 
- 
To assess the preliminary efficacy of HH2710;. 
- 
To explore the changes of the pharmacodynamic (PD) markers of 
HH2710.  
Exploratory endpoints: 
- 
ORR, DoR, DCR, PFS and TTR;. 
- 
Changes in PD markers of HH2710 efficacy including 


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phosphorylation of RSK (pRSK) and total RSK. 
Study design 
This is a First-in-Human, open-label, multicenter, Phase I/II study which is 
composed of a Phase I dose escalation stage, Phase I dose expansion stage and 
a Phase II dose extension stage. HH2710 will be administered orally on a 
continuous once daily (QD) or twice daily (BID) schedule, 21 days as a 
“Cycle”. 
Phase I: Dose escalation 
The accelerated titration (ATD) incorporated with Bayesian optimal interval 
(BOIN) design will be used to assess the safety and tolerability, and to help to 
find the maximum tolerated dose (MTD), and/or to establish the recommended 
phase 2 dose (RP2D) combined with data from other sources. 
A maximum sample size is 58 patients for the dose escalation (ATD + BOIN). 
The total number of patients will depend upon the number of dose escalations 
actually needed. 
Accelerated titration part: 
One patient per cohort will be assigned to receive HH2710. The first three 
patients will take HH2710 once daily (QD) in cycle 1 day 1 for the single dose 
PK testing, from the second day, HH2710 will be administered orally on a 
continuous twice daily (BID). 
The proposed dose level in accelerated titration stage is 25mg, 50mg and 
100mg twice daily (BID), It may be adjusted according to the available data. 
BOIN design part: 
When there is an adverse event of grade≥2 occurs, the dose escalation process 
will shift to a BOIN design, in which at least 3 patients will be assigned per 
treatment cohort. (ATD + BOIN design details please see Section 6.2.3) 
Part A (25/50/100 mg BID + QD dose escalation cohorts ): 
To date 18 Jan 2022, 22 patients were enrolled in the dose escalation stage of 
6 dose levels as 25mg BID (n=3), 50mg BID (n=3), 100mg BID (n=4), 400mg 
QD (n=4), 600mg QD(n=4), and 800mg QD (n=4), 4 patients were enrolled 
in the 600mg QD expansion cohort. PK data from 22 enrolled patients showed 
HH2710 was slowly eliminated after oral administration, the accumulation of 
the systemic exposure of HH2710 at steady state was about 3-4 fold. The half-
life (t1/2)of HH2710 ranged from 8.42 to 10.9 hr, suitable for once daily 
dosing.   
Based on the safety data at 6 dose levels, HH2710 was well tolerated from 25 
mg BID to 400 mg QD. However, 1 of 4 patients at 800 mg dose cohort 
experienced DLT (Grade 3 Acneiform rash). 3 of 26 patients developed 
Grade 1-2 eye toxicity, 2 patients were from the 600mg dose group, and 1 
from 800mg dose. Since the drug-related factor may have contributed, we 


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have de-escalated to 300mg QD dose.  6.2.2And further dosing frequency and 
dose level may be adjusted based on available safety and PK data.  
Part B (Additional BID dose escalation cohorts ): 
In order to determine the RP2D, additional BID dosing regimens will also be 
evaluated using BOIN design starting from 200mg BID dose and the total 
sample size in Part B is up to approximately 18 subjects. 
After the escalation is completed, select the MTD based on the isotonic 
regression as specified in [64]. Specifically, select the MTD for which the 
isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there 
are ties, select the higher dose level when the isotonic estimate is lower than 
the target toxicity rate and select the lower dose level when the isotonic 
estimate is greater than or equal to the target toxicity rate. 
Dose expansion stage:  
Additional up to 15 patients per cohort may be included in order to further 
evaluate the safety, PK and anti-tumor activities among biomarker-selected 
patients. The dose for provisional cohort of expansion phase will be based on 
available safety, PK/PD, preliminary efficacy data.  Patients enrolled could 
have different tumor types but with specific MAPK pathway genetic 
alteration (the same requirement as in phase II). The total number of patients 
will depend upon the number of dose expansions necessary. 
Phase II: Dose Extension 
This is an open-label, multicenter, dose extension stage at RP2D to explore 
the response of patients with particular tumor types harboring MAPK genetic 
alteration. A maximum of 108 patients will be enrolled. 
Patients enrolled will be divided into four cohorts once RP2D is defined and 
each of them focuses on specific tumors with specified genetic alteration 
through molecular screening. (See details in section 4.1): 
- 
Cohort 1: Patients with BRAF/NRAS (mutation sites as follows: 
NRAS G13V, NRAS Q61, BRAF V600, BRAF G469A, L485W, 
L597Q, T599dup) mutated melanoma; 
- 
Cohort 2: Patients with BRAF/NRAS (mutation sites as follows: 
NRAS G13V, NRAS Q61, BRAF V600, BRAF G469A, L485W, 
L597Q, T599dup) mutated non-small cell lung cancer; 
- 
Cohort 3: Patients with BRAF V600 mutated Langerhans Cell 
Histiocytosis Syndrome (LCH)/ Erdheim-Chester disease (ECD); 
- 
Cohort 4: Patients with RAS/RAF/MEK/ERK mutated tumors that 
are not included in other cohorts. 
Population 
Phase I 


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For the dose escalation stage, patients who have been diagnosed with 
histologically or cytologically documented, unresectable/metastatic tumors 
that are refractory or intolerant to standard therapy or for whom no curative 
standard therapy exists.  
- 
 For LCH/ECD: Eligible patients must have multifocal disease 
and the diagnosis must be confirmed by pathological evaluation 
of the affected tissue. 
For the dose expansion stage, patients must have been diagnosed with 
histologically or cytologically documented, unresectable/metastatic tumors 
harboring MAPK pathway genetic alterations. Patients with a BRAF V600 
mutation must have progressed on or after standard therapy, including 
BRAF and/or MEK inhibitors (≤3 lines).  
Phase II 
Patients must have been diagnosed with histologically or cytologically 
documented, unresectable/metastatic tumors harboring genetic alterations of 
the genes of MAPK pathway. Patients with a BRAF V600 mutation must 
have progressed on or after standard therapy, including BRAF and/or MEK 
inhibitors (≤3 lines). Patients will be enrolled in Cohorts 1-4 depending upon 
their tumor type.  
Inclusion criteria 
1. Provide signed and dated informed consent prior to initiation of any study-
related procedures; 
2. Male or female patients aged ≥ 18 years; 
3. Phase I dose escalation stage: Patients who have been diagnosed with 
histologically or cytological documented, unresectable/metastatic tumors 
that are refractory or intolerant to standard therapy or for whom no curative 
standard therapy exists.   
- 
For LCH/ECD: Eligible patients must have multifocal disease and the 
diagnosis must be confirmed by pathological evaluation of the 
affected tissue. 
4. Phase I expansion stage and Phase II stage: Histologically or cytologically 
documented unresectable/metastatic tumors with evidence of genetic 
mutations affecting MAPK pathway is required. Patients with a BRAF 
V600 mutation must have progressed on or after standard therapy, 
including BRAF and/or MEK inhibitors (≤3 lines). Patients entering the 
Phase 2 portion of the trial will be enrolled in Cohorts 1-4 depending upon 
their tumor type.   
- 
Cohort 1: Patients with BRAF/NRAS (mutation sites as follows: 
NRAS G13V, NRAS Q61, BRAF V600, BRAF G469A, L485W, 
L597Q, T599dup) mutated melanoma; 
- 
Cohort 2: Patients with BRAF/NRAS (mutation sites as follows: 


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NRAS G13V, NRAS Q61, BRAF V600, BRAF G469A, L485W, 
L597Q, T599dup) mutated non-small cell lung cancer; 
- 
Cohort 3: Patients with BRAF V600 mutated Langerhans Cell 
Histiocytosis Syndrome (LCH)/ Erdheim-Chester disease (ECD); 
- 
For LCH/ECD: Eligible patients must have multifocal disease 
and the diagnosis must be confirmed by pathological evaluation 
of the affected tissue.  
- 
Cohort 4: Patients with RAS/RAF/MEK/ERK mutated tumor types 
that are not included in other cohorts. 
5. Patients in the Phase I dose escalation portion of the trial may have 
measurable (per RECIST v1.1) or evaluable disease. Patients in the Phase 
I expansion and Phase II portions of the trial must have measurable disease 
per RECIST v1.1. 
6. Eastern Cooperative Oncology Group (ECOG) performance status≤ 1.  
7. Predicted life expectancy of ≥ 3 months; 
8. Adequate renal function defined as a creatinine clearance ≥ 60 mL/min 
(using Cockcroft-Gault formula, see Appendix 14.3); 
9. Adequate hepatic function [total bilirubin ≤ 1.5 x UNL; AST (aspartate 
aminotransferase) and ALT (alanine aminotransferase) ≤ 3 x UNL or ≤ 5 
x UNL if due to liver involvement by tumor]; 
10. Adequate cardiac function, > institutional lower limit of normal e.g., left 
ventricular ejection fraction (LVEF) of ≥ 50% as assessed by 
ultrasound/echocardiography 
(ECHO) 
or 
multi-gated 
acquisition 
(MUGA) ; corrected QT interval (QTcF) < 460 ms (male patients), < 470 
ms (female patients) (using QTc Fridericia's formula. See Appendix 14.6); 
11. Adequate bone marrow function, patients must not have required 
blood transfusion or growth factor support ≤ 7 days before sample 
collection for the following ： 
• 
Absolute neutrophil count ≥ 1.5 × 109/L; 
• 
Hemoglobin ≥ 9 g/dL;  
• 
Platelet count ≥100 × 109/L; 
• 
International normalized ratio (INR) ≤ 1.5; 
• 
Activated partial prothrombin time (APTT) ≤ 1.5 × ULN; 
12. Willing and able to participate in the study and comply with all study 
requirements; 
Exclusion criteria 
Patients eligible to be included in this study are prohibited from having any of 
the following criteria: 


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1. Gastrointestinal condition which could impair absorption of study 
medication; 
2. Congenital long QT syndrome, or any known history of torsade de pointes 
(TdP), or family history of unexplained sudden death; 
3. Clinically uncontrolled hypertension (after standard antihypertensive 
treatment, systolic blood pressure ≥ 140 mmHg and/or diastolic blood 
pressure ≥ 90 mmHg); 
4. Undergone a bone marrow or solid organ transplant; 
5. Any toxicities from prior treatment that have not recovered to ≤ CTCAE 
Grade 1 before the start of study drug, with the exception of hair loss or 
fatigue;  
6. Patients who have previously participated in clinical trials of ERK 
inhibitors drug; 
7. Allergic to similar drugs or their excipients; 
8. HIV (human immunodeficiency virus) infection, active hepatitis B or 
hepatitis C patients (HBsAg positive patients also detected HBV (hepatitis 
B virus) DNA ≥ 103 copies or ≥ 200 IU/ml; HCV antibody test results are 
positive, and HCV (hepatitis C virus) RNA PCR test results are positive); 
9. Uncontrolled or severe intercurrent medical condition: 
- 
Unstable angina pectoris ≤3 months prior to starting study drug; 
- 
Acute myocardial infarction ≤3 months prior to starting study drug; 
10. Symptomatic CNS metastases that are neurologically unstable or 
requiring increasing doses of steroids to control CNS disease. Note: 
Controlled CNS metastases are allowed. Radiotherapy or surgery for CNS 
metastases must have been completed >2 weeks prior to study entry. No 
new neurologic deficits on clinical examination and no new findings on 
CNS imaging are permitted. Steroid use for management of CNS 
metastases must be at a stable dose for two weeks preceding study entry; 
11. Any cancer-directed therapy (chemotherapy, radiotherapy, hormonal 
therapy, biologic or immunotherapy, Chinese medicine/Chinese patent 
medicine with anti-tumor effect, etc.) within 28 days or 5 half-lives, 
whichever is shorter; 
12. Major surgery within 4 weeks prior to first dose; 
13. Any use of an investigational drug within 28 days or 5 half-lives 
(whichever is shorter) prior to the first dose of HH2710; 
14. Pregnant or breast-feeding women; 
15. Severe chronic or active infections requiring systemic antibacterial, 
antifungal or antiviral therapy, including tuberculosis infection, etc 
• 
Severe infections within 4 weeks prior to the first dose, including but 


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not limited to hospitalization for complications of infection, 
bacteremia, or severe pneumonia.  
• 
Received therapeutic oral or IV antibiotics within 2 weeks prior to 
the first dose of study drug. 
16. Any important or severe medical illness or abnormal laboratory finding 
that would increase the risk of participating in this study; 
17. A history or current evidence/risk of retinal vein occlusion, central serous 
retinopathy or choroidneovascularization (CNV) ; 
18. Concurrent therapy with any other investigational agent; 
19. Concomitant malignancies or previous malignancies with less than 2 
years disease-free interval at the time of enrollment; (But basal cell 
carcinoma skin cancer, cervical CIS(carcinoma in situ), CIS of the breast, 
localized or low Gleason grade prostate cancer, and < T2 bladder cancer 
can be included) 
20. Current treatment with agents including vitamins, supplements, and 
herbal supplements that are metabolized solely through CYP3A4 (see 
Appendix 14.7); 
21. Severe chronic obstructive pulmonary disease, severe asthma, 
pneumoconiosis, asbestosis and other occupational lung diseases.  
22. A history of acute or chronic pancreatitis, surgery of the pancreas, or any 
risk factors that may increase the risk of pancreatitis; 
23. Contraception (See Appendix 4  
Women of child-bearing age 
and contraceptive measures): 
Patients who do not meet the following conditions will be excluded,  
- For women: Negative pregnancy test for females of child-bearing 
potential; must be surgically sterile, postmenopausal (defined as no 
menstrual cycle for at least 12 consecutive months), or compliant with 
an acceptable contraceptive regimen (2 highly effective forms, such as 
oral contraceptives, condom with spermicide, etc.) during and for 6 
months after the treatment period. Abstinence is not considered an 
adequate contraceptive regimen; 
- For men: Must be surgically sterile, or compliant with a contraceptive 
regimen (as above) during and for a minimum of 6 months after the 
treatment period. 
Investigational and 
reference therapy 
HH2710 
Efficacy assessments 
Tumor assessment per RECIST v1.1 


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Safety assessments 
Incidence, type and severity of Adverse Events (AEs), physical examination 
findings, clinical laboratory values, vital signs and Electrocardiograms 
(ECGs). 
Other assessments 
- 
Plasma PK parameters; 
- 
Pharmacodynamics assessment on pre- and post-treatment newly 
obtained tumor samples and peripheral blood mononuclear cells 
(PBMCs); 
- 
The correlation between biomarkers and the response of HH2710. 
Data analysis 
The study data will be analyzed and reported based on all patients’ in Phase I 
and Phase II up to the time when all patients have completed at least one cycle 
of treatment or discontinued the study. 
The study is descriptive in nature and is not designed to provide definitive 
results regarding antitumor activity. Descriptive statistics will be used to 
summarize all baseline patient characteristics, treatment administration, safety 
variables, and signs of antitumor activity.  
All patients who receive at least one dose of HH2710 will be included in the 
safety analysis. Incidence of serious and non-serious AEs, including those that 
are dose limiting, will be tabulated by dose, system organ class, and preferred 
term. 
All variables obtained at different observation time points will be statistically 
described according to the dose cohorts, unless a statistical description of 
certain time points is not specified in the study protocol. In general, descriptive 
variables are statistically described using number of observations, mean, 
median, standard deviation, minimum and maximum values, Q1 and Q3 
values, while categorical variables use different frequency types and their 
relative percentages. A safety analysis of DLT and adverse events, as well as 
other safety indicators for HH2710, will be performed to guide dose 
escalation. The final analysis of the study will be based on data collected 
throughout the study. 
The sample size for Phase I of this study was determined by clinical 
considerations. A maximum sample size is 58 patients for the dose escalation 
(ATD + BOIN) to assess dose limiting toxicities (DLT), maximum tolerated 
dose (MTD), and the recommended Phase 2 dose (RP2D). 
For Phase I expansion, additional up to 15 patients per cohort may be included 
in order to further evaluate the safety, PK and anti-tumor activity among 
biomarker-selected patients. One or more dose levels and dosing frequencies 
(QD, or BID) may be expanded based on the available data. Patients enrolled 
could have different tumor types with specific MAPK pathway genetic 
alteration information. The total number of patients will depend upon the 
number of dose expansions necessary. 


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In Phase II, a maximum of 108 patients with advanced tumors harboring 
MAPK genetic alterations tested through molecular screening, will be 
recruited into four cohorts to seek the evidence of response. 
Key words 
Phase I/II, HH2710, ERK inhibitor 
 
 
 


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1 Background 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment 
A critical hallmark of carcinogenesis is the activation of cell-growth signaling cascades 
independent of appropriate growth stimulation [1]. One of cell growth control circuits is the 
mitogen-activated protein kinase (MAPK) pathway. In this pathway, growth ligands signal activate 
surface receptors, promote growth via downstream effectors in a kinase cascade system: RAS 
family GTPases activate RAF family protein kinases, which in turn trigger a phosphorylation 
cascade involving mitogen-activated protein kinase/extracellular signal-related kinase (MEK) and 
extracellular signal-regulated kinase (ERK) family kinases. ERK kinases activate a series of direct 
effectors, such as c-Myc/N-Myc/ER/c-Fos/Stat1/3 etc., which ultimately translate growth 
signaling into essential cellular functions including cell division, proliferation and cell 
survival(See figure 1-1). 
Figure 1-1. ERK regulates both cytosolic targets and nuclear transcription factors, thus 
promoting proliferation, survival and other malignant phenotypes. 
Aberrant activation of the MAPK pathway and genetic alteration of its component is ubiquitous in 
cancer. Genetic alteration often causes constitutive activation of the signaling cascade in the 
absence of appropriate ligands. For example, members of the RAS GTPase family (KRAS, NRAS, 
and HRAS) were demonstrated to exhibit spontaneous, activating mutations in a variety of cancers, 


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including non-small cell lung, melanoma, pancreatic, and colorectal malignancies [2]. As an 
example, members of the RAF GTPase family BRAF mutation can be detected in melanoma, 
colorectal tumors, lung cancer, kidney cancers, ovarian cancers, hairy cell leukemia, pilocytic 
astrocytoma, breast, cholangiocarcinoma, chronic lymphocytic leukemia, Langerhans cell 
histiocytosis Syndrome (LCH), Erdheim-Chester disease (ECD), papillary thyroid cancer, prostate 
cancer, Glioblastoma, Ganglioglioma and many other related disease types [3].  
Before 2010, the standard therapy for most patients with advanced melanoma was chemotherapy, 
which had low response rates and minimal impact on survival [4]. In 2002, activating missense 
mutations in the BRAF gene were identified in 40% to 60% of melanomas [5]. These BRAF 
mutations result in constitutive activation of the BRAF kinase protein and thus promote 
hyperactivation of the mitogen-activated protein kinase (MAPK) signaling pathway, an essential 
regulator of cell proliferation and survival [6]. Targeting aberrant MAPK signaling via the 
selective inhibition of mutant BRAF as well as the downstream protein mitogen-activated protein 
kinase (MEK) has shown significant antitumor activity in melanoma patients with BRAF-mutant 
melanoma [7][8][9]. 
In addition to BRAF, several other genes are commonly mutated in melanoma, and these may also 
provide novel therapeutic opportunities. The NRAS gene is mutated in 10% to 30% of cutaneous 
melanomas, and this leads to a constitutively active NRAS protein capable of stimulating the 
MAPK and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways [10]. 
Activating mutations in the BRAF gene, first described in lung cancers in 2002[5][11], promote 
growth and survival of cancer cells that harbor BRAF gene mutation and are extremely sensitive 
to selective BRAF inhibitor therapy across multiple tumor types[12].  
BRAF mutations are present in approximately 2–4% of lung adenocarcinomas, and approximately 
one-half are V600E mutations [5][13][14]. The clinical outcome in patients with BRAF V600E 
mutations is associated with shorter overall survival (OS) and lower response rates to platinum-
based chemotherapy than in patients with wild-type BRAF [15][16][17]. 
A basket study exploring the response of vemurafenib in patients with a variety of solid tumors 
and hematologic malignancies, enrolled a cohort of 19 patients with BRAF V600E mutated non-
small cell lung cancer (NSCLC) and demonstrated a promising overall response rate (ORR) of 42% 
[18], a cohort of 14 patients with BRAF V600E mutated Langerhans Cell histiocytosis Syndrome 
(LCH)/Erdheim-Chester disease (ECD) and demonstrated a promising overall response rate (ORR) 
of 43% [18]. 
Dabrafenib and trametinib used as single drug and combination therapy are approved in FDA and 
for treatment of melanoma, NSCLC, advanced undifferentiated thyroid carcinoma [19]. 
Vemurafenib and Cobimetinib are approved on the market too. But these inhibitors target to BRAF 
and MEK are limited by intrinsic and acquired resistance. 


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The RAS/RAF/MEK/ERK pathway is activated by many extracellular stimuli such as cytokines, 
neurotransmitters, hormones, cellular stress and cell adhesion which are important in driving the 
proliferation and promoting the survival of cancer cells, etc. After receptor ligation, Shc, Src 
homology (SH)-2, a SH2-domain containing protein, becomes associated with the c-terminus of the 
cytokine receptor [20][21][22]. Shc recruits the GTP-exchange complex Grb2/Sos resulting in the 
loading of membrane bound Ras with GTP[23][24]. Ras: GTP then recruits Raf to the membrane 
where it becomes activated, likely via a Src-family tyrosine kinase [25][26][27]. Raf is responsible 
for phosphorylation of the mitogen associated/extracellular regulated kinase-1 (MEK1)[28][29]. 
MEK1 phosphorylates extracellular regulated kinases 1 and 2 (ERKs 1 and 2) on specific threonine 
and tyrosine residues [28][29][30]. Activated ERK1 and ERK2 serine/threonine kinases 
phosphorylate and activate a variety of substrates including p90Rsk1[31][32][33][34][35]. p90Rsk1 
can activate the cyclic-AMP response element binding protein (CREB) transcription factor [33]. 
Moreover, ERK can translocate to the nucleus and phosphorylate additional transcription factors such 
as Elk1, CREB and Fos which bind promoters of many genes, including IL-3, a cytokine important 
in stimulating the growth and survival of many cancer cells. The RAF/MEK/ERK  pathway can also 
modulate the activity of many proteins involved in apoptosis including: Bcl-2, Bad, Bim, Mcl-1, 
caspase 9, and Survivin [36][37].  
ERK inhibition has the potential to overcome or avoid resistance from upstream mutations[38]. 
The ERK family kinases are downstream components of MAPK signaling pathway that have been 
therapeutically targeted for years, there are no drugs is approved on the market so far. The ERK 
target drug BVD523 showed curative effect in melanoma, NSCLC, gallbladder adenocarcinoma, 
glioblastoma multiforme etc. Responses occurred in patients with NRAS-, BRAF V600-, and non-
V600 BRAF-mutant solid tumors, with an acceptable safety profile. The most common treatment 
related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis 
acneiform (31%)[39][40]. HH2710 is a small-molecule inhibitor of ERK1/2 kinases that we plan to 
explore in various tumors. Understanding the safety, tolerability and efficacy of HH2710 will be 
helpful to the drug of targeted therapies that can be used against the activated MAPK signaling 
pathway in many malignancies. 
KRAS and NRAS mutations in RAS family genes occur in approximately 30% of all human cancers 
[41]. KRAS mutations prevalent in pancreatic (>90%)[42], colorectal (30%–50%)[43], biliary tract 
(3%–50%)[44], lung (25–30%)[45], ovarian (15%–39%)[46], and endometrial (18%) cancers[47], 
and NRAS mutations prevalent in melanoma (20%)[48].  
The most notably BRAF at codon V600 mutations in RAF family genes are frequent, particularly 
in malignant melanomas (50%)[49], and in approximately 7% of a wide range of other 
cancers[5][50]. Atypical BRAF alterations (non-V600) are sporadically in numerous tumor types.  
BRAF inhibitors (Approved drug vemurafenib and dabrafenib) are effective in BRAF V600–
driven tumors,but have not been shown to be effective against BRAF non-V600 mutations. The 
current understanding of the mechanism by which this phenomenon occurs that BRAF V600 


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alterations can act as monomers to drive signaling, whereas specific atypical BRAF non-V600 
alterations act in a dimer-dependent manner [51].  
Mutations in MEK or ERK are rare. MEK mutations occurring in 5% to 8% of melanomas [49][52], 
and ERK mutations occurring in cervical cancer (8%)[53] and head and neck squamous cell 
carcinoma (1.5%)[54]. MEK inhibitors (Approved drug trametinib and cobimetinib) combined 
with BRAF inhibitor/or used as a single drug are effective in BRAF V600E/K driven tumors,but 
have very limited efficacy in BRAF non-V600 mutations.  Collectively, activating mutations of 
MAPK/ERK pathway components are frequent events in a range of cancer types. Drugs targeting 
other components of the MAPK pathway exhibit promising therapeutic activity, while also being 
limited by unique toxicities and limited duration of efficacy.  
1.2 
Introduction to investigational treatment(s) 
1.2.1 Overview of HH2710 
The chemical name of HH2710 is 2-(2-Chloropyridin-3-yl)-1-(7-fluoro-5-(2-((1-methyl-1H-
pyrazol-5-yl) amino) pyridin-4-yl) indolin-1-yl) ethan-1-one. The medication class is tumor target 
interventional treatment. 
HH2710 is a small molecule that potently inhibits both ERK1 and ERK2 protein kinases in the 
nanomolar range. The kinase selectivity assessment towards a panel of over 400 protein kinases 
showed that HH2710 barely inhibited other kinases at a concentration up to 1 μM, except the 
substantial inhibition against ERK1 (MAPK1), ERK2 (MAPK2) and the MAPK pathway 
upstream kinases MEK and RAF proteins. Cellular assays largely excluded the impact of HH2710 
on upstream kinases MEK and RAF. HH2710 potently inhibits growth and survival in cultured 
cancer cell lines; melanoma, colorectal and pancreatic lines harboring BRAF or RAS mutations are 
among those most susceptible to the drug. Orally administered HH2710 is effective as a single agent 
in animals bearing ectopic tumor xenografts, again preferentially in cancers where activating 
mutations in the MAPK pathway cause abundant ERK kinase activation. 
HH2710 will be administered orally in humans. The free base of HH2710 was selected for 
manufacture of drug product in capsule form. Storage temperature: 10-30 ºC , protected from light. 
More information is available in the Investigator’s Brochure (IB) for HH2710. 
1.2.1.1 Preclinical experience 
1.2.1.1.1 
Preclinical drug metabolism and pharmacokinetics 
Pharmacokinetic studies conducted in Sprague-Dawley rats and Beagle dogs suggest that HH2710 
has an acceptable pharmacokinetic behavior. After intragastric administration, HH2710 is 
absorbed fast with a t1/2 of 1.68~3.60 hrs (rat) and 1.40~2.54 hrs (dog), respectively. Within the 
dosage range of 10 to 40 mg/kg (rats, fasting) and 3 to 12 mg (dogs, fasting), the exposure of 
HH2710 is greater than dose proportional following intragastric gavage, and the bioavailability 


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was 46.9 – 86.5% (rat) and 47.8 – 72.6% (dog) in these two species. After intragastric 
administration of 10 to 40 mg/kg HH2710 to rats, the mean HH2710 Cmax values were 2.95 to 10.6 
µg/mL, and the mean HH2710 AUC 0-t values were 13.1 to 96.4 µg·h/mL, respectively. After single 
intragastric administration of 3 to 12 mg/kg HH2710 to dogs, the mean HH2710 Cmax values were 
0.74 to 3.50 µg/mL, and the mean HH2710 AUC 0-t values were 3.44 to 20.9 µg·h/mL, respectively.  
After the rats were given intragastric administration of HH2710, it was mainly distributed in the 
adrenal gland, liver, gastrointestinal tract, kidney and pancreas. The apparent volume of 
distribution at steady state (Vss/F) of rats and dogs was 0.562 and 1.14 L/kg, respectively. HH2710 
did not easily pass blood brain barrier and hardly entered blood cells. The value of apparent total 
plasma clearance was low with the value of 5.93 (rat) and 7.29 (dog) mL/min/kg. There is no sex 
difference in exposure and no obvious accumulation over consecutive daily administration for a 
week. Elimination is by metabolism (CYP3A) then excretion mainly in feces. Monooxidated 
metabolite HH3529 is the major metabolite of HH2710 produced through CYP3A.  
The major metabolite HH3529: After a multiple intragastric administration of 10, 20 and 40 mg/kg 
HH2710 to rats, the exposures of HH3529 were approximately 57-121% of those of HH2710, 
increased proportionately with dose. Plasma concentrations of HH3529 peaked at 2-4 hours post-
dose. After a multiple intragastric administration of 3, 6 and 12 mg/kg HH2710 to dogs, the 
exposures of HH3529 were only approximately 3% of those of HH2710. 
HH2710 is a high permeability drug and can be rapidly distributed throughout the body with high 
plasma protein binding fraction. HH2710 has moderate inhibitory activity on CYP2C8, CYP2C9, 
CYP2C19 and CYP3A4/5 with IC50s of 4.37 µM, 4.52 µM, 8.75 µM, 8.38 µM, and 7.03 µM
, and 
has potential induction effect on CYP2B6 and CYP3A4 at 10 µM  in vitro. HH2710 is a potential 
substrate of efflux transporter P-gp.  
1.2.1.1.2 
Preclinical pharmacology and pharmacodynamics studies 
Preclinical studies have shown that HH2710 specifically inhibits the activity of ERK1/2 kinases, 
leading to significant anti-tumor activity in vitro and in vivo. 
In vitro pharmacodynamics study 
HH2710 is a specific inhibitor of ERK1/2.  
HH2710 exhibits potent inhibition on the serine/threonine kinase activity of recombinant ERK1/2 
in vitro, with half maximal inhibitory concentration (IC50) values of 4.5 ± 1. 7, 4.9 ± 0.8 nM, 
respectively. Biochemical test against a broad spectrum of 412 protein kinases did not observe the 
apparent activity towards most kinases at a concentration up to 1 µM except marginal activity 
against the upstream RAF and MEK. Further enzymatic kinetic assay using a competitive assay 
by introducing increasing concentrations of ATP show that HH2710 is an ATP-competitive 
inhibitor, which fits the most common mechanism of small-molecule kinase inhibitors. 
The cellular activity of HH2710 against ERK1/2 kinase was measured by examine the direct 
substrate molecule RSK in MAPK pathway activated cancer cell lines, namely Colo-205 colorectal 


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cancer and A375 melanoma cancer cell lines both bearing BRAF V600E mutation. HH2710 
significantly inhibited RSK phosphorylation in a dose-dependent manner.  
HH2710 inhibits the growth of cancer cells with MAPK activation. 
The cellular anticancer activity of HH2710 was assessed in a panel of cancer cells with MAPK 
activation in particular BRAF and KRAS activating mutation. Cancer cells without detectable 
genetic alterations in MAPK pathway molecules (designated as wild type) were chosen as control. 
HH2710 effectively inhibits the proliferation of cancer cells with BRAF or KRAS activating 
mutation, though the potency towards different cell lines are variable. Wild type cells in general 
showed much less sensitivity to HH2710, with IC50 > 10 μM.  
In vivo pharmacodynamics study 
HH2710 inhibits the tumor growth in xenograft models via targeting ERK1/2. 
The anti-tumor efficacy of HH2710 in vivo was examined in three human xenograft models Colo-
205 (BRAF-V600E) colon carcinoma, A375 (BRAF-V600E) melanoma, and MiaPaCa-2 (KRAS-
G12C) pancreatic cancer. In Colo-205 model, HH2710 showed significant antitumor activity at 
the dosage of 15, 30 and 60 mg/kg (twice per day, given orally) with the relative tumor volume at 
the endpoint (T/C value) of 45.47%, 29.31% and 21.32% respectively. In this model, HH2710 at 
30 mg/kg was more effective than with the same dose of BVD-523 in controlling tumor growth. 
The similar tumor growth inhibitory effect of HH2710 was also observed on the other two 
xenograft models. HH2710 at dosage of 25-100 mg/kg (twice per day, given orally) caused a dose-
dependent suppression of tumor growth with no obvious toxicity observed. Remarkable growth 
inhibition was observed at the dosage of 100 mg/kg, yielding the T/C values were 17.11-18.82% 
(A375) and 24.90-36.75% (MiaPaCa-2), respectively. Along with the tumor growth inhibition, the 
intra-tumoral level of RSK phosphorylation was dose-dependently decreased compared with the 
vehicle growth, indicating the diminished ERK signaling in tumor tissues.  
We also evaluated the in vivo efficacy of HH2710 on single dose daily. The results indicated that 
HH2710, under the same total daily dosage, exhibited comparable efficacy on single dose to that 
of dose twice per day in two tested models, suggesting a potential advantage in reducing dosing 
frequency compared with the leading compound BVD-523.  
In summary, HH2710 specifically inhibits the activity of ERK1/2 kinase, yielding significant anti-
tumor activity in different types of tumors with MAPK pathway activation. The antitumor activity 
in vivo is improved compared with the clinical leading compound BVD523. 
1.2.1.1.3 
Safety and toxicity studies 
In conclusion, under the conditions of this study, after a single dose of HH2710 30, 100 or 300 
mg/kg via oral gavage in SD (Sprague Dawley) rats, the test article was well-tolerated both in 
female and male animals, and the Maximum Tolerated Dose (MTD) was greater than 300 mg/kg. 
After Beagle dogs were given a single dose of HH2710 100, 300 or 1000 mg/kg via oral gavage, 
the test article was tolerated in all dose groups, vomit and soft/fluid feces were mainly observed 


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post-dose, no abnormal change was found by gross observation during necropsy, and the maximum 
tolerated dose (MTD) was greater than 1000 mg/kg. 
After SD rats were given 15, 50 and 150/100 mg/kg/day HH2710 via oral gavage, once daily, for 
28 consecutive days, death occurred in the animals administered with the test article at 150 
mg/kg/day since Day 5 and animals could tolerate when the dose was adjusted to 100 mg/kg/day 
from Day 9; the highest non-severe toxic dose (HNSTD) in females and males was 50 mg/kg/day 
(on Day 28, the mean AUC0-t of HH2710 in females and males were 93500 ng·h/mL and 71500 
ng·h/mL, respectively; and the mean AUC
0-t of its major metabolite HH3529 in females and males 
were 52100 ng·h/mL  and 63400 ng·h/mL, respectively), and the main target organs of toxicity 
were considered to be immune tissue/organ, kidney, liver, heart, lung, kidney, femur, adrenal gland, 
pancreas and reproductive organs, in addition,, multiple organs/tissues (parenchyma/ vascular) 
mineralization was also noted. At the end of recovery phase, all the changes except tissue 
mineralization recovered or showed a recovery trend. After Beagle dogs were given 5, 15 and 
60/30 mg/kg/day HH2710 via oral gavage, once daily, for 28 consecutive days, the dose of 60 
mg/kg/day HH2710 was not tolerated by the animals and hence the dose was adjusted to 30 
mg/kg/day, which was tolerated by most animals; the highest non-severe toxic dose (HNSTD) in 
male and female animals was 15 mg/kg/day (on Day 28, the mean AUC0-t of HH2710 in female 
animals and male animals were 35200 ng·h/mL and 27100 ng·h/mL and the mean AUC
0-t of its 
major metabolite HH3529 in female animals and male animals were 649 ng·h/mL  and 487 
ng·h/mL, respectively), and the main target organs of toxicity were considered to be hemato-
lymphoid tissues/organs, epithelial mucosal tissues, lungs, kidneys, heart, liver, male reproductive 
system, pancreas, gallbladder and adrenal glands, and the above changes in these tissues/organs 
were restored by the end of recovery phase.  
After the SD rats were given a single dose of the vehicle or HH2710 (15, 50 and 100 mg/kg) via 
oral gavage, no significant drug-related changes were noted in the tidal volume (TV), respiratory 
minute volume (MV) or respiratory frequency (Rf) of animals in the HH2710 dose groups at each 
time point, and no significant impact on the central nervous system was observed. 
After conscious Beagle dogs were given a single dose of HH2710 (5, 20 and 100 mg/kg) via oral 
gavage, increased heart rate (HR),  decreased PR interval and decreased QT interval without 
changes in corrected QT (QTcR) in both genders, decreased of systolic blood pressure (SBP), 
diastolic blood pressure (DBP) and mean blood pressure (MBP) in the males and decreased of SBP 
in the females were found at 100 mg/kg. All these changes were resolved within the observation 
period. And a slightly decreased of body temperature was temporarily noted at 3 hrs post-dose in 
the males of 100 and 20 mg/kg groups.  No test article-related arrhythmia was observed in all 
animals. 
In Ames test, HH2710 is not mutagenic to Salmonella typhimurium. In chromosomal aberration 
test, HH2710 did not induce chromosome aberrations in cultured CHL cells. In bone marrow 


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micronucleus test, HH2710 could not induce an increase in the micronucleated polychromatic 
erythrocyte of rat bone marrow. 
In the human ether-a-go-go-related gene (hERG) study, in human embryonic kidney cell lines 
(hERG-HEK293) steadily expressing hERG channels, the hERG current inhibition rate by 
HH2710 at 0.3, 1, 3, 10 and 30 µmol/L was 1.1%, 6.9%, 17.8%, 41.1% and 73.2%, respectiv ely; 
and the IC50 value was 12.8 μmol/L. 
1.2.1.2 Clinical experience 
This is a first-in-human Phase I/II study. As of cutoff date 18 Jan 2022, 22 patients were enrolled 
in the dose escalation stage of 6 dose levels as 25mg BID (n=3), 50mg BID (n=3), 100mg BID 
(n=4), 400mg QD (n=4), 600mg QD(n=4), and 800mg QD (n=4), 4 patients were enrolled in the 
600mg QD expansion cohort     
Based on the safety data at 6 dose levels, HH2710 was well tolerated from 25 mg BID to 400 mg 
QD. However, 1  of 4 patients at 800 mg dose cohort experienced DLT (Grade 3 Acneiform rash). 
3 of 26 patients developed Grade 1-2 eye toxicity, 2 patients were from the 600mg dose group, 
and 1 from 800mg dose,  the AE outcome is following and drug-related factor may have 
contributed. 
1.2.1.3 Biomarker strategy 
1.2.1.3.1 
Genetic Biomarkers for molecular screening 
The alteration status of the MAPK signal pathway genes, such as RAS, RAF, MEK and ERK, will 
be used as genetic biomarkers for molecular screening to assess the eligibility of patient enrollment. 
For the Phase I dose escalation, the biomarker information will not be used as the criterial for 
enrollment, and the information will be collected and documented if available. For the Phase I 
dose expansion stages, the biomarker information will be collected and documented if available, 
where the test results of these biomarker from local laboratories will be used as one of the inclusion 
criteria for enrollment, and if the archival/fresh tumor tissue samples are available with signed 
consent, these samples will be collected for central testing in the future studies. For Phase II, the 
gene alteration status will be assessed through central testing, and in the case where the gene 
alteration status already known from local laboratories prior to central testing, the archival/fresh 
tumor tissue samples will be collected for central testing under signed consent. 
1.2.1.3.2 
Potential pharmacodynamics (PD) biomarker 
In order to determine the on-target inhibition effect of ERK by HH2710, the phosphorylation of 
RSK (pRSK) and total RSK will be measured using blood samples from selected patients of  Phase 
I stage. 


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1.2.2 Known potential risk 
Based on mechanism of action, nonclinical study data, clinical safety data, and the same class drug 
safety profile of HH2710, hematological toxicity, hepatoxicity, nephrotoxicity, cardiotoxicity, 
interstitial lung disease and pancreatic toxicity are assessed as important potential risks. 
Hematological toxicity  
Hematological parameters changes were observed in 28-day repeat-dose toxicity study of HH2710 
in dog. In HH2710 clinical data, the most common Hematological toxicity events were anemia, 
followed by leukopenia, neutropenia, and thrombocytopenia, and most of the adverse events were 
CTCAe1/2 grade. 
Hepatoxicity 
In 28-day repeat-dose toxicity study of HH2710 in rat, clinical pathology changes at  15 mg/kg/day, 
50 mg/kg/day and 150/100 mg/kg/day dose level included increase in ALT, AST in both males 
and females. In HH2710 clinical data, the common hepatotoxic events were AST, ALT, ALP and 
GGT increased, and most of the hepatotoxic events were CTCAE grade 1/2.  
Nephrotoxicity 
In 28-day repeat-dose toxicity study of HH2710 in rat, clinical pathology changes at 50 mg/kg/day 
dose level on Day 29 included increase in CREA in males, and clinical pathology changes at 
150/100 mg/kg/day dose level included increase in CREA in both gender on Day 29. No significant 
nephrotoxicity was observed in current clinical data. 
Cardiotoxicity 
The preclinical evidence suggests that following a single dose of HH2710 in conscious beagle 
dogs at 100 mg/kg, HH2710 could increase HR, decrease PR interval and QT interval without 
changing the corrected QT (QTcR) in both genders; and also decrease systolic arterial blood 
pressure (SBP), diastolic arterial blood pressure and mean atrial blood pressure in the males and 
decrease SBP in the females. The above changes can be recovered within the observation period 
of 25 hr. No significant cardiotoxicity was observed in current clinical data.  
Interstitial lung disease 
The preclinical evidence suggests chronic inflammation and alveolar macrophage aggregation in 
lungs were observed following HH2710 treatment at >=15 mg/kg/day dose level in 28-day repeat-
dose toxicity study in rat. Interstitial lung disease cases were observed but causal relationship with 
study drug could not been figured out. 
Pancreatic toxicity 
In 28-day repeat-dose toxicity study in SD rats and Beagle dog, pancreas was one of the main 
target organs. No significant pancreatic toxicity was observed in current clinical data.  


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Besides ophthalmic toxicity and dermal toxicity also need to be monitored. 
Inclusion and exclusion criteria and discontinuation criteria have been included in the protocol to 
minimize the risks described above. 
HH2710 selectively inhibited ERK1 (MAPK1) and ERK2 (MAPK2). HH2710 potently inhibits 
growth of cultured cancer cell lines and xenograft models; melanoma, colorectal and pancreatic 
lines harboring BRAF, or RAS mutations are among those most susceptible to the drug. Overall, 
the observed safety of HH2710 is consistent with its mechanism of action and observations in non-
clinical studies and is like that of other MAPK pathway mutation inhibitors. Safety data and risk 
characteristics will be continuously monitored, and safety risks will continue to be controlled 
reasonably and effectively. 
2 Rationale 
2.1 
Study rationale and purpose 
HH2710 is developed by Haihe Biopharma Co., Ltd. HH2710 is a highly potent, selective, 
reversible, ATP-competitive ERK1/2 inhibitor.  
Most of the current oncology drug discovery and development work has shifted towards 
molecularly targeted therapies. A key focus has been on identifying inhibitors against components 
of pathways that drive tumor cell proliferation, survival, and metastasis such as MAPK pathway. 
MAPK signaling pathway plays a critical role in tumorigenesis through the RAS–RAF–MEK–
ERK kinase cascade. ERK1/2, as the terminal master kinase of this MAPK pathway, influences 
cellular proliferation, differentiation, and survival through a variety of mechanisms [55]. Genetic 
alterations of MAPK pathway components are common in many cancer types. 
The rationale for development of an ERK inhibitor in patients with MAPK pathway genetic 
alteration cancer would be that MAPK pathway genetic alteration activates the MAPK pathway, 
ERK is a key kinase of MAPK, ERK inhibition may be able to overcome some of resistance to 
upstream target drug therapy. Targeting the downstream MAPK kinase, ERK, could possibly 
evoke a unique and desirable balance of durable efficacy and suitable tolerability. Therefore, 
downstream inhibition of ERK is a promising therapeutic method to explore. The purpose of the 
study will therefore be to assess the anti-tumor activity of the ERK inhibitor in patients with MAPK 
pathway genetic alteration. 
Based on the results from preclinical research HH2710 effectively inhibits proliferation and colony 
formation of a variety of tumor cell lines and the growth of tumors in a variety of mouse xenograft 
models (See Section 1.2.1). As such, HH2710 may represent a valuable addition to the current 
drugs useful for treating patients whose cancers exhibit the aberrant MAPK pathway activity. 
Therefore, development of HH2710 might address important unmet medical needs. 
 


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2.2 
Rationale for the study design 
This is a first-in-human study of HH2710 and is designed as an open-label, multicenter, Phase I/II 
study which is composed of a Phase I dose escalation and dose expansion stage and a Phase II dose 
extension stage.  
Phase I: In Phase I dose escalation stage, the Bayesian optimal interval (BOIN) design 
incorporated with an accelerated titration designs (ATD) will be used to assess the safety and 
tolerability, and furthermore, to help find the maximum tolerated dose (MTD), and/or to establish 
the recommended phase 2 dose (RP2D) combined with data from other sources. The advantage of 
the ATD is to reduce the number of patients exposed to an ineffective dose, ensuring that patients 
can receive a higher and more effective dose. The rationale of employing the BOIN design 
[56][55][57] to find the MTD is that the BOIN design is implemented in a simple way similar to 
the traditional “3+3” design, but is more flexible and effective compared to those of the complex 
model-based designs, such as the continual reassessment method (CRM)[58]. 
In Phase I dose expansion stage, based on the FDA guidance "Expansion Cohorts: Use in First-In-
Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics Guidance for 
Industry", additional up to 15 patients per cohort may be included in order to further explore the 
safety, PK and anti-tumor activity among biomarker-selected patients. One or more dose levels 
may be expanded based on the available data. 
Phase II: Dose extension stage: This stage is an open-label, dose extension study at RP2D to 
explore the anti-tumor response of patients with particular tumor types and/or cancers harboring 
MAPK genetic alteration. Because data on drugs targeting the upstream signaling molecules of the 
MAPK signaling pathway and clinical trial data for drugs targeting ERK (BVD523) suggest that 
melanoma, non-small cell lung cancer (NSCLC), Langerhans Cell Histiocytosis Syndrome (LCH)/ 
Erdheim-Chester disease (ECD), and thyroid cancer have certain effects [7][39][59]. Therefore, 
we prefer to focus on these cancers first and explore them separately. We monitor the efficacy 
endpoint using the Bayesian optimal phase 2 (BOP2) design [60] to avoid the treatment is 
inefficacious. Other tumor types with MAPK pathway alteration will be explored on efficacy once 
these tumor types find to be responsive to an efficacy signal. 
The correlation of biomarker of this target and efficacy is not clear yet so we adopt adaptive design 
to screening for biomarker and population. See Section 4.2. 
Clinical studies showed that the dose level identified using the “3+3” design often inaccurate, let 
patients receive either a sub-therapeutic or an overly toxic treatment. This results in a higher failure 
rate for the investigational drug in the later Phase I/II, II or III trial. To overcome this shortcoming, 
we used the novel Bayesian Optimal Interval design (BOIN) to search for the maximum tolerated 
dose of HH2710. The BOIN design is a model-assisted design where it minimizes the decision 
error during the dose escalation/de-escalation. Then, an isotonic regression is used to estimate the 
MTD that is closest to the pre-determined target toxicity rate. Several simulation studies showed 


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that BOIN design possesses a higher accuracy as the CRM design and at the same time, minimizes 
the chances of exposing patients to the sub-therapeutic and overly toxic environments. Moreover, 
BOIN design is more transparent and easier to implement in practice, similar to the “3+3” design.  
In Phase II, the go/no-go decision is made by evaluating a set of posterior probabilities of the 
events of interest at each interim, which is optimized to maximize power or minimize the number 
of patients under the null hypothesis. The proposed design explicitly controls the type I error rate, 
thereby bridging the gap between Bayesian design and frequentist designs. In addition, the 
stopping boundary of the proposed design can be enumerated prior to the onset of the study. These 
features make the method design accessible to a wide range of users and regulatory agencies, and 
particularly easy to implement in practice. Simulation studies show that it has favorable operating 
characteristics with higher power and lower risk of incorrectly terminating the study than some 
existing designs. 
2.3 
Rationale for dose and regimen selection 
Starting dose, dose escalation, the cohort size for dose expansion and extension are based upon 
accepted methodology for oncology Phase I/II study design. The 21-day dose limiting toxicities 
(DLT) assessment period was selected as the major toxicities leading to cessation of dose 
escalation in such studies (hematological, gastrointestinal, liver enzymes) are anticipated to present 
within this duration. 
The selection of the starting dose is based on the following consideration: 1) the PK-PD 
relationship established in human tumor xenograft mouse models, 2) the estimated human 
exposure of HH2710 obtained by allometric scaling modeling of dog and rat PK parameters, 3) 
and the toxicology studies data in rat and dog. 
The starting dose for the Phase I study of HH2710 in patients with advanced tumors were 
calculated in accordance with the International Conference on Harmonization (ICH S9) guidance 
“Nonclinical Evaluation for Anticancer Pharmaceuticals”. The guidance recommends the starting 
dose should be based on either 1/10 of the severely toxic dose in 1/10 of animals (STD10) in rodent 
toxicity study or 1/6 of the HNSTD observed in non-rodent studies. 
The starting dose for HH2710 in the first-in-human study was derived from 28-day GLP toxicology 
studies performed in rodent and non-rodent species and calculated as described by Senderowicz [61]. 
HH2710 safety profile was investigated in 4-week GLP toxicology studies in SD rats (15, 50 and 
150/100 mg/kg/day) and Beagle dog (5, 15 and 60/30 mg/kg/day).  
The rodent (SD rat) STD10 was considered to be between 50 and 100 mg/kg/day. Therefore 50 
mg/kg/day has been used in this calculation. Converting this dose to a human equivalent dose (HED), 
and applying a 10-fold safety factor, translates to a safe starting dose of 48.6 mg/day.  
The HNSTD in Beagle dog was 15 mg/kg/day. Converting this dose to a HED and applying the 6-
fold safety margin, a safe starting dose of 81.15 mg/day was calculated.  


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In considerate of the dosing convenience, the proposed starting dose for the first Phase I/II clinical 
study with HH2710 in cancer patients (HH2710-G101) was 50 mg/day [62]. It is reasonable to 
administer twice daily (BID) that is 25mg twice daily.  
The modeling was established based on 1) the results of human PK parameters predicted by HH2710 
preclinical PK data, 2) the PK-PD relationship established in human tumor xenograft mouse models, 
3) the estimated human exposure of HH2710 obtained by allometric scaling modeling of dog and 
rat PK parameters, 4) and the toxicology studies data in rat and dog. 
According to the effect of HH2710 and BVD523 on the anti-tumor effect of BRAF-mutant COLO 
205 cells in vitro and the modeling result, the concentration of HH2710 and BVD523 was inhibited 
by the corresponding concentration of COLO 205 cells, the relationship between PK/PD was 
established and the human onset effective dose was predicted to be 314mg BID. The preclinical in 
vivo pharmacodynamics test of HH2710 showed that the effective dose of tumor suppressive effect 
in nude mice was 60mg/kg BID, and the human equivalent dose (HED) was: HED = 60 
mg/kg*(3/37) *60kg ≈ 292mgBID. By comprehensive consideration, the onset effective dose in 
human is 300mg BID. 
The 28-day repeated toxicological experiments in HH2710 preclinical animals showed that species 
sensitivity of HH2710 is similar in Beagle dogs and rats. It is preliminarily assumed that HNSTD 
is a critical toxic dose with ≥2 adverse events (AE) occurred, and the metabolic characteristics in 
humans are similar to those in Beagle dogs and rats. The HNSTD of HH2710 in rats and Beagle 
dogs was determined to be 50 mg/kg/day and 15 mg/kg/day, respectively, and converted to human 
equivalent dose (HED), both of which were 487 mg/day. It is expected that the study drug-related 
≥Grade 2 AE will begin to appear in the 487 mg/day.  
According to toxicity study results and modeling analysis, HH2710 had lower toxic exposure in 
Beagle dogs, thus the dose of 903 mg/day in human was selected as the critical toxic dose. 
The effective dose in human is 300mg twice daily (BID), the critical toxic dose is 450 mg/day or 
350mg ~ 450 mg twice daily (BID). When the critical toxic dose is reaching, the safety of patients 
must be closely monitored. For a detailed description of all methodologies used, please refer to the 
Haihe HH2710 Dosing Documents. 
According to the non-clinical data and the modeling results, the preliminary plan of dose escalation 
including different doses to determine the safety, tolerability, PK/PD of HH2710. Dosing 
frequency and dose level may be adjusted after Safety Monitoring Committee (SMC) discussion 
during the study base on available  safety, PK/PD and preliminary efficacy data. To date 18-Jan, 
2022, 22 patients were enrolled in the dose escalation stage of 6 dose levels as 25mg BID (n=3), 
50mg BID (n=3), 100mg BID (n=4), 400mg QD (n=4), 600mg QD (n=4), and 800mg QD (n=4), 
4 patients were enrolled in the 600mg QD expansion cohort. PK data from 22 enrolled patients 
showed HH2710 was slowly eliminated after oral administration, the accumulation of the systemic 
exposure of HH2710 at steady state was about 3-4 folds. The half-life (t1/2) of HH2710 ranged 
from 8.42 to 10.9 hrs, suitable for once daily dosing. The HH2710 systemic exposure showed a 


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dose-related increase from 25mg BID to 800mg QD. No apparent dose- or time-dependence of PK 
was observed upon single and multiple dose administration.  Based on the available PK and safety 
data, the sponsor decided to suspend 800mg QD escalation cohort and 600mg QD expansion 
cohort.  
To determine the recommended phase II dose (RP2D), the sponsor plans to further evaluate the 
tolerability, biological activity, PK/PD, and preliminary efficacy of HH2710 at more dose levels 
with different dosing frequencies (QD or BID). In addition to the current QD dosing cohorts 
(designated as Part A), sponsor may add BID dosing cohorts in Part B  based on available evidence. 
Part B will start from 200mg BID dose level. During the study, the Sponsor and Investigators may 
request that one or several dose level cohorts to be expanded to get more PK/PD and safety data, 
or that insert an intermediate dose between 2 adjacent planned escalation doses to be explored. 
Such requests will be discussed with the Investigator(s), Sponsor and Medical Monitor, and should 
be based on all data available at that time, including safety and clinical activity, determinations of 
pharmacokinetics, pharmacodynamics, and cumulative toxicity.  
 
 


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3 Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 
Table 3-1 Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer 
to 
Section 10.5 
Phase I :  
- 
To evaluate the safety and 
tolerability 
of 
HH2710 
administered 
orally 
in 
patients 
with 
advanced 
tumors; 
- 
To identify the Maximum 
Tolerated 
Dose 
(MTD) 
and/or Recommended Phase 
II dose (RP2D). 
Phase I:  
- Safety and Tolerability: The incidence, type, and 
severity of adverse events (AEs) assessed 
according to the National Cancer Institute-
Common Terminology Criteria for Adverse 
Events 
(NCI-CTCAE) 
V5.0, 
physical 
examination findings, clinical laboratory values, 
vital signs and Electrocardiograms (ECGs); 
- The MTD, if any, and RP2D for HH2710 will be 
determined based on safety, tolerability, PK, 
preliminary efficacy, and other available data. 
 
Phase II:  
- 
To 
evaluate 
efficacy 
of 
HH2710 in patients with 
advanced tumors with MAPK 
signaling pathway genetic 
alterations, 
at 
the 
recommended phase 2 dose 
(RP2D). 
Phase II： 
- Tumor objective response rate (ORR) based on 
RECIST v1.1. 
 
 Secondary 
 
Refer 
to 
Section 10.5 
Phase I: 
- 
To 
characterize 
the 
pharmacokinetic profiles of 
HH2710 
and 
selected 
metabolites 
when 
administered 
orally 
in 
patients 
with 
advanced 
tumors. 
Phase I:  
- Peak plasma concentration (Cmax), peak time 
(tmax), area under the plasma concentration-
time curve from time 0 to time (t) (AUC0-t), 
plasma elimination half-life (t1/2), plasma 
clearance rate constant (λz), apparent clearance 
(CL/F), apparent volume of distribution (Vz/F). 
 


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Objective 
Endpoint 
Analysis 
Phase II 
- 
To evaluate the efficacy of 
HH2710 in advanced tumor 
patients 
with 
MAPK 
signaling pathway genetic 
alterations; 
- 
To evaluate the safety of 
HH2710. 
Phase II 
- Efficacy: The duration of response (DoR), 
progression-free survival (PFS), disease control 
rate (DCR), time to response (TTR), time to 
progression (TTP), and 1-year overall survival 
(OS) rate; 
- Safety: The incidence, type, and severity of 
adverse events (AEs) assessed according to the 
National 
Cancer 
Institute-Common 
Terminology Criteria for Adverse Events (NCI-
CTCAE) V5.0, physical examination findings, 
clinical laboratory values, vital signs and 
Electrocardiograms (ECGs). 
 
Exploratory 
 
Refer 
to 
Section 10.6  
Phase I:  
- 
To assess the preliminary 
efficacy of HH2710; 
- 
To explore the changes of the 
pharmacodynamics 
(PD) 
markers of HH2710.  
Phase I:  
- ORR, DoR, DCR, PFS and TTR; 
- Changes in PD markers of HH2710 efficacy 
including phosphorylation of RSK (pRSK) and 
total RSK.  
 


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4 Study design 
4.1 
Description of study design 
This is an open-label, multicenter, first-in-human Phase I/II study which is composed of a Phase I 
dose escalation stage, phase I dose expansion stage and a Phase II dose extension stage. HH2710 
will be administered orally on a continuous twice daily (BID) schedule, 21 days as a “Cycle” 
Phase I: Dose escalation 
The accelerated titration (ATD) incorporated with Bayesian optimal interval (BOIN) design will 
be used to assess the safety and tolerability, and furthermore, to help find the maximum tolerated 
dose (MTD), and/or to establish the recommended phase 2 dose (RP2D) combined with data from 
other sources. 
A maximum sample size is 58 patients for the dose escalation (ATD + BOIN). The total number 
of patients will depend upon the number of dose escalations actually needed. 
Accelerated titration part: 
One patient per cohort will be assigned to receive HH2710. The first three patients will take 
HH2710 once daily (QD) in cycle 1 day 1 for the single dose PK testing, from the second day, 
HH2710 will be administered orally on a continuous twice daily (BID). 
The proposed dose level in accelerated titration stage is 25mg, 50mg and 100 mg twice daily (BID). 
It may be adjusted according to the available data. Because one subject at 25mg had adverse event 
grade≥2, the dose escalation process was shift to a BOIN design at 25mg dose level. 
BOIN design part:  
When there is an adverse event of grade≥2 occurs, the dose escalation process will shift to a BOIN 
design, in which at least 3 patients per treatment cohort will be assigned (ATD + BOIN design 
details please see Section 6.2.3) 
Part A (25/50/100 mg BID + QD dose escalation cohorts): 
To date 18 Jan 2022, 22 patients were enrolled in the dose escalation stage of 6 dose levels as 
25mg BID (n=3), 50mg BID (n=3), 100mg BID (n=4), 400mg QD (n=4), 600mg QD(n=4), and 
800mg QD (n=4), 4 patients were enrolled in the 600mg QD expansion cohort PK data from 22 
enrolled patients showed HH2710 was slowly eliminated after oral administration, the 
accumulation of the systemic exposure of HH2710 at steady state was about 3-4 fold. The half-life 
(t1/2) of HH2710 ranged from 8.42 to 10.9 hr, suitable for once daily dosing.   
Based on the safety data at 6 dose levels, HH2710 was well tolerated from 25 mg BID to 400 mg 
QD. However, 1  of 4 patients at 800 mg dose cohort experienced DLT (Grade 3 Acneiform rash). 
3 of 26 patients developed Grade 1-2 eye toxicity, 2 patients were from the 600mg dose group, 


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and 1 from 800mg dose. Since the drug-related factor may have contributed, we have de-escalated 
to 300mg QD dose.  And further dosing frequency and dose level may be adjusted based on 
available safety and PK data.  
Part B (Additional BID dose escalation cohorts ): 
In order to determine the RP2D, additional BID dosing cohorts may also be evaluated  based on 
available clinical data using BOIN design starting from 200mg BID dose and the total sample size 
in Part B is up to approximately 18 subjects. After the escalation is completed, select the MTD 
based on the isotonic regression as specified in [64]. Specifically, select the MTD for which the 
isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, select the 
higher dose level when the isotonic estimate is lower than the target toxicity rate and select the 
lower dose level when the isotonic estimate is greater than or equal to the target toxicity rate. 
Dose expansion stage: 
Additional up to 15 patients per cohort may be included in order to further explore the safety, PK 
and anti-tumor activities among biomarker-selected patients. The dose for provisional cohort of 
expansion phase will be based on available safety, PK/PD and preliminary efficacy data. Patients 
enrolled could have different cancer types but must be confirmed with specific MAPK pathway 
genetic alteration (the same requirement as in phase II). The total number of patients will depend 
upon the number of dose expansions necessary. 
 
Phase II Dose extension: 
This is an open-label, multicenter, dose extension stage at RP2D to explore the response of patients 
with particular tumor types harboring MAPK genetic alteration. A maximum of 108 patients will 
be enrolled. 
Patients enrolled will be divided into four cohorts once RP2D is defined and each of them focuses 
on specific tumors with specific genetic alteration, which NGS (next generation sequencing) will 
be used to detect, described as follows:  
- Cohort 1: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, NRAS Q61, 
BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated melanoma; 
- Cohort 2: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, NRAS Q61, 
BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated non-small cell lung cancer; 
- Cohort 3: Patients with BRAF V600 mutated Langerhans Cell Histiocytosis Syndrome (LCH)/ 
Erdheim-Chester disease (ECD); 
- Cohort 4: Patients with RAS/RAF/MEK/ERK mutated tumors that are not included in other 
cohorts. 
The sample size in Cohort 1 and Cohort 2 is justified according to the Bayesian optimal phase 2 
(BOP2) design [60]. Specifically, let 𝑛 denote the interim sample size and 𝑁 denote the maximum 


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Protocol No. HH2710-G101 
sample size. Let 𝑝𝑒𝑓𝑓 denote the probability of efficacy (response rate) and define the null 
hypothesis𝐻0: 𝑝𝑒𝑓𝑓≤0.05, representing that the treatment is inefficacious. We will stop enrolling 
patients and claim that the treatment is not promising if 
- 
𝑃𝑟(𝑝𝑒𝑓𝑓> 0.05|𝑑𝑎𝑡𝑎) < 𝜆(
𝑛
𝑁)𝛼, 
where 𝜆=0.75 and 𝛼=0.2 are design parameters optimized to minimize the chance of incorrectly 
claiming that an efficacious treatment is not promising (i.e., type II error) under the alternative 
hypothesis 𝐻1: 𝑝𝑒𝑓𝑓= 0.16, while controlling the type I error rate at 0.1 (i.e., the chance of 
incorrectly claiming that an inefficacious treatment is promising is no more than 10%). Assuming 
a Beta (0.05,0.95) prior distribution for 𝑝𝑒𝑓𝑓, the above decision rule corresponds to the following 
stopping boundaries and yields a statistical power of 0.8201 under 𝐻1: 
Table 4-1 Optimized stopping boundaries for cohort 1 and cohort 2 in Phase II 
# patients treated 
Stop if # responses <= 
23 
1 
36 
3 
Based on Table 10-1, we will perform an interim analysis for the first 23 patients. When at least 
2 patients experience CR or PR or SD(SD≥6m) events, the study will continue recruiting up to 13 
more patients in the second stage. When the total number of patients reaches the maximum sample 
size of 36, we reject the null hypothesis and conclude that the treatment is promising if the number 
of responses is greater than 3; otherwise we conclude that the treatment is not promising. An 
internal data review committee will use information collected from patients in the first stage to 
determine whether additional recruitment should be continued and if continued, whether 
biomarkers and/or indications need to be adjusted and whether amendment(s) to the protocol 
should be implemented for a better assessment of anti-tumor response.  
The planned sample size for cohort 3 and cohort 4 are 9 patients and 27 patients, respectively. For 
detailed information on the sample size of the study, please refer to Section 10.4. of this protocol. 
Figure 4-1 Study Flow Chart 
 


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4.2 
Timing of interim analyses and design adaptations 
There are three planned interim analyses during the study. One is performed for the determination 
of RP2D when Phase I completes. The other two are conducted for futility evaluation for the first 
23 patients in each of cohort 1 and cohort 2 when these patients have completed the assessment. 
Any additional interim analyses can be conducted as requested by the sponsor for safety and/or 
efficacy monitoring while the study is ongoing. 
A sponsor-led data review committee will be used during the study. In Phase I, safety data will be 
reviewed by the committee after a minimum of 3 patients have been enrolled into each dose level 
and received treatment. Once the dose escalation stage completes, the committee will review safety 
data as well as data from other sources (e.g. efficacy, PK/PD) to determine the RP2D for Phase II.   
In Phase II, the efficacy review will be conducted for each cohort by the committee when cohort 
1 and cohort 2 have recruited and completed the assessment for the first 23 patients. For safety, 
the committee will review data when every 6 or 12 patients who have recruited and received 
treatments in all cohorts. Following the data review, the committee will decide as to whether the 
cohort may continue, whether amendment(s) to the protocol should be implemented, or whether 
the study should be stopped. The proposed interim analysis sketch map for cohort 1 and 2 is shown 
below in 错误!未找到引用源。2. 
Figure 4-2 the proposed interim analysis sketch map for cohort 1 and 2 


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Notes: SD≥6 months 
4.3 
Definition of end of the study 
The study will end when the treatment period, safety follow-up, disease follow-up and survival 
follow-up have completed for all patients as described in Section 7.1. 
Completion of the survival follow-up period will occur once a minimum of 80% of patients in the 
Phase II stage have died, have been lost to follow-up, or have been followed for survival for 
minimum 12 months after the first dose of study treatment, see Section 7.1. 
The disease and survival follow-up evaluations might not be completed in case Haihe decides to 
stop enrollment prematurely. In such cases, end of study will be upon the Study Evaluation 
Completion (SEC) or the last patient treated, including the completion of the safety follow-up 
period. 
See Section 10.5 Statistical Methods and Data Analysis for details of timing of the primary 
analysis and final reporting of data. 
4.4 
Early study termination 
The study can be terminated at any time for any reason (such as safety or efficacy) by Haihe.  
Should this be necessary, the patient should be seen as soon as possible and the same assessments 
should be performed as described in Section 7.1.4.1 for a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing Institutional Review Boards (IRBs) and/or ethics committees (ECs) of 
the early termination of the study. 
Patients with BRAF/NRAS (mutation sites as follows: 
NRAS G13V, NRAS Q61, BRAF V600, BRAF G469A, 
L485W, L597Q, T599dup) mutated melanoma/NSCLC 
23 patients 
≤1PR/CR/SD  
Study concludes 
>1PR/CR/SD continue recruitment 
strategy 
Ensure candidate 
predictive markers is 
representative 
Biomarker adjustment if needed 
Expansion to about 36 patients 


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5 Population 
5.1 
Patient population 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
Phase I 
For the dose escalation stage, patients who have been diagnosed with histologically or 
cytologically documented, unresectable/metastatic tumors that are refractory or intolerant to 
standard therapy or for whom no curative standard therapy exists.  
- For LCH/ECD: Eligible patients must have multifocal disease and the diagnosis must be 
confirmed by pathological evaluation of the affected tissue.  
For the dose expansion stage, patients must have been diagnosed with histologically or 
cytologically documented, unresectable/metastatic tumors harboring MAPK pathway genetic 
alterations. Patients with a BRAF V600 mutation must have progressed on or after standard 
therapy, including BRAF and/or MEK inhibitors (≤3 lines). .  
Phase II 
Patients must have been diagnosed with histologically or cytologically documented, 
unresectable/metastatic tumors harboring MAPK pathway genetic alterations. Patients with a 
BRAF V600 mutation must have progressed on or after standard therapy, including BRAF and/or 
MEK inhibitors (≤3 lines). Patients will be enrolled in Cohorts 1-4 depending upon their tumor 
type.  
In some cases, re-screening is allowed, details refer to Section 7.1.2. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
1. Provide signed and dated informed consent prior to initiation of any study-related 
procedures; 
2. Male or female patients aged ≥ 18 years; 
3. Phase I dose escalation stage: Patients who have been diagnosed with histologically or 
cytological documented, unresectable/metastatic tumors that are refractory or intolerant to 
standard therapy or for whom no curative standard therapy exists.   
- 
For LCH/ECD: Eligible patients must have multifocal disease and the diagnosis must 
be confirmed by pathological evaluation of the affected tissue.  
4. For Phase I expansion stage and Phase II stage: Histologically or cytologically documented 
unresectable/metastatic tumors with evidence of genetic mutations affecting MAPK 


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pathway is required. Patients with a BRAF V600 mutation must have progressed on or after 
standard therapy, including BRAF and/or MEK inhibitors (≤3 lines). Patients entering the 
Phase 2 portion of the trial will be enrolled in Cohorts 1-4 depending upon their tumor 
types.   
- 
Cohort 1: Patients with BRAF/NRAS (mutation sites including: NRAS G13V, NRAS 
Q61, BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated melanoma; 
- 
Cohort 2: Patients with BRAF/NRAS (mutation sites including: NRAS G13V, NRAS 
Q61, BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated non-small cell 
lung cancer; 
- 
Cohort 3: Patients with BRAF V600 mutated Langerhans Cell Histiocytosis 
Syndrome (LCH)/ Erdheim-Chester disease (ECD); 
- 
For LCH/ECD: Eligible patients must have multifocal disease and the 
diagnosis must be confirmed by pathological evaluation of the affected 
tissue. 
- 
Cohort 4: Patients with RAS/RAF/MEK/ERK mutated tumor types that are not 
included in other cohorts. 
5. Patients in the Phase I dose escalation portion of the trial may have measurable (per 
RECIST v1.1) or evaluable disease. Patients in the Phase I dose expansion and Phase II 
portions of the trial must have measurable disease per RECIST v1.1. 
6. Eastern Cooperative Oncology Group (ECOG) performance status≤1.  
7. Predicted life expectancy ≥ 3 months; 
8. Adequate renal function defined as a creatinine clearance ≥ 60mL/min (using Cockcroft-
Gault formula, see Appendix 14.3)]; 
9. Adequate hepatic function [total bilirubin ≤ 1.5 x UNL; AST (aspartate aminotransferase) 
and ALT (alanine aminotransferase) ≤ 3 x UNL or ≤ 5 x UNL if due to liver involvement 
by tumor]; 
10. Adequate cardiac function, > institutional lower limit of normal e.g., left ventricular 
ejection fraction (LVEF) of ≥ 50% as assessed by ultrasound/echocardiography (ECHO) 
or multi-gated acquisition (MUGA); corrected QT interval (QTcF) < 460 ms (male 
patients), <470ms (female patients) (using QTc Fridericia's formula. See Appendix 14.6);  
11. Adequate bone marrow function ：patients must not have required blood transfusion or 
growth factor support ≤ 7 days before sample collection for the following ：, 
• 
absolute neutrophil count ≥ 1.5 × 109/L; 
• 
hemoglobin ≥ 9g/dL;  


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• 
platelet count ≥100 × 109/L; 
• 
International normalized ratio (INR) ≤ 1.5;  
• 
activated partial prothrombin time (APTT) ≤ 1.5 × ULN; 
12. Willing and able to participate in the trial and comply with all trial requirements; 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Gastrointestinal condition which could impair absorption of study medication; 
2. Congenital long QT syndrome, or any known history of torsade de pointes (TdP), or family 
history of unexplained sudden death; 
3. Clinically uncontrolled hypertension (after standard antihypertensive treatment, systolic 
blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg); 
4. Undergone a bone marrow or solid organ transplant; 
5. Any toxicities from prior treatment that have not recovered to ≤ CTCAE Grade 1 before 
the start of study drug, with the exception of hair loss or fatigue; 
6. Patients who have previously participated in clinical trials of ERK inhibitors drug; 
7. Allergic to similar drugs or their excipients; 
8. HIV(human immunodeficiency virus) infection, active hepatitis B or hepatitis C patients 
(HBsAg positive patients also detected HBV(hepatitis B virus) DNA ≥ 103 copies or ≥ 200 
IU/ml; HCV (hepatitis C virus) antibody test results are positive, and HCV RNA PCR test 
results are positive); 
9. Uncontrolled or severe intercurrent medical condition: 
- 
Unstable angina pectoris ≤3 months prior to starting study drug; 
- 
Acute myocardial infarction ≤3 months prior to starting study drug; 
10. Symptomatic CNS metastases that are neurologically unstable or requiring increasing 
doses of steroids to control CNS disease. Note: Controlled CNS metastases are allowed. 
Radiotherapy or surgery for CNS metastases must have been completed >2 weeks prior to 
study entry. No new neurologic deficits on clinical examination and no new findings on 
CNS imaging are permitted. Steroid use for management of CNS metastases must be at a 
stable dose for two weeks preceding study entry; 
11. Any cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or 
immunotherapy, Chinese medicine/Chinese patent medicine with anti-tumor effect,etc.) within 28 
days or 5 half-lives, whichever is shorter; 


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12. Major surgery within 4 weeks prior to first dose; 
13. Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) 
prior to the first dose of HH2710; 
14. Pregnant or breast-feeding women; 
15. Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral 
therapy, including tuberculosis infection, etc 
• 
Severe infections within 4 weeks prior to the first dose, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia.  
• 
Received therapeutic oral or IV antibiotics within 2 weeks prior to the first dose of study 
drug 
16. Any important medical illness or abnormal laboratory finding that would increase the risk 
of participating in this study; 
17. A history or current evidence/risk of retinal vein occlusion, central serous retinopathy or 
choroidneovascularization (CNV). 
18. Concurrent therapy with any other investigational agent; 
19. Concomitant malignancies or previous malignancies with less than 2 years disease-free 
interval at the time of enrollment; (But basal cell carcinoma skin cancer, cervical 
CIS(carcinoma in situ), CIS of the breast, localized or low Gleason grade prostate cancer, 
and < T2 bladder cancer can be included;  
20. Current treatment with agents including vitamins, supplements, and herbal supplements 
that are metabolized solely through CYP3A4(See Appendix 14.7);  
21. Severe chronic obstructive pulmonary disease, severe asthma, pneumoconiosis, asbestosis 
and other occupational lung diseases.  
22. A history of acute or chronic pancreatitis, surgery of the pancreas, or any risk factors that 
may increase the risk of pancreatitis; 
23. Contraception (See Appendix 4  
Women of child-bearing age and contraceptive 
measures): 
 Patients who do not meet the following conditions will be excluded, 
- For women: Negative pregnancy test for females of child-bearing potential; must be 
surgically sterile, postmenopausal (defined as no menstrual cycle for at least 12 
consecutive months), or compliant with an acceptable contraceptive regimen (2 highly 
effective forms, such as oral contraceptives, condom with spermicide, etc.) during and 
for 6 months after the treatment period. Abstinence is not considered an adequate 
contraceptive regimen; 
 


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- For men: Must be surgically sterile, or compliant with a contraceptive regimen (as 
above) during and for a minimum of 6 months after the treatment period. 
6 Treatment 
6.1 
Study treatment 
A treatment cycle is defined as 21 days for the purposes of scheduling procedures and evaluations. 
The investigational product in the study is shown as below: 
- 
Active ingredient: HH2710; 
- 
Strength: 25 mg capsule,100 mg capsule; 
- 
Excipients: include but not limit to Lactose, Silicified Microcrystalline Cellulose, Talc, 
Colloidal silicon Dioxide, Crospovidone, and Magnesium Stearate; 
- 
Storage temperature: 10-30 ºC , protected from light. 
6.1.1 Dosing regimen 
The dosing and treatment schedule, as shown in the below.  
Table 6-1 Proposed Dose and treatment schedule of Phase I  
Bayesian optimal interval (BOIN) design incorporated with an accelerated titration Schedule of HH2710 
Dose Level Dose of HH2710 
Patient 
Pharmaceutical form 
and route of 
administration 
Frequency and/or Regimen 
Level 1 
25mg 
3 
Capsules for oral use 
QD at C1D1, then BID from C1D2 (21 days/cycle) 
Level 2 
50mg 
3 
Capsules for oral use 
BID (21 days/cycle) 
Level 3 
100mg 
3+N# 
Capsules for oral use 
BID (21 days/cycle) 
Level 4 
300mg 
3+N# 
Capsules for oral use 
QD (21 days/cycle) 
Level 5 
400mg  
(Total daily dose*) 
3+N 
Capsules for oral use 
QD/BID (21 days/cycle) 
Level 6 
600mg  
(Total daily dose*) 
3+N 
Capsules for oral use 
QD/BID (21 days/cycle) 


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Level 7 
800mg  
(Total daily dose*) 
3+N 
Capsules for oral use 
QD/BID (21 days/cycle) 
#: The number of pts enrolled in each dose is specified by the BOIN rules; 
*：Proposed daily dose is the total dose each day with QD or BID dose frequency. 
Dosing frequency and dose level may be adjusted on the basis of available pharmacokinetic data and safety. 
Table 6-2 Dose and treatment schedule of Phase II 
Dose extension Schedule of HH2710 
Dose Level 
Dose of HH2710 
Pharmaceutical form and route of 
administration 
Frequency and/or Regimen 
1 
RP2D  
Capsules for oral use 
QD or BID (21 days/cycle) 
In Phase I, the first 3 patients will be administered orally (in the fasted state) HH2710 capsule once 
daily (QD) at the first day, then sampling for PK, from the second day, HH2710 capsule will be 
administered orally on a continuous twice daily (BID) schedule, on a flat scale of mg/day and not 
individually adjusted by weight or body surface area. The fourth and later patients will be 
administered with HH2710 capsule twice daily (BID) from the first day of cycle 1, patients will 
be instructed to take their study medication 12±2 hour interval . Based on human PK data, from the 
fourth dose level, the patients will be administered with HH2710 capsule once daily (QD). The 
Investigator must instruct the patient to take the study drug exactly as prescribed.  
- 
Except on days of single dose PK sampling, patients should take HH2710 capsule follow the 
doctor's advice at approximately the same time each day starting at Cycle 1 Day 1, Patient 
should not eat until 2 hours after HH2710 administration. 
- 
Each dose of HH2710 is to be taken with a glass of water (at least 8 ounces–approximately 
250 mL) and consumed over as short a time as possible (i.e., Not slower than 1 capsule every 
2 minutes). 
- 
Patients should be instructed to swallow the capsules whole and not to chew them. 
- 
Patients will be instructed to take their study medication follow the doctor's advice. The study 
medication should be taken with at least 8 ounces water at the same time each day in the fasted 
state (2 hours before food or 2 hours after food). If a dose is not taken within 2 hours of the 
planned dosing time, the missed dose should not be replaced.  
- 
On days when PK blood samples are to be collected, patients will be instructed to hold their 
dose until arrival at the study site. HH2710 will be administered at the site in the morning. 
The exact time of drug administration should be recorded in the appropriate eCRF (Electronic 
Case Report/Record Form). The PK blood draws will be supervised by a member of the 


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research team. If a patient vomits within 4 hours of HH2710 dosing, the time and severity of 
vomiting should be recorded on the eCRF. 
- 
Patient who is observed to vomit an intact capsule after dosing in the clinic during the PK 
measurements may receive a substitute dose of drug. However, patients should be instructed 
NOT to take a substitute capsule if vomiting occurs after self-dosing at home. Missed doses 
should be skipped and not taken as a double dose at the next dosing time point. 
- 
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the source document and/or drug account record eCRF page.  
6.1.2 Treatment duration 
All patients will be treated with HH2710 orally, beginning on Cycle 1 Day 1. Each cycle will have 
21 days, until he/she meets the criteria for withdrawal (Section 7.1.4.1 and 6.3) 
6.2 
Dose escalation guidelines  
Phase I Dose escalation stage: the Bayesian optimal interval (BOIN) design incorporated with an 
accelerated titration will be used to assess the safety and tolerability, and furthermore, to help find 
the MTD, and/or to establish the RP2D combined with data from other sources. 
6.2.1 Starting dose  
The selection of the starting dose is based on the following consideration: 1) the PK-PD 
relationship established in human tumor xenograft mouse models, 2) the estimated human 
exposure of HH2710 obtained by allometric scaling modeling of dog and rat PK parameters, 3) 
and the toxicology studies data in rat and dog. 
The starting dose for the Phase I study of HH2710 in patients with advanced tumors were 
calculated in accordance with the International Conference on Harmonization (ICH S9) guidance 
“Nonclinical Evaluation for Anticancer Pharmaceuticals”. The guidance recommends the starting 
dose should be based on either 1/10 of the severely toxic dose in 10% of animals (STD10) in rodent 
toxicity study or 1/6 of the HNSTD observed in non-rodent studies. 
The starting dose for HH2710, for patients enrolled in this study, is set at 25 mg twice daily (BID), 
orally administered continuously. The selection of the starting dose follows the ICH S9 guidelines 
for choosing a starting dose for a first-in-human conducted in patients with cancer, and is shown 
in Table 6-1. 
HH2710 safety profile was investigated in 4-week GLP toxicology studies in SD rats (15, 50 and 
150/100 mg/kg/day) and Beagle dog (5, 15 and 60/30 mg/kg/day).  
The rodent (SD rat) STD10 was considered to be between 50 and 100 mg/kg/day. Therefore 50 
mg/kg/day has been used in this calculation. Converting this dose to a human equivalent dose 
(HED) and applying a 10-fold safety factor, translates to a safe starting dose of 48.6 mg/day.  


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The HNSTD in Beagle dog was 15 mg/kg/day. Converting this dose to a HED and applying the 6-
fold safety margin, a safe starting dose of 81.15mg/day was calculated.  
Consider the convenience of medication, the recommended safe starting daily dose has been 
adjusted to 50 mg/day in this protocol. 
Table 6-3 Calculation of the MRSD for HH2710 
Species 
STD10 or 
HNSTD 
(mg/kg/day) 
1/10 STD (rat) 
1/6 HNSTD (dog) 
Conversion 
Factora 
HED 
(mg/kg/day) 
MRSDb 
(mg/day) 
rat 
50 
5 
0.162 
0.81 
48.6 
dog 
15 
2.5 
0.541 
1.35 
81.15 
 
HED = (1/10 STD or 1/6 HNSTD) * Conversion Factor 
a Conversion factor from 2005 FDA guidance [63] 
b Assumes a 60 kg human 
6.2.2 Provisional dose levels 
Table 6-4 describes the starting dose and the dose levels that may be evaluated during this study. 
Table 6-4 Provisional dose levels 
Dose level 
Proposed daily dose*  
(BID/QD) 
Increment from previous 
dose 
-1** 
25 mg QD 
-50% 
1  
25 mg (BID) 
(starting dose) 
2 
50 mg (BID) 
100% 
3 
100 mg (BID) 
100% 
4 
300 mg (QD) 
50% 
5 
400 mg (BID/QD) 
33% 
7 
600 mg (BID/QD) 
50% 
8 
800 mg (BID/QD) 
33% 


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Dose level 
Proposed daily dose*  
(BID/QD) 
Increment from previous 
dose 
*It is possible for additional and/or intermediate dose levels to be added during the course of the study. 
Cohorts may be added at any dose level below the MTD in order to better understand safety, PK or PD. 
Proposed daily dose is the total dose each day with QD or BID dose frequency. 
**Dose level -1 represent treatment doses for patients requiring a dose reduction from the starting dose level.  
The starting dose level rationale see Section 错误!未找到引用源。. 
According to the non-clinical data and the modeling results, the preliminary plan of dose escalation 
including different doses (25mg, 50mg, and 100mg, BID;300mg QD, 400mg (BID/QD), 600mg 
(BID/QD), and 800mg (BID/QD)). 
 When 800mg QD escalation cohort and 600mg QD expansion cohort suspended due to safety 
concerns, 300mg QD dose level has been added to explore before or while proceeding with further 
dose escalation. In addition, an alternative BID dosing regimen starting from 200mg is also re-
initiated to better understand the safety, tolerability and PK of HH2710 in dose escalation stage. 
6.2.3 Guidelines for dose escalation and determination of (MTD/RP2D) 
Phase I dose escalation stage: 
The ATD + BOIN design is described as follows. Suppose the target toxicity rate for the MTD is 
ϕ= 0.3 and the maximum sample size is 58 including up to 40 subjects for 25/50/100 mg BID + 
QD dose escalation cohorts (Part A) and up to 18 subjects for the additional BID dose escalation 
cohorts (Part B). Part B dose escalation will be conducted separately using BOIN design. We will 
enroll and treat patients in cohorts of size 3. To guide dose-escalation decisions, if the observed 
DLT rate at the current dose is ≤ 0.236, the next cohort of patients will be treated at the next higher 
dose level; if it is ≥ 0.359, the next cohort of patients will be treated at the next lower dose level. 
For the purpose of overdose control, doses j and higher levels will be eliminated from further 
examination if Pr(pj> 0.3 | data) > 0.95, where pj is the true DLT rate of dose level j, j= 1,⋯,7. 
When the lowest dose is eliminated, stop the trial for safety. The trial design is illustrated in Figure 
6-1 and described through the following three steps: 
1. Perform accelerated titration as follows: treat the first patient at dose level 1. If no ≥ Grade 2 
adverse event is observed, escalate the dose to the next higher level. Continue this one-patient-
per-dose dose escalation process until any Grade ≥ 2 adverse event is observed or a dose level 
of 200 mg is reached, and then treat an additional 2 patients (at least 3 patients at that and all 
subsequent dose levels) at the first occurrence of a Grade 2 toxicity (i.e., the accelerated 
titration design should cease) or a dose level of 200 mg is reached. Hereafter, patients are 
treated in cohorts of size 3 as described in steps 2 and 3.  
2. To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according 
to the rule displayed in Table 6-5. When using Table 6-5, please note the following: 


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a. “Eliminate” means that we eliminate the current and higher doses from the trial to prevent 
treating any future patients at these doses because they are overly toxic. 
b. When we eliminate a dose, automatically de-escalate the dose to the next lower level. When 
the lowest dose is eliminated, stop the trial for safety. In this case, no dose should be selected 
as the MTD.  
c. If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, we treat 
the new patients at the current dose. 
d. If the current dose is the lowest dose and the rule indicates dose de-escalation, treat the 
new patients at the lowest dose unless the number of DLTs reaches the elimination boundary, 
at which point terminate the trial for safety. 
e. If the current dose is the highest dose and the rule indicates dose escalation, treat the new 
patients at the highest dose. 
3. Repeat step 2 until the maximum sample size (i.e., 40 for Part A or 18 for Part B) is reached 
or stop the trial if the maximum number of patients treated at the current dose reaches (i.e., 15 
for Part A or 12 for Part B). 
Figure 6-1 Flowchart for study conduct using the BOIN design 


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Table 6-5 Dose escalation/de-escalation rule for the BOIN Design 
 
Dose expansion stage: 
In order to further explore the safety, pharmacokinetics and efficacy during dose-escalation, dose 
expansion cohorts will be added in Phase I stage of the study. We plan to recruit up to 15 patients 
per cohort.  


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Patients with different cancer types enrolled in the dose expansion stage must have confirmation 
of specific MAPK pathway genetic alteration. During the study, the sponsor and investigators may 
request  one or several dose levels and different  dose regimens (QD, or BID)  cohorts to further 
explore more PK and PD data. Such requests will be discussed with the investigator(s), sponsor 
and medical monitor(s), and should be based on all data available at that time, including safety and 
clinical activity, determinations of pharmacokinetics, pharmacodynamics, and cumulative toxicity. 
There are no specific stopping criteria for this part of the study, however, emerging data from the 
expansion phase will be monitored regularly by the data review committee. 
MTD estimation:  
After the escalation is completed, select the MTD based on the isotonic regression as specified in 
[64]. Specifically, select the MTD for which the isotonic estimate of the toxicity rate is closest to 
the target toxicity rate. If there are ties, select the higher dose level when the isotonic estimate is 
lower than the target toxicity rate and select the lower dose level when the isotonic estimate is 
greater than or equal to the target toxicity rate. 
Biologically Effective Dose (BED) 
The Biologically Effective Dose (BED) is the dose chosen by the sponsor and is based on all 
available preclinical data and clinical safety, efficacy, PK, and PD data. 
Definition of RP2D 
The RP2D is defined as the dose level chosen by the sponsor (in consultation with the 
investigators) for the dose extension in Phase II, based on safety, tolerability, efficacy, PK, and 
PD data collected during the dose escalation stage and/or phase I dose expansion of the study. 
RP2D maybe adjust if not suitable. 
Determination of RP2D 
Prior to beginning the phase II stage, there will be a comprehensive review of all safety, PK, and/or 
PD data from cycle 1 and subsequent cycles of phase I dose escalation and expansion to determine 
the risk/benefit profile of the MTD. Based on this review, the phase II stage will begin at the 
MTD/RP2D if the MTD is tolerated. The dose studied in phase II stage, MTD/RP2D, is defined 
as final recommended dose.  
If the MTD is not found when the dose is increased to the maximum dose, or if the risk and benefit 
ratio of the MTD is not suitable for RP2D, then the Biologically Effective Dose (BED) is 
determined based on all available preclinical data and clinical safety, efficacy, PK and PD data. 
This BED was chosen as the recommended dose of Phase II recommended dose (RP2D). 
6.2.3.1 Implementation of Dose Escalation Decisions 
To implement dose escalation decisions, the available toxicity information (including adverse 
events and laboratory abnormalities that are not DLTs), and/or the available PK and PD 
information will all be evaluated by the investigators and Haihe clinical study personnel (including 


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the study physician and statistician) during a dose decision meeting by teleconference. Drug 
administration at the next higher dose level may not proceed until the investigator receives written 
confirmation from Haihe indicating that the results of the previous dose level were evaluated and 
that it is permissible to proceed to a higher dose level.  
6.2.3.2 Dose cohort modification 
Provisional dose level cohorts are listed in Table 6-4. Possible changes in dose administration 
according to the BOIN include but are not limited to: 
- 
Enrollment of a new cohort to the current dose level; 
- 
Enrollment of a new cohort to a dose below the starting dose for the study; 
- 
Enrollment of a new cohort to an intermediate dose between the current and preceding 
dose; 
- 
Enrollment of a new cohort to an intermediate dose between the current and the next 
planned dose; 
- 
Termination of any further escalation of study drug. 
6.2.3.3 Intra-Patient dose escalation 
Intra-patient dose escalation is not permitted at any time with the first four cycles of treatment. 
After the first four cycle is completed, individual patients may be considered for treatment at a 
dose of HH2710 higher than the dose to which they were initially assigned. In order for a patient 
to be treated at a higher dose of HH2710, he or she must have tolerated the lower dose for at least 
two cycles of therapy (i.e. he or she must not have experienced any HH2710-related toxicity 
CTCAE grade ≥ 2 at the lower dose originally assigned). Moreover, the new, higher dose with 
which the patient is to be treated must be a dose that has completed DLT evaluation and has not 
exceeded the maximum tolerated dose (MTD). There is no limit to the number of times a patient 
may have his or her dose of HH2710 increased. For any further increase after the initial intra-
patient dose escalation, the following rules apply: the patient must have experienced no CTCAE 
grade ≥ 2, HH2710-related toxicity over at least two cycles of therapy at the lower dose, and the 
higher dose being considered must have been fully DLT evaluated and shown not to exceed the 
MTD. Consultation and agreement with Haihe must occur prior to any intra-patient dose escalation 
occurring. These changes must be recorded on the Dosage Administration Record eCRF. Data 
from the first cycle of treatment at the new dose level will not be formally included into the 
statistical model describing the relationship between dose and occurrence of DLT. However, this 
data will be incorporated into the clinical assessment of safety within a dose escalation 
teleconference. 
6.2.4 Definitions of dose limiting toxicities (DLTs) 
DLT is defined as: any toxicity meeting the specified criteria and considered at least possibly 
related to HH2710 (i.e., any toxicity for which a clear alternative etiology such as disease 


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progression has not been identified) should be considered a DLT  per National Cancer Institute 
Common Terminology Criteria for Adverse events (NCI-CTCAE V5.0) standard, which met any 
of the following, NCI-CTCAE V5.0 will be used for all grading, and compliance of 80% (i.e. 17 
of 21 days) in Cycle 1 is required for a patient to be included in the DLT evaluation. For the 
purpose of dose-escalation decisions, DLTs will be considered and included in the BOIN. The 
criteria for defining dose-limiting toxicities see Table 6-6. 
Table 6-6 Criteria for defining dose-limiting toxicities 
TOXICITY 
DLT CRITERIA 
Blood and lymphatic system 
disorders 
≥ Grade 4 hematologic toxicity  
Grade 3 thrombocytopenia with bleeding or with requirement of transfusion 
of platelets 
Any grade febrile neutropenia  
Note: Given the high frequency of events related to underlying disease in 
subjects of  LCH, the investigator should confirm the causality of these events 
before judgement of DLTs, based on severity or duration is longer than that 
expected with standard-of-care treatment or other clinical evidence 
Cardiac disorders  
Asymptomatic decrease of LVEF > 10% compared to baseline and the LVEF 
is below the institution’s LLN b. 
Left ventricular systolic dysfunction CTCAE Grade ≥ 3 
Other cardiac disorders CTCAE Grade ≥ 3 
Vascular disorders 
Hypertension 
Persistent hypertension CTCAE Grade ≥ 3 requiring more than one drug or 
more intensive therapy than previously administered. 
General disorders and 
administration site 
conditions  
Fatigue CTCAE Grade 3 for > 72 hours 
Skin and subcutaneous 
tissue disorders: 
Rash and/or photosensitivity 
Rash/photosensitivity CTCAE Grade 3 for > 72 hours despite skin toxicity 
treatment, photosensitivity Grade 4  
Eye disorders 
Any grade of  retinal vein occlusion (RVO) 
Gastrointestinal disorders  
Diarrhea CTCAE Grade 3 > 72 hrs., despite the use of anti-diarrhea therapy; 
Diarrhea Grade 4 
Nausea/ vomiting CTCAE Grade 3 > 72 hrs., despite the use of anti-emetic 
therapy; Vomiting Grade 4  


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TOXICITY 
DLT CRITERIA 
Pancreatitis CTCAE Grade ≥ 3 
Investigationsa 
 
Blood bilirubin CTCAE Grade ≥ 3 
ALT/AST > 3 ULN and concomitant TBL > 2 ULN in the absence of 
evidence of biliary obstruction (i.e., significant elevation of ALP) or some 
other explanation of the injury (e.g., viral hepatitis, alcohol hepatitis) of any 
duration (i.e. Hy’s law) 
AST or ALT CTCAE Grade 3 for > 72 hours 
AST or ALT CTCAE Grade 4 
Serum alkaline phosphatase CTCAE Grade 3 
Serum lipase and/or serum amylase (asymptomatic) CTCAE Grade 3 > 72 
hours 
Serum lipase and/or serum amylase CTCAE Grade 4 
Serum creatinine CTCAE Grade ≥ 3 
Serum CK/CPK CTCAE Grade 3 for > 72 hours 
Serum CK/CPK CTCAE Grade 4 
Neutrophil count CTCAE Grade 3 for > 72 hours 
Neutrophil count CTCAE Grade 4 
Platelet count CTCAE Grade 3 with signs of bleeding 
Platelet count CTCAE Grade 4 
ECG QTc interval prolonged CTCAE ≥ Grade 3 
 
Electrolyte imbalance Grade 4; Asymptomatic electrolyte imbalance Grade 3 
> 72 hours 
Other hematologic & non-
hematologic toxicities 
Any other CTCAE Grade ≥ 3 toxicity except: 
Lymphocyte count decreased (lymphopenia) CTCAE Grade ≥ 3 unless 
clinically significant 
Other clinically significant/unacceptable toxic events not listed, judged by the SMC as DLT;  


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TOXICITY 
DLT CRITERIA 
All AEs of the specified grade and toxicity must be considered a DLT if they cannot definitively be 
attributed to disease progression or other extraneous cause. 
a For any CTCAE Grade 3 or 4 hepatic toxicity that does not resolve within 7 days to CTCAE Grade ≤ 1 (or 
CTCAE Grade ≤ 2 if liver infiltration with tumor present), an abdominal CT scan must be performed to 
assess if it is related to disease progression. 
CTCAE V5.0 will be used for all grading.  
Patients may receive supportive care (e.g. Packed red blood cells) as per local institutional guidelines. 
G-CSF may be used to treat patients who have developed dose-limiting neutropenia, as per institutional 
guidelines, following discontinuation of HH2710 treatment. Optimal therapy for vomiting or diarrhea will be 
based in institutional guidelines, with consideration of the prohibited medications listed in this protocol. 
Grade 3 laboratory investigations other than serum creatinine, bilirubin, AST or ALT will not be considered 
a DLT unless they are associated with clinical manifestations and judged by the SMC. 
For the exceptions provided, the Grade 3 AEs should resolve to ≤ Grade 1 within 72 hours 
In order to define DLT, patients should not be prophylactically prescribed antiallergic drugs 
support, antiemetics, antidiarrheals, or antipyretics. If a patient experiences grade 2 or greater 
nausea, diarrhea, vomiting, and/or skin lesion, medical intervention should occur. 
The investigator must notify the Sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. Prior to enrolling patients into a higher dose level, 
CTCAE grade ≥ 2 adverse events will be reviewed for all patients at the current dose level. 
The study will set up a Safety Monitoring Committee (SMC) to oversee safety, dose escalation 
decisions, MTD or BED, recommended doses for Phase II, determination of RP2D, and other key 
research decisions. At each dose level (DL), the SMC will determine the number of patients 
enrolled in the next DL, the dose increase, and the frequency of the most appropriate use based on 
all available PK and safety data (once daily [QD] or twice daily [BID]). However, if the sponsor's 
opinion differs from SMC, the decision process will be described in the SMC charter. SMC 
members include at least the main investigator, a PK expert, a drug safety physician, and a medical 
monitor. The investigator will continue to monitor the safety of all patients until the end of the 
safety follow-up visit (SFUV). 
6.3 
Dose modifications 
6.3.1 Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. The following guidelines 
need to be applied:  
These changes must be recorded on the Dosage Administration Record CRF. 


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All dose modifications should be based on the worst preceding toxicity. 
Each patient is only allowed 2 dose reductions as showed in Table 6-7. 
If a patient requires a dose interruption of > 14 days from the intended day of the next scheduled 
dose, then the patient must be discontinued from the study. Patients who discontinue the study for 
a study related adverse event or an abnormal laboratory value must be followed as described in 
Table 6-. 
Table 6-7 Dose adjustment of HH2710 
 
HH2710(mg) 
Dose  
Starting Dose  
First dose reduction 
75% of the starting dose* 
Second dose reduction  
50% of the starting dose* 
* The actual reduced dose should take into account the drug specification 
Adjust reference values in the table below according to the CTCAE V5.0 used in the study.  
The criteria for interruption and re-initiation of HH2710 treatment is showed in Table 6-


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Table 6-8 Criteria for interruption, re-initiation of HH2710 treatment and permanently discontinuation 
Recommended dose modifications for HH2710 
Worst toxicity 
CTCAE Gradea (value) 
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosingb 
No toxicity 
Maintain dose level 
Investigations (Hematologic) 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1500/mm3) 
Maintain dose level 
Grade 2 (ANC < 1500 - 1000/mm3) 
Maintain dose level 
Grade 3 (ANC < 1000 - 500/mm3) 
Discontinue HH2710: 
- If elevation lasts for ≤ 7 days: Resume treatment 1 same dose level 
- If elevation lasts for >7 days: Resume treatment at â 1 dose level 
Grade 4 (ANC < 500/mm3) 
Discontinue dose until resolved to ≤ Grade 2, then â 1 dose level 
If there is no recovery to ≤ Grade 2 or there is recurrent grade 3 or 4 neutropenia, G-CSF/Neulasta may 
be given at physician discretion. 
If no recovery to ≤ Grade 2, permanently discontinue HH2710  
Thrombocytopenia 
Grade 1 (PLT < LLN - 75,000/mm3) 
Maintain dose level 
Grade 2 (PLT < 75,000 - 50,000/mm3) 
Maintain dose level 


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Recommended dose modifications for HH2710 
Worst toxicity 
CTCAE Gradea (value) 
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosingb 
Grade 3 (PLT < 50,000 - 25,000/mm3) 
Discontinue dose until resolved to ≤ Grade 2, then: 
- If resolved in ≤ 7 days, then maintain dose level 
- If resolved in > 7 days, then â 1 dose level  
If no recovery to ≤ Grade 2, permanently discontinue HH2710  
Second occurrence: discontinue until toxicity resolves to ≤ Grade 2, reduce to by 
another dose level. 
3rd occurrence permanently discontinue HH2710. 
Grade 4 (PLT < 25,000/mm3) 
Discontinue dose until resolved to ≤ Grade 2, then â 1 dose level 
If no recovery to ≤ Grade 2, permanently discontinue HH2710  
Second occurrence: discontinue until toxicity resolves to ≤ Grade 2, reduce to by 
another dose level. 
3rd occurrence permanently discontinue HH2710. 
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 
38.5°C)  
Discontinue dose until resolved, then â 1 dose level 
First episode 
Discontinue HH2710 until afebrile and ANC > 1000. 
Add Filgrastim/Neulasta per physician discretion. 
Second episode 
Discontinue HH2710 until afebrile and ANC >1000. 
Add Filgrastim/ Neulasta per treating physician discretion. 
Restart HH2710 at dose reduced by one dose level and monitor as clinically. 


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Recommended dose modifications for HH2710 
Worst toxicity 
CTCAE Gradea (value) 
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosingb 
Third episode 
Discontinue HH2710 until afebrile and ANC >1000. 
Add Filgrastim/ Neulasta per treating physician discretion. 
Restart HH2710 reduced by another dose level and monitor as clinically indicated. 
Fourth episode 
Permanently discontinue HH2710 and continue follow-up protocol. 
Investigations (Hematologic) for LCH 
Manage as per institutional standard or global guidance. 
Investigations (Renal) 
Serum creatinine 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
Grade 2 (>1.5 - 3.0 x baseline; > 1.5 - 3.0 x ULN) 
Discontinue dose until resolved to ≤ Grade 1 or baseline, then maintain dose level 
Grade 3 (>3.0 x baseline; > 3.0 - 6.0 x ULN) 
Permanently discontinue HH2710  
Grade 4 (> 6.0 x ULN) 
Permanently discontinue HH2710  
Investigations (Hepatic)* 
Bilirubin 
Grade 1 (>ULN - 1.5 x ULN if baseline was normal; > 
1.0 - 1.5 x baseline if baseline was abnormal) 
Maintain dose level 


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Recommended dose modifications for HH2710 
Worst toxicity 
CTCAE Gradea (value) 
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosingb 
Grade 2 (>1.5 - 3.0 x ULN if baseline was normal; >1.5 
- 3.0 x baseline if baseline was abnormal) 
Discontinue dose until resolved to ≤ Grade 1, then: 
- If resolved in ≤ 7 days, then maintain dose level  
- If resolved in > 7 days, then ↓ 1 dose level 
Grade 3 (>3.0 - 10.0 x ULN if baseline was normal; >3.0 
- 10.0 x baseline if baseline was abnormal) 
Discontinue dose until resolved to ≤ Grade 1, then: 
- If resolved in ≤ 7 days, then ↓ 1 dose level  
- If resolved in > 7 days, then discontinue patient from study drug treatment 
Grade 4 (>10.0 x ULN if baseline was normal; >10.0 x 
baseline if baseline was abnormal) 
Permanently discontinue HH2710 
AST or ALT 
Grade 1 (>ULN - 3.0 x ULN if baseline was normal; 1.5 
- 3.0 x baseline if baseline was abnormal  
Maintain dose level 
Grade 2 (>3.0 - 5.0 x ULN if baseline was normal; >3.0 
- 5.0 x baseline if baseline was abnormal) 
Maintain dose level 
Grade 3 (>5.0 - 20.0 x ULN if baseline was normal; >5.0 
- 20.0 x baseline if baseline was abnormal) 
Discontinue dose until resolved to ≤ Grade 1 (or ≤ Grade 2 if liver metastases present), then: 
- If resolved in ≤ 7 days, then maintain dose level  
- If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (>20.0 x ULN if baseline was normal; >20.0 x 
baseline if baseline was abnormal) 
Permanently discontinue HH2710 


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Recommended dose modifications for HH2710 
Worst toxicity 
CTCAE Gradea (value) 
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosingb 
ALT/AST > 3 ULN and concomitant TBL > 2 ULN in 
the absence of evidence of biliary obstruction (i.e., 
significant elevation of ALP) or some other explanation 
of the injury (e.g., viral hepatitis, alcohol hepatitis) of 
any duration (i.e. Hy’s law) 
 
Permanently discontinue HH2710 
Investigation (metabolic)** 
amylase and/or lipase elevation 
 
Grade 1 (> ULN - 1.5 x ULN) 
Grade 
2 
(>1.5-2.0xULN; 
>2.0-5.0xULN 
and 
asymptomatic) 
Grade 3 (>2.0 - 5.0 x ULN with signs or symptoms; >5.0 
x ULN and asymptomatic) 
 
Grade 4 (>5.0 x ULN and with signs or symptoms) 
Maintain dose level 
Maintain dose level 
 
Discontinue dose of until resolved to Grade ≤ 2, then: 
- If resolved in ≤ 7 days, then maintain dose level  
- If resolved in > 7 days, then ↓ 1 dose level 
Permanently discontinue HH2710. 
Cardiac general  
Grade 1 or 2 
Grade 3 
Grade 4 
Maintain dose level 
Discontinue dose until resolved to ≤ Grade 1, then â 1 dose level 
Discontinue dose and discontinue patient from study drug treatment 


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Protocol No. HH2710-G101 
Recommended dose modifications for HH2710 
Worst toxicity 
CTCAE Gradea (value) 
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosingb 
Electrocardiogram QT corrected (QTc) interval prolonged  
Grade 1 or 2 Heart Failure 
Grade 3 Heart Failure 
Grade 4 Heart Failure 
Maintain dose level 
Permanently discontinue HH2710 and discontinue patient from study drug treatment 
Permanently discontinue HH2710 and discontinue patient from study drug treatment 
Grade 2 Ejection Fraction (EF) Decreased (resting EF: 
50-40%; or 10-19% drop from baseline) 
 
Grade 3-4 EF Decreased (resting EF 39-20%; or ≥20% 
drop from baseline) 
Discontinue HH2710 until ejection fraction returns to a value greater than the institutional lower limit 
of normal and the absolute decrease from baseline is < 15%, then maintain dose level.  
 
Permanently discontinue HH2710 
Grade 1 and 2 (QTcF 450-500ms) 
Grade 3 (QTcF ≥501 ms on at least two separate ECGs) 
 
 
Grade 4 (QTcF ≥501 ms or >60 ms change from 
baseline and Torsades de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of serious) 
Maintain dose level 
Discontinue dose until resolved to Grade ≤ 2, then: 
- If resolved in ≤ 7 days, then maintain dose level  
- If resolved in > 7 days, then ↓ 1 dose level 
Permanently discontinue HH2710 
Eye disorders  
Retinal vein occlusion (RVO) 
Permanently discontinue HH2710. 


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Protocol No. HH2710-G101 
Recommended dose modifications for HH2710 
Worst toxicity 
CTCAE Gradea (value) 
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosingb 
Other Grade 1 or 2 eye AEs 
Discontinue dose until resolved to baseline,  HH2710 could be restarted after assessed by 
ophthalmologist and investigator, maintain dose level or one dose level reduced as 
clinically indicated. 
≥ Grade 3 ocular/vision symptoms interfering with 
ADL (Activities of daily living) or requiring medical 
intervention  
Permanently discontinue HH2710. 
Vascular disorders 
Hypertension 
 
Grade 1 and 2 
Grade 3 
Grade 4 
Maintain dose level 
Discontinue dose until resolved ≤ Grade 1, then ↓ 1 dose level 
Permanently discontinue HH2710 
Gastrointestinal 
Pancreatitis 
 
Grade 2  
Grade ≥ 3  
Maintain dose level 
Permanently discontinue HH2710 
Diarrhea*** 
 
Grade 1 and 2 
Maintain dose level, but initiate anti-diarrhea therapy 


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Protocol No. HH2710-G101 
Recommended dose modifications for HH2710 
Worst toxicity 
CTCAE Gradea (value) 
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosingb 
Grade 3 
Grade 4 
Discontinue dose until resolved to ≤ grade 1, then ↓ 1 dose level 
Permanently discontinue HH2710 
Skin and subcutaneous tissue disorders  
Rash/photosensitivity 
Grade 1 and 2 
 
Grade 3, despite skin toxicity therapy 
 
 
Grade 4, despite skin toxicity therapy 
Maintain dose level. Consider to initiate institute appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids and low-dose systemic corticosteroids)  
Discontinue dose until resolved to Grade ≤ 1, then: 
- If resolved in ≤ 7 days, then↓ 1 dose level 
- If resolved in > 7 days, then discontinue HH2710 
Permanently discontinue HH2710 
General disorders and administration site conditions 
Fatigue/ Asthenia 
Grade 1 or 2 
Grade 3 
Maintain dose level 
Discontinue dose until resolved to ≤ grade 1, then: 
- If resolved in ≤ 7 days, then maintain dose level 
- If resolved in > 7 days, then ↓f resolved in 
Other adverse events**** 


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Protocol No. HH2710-G101 
Recommended dose modifications for HH2710 
Worst toxicity 
CTCAE Gradea (value) 
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosingb 
Grade 1 or 2 
Grade 3 
Grade 4 
Maintain dose level 
Discontinue dose until resolved to ≤ grade 1, then↓1 dose level 
Permanently discontinue HH2710Discontinue dose for ≥ grade 3 vomiting or grade 3 nausea only if the 
vomiting or nausea cannot be controlled with optimal antiemetic (as per local practice) 
All dose modifications should be based on the worst preceding toxicity. 
a Common Toxicity Criteria for Adverse Events (CTCAE V5.0) 
b If the investigator considers it to be at patient’s best interest to resume therapy before the toxicity has resolved to Grade 1 or 2 mentioned above, this may be 
permitted on a case by case basis, following discussion with Haihe. 
* Note: If Grade 3 or 4 hyper-bilirubinemia is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per 
institutional guidelines (e.g., review of peripheral blood smear and haptoglobin determination), then ↓ 1 dose level* and continue treatment at the discretion of the 
investigator. 
**Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed within 1 week of the first occurrence of any ≥ Grade 
3 of amylase and/or lipase. If asymptomatic Grade 2 elevations of lipase and/or amylase occur again at the reduced dose, patients will be discontinued permanently 
from study treatment. 
***Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea 
****Note: This is a general guidance for the other AEs except the above mentioned, and it is recommended that the specialists were involved for special case, and 
AE must be under adequate treatment before discontinuing. 


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Protocol No. HH2710-G101 
6.3.2 Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first.  
Appropriate clinical experts such as ophthalmologist, endocrinologist, dermatologist, psychiatrists 
etc. should be consulted as deemed necessary.  
Table 6-9 outlines the follow-up evaluation recommended for toxicities of specific types and 
CTCAE grades. 
Table 6-9 Follow-up evaluations for selected toxicities 
TOXICITY 
FOLLOW-UP EVALUATION 
Blood and lymphatic system 
disorders 
Test twice weekly until ≤ CTCAE grade 1, then restart treatment. 
Continue to test weekly until resolution to baseline or stabilization. 
Investigations (hematologic) 
Neutropenia ≥ CTCAE 
grade 3  
Thrombocytopenia ≥ 
CTCAE grade 3 
Test twice weekly until ≤ CTCAE grade 1, then restart treatment. 
Continue to test weekly until resolution to baseline or stabilization. 
Perform physical exam for check on bruising in case of major 
thrombocytopenia. 
Investigations (hepatic) 
Total bilirubin ≥ 2 x ULN  
OR 
AST/ALT ≥ CTCAE grade 
3 (> 5 x ULN) 
Test twice weekly until ≤ CTCAE grade 1, (or ≤ CTCAE grade 2 for ALT/AST 
if liver metastases are present) then restart treatment. 
Continue to test weekly until resolution to baseline or stabilization.  
Patients with total bilirubin > ULN (any duration) should have fractionation of 
bilirubin into total/direct or indirect/direct components and any additional 
work-up 
as 
clinically 
indicated 
by 
these 
results. 
Follow-up 
of 
hyperbilirubinemia should proceed as per the guidelines above, irrespective of 
the results of fractionation. 
Investigations (metabolic) 
Amylase or lipase ≥ CTCAE 
grade 3 
Test twice weekly until ≤ CTCAE grade 2, then restart treatment. 
Continue to test weekly until resolution to ≤ CTCAE grade 1 or stabilization. 
A CT scan or equivalent imaging procedure to assess the pancreas, liver, and 
gallbladder is recommended within 7 days of the first occurrence of any ≥ 


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Protocol No. HH2710-G101 
CTCAE grade 3 result, to exclude disease progression or potential other liver 
disease.  
In patients with serum triglycerides ≥ 500 mg/dL, urine amylase also needs to 
be tested. 
Cardiac disorders  
ECG abnormalities 
indicative of ischemic event 
Monitor toxicity until resolution to grade 1 or baseline. If applicable, monitor 
ECGs twice weekly until normalization or stabilization. 
Investigations (creatinine) 
creatinine≥ CTCAE grade 3 
If serum creatinine ≥ CTCAE grade 3 has been demonstrated, this parameter 
must be repeated at least twice a week until resolution to ≤ CTCAE grade 1 or 
baseline, and then at least weekly until either initiation of re-treatment or until 
stabilization. Patients will be instructed to increase hydration until resolution to 
≤ CTCAE grade 1 or baseline. 
Ophthalmological disorders 
Follow the advice of an ophthalmologist 
 
 
6.3.3 Anticipated risks and safety concerns of the study drug 
Overall, appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this protocol. Recommended guidelines for 
prophylactic or supportive treatment for expected toxicities, including management of study-drug 
induced adverse events, i.e., skin toxicity and diarrhea are provided in IB. Refer to preclinical 
toxicity and or clinical data of other MAPK drugs found in the IB. 
6.4 
Concomitant medications 
6.4.1 Permitted concomitant therapy 
The patient must be told to notify the investigational site about any new medications he/she takes 
after the start of the study drug. All medications (other than study drug) and significant non-drug 
therapies (including physical therapy, herbal/natural medications and blood transfusions) 
administered during the study must be listed on the Concomitant Medications or the Procedures 
and Significant Non-Drug Therapies CRF. 
6.4.2 Permitted concomitant therapy requiring caution and/or action  
HH2710 inhibits CYP2C8, CYP2C9, CYP2C19, CYP3A4/5 (midazolam, as substrate) and 
CYP3A4/5 (testosterone, as substrate) in vitro with IC50s of 4.37 µM, 4.52 µM, 8.75 µM, 8.38 µM, 
and 7.03 µM. The drug-drug interaction potential of HH2710 due to inhibition of CYP2C8, 
CYP2C9, CYP2C19 and CYP3A4/5 is low based on its clinical exposure. Caution should be taken 


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when substrates of CYP2C8, CYP2C9, CYP2C19 and CYP3A4/5 are combined with HH2710, in 
particular those with a narrow therapeutic margin. 
HH2710 induces CYP2B6 and CYP3A4 at 10 μM in vitro. The drug-drug interaction potential of 
HH2710 due to induction of CYP2B6 and CYP3A4 is low based on its clinical exposure. Caution 
should be taken when sensitive substrates of CYP2B6 and CYP3A4 are combined with HH2710. 
6.4.3 Prohibited concomitant therapy 
Anticancer therapy (chemotherapy, biologic or radiation therapy, surgery or Chinese 
medicine/Chinese patent medicine with anti-tumor effect) other than the study treatments must not 
be given to patients while the patient is on the study. If such agents are required for a patient, then 
the patient must be discontinued from the study. 
In vitro data indicate Drug HH2710 is metabolized primarily by CYP3A, therefore strong 
inhibitors of CYP3A4 (e.g., clarithromycin, itraconazole, ketoconazole, telithromycin, etc.) and 
strong CYP3A4 inducers (e.g., carbamazepine, rifampicin, St. John’s wort, etc.) should be avoided. 
Gastric acid reducing agents and sensitive substrates of CYP2C8, CYP2C9, and CYP2C19 also 
should be avoided. Refer to Appendix 14.7 for a list of prohibited medications. This list may not 
be comprehensive. 
Current treatment with agents including vitamins, supplements, and herbal supplements that are 
metabolized solely through CYP3A4 should be prohibited. 
In vitro data indicate HH2710 is a potential P-gp substrate. Strong P-gp inhibitor will likely 
increase the exposure level of HH2710. Strong P-gp inhibitor should be avoided (Refer to 
Appendix 14.8). 
6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when the 
patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the study. The Patient No. consists of the Site Number 
(Site No.) (As assigned by Haihe to the investigative site) with a sequential patient number suffixed 
to it, so that each patient is numbered uniquely across the entire database. Upon signing the 
informed consent form, the patient is assigned to the next sequential Patient No. available to the 
investigator through the iMedidata electronic data collection (EDC) interface.  
6.5.2 Treatment assignment or randomization 
No randomization is needed in this study. The treatment assignment is decided by the investigator. 


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6.5.3 Treatment blinding 
Not applicable. This is an open-label study. 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) HH2710 will be dispensed to the patient by authorized 
site personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
Table 6-8 Preparation and dispensing 
Study treatments 
Dispensing 
Preparation 
HH2710 
Capsules including instructions for administration are 
dispensed by study personnel on an outpatient basis. 
Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least their 
next scheduled study visit. 
Not applicable 
6.6.1 Study drug packaging and labeling 
The study medication packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the treatment arms and a [specific visit or dose/dose 
level]. Responsible site personnel will identify the study treatment package(s) to dispense to the 
patient according to the designed dosage. Site personnel will add the patient number on the label. 
Immediately before dispensing the package to the patient, site personnel will detach the outer part 
of the label from the packaging and affix it to the source document (Drug Label Form) for that 
patient’s unique patient number. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and the medication number but no 
information about the patient. 
The packaging of study drug HH2710 is capsule in bottle.  
The HH2710 capsules will be provided in an open-labeled packaging with space to enter the 
patient’s identification number. The label will also include name/drug code and quantity of 
HH2710, clinical protocol number, batch number, administration instructions, storage instructions, 
and expiry date. 
The contents of the label will be in accordance with all applicable regulatory requirements. 


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6.6.2 Drug supply and storage 
Study drug HH2710 will be centrally supplied by Haihe. Study drug must be received by 
designated personnel at the study site, handled and stored safely and properly, and kept in a secured 
location to which only the investigator and designated site personnel have access. Upon receipt, 
the study drug should be stored according to the instructions specified on the drug labels and in 
the IB.  
6.6.3 Study drug compliance and accountability 
6.6.3.1 Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug Accountability 
Form. This information must be captured in the source document at each patient visit. 
6.6.3.2 Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing of 
study drug in a drug accountability log. Drug accountability will be noted by the field monitor 
during site visits and at the completion of the study. Patients will be asked to return all unused 
study drug and packaging on a regular basis, at the end of the study or at the time of study drug 
discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Haihe monitor or to the Haihe address provided in the investigator folder 
at each site.  
6.6.4 Disposal and destruction 
The unused, waste or returned study drug supply can be destroyed by the third party authorized by 
the sponsor 
7 Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 list all the assessments and indicates with an “X”, the visits when they are performed. 
All data obtained from these assessments must be supported in the patient’s source documentation.  
Screening evaluation must be performed ≤28 days of cycle 1 Day 1 except for the pregnancy test 
which is to be performed within 3 days prior to the first dose of study treatment. Laboratory and 
radiological assessments performed as part of standard of care prior to signing informed consent 


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may be used if performed within the screening time window. The time window for tumor biopsies 
in the Phase I/II may be longer than 28 days. 
During the course of the study visits, test and/or procedures should occur on schedule whenever 
possible. From C2D8, a visit window of +/- 3 days is allowed (with the exception of 30 days safety 
follow-up visit, for which a visit window of +7 days is allowed). 
There is a +/- 7 days window on, tumor response assessment and chest radiological examination 
after starting study drug. 
In particular, full PK sampling with multiple post-dose time points on Day 1 and Day 15 of cycle 
1 and other days should be performed on the specified days. (Please refer to PK sampling schedule 
Table 7- 7-2 and 错误!未找到引用源。7-3 ). The first three patients should perform single dose 
full PK sample collecting in the first day. 
The assessment type please see Section 7.2. 
Unscheduled visit: Additional visits can be performed as appropriate and at the discretion of the 
investigator   
 


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Table 7-1 Visit evaluation Schedule of Assessments and Procedures 
 
 
Screening period 
 Study treatment period 
 
follow up period 
Visit name 
Protocol 
Section 
0 
molecu
lar 
screeni
ng 
 
 
Cycle 1 
Day 1 through 21 
 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21d/cycle, 
visit on 1st 
day of 
every 2 
cycles 
End of 
treatment visit 
(EOT)/early 
discontinuation 
(Section 7.1.4) 
Safety follow up Progress Disease 
follow up 
Survival 
follow-up 
(Section 
7.1.5.2) 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
Tx 
Within 7 days 
of the last dose 
30 days after the 
last dose. 
Once every 6 
weeks after the 
final dose 
Every 3 
months, to 1 
year 
Visit Day 
 
 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ±3  
36 ± 3 
43 ± 3  
N/A 
＋ 7 
± 7  
± 7  
Obtain molecular 
screening consent (Phase I 
expansion and Phase II 
extension) 
7.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
7.1.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
5.2, 5.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Biomarker detection 
7.1.1 
X1 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history/tumor 
history/tumor treatment 
history 
7.1.2.2 
 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Tumor diagnosis and 
severity 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication/treatment 
7.1.2.2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Protocol No. HH2710-G101 
 
 
Screening period 
 Study treatment period 
 
follow up period 
Visit name 
Protocol 
Section 
0 
molecu
lar 
screeni
ng 
 
 
Cycle 1 
Day 1 through 21 
 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21d/cycle, 
visit on 1st 
day of 
every 2 
cycles 
End of 
treatment visit 
(EOT)/early 
discontinuation 
(Section 7.1.4) 
Safety follow up Progress Disease 
follow up 
Survival 
follow-up 
(Section 
7.1.5.2) 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
Tx 
Within 7 days 
of the last dose 
30 days after the 
last dose. 
Once every 6 
weeks after the 
final dose 
Every 3 
months, to 1 
year 
Visit Day 
 
 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ±3  
36 ± 3 
43 ± 3  
N/A 
＋ 7 
± 7  
± 7  
Demography 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
7.2.1.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Measure height (cm) 
7.2.1.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Measure weight (kg) 
7.2.1.3 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
 
ECOG 
7.2.1.4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signs 
7.2.1.2 
 
X 
X6 
X 
X6 
X 
X 
X 
X 
X 
 
 
 
Ophthalmology exam 
7.2.1.1 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
Pregnancy test 
7.2.1.5 
 
X 
X3 
 
 
X4 
 
 
X4 
X4 
 
 
 
Study drug dispensed 
6.6.3 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study drug administration 
6.1.1 
 
 
X5 
X 
X 
X 
X 
X 
X 
 
 
 
 
Blood Pharmacokinetic 
samples (Phase I dose 
escalation)9 
7.2.2.1 
 
 
X 
 
X 
X 
 
 
X 
 
 
 
 


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Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
 
 
Screening period 
 Study treatment period 
 
follow up period 
Visit name 
Protocol 
Section 
0 
molecu
lar 
screeni
ng 
 
 
Cycle 1 
Day 1 through 21 
 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21d/cycle, 
visit on 1st 
day of 
every 2 
cycles 
End of 
treatment visit 
(EOT)/early 
discontinuation 
(Section 7.1.4) 
Safety follow up Progress Disease 
follow up 
Survival 
follow-up 
(Section 
7.1.5.2) 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
Tx 
Within 7 days 
of the last dose 
30 days after the 
last dose. 
Once every 6 
weeks after the 
final dose 
Every 3 
months, to 1 
year 
Visit Day 
 
 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ±3  
36 ± 3 
43 ± 3  
N/A 
＋ 7 
± 7  
± 7  
Blood Pharmacokinetic 
samples (Phase I dose 
expansion and Phase II)10 
7.2.2.1 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Pharmacodynamic samples 
(Phase I only) 
7.2.3 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Tumor assessment by 
RECIST v1.1(CT 
MRI,etc) 
7.2.5 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
Hematology 
7.2.1.5 
 
X 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood chemistry 
 
 
X 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
 
 
X 
X7 
If clinically indicated 
X 
 
 
Coagulation 
 
 
X 
X7 
X 
 
 
Thyroid function 
 
 
X 
X8 
X 
 
 
HBV, HCV, HIV test11 
7.2.1.5 
 
X 
 
 
 
 
 
 
 
 
 
 
 


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Protocol No. HH2710-G101 
 
 
Screening period 
 Study treatment period 
 
follow up period 
Visit name 
Protocol 
Section 
0 
molecu
lar 
screeni
ng 
 
 
Cycle 1 
Day 1 through 21 
 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21d/cycle, 
visit on 1st 
day of 
every 2 
cycles 
End of 
treatment visit 
(EOT)/early 
discontinuation 
(Section 7.1.4) 
Safety follow up Progress Disease 
follow up 
Survival 
follow-up 
(Section 
7.1.5.2) 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
Tx 
Within 7 days 
of the last dose 
30 days after the 
last dose. 
Once every 6 
weeks after the 
final dose 
Every 3 
months, to 1 
year 
Visit Day 
 
 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ±3  
36 ± 3 
43 ± 3  
N/A 
＋ 7 
± 7  
± 7  
Electrocardiogram (ECG) 
7.2.1.7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECHO cardiogram or 
MUGA 
7.2.1.6 
 
X 
At the investigator’s discretion if there are signs or symptoms of cardiotoxicity. 
X 
 
 
Troponin 
7.2.1.5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse events (AEs) 
8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Compliance by pill count 
6.6.3 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Obtain unused drug 
6.6.3 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Anti-tumor treatment 
information and survival 
7.1.5 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival 
7.1.5.2 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Table footnotes: 
1. 
The local report of MAPK pathway gene status  must be documented in the source files at the site, if enrollment eligible patient’s MAPK pathway gene status has been 
determined by local laboratory testing. For phase Ib/II, Each enrollment eligible patient must provide adequate archival and/or freshly FFPE tumor samples, which will be used 
for a MAPK pathway gene status determination at a Sponsor Designated Central Laboratory. 


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Protocol No. HH2710-G101 
2. 
Full medical history at screening, review/update of history only at subsequent visits. 
3. 
Serum pregnancy test is mandatory at screening visit. After screening and baseline, urine pregnancy test which if positive, confirm with serum test. Whereas serum pregnancy 
test is required at EOT visit.  Note that procedures performed during screening within 3 days prior to dosing do not need to be repeated on C1D1.  
4. 
After screening and baseline, urine pregnancy test which if positive, confirm with serum test. 
5. 
Study drug to be taken QD at cycle1 day 1, and study drug to be taken twice daily (BID) from second day of cycle 1 only in the first 3 patients. The fourth and later patients 
will be administered with HH2710 capsule twice daily (BID) from the first day of cycle 1. From the fourth dose level. The patients will be administered with HH2710 
capsule once daily (QD) orBID. The investigator should instruct the patient when dispensing the drug. Vital sign exam is detected at pre-dose, and 2h, 4h, after dose in 
C1D1, and C1D15, and be detected pre-dose in other setting time points. 
6. 
On C1D1 and C1D15, vital sign exam should be detected at pre-dose, 2h after dose, and 4h after dose. At other time points, the vital signs exam can be detected at 
pre-dose. 
7. 
If the Screening results within 7 days before C1D1 are judged to be normal by the investigator, C1D1 may be waived. 
8. 
If the Screening results within 28 days before C1D1 are judged to be normal by the investigator, C1D1 may be waived. 
9. 
Dense pharmacokinetic sampling will be done in the dose escalation portion of the trial. Sparse pharmacokinetic sampling will be done every two cycles prior to Day 1 dosing in 
all patients in the dose escalation between Cycle 1 (not included) to Cycle 9 (including Cycle 9)( Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1 , Cycle 9 Day 1 ).A pre-dose 
sample is included in Table 7-3 for patients in the dose escalation portion of the trial.  
10. 
Sample at pre-dose, 2h, 4h, 6h and 8h post dose will also be obtained at Cycle 1 Day 1 and Cycle 1 Day 15 for patients in the phase I dose expansion stage and Phase II portions 
of the trial.  
11. 
If HCV antibody test result is positive, HCV RNA test should be conducted, and HBsAg antigen positive patients should be tested for HBV DNA level.


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Protocol No. HH2710-G101 
 
7.1.1 Molecular screening  
For the Phase I does escalation, patients with regardless of MAPK pathway gene alteration status 
can participate clinical screening. If enrollment eligible patient’s MAPK pathway gene status has 
been determined by local laboratory testing, the pre-existing test result should be submitted for 
documentation (applicable in all sites).  
 For the Phase I expansion stage, local laboratory test results of MAPK pathway gene alteration 
status will be used to determine the eligibility of patient  participating in clinical screening 
procedure. Each enrollment eligible patient must provide adequate archival and/or fresh FFPE 
tumor samples, which will be used for a MAPK pathway gene status determination at a Sponsor 
Designated Central Laboratory (only applicable in China sites). The MAPK pathway gene status 
from local labs should be confirmed by investigator, and must be documented in the source files 
at the sites (applicable in all sites).  
For the Phase II stage, patients with known MAPK pathway gene mutations from previous local 
laboratory testing can participate in clinical screening procedures. For enrolled patients with a pre-
existing known MAPK pathway gene status, archival and/or fresh FFPE tumor samples must be 
provided for a confirmatory detection of MAPK pathway gene status by a Sponsor Designated 
Central Laboratory. The MAPK pathway gene status from local labs should be confirmed and 
recorded by investigator, and must be documented in the source files at the sites (applicable in all 
sites). 
Alternatively, for patients without known MAPK pathway gene mutation, archival and/or fresh 
FFPE tumor biopsy samples must be provided for the MAPK pathway gene mutation pre-screening 
test by the Sponsor Designated Central Laboratory. In order to avoid false negatives in the use of 
tissue blocks that were archived prior to treatment failure, freshly collected or archived after a 
treatment failure, tissue samples can be collected from patients with previous standard treatments, 
chemotherapy intolerance, or patients who are clinically unsuitable for chemotherapy.  
The detailed instructions for the sample collection, handling and shipping are outlined in the 
(HH2710-G101 Laboratory Manual). 
Tumor samples (or its derivatives) may be stored for up to 10 years (or comply with local laws 
and regulations, whichever comes with longer time window), and may be used to develop and 
validate future HH2710 companion diagnostic tests and for additional exploratory work to further 
elucidate the mechanism of disease recurrence. 
 


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Protocol No. HH2710-G101 
 
7.1.2 Screening examination 
Written informed consent needs to be obtained from the patient prior to any screening procedures 
for main study. The patient will undergo screening procedures as part of screening visit, as 
indicated in the assessment schedule ( 
 
Screening period 
 Study treatment period 
 
follow up period 
ame 
Protocol 
Section 
0 
molecu
lar 
screeni
ng 
 
 
Cycle 1 
Day 1 through 21 
 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21d/cycle, 
visit on 1st 
day of 
every 2 
cycles 
End of 
treatment visit 
(EOT)/early 
discontinuation 
(Section 7.1.4) 
Safety follow up Progress Diseas
follow up 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
Tx 
Within 7 days 
of the last dose 
30 days after the 
last dose. 
Once every 6 
weeks after the
final dose 
Day 
 
 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ±3  
36 ± 3 
43 ± 3  
N/A 
＋ 7 
± 7  
olecular 
ent (Phase I 
nd Phase II 
ion) 
7.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
consent 
7.1.2 
 
X 
 
 
 
 
 
 
 
 
 
 
xclusion 
ria
5.2, 5.3 
 
X 
 
 
 
 
 
 
 
 
 
 
detection 
7.1.1 
X1 
X 
 
 
 
 
 
 
 
 
 
 
ory/tumor 
r treatment 
ry 
7.1.2.2 
 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
nosis and 
ity 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
mitant 
treatment 
7.1.2.2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
raphy 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
amination 
7.2.1.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ight (cm) 
7.2.1.3 
 
X 
 
 
 
 
 
 
 
 
 
 
eight (kg) 
7.2.1.3 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
OG 
7.2.1.4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
igns 
7.2.1.2 
 
X 
X6 
X 
X6 
X 
X 
X 
X 
X 
 
 


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Protocol No. HH2710-G101 
 
 
Screening period 
 Study treatment period 
 
follow up period 
ame 
Protocol 
Section 
0 
molecu
lar 
screeni
ng 
 
 
Cycle 1 
Day 1 through 21 
 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21d/cycle, 
visit on 1st 
day of 
every 2 
cycles 
End of 
treatment visit 
(EOT)/early 
discontinuation 
(Section 7.1.4) 
Safety follow up Progress Diseas
follow up 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
Tx 
Within 7 days 
of the last dose 
30 days after the 
last dose. 
Once every 6 
weeks after the
final dose 
Day 
 
 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ±3  
36 ± 3 
43 ± 3  
N/A 
＋ 7 
± 7  
ogy exam 
7.2.1.1 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
cy test 
7.2.1.5 
 
X 
X3 
 
 
X4 
 
 
X4 
X4 
 
 
dispensed 
6.6.3 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ministration 
6.1.1 
 
 
X5 
X 
X 
X 
X 
X 
X 
 
 
 
macokinetic 
ase I dose 
ion)9 
7.2.2.1 
 
 
X 
 
X 
X 
 
 
X 
 
 
 
macokinetic 
ase I dose 
d Phase II)10 
7.2.2.1 
 
 
X 
 
X 
 
 
 
 
 
 
 
dynamic 
ase I only) 
7.2.3 
 
 
X 
 
X 
 
 
 
 
 
 
 
ssment by 
v1.1(CT 
etc) 
7.2.5 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
ology 
7.2.1.5 
 
X 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
 
emistry 
 
 
X 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
 
ysis 
 
 
X 
X7 
If clinically indicated 
X 
 
ation 
 
 
X 
X7 
X 
 
unction 
 
 
X 
X8 
X 
 
HIV test11 
7.2.1.5 
 
X 
 
 
 
 
 
 
 
 
 
 
gram (ECG) 
7.2.1.7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
iogram or 
GA 
7.2.1.6 
 
X 
At the investigator’s discretion if there are signs or symptoms of cardiotoxicity. 
X 
 


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Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
 
 
Screening period 
 Study treatment period 
 
follow up period 
ame 
Protocol 
Section 
0 
molecu
lar 
screeni
ng 
 
 
Cycle 1 
Day 1 through 21 
 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21d/cycle, 
visit on 1st 
day of 
every 2 
cycles 
End of 
treatment visit 
(EOT)/early 
discontinuation 
(Section 7.1.4) 
Safety follow up Progress Diseas
follow up 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
Tx 
Within 7 days 
of the last dose 
30 days after the 
last dose. 
Once every 6 
weeks after the
final dose 
Day 
 
 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ±3  
36 ± 3 
43 ± 3  
N/A 
＋ 7 
± 7  
nin 
7.2.1.5 
 
X 
 
 
 
 
 
 
 
 
 
 
nts (AEs) 
8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
y pill count 
6.6.3 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
sed drug 
6.6.3 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
treatment 
nd survival 
7.1.5 
 
 
 
 
 
 
 
 
 
 
X 
X 
val 
7.1.5.2 
 
 
 
 
 
 
 
 
 
 
 
 
), to determine if the patient is eligible for study participation. However, the results of routine tests 
may be useful even if they are performed prior to obtaining informed consent. The procedures 
must be performed with 28 days of treatment start (unless otherwise specified). If some indicators 
are abnormal and do not meet the inclusion/exclusion criteria, but it is possible to recover in a short 
time, these indicators can be redetected. 
Medical History 
A full medical history will include evaluation (past or present) of the following systems and/or 
conditions: general, head and neck, eyes, ears, nose, throat, chest/respiratory, heart/cardiovascular, 
gastrointestinal/liver, urogenital, musculoskeletal/extremities, skin, neurological/psychiatric, 
endocrine/metabolic, hematological/lymphatic, allergies/drug sensitivities, past surgical 
procedures, substance abuse or any other diseases or disorders. 
Full medical history is needed at screening, review/update of history only is performed at 
subsequent visits.  
7.1.2.1 Information to be collected on screening failure 
A patient who signed an ICF but failed to be started on treatment for any reason will be considered 
a screen failure. Both, patients who signed a molecular pre-screening ICF but are considered 
ineligible after molecular pre-screening or fail to have a result report (i.e. no tumor in sample, poor 


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Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
 
sample quality, assay failure), as well as patients, who are found not eligible after signing the main 
study ICF will be considered as screening failures and data will be handled in the same manner. 
The screening failure reason will be entered on the Screening Phase Disposition eCRF Page. 
The demographic information, informed consent, and inclusion/exclusion pages must also be 
completed for Screening Failure patients. No other data will be entered into the clinical database 
for patients who are screening failures, unless the patient experienced a Serious Adverse Event 
during the molecular screening and/or screening period (Section 8.2.2 for SAE reporting details). 
Physical examinations should be symptom driven after the Screening Visit. Ophthalmological 
examinations will be performed by an ophthalmologist at screening, at each visit of C1, day 1 of 
C2, then day 1 of every 2 cycles. 
7.1.2.2 Patient demographics and other screening/baseline characteristics 
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, diagnosis and extent of tumor, details of prior anti-neoplastic 
treatments, prior medication, procedures, and significant non-drug therapies, Hepatitis B and C 
status and any other assessments that are done for the purpose of determine eligibility for inclusion 
in the study. 
Full medical history at screening, review/update of history only at subsequent visits. 
7.1.3 Treatment period 
Patient may continue treatment of HH2710 until the patient experienced unacceptable toxicity, 
disease progression, and/or treatment is discontinued at the discretion of the investigator or by 
patient refusal (For details, see Section 7.1.4) 
7.1.4 End of treatment visit including study completion and premature withdrawal 
7.1.4.1 Early discontinuation of the study 
Termination of treatment includes early termination of treatment (discontinuation of dose due to 
the reason other than disease progression) and end of treatment (due to disease progression). If the 
blood routine, blood biochemistry, urine test, coagulation function, 12-lead ECG, serum/urine 
pregnancy test (if applicable) results within 7 days before termination of treatment evaluated by 
the investigator are normal, these checks can be waived. 
When the patient terminates the study treatment, a visit should be scheduled as soon as possible, 
and the time should be scheduled within 7 days of the last study of drug administration or the 
decision to prematurely terminate the study drug treatment, at which time all the examination  
listed in the end of treatment (EOT) visit are required to be evaluated. If the patient decides to 
withdraw from the study during a routine visit, the visit is treated as an EOT visit and the patient 
does not need to return to the research site to receive the visit. 


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Protocol No. HH2710-G101 
 
The completion of the treatment end page should be completed and the date and reason for the 
patient to stop the study treatment should be filled out. If the patient withdraws from the study 
early or the patient does not return to the interview, the investigator must determine the primary 
reason for the patient to withdraw from the study early and record this information on the EOT 
eCRF page. 
The end of treatment visit is not considered the end of the study. 
Patients may discontinue from the study treatment for reasons that include, but are not limited to, 
the following: 
• Radiographic disease progression per RECIST v1.1 
• Pregnancy 
• Any medical condition that the investigator determines may jeopardize the patient’s 
safety, if he or she were to continue the study treatment 
• Use of any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents  for the treatment of cancer). 
• Patient noncompliance 
It is agreed that for reasonable cause, either the Investigator or the Sponsor may terminate this study, 
provided a written notice is submitted at a reasonable time in advance of intended termination. If 
discontinuation is by the investigator, notice is to be submitted to Haihe Biopharma Co., Ltd. If 
discontinuation is by the Sponsor, notice will be provided to each investigator. 
Patients may discontinue study for reasons which include, but are not limited to, the following:  
• Patient withdrawal of consent 
• Death 
• Lost to follow up 
• Patients have completed all study assessments 
 
7.1.4.2 Criteria for patient premature withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. If a patient who does not meet enrollment criteria is inadvertently enrolled, 
that patient should be withdrawn from the study and the Sponsor or contracted CRO (Contract 
Research Organization) must be contacted. An exception may be granted in rare circumstances 
when a subject is enrolled who does not meet the inclusion/exclusion criteria of the protocol, but 
where there is a compelling safety reason to allow the patient to continue treatment (such as, 
compassion use). the Investigator must obtain documented approval from the Sponsor or Sponsor 
designee to allow the patient to continue in the study. 
In addition, patients will be withdrawn from study drug  in the following circumstances: 


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Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
 
- 
The Investigator decides that the patient should be withdrawn. If this decision is made because 
of an intolerable AE or a clinically significant laboratory value, the study drug is to be 
discontinued and appropriate measures are to be taken. The contracted CRO or its designee is 
to be notified immediately; 
- 
The patient is unwilling to continue in the study. Withdrawal of informed consent; 
- 
Lack of compliance with protocol; 
- 
The Investigator or the Sponsor, for any reason, stops the study; 
- 
Disease progression (at the discretion of the PI); 
- 
Patient becomes pregnant (withdrawal is required); 
- 
Patient is lost to follow-up. 
Patients who discontinue the study early will have early termination procedures performed as 
shown in the Schedule of Events.  
Patients will also to be withdrawn at any time if the Investigator concludes that it would be in the 
patient’s best interest for any reason. Protocol violations do not lead to patient withdrawal unless 
they constitute a significant risk to the patient’s safety. Patients can voluntarily withdraw from the 
study for any reason at any time. They are to be considered withdrawn if they state an intention to 
withdraw, fail to return for visits, became lost to follow up for any reason. 
7.1.4.3 Replacement policy 
Phase I Dose escalation stage:  
Patents who are withdrawn from the study will be replaced except those who withdrew because of 
an intolerable drug-related AE during the DLT observation period in phase I dose escalation. 
Patients will not be replaced on study. However, if a subject is considered as non-evaluable 
enrollment of a new patient to the current cohort will be considered if there is less than the required 
number of evaluable patients. During the DLT observation period, patients who are withdrawn 
from the study will be replaced except those who withdrew because of an intolerable drug-related 
AE. Enrollment of new patients may be considered until at least the minimum number or at most 
the maximum number of evaluable patients is achieved within the cohort. Minimum and maximum 
numbers of evaluable patients per cohort are defined in Section 错误!未找到引用源。. 
Phase I Expansion and Phase II stage:  
During the Phase I dose expansion and Phase II stage, no replacements will be needed. 


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Protocol No. HH2710-G101 
 
7.1.5 Follow up period 
7.1.5.1 Safety follow up  
All patients must have safety follow up evaluations for 30 days, after the last dose of study 
treatment.  
- 
Collection of AEs/SAEs, except for AEs/SAEs that occur after starting new antitumor 
treatment; 
- 
ECG, Clinical lab test (blood routine, blood biochemistry, urine tests, thyroid function, and 
coagulation); 
- 
New antitumor treatment and survival condition; 
- 
Concomitant medication/treatment; 
- 
Tumor evaluation will be continued in patients who discontinue treatment not for progressive 
disease until progressive disease, withdrawal of informed consent form, loss to follow-up, 
death or termination of study, whichever occurs first. 
Follow-up of progressive disease 
Patients who discontinue study treatment without disease progression will continue to receive a 6-
week tumor assessment (CT or MRI) until malignant tumor progression and/or subsequent 
initiation of systemic anticancer therapy (whichever is earlier). 
7.1.5.2 Follow-up of survival  
Telephone follow-up will be conducted every 3 months since the occurrence of progressive disease 
or the starting of new antitumor treatment to collect patients’ information on subsequent antitumor 
treatment and survival condition. It was completed 1 year after disease progression or initiation of 
new anti-tumor therapy. If patients have started new antitumor treatment after the final dose prior 
to end-of-treatment visit, they will directly enter the survival visit without receiving the end-of-
treatment visit. 
If patients terminate treatment prior to the occurrence of progressive disease, they should take part 
in survival follow-up to collect patients’ information on subsequent antitumor treatment and 
survival condition. 
Patients lost to follow up should be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source documents 
steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 


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Protocol No. HH2710-G101 
 
7.2 
Assessment types 
7.2.1 Safety assessments 
Safety will be monitored by assessing (Vital sign laboratory test result, ECG etc) as well as 
collecting of the adverse events at every visit. For details on AE collection and reporting, refer to 
Section 8. 
7.2.1.1 Physical examination 
A complete physical examination will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular and neurological. If indicated based on medical history and/or symptoms, rectal, external 
genitalia, breast, and pelvic exams will be performed. 
Physical examinations should be symptom driven after the Screening Visit. 
Ophthalmological examinations will be performed by an ophthalmologist at screening, at each 
visit of C1, day 1 of C2, then day 1 of every 2 cycles. 
Significant findings that were present prior to the signing of informed consent must be included in 
the Medical History page on the patient’s CRF. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event page of the patient’s CRF. 
7.2.1.2 Vital signs 
Vital sign exam is detected at pre-dose, and 2h, 4h, after dose in C1D1, and C1D15, and be detected 
pre-dose in other setting time points. 
Vital signs include pulse/heart rate, respiratory rate, temperature, blood pressure measurements. 
After the patient has been sitting for five minutes, with back supported and both feet placed on the 
floor, systolic and diastolic blood pressure will be measured with an appropriately sized cuff. If 
the result is abnormal, repeat the measurement or change the instrument measurement to confirm. 
The repeat sitting measurements will be made at 1-2 minute intervals. In case the cuff sizes 
available are not large enough for the patient's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used. 
7.2.1.3 Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured. (Note: CRFs are designed to collect the data in the units they 
are measured in; e.g., height in cm or in and weight in kg).See  


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Protocol No. HH2710-G101 
 
 
Screening period 
 Study treatment period 
 
follow up period 
ame 
Protocol 
Section 
0 
molecu
lar 
screeni
ng 
 
 
Cycle 1 
Day 1 through 21 
 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21d/cycle, 
visit on 1st 
day of 
every 2 
cycles 
End of 
treatment visit 
(EOT)/early 
discontinuation 
(Section 7.1.4) 
Safety follow up Progress Diseas
follow up 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
Tx 
Within 7 days 
of the last dose 
30 days after the 
last dose. 
Once every 6 
weeks after the
final dose 
Day 
 
 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ±3  
36 ± 3 
43 ± 3  
N/A 
＋ 7 
± 7  
olecular 
ent (Phase I 
nd Phase II 
ion) 
7.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
consent 
7.1.2 
 
X 
 
 
 
 
 
 
 
 
 
 
xclusion 
ria
5.2, 5.3 
 
X 
 
 
 
 
 
 
 
 
 
 
detection 
7.1.1 
X1 
X 
 
 
 
 
 
 
 
 
 
 
ory/tumor 
r treatment 
ry 
7.1.2.2 
 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
nosis and 
ity 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
mitant 
treatment 
7.1.2.2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
raphy 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
amination 
7.2.1.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ight (cm) 
7.2.1.3 
 
X 
 
 
 
 
 
 
 
 
 
 
eight (kg) 
7.2.1.3 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
OG 
7.2.1.4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
igns 
7.2.1.2 
 
X 
X6 
X 
X6 
X 
X 
X 
X 
X 
 
 
ogy exam 
7.2.1.1 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
cy test 
7.2.1.5 
 
X 
X3 
 
 
X4 
 
 
X4 
X4 
 
 
dispensed 
6.6.3 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ministration 
6.1.1 
 
 
X5 
X 
X 
X 
X 
X 
X 
 
 
 


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Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
 
 
Screening period 
 Study treatment period 
 
follow up period 
ame 
Protocol 
Section 
0 
molecu
lar 
screeni
ng 
 
 
Cycle 1 
Day 1 through 21 
 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21d/cycle, 
visit on 1st 
day of 
every 2 
cycles 
End of 
treatment visit 
(EOT)/early 
discontinuation 
(Section 7.1.4) 
Safety follow up Progress Diseas
follow up 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
Tx 
Within 7 days 
of the last dose 
30 days after the 
last dose. 
Once every 6 
weeks after the
final dose 
Day 
 
 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ±3  
36 ± 3 
43 ± 3  
N/A 
＋ 7 
± 7  
macokinetic 
ase I dose 
ion)9 
7.2.2.1 
 
 
X 
 
X 
X 
 
 
X 
 
 
 
macokinetic 
ase I dose 
d Phase II)10 
7.2.2.1 
 
 
X 
 
X 
 
 
 
 
 
 
 
dynamic 
ase I only) 
7.2.3 
 
 
X 
 
X 
 
 
 
 
 
 
 
ssment by 
v1.1(CT 
etc) 
7.2.5 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
ology 
7.2.1.5 
 
X 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
 
emistry 
 
 
X 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
 
ysis 
 
 
X 
X7 
If clinically indicated 
X 
 
ation 
 
 
X 
X7 
X 
 
unction 
 
 
X 
X8 
X 
 
HIV test11 
7.2.1.5 
 
X 
 
 
 
 
 
 
 
 
 
 
gram (ECG) 
7.2.1.7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
iogram or 
GA 
7.2.1.6 
 
X 
At the investigator’s discretion if there are signs or symptoms of cardiotoxicity. 
X 
 
nin 
7.2.1.5 
 
X 
 
 
 
 
 
 
 
 
 
 
nts (AEs) 
8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
y pill count 
6.6.3 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
sed drug 
6.6.3 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 


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Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
 
 
Screening period 
 Study treatment period 
 
follow up period 
ame 
Protocol 
Section 
0 
molecu
lar 
screeni
ng 
 
 
Cycle 1 
Day 1 through 21 
 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21d/cycle, 
visit on 1st 
day of 
every 2 
cycles 
End of 
treatment visit 
(EOT)/early 
discontinuation 
(Section 7.1.4) 
Safety follow up Progress Diseas
follow up 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
Tx 
Within 7 days 
of the last dose 
30 days after the 
last dose. 
Once every 6 
weeks after the
final dose 
Day 
 
 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ±3  
36 ± 3 
43 ± 3  
N/A 
＋ 7 
± 7  
treatment 
nd survival 
7.1.5 
 
 
 
 
 
 
 
 
 
 
X 
X 
val 
7.1.5.2 
 
 
 
 
 
 
 
 
 
 
 
 
, 错误!未找到引用源。. 
7.2.1.4 Eastern Cooperative Oncology Group Performance 
ECOG performance scores (Appendix 14.2) will be assessed within 14 days prior to the first dose 
and subsequent visits including the SFUV. 
7.2.1.5 Laboratory evaluations 
Laboratory tests include blood routine, blood biochemistry, urine tests, thyroid function, and 
coagulation. If the results of within 7 days before C1D1 are judged to be normal by the investigator, 
the blood routine, blood biochemistry, urine test, and coagulation function of C1D1 may be 
waived; if the thyroid function test C1D1 can be provided within 28 days by the regular medical 
institution issued, and there is no abnormal report on the thyroid function test with normal range, 
the C1D1 examination can be exempted. After Cycle 2, clinical chemistry (to include calcium and 
inorganic phosphorus), hematology may be performed once per cycle or more frequently at the 
investigator’s discretion. 
Hematology: red blood cell count, hemoglobin, hematocrit, reticulocyte count, neutrophil, 
lymphocyte, eosinophil, mononuclear cell, basophil, platelet count. 
Blood chemistry including LFTs and KFTs: LFTs include total protein, albumin, total and direct 
bilirubin, ALT, AST, gamma-glutamyl transferase, creatine phosphokinase (CK/CPK), alkaline 
phosphatase and lactate dehydrogenase; KFTs include blood urea nitrogen, creatinine and uric 
acid; other blood chemistry includes blood glucose, chloride, sodium, potassium, calcium, 
phosphate, amylase, and lipase, lactate dehydrogenase (LDH), CKMB (Creatine Kinase MB 
Isoenzyme). 


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Protocol No. HH2710-G101 
 
Coagulation function tests: prothrombin time (PT), activated partial prothrombin time (APTT) and 
international normalized ratio (INR); 
Serum virology: HBV, HCV, and HIV. If HCV antibody test result is positive, HCV RNA test 
should be conducted, and HBsAg antigen positive patients should be tested for HBV DNA level. 
Thyroid: T3 [free], T4 [free], TSH 
Urinalysis: gravity, protein, glucose and blood will be performed. Any significant findings on 
dipstick will be followed up with a microscopic evaluation where WBC and RBC sediments will 
also be measured. 
Blood samples for hematology, blood chemistry and coagulation tests, and urine samples for 
urinalysis will be collected according to the schedule shown in Table 7-1 ,Table 7-2 and Table 
7-3. 
Blood sampling for viral serology will be performed at screening for detection of HBV, HCV, and 
HIV according to local practice. 
Pregnancy assessment: For child-bearing potential patients: Pregnancy  test for pregnancy is 
performed on C1D1, C2D1, and every 2 cycles from Cycle 3when applicable. Serum pregnancy 
test is mandatory at screening visit. After screening and baseline, urine pregnancy test which if 
positive, confirm with serum test. Whereas serum pregnancy test is required at EOT visit. If needed, 
Serum HCG (β-HCG) will be examined. 
Clinical laboratory tests will be reviewed for results of potential clinical significance at all time 
points throughout the study. The Investigator will evaluate any change in laboratory values. If the 
Investigator determines a laboratory abnormality to be clinically significant, it is considered a 
laboratory AE; however, if the abnormal laboratory value is consistent with a current diagnosis, it 
may be documented accordingly. 
Cardiac function test: Troponin will be measured at screening. And any indication of abnormalities 
may result in further investigations. 
7.2.1.6 Echocardiogram or MUGA (multiple gated acquisition) scan 
Left ventricular ejection fraction (LVEF) should be measured at screening, at the investigator’s 
discretion if there are signs or symptoms of cardiotoxicity during the study, and at the SFUV. 
LVEF can be measured via echocardiogram or MUGA scan. A delegated qualified staff should be 
responsible for LVEF measurement. LVEF must be within normal range. 
7.2.1.7 12-lead Electrocardiogram  
A standard 12-lead ECG will take place on screening and subsequent visits. Patients should be 
supine for 5 minutes prior to the ECG. ECGs will be obtained prior to dosing(-60min), one hour 
post-dose(±20min) , three hours post-dose(±30min) , four hours post-dose(±30min) , and eight 
hours post-dose(±60min)  on Cycle 1 Day 1 and Cycle 2 Day 1. ECG measurement timepoints will 


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Protocol No. HH2710-G101 
 
match PK sampling timepoints, ECG measurement must be taken within 15 min before PK 
sampling at each time points. The timepoints may be modified when the PK data (HH2710 and 
selected metabolites) in humans is available.  
Standard ECG parameters, including heart rate, QRS, PR, RR, QT, and the QT interval corrected 
for heart rate using Frederica‘s formula will be measured. 
ECG trace report will be collected and archived at patient chart and study file respectively. 
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present when the patient signed informed consent should be 
reported on the Medical History CRF page. Clinically significant findings must be discussed with 
Haihe prior to enrolling the patient in the study. New or worsened clinically significant findings 
occurring after informed consent must be recorded on the Adverse Events CRF page. 
7.2.2 Pharmacokinetics 
7.2.2.1  Blood sample schedule  
Study drug will be taken QD at cycle1 day 1 and twice daily from the second day of cycle 1 in the 
first 3 patients. First dose in clinic on days when PK sampling occurs i.e., Cycle 1 Day 1 and Cycle 
1 Day15, remaining doses on all other days to be self-administered by patient. 
In order to detect PK of a single administration, for the first 3 patients, a single administration will 
be given on the first day, administration twice daily from the second day. Patients will undergo 
serial blood sampling 2ml for PK analysis during cycle 1 on day 1 at pre-dose and 15min, 30min, 
1, 2, 3, 4, 6, 8 hours post-dose, and 12 hours post-dose (if available); on day 2 at pre-dose; on 
cycle1 day 7 (pre-dose), cycle1 day 10 (pre-dose), day 15 at pre-dose and 15min, 30min, 1, 2, 3, 
4, 6, and 8 hours post-dose, and 12 hours post dose (if available); and day 16 at pre-dose. On day 
22, prior to dose administration, a final blood sample was collected for pharmacokinetic analyses. 
See Table 7-2, 错误!未找到引用源。3. 
Serial blood samples will be collected from all patients to assess single dose and multiple dose 
plasma PK of HH2710 and its metabolite. PK parameters will be derived from each individual 
plasma concentration-time profiles. Refer to Section 10.6.4 for list of PK parameters that will be 
estimated.  
PK blood sample collection and handling 
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a 
forearm vein. At specified time points described in Table 7-2 and 错误!未找到引用源。3, 2 mL 
blood draws will be collected into tubes containing K2 EDTA and gently inverted several times to 
thoroughly mix the anticoagulant. Tubes will be centrifuged to separate plasma and plasma will 


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Protocol No. HH2710-G101 
 
immediately be transferred into labeled 2 mL polypropylene screw-cap tubes. Plasma samples will 
be placed in a freezer in an upright position until shipment to the bioanalytical laboratory for 
analysis.  
All sampling is relative to the ingestion of HH2710. On days and time points where blood PD 
samples are to be drawn, the PK sample must be drawn first. The exact collection date and time of 
all samples must be documented on the PK blood collection CRF pages. The date and exact time 
of dosing, as well as the date and actual time of blood sampling must be recorded on the CRF. 
Refer to the [HH2710-G101 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples. 
Intensive PK sampling will be done in the dose escalation portion of the trial. Additional PK 
sampling will be drawn every two cycles prior to Day 1 dosing in all patients in the dose escalation 
between Cycle 1 to Cycle 9 (e.g. Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1) 
(Table 7-2).  
PK samples at pre-dose, 2h,, 4h, a 6h, 8h, and 24h post dose will also be obtained at Cycle 1 Day 
1 and Cycle 1 Day 15 for patients in the Phase I dose expansion stage and Phase II portions of the 
trial (Table 7-3).  
 
Table 7-2: PK blood sampling time for Phase I dose escalation stage 
CxDx 
C1D1 
C1D1 
C1D1 
C1D1 
C1D1 
C1D1 
C1D1 
C1D1 
C1D1 
C1D1 
C1D2 
C1D7 
C1D10 
C1D15 
C1D15 
No. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Time 
pre-dose 
15min 
30min 
1h 
2h 
3h 
4h 
6h 
8h 
12h  
(If 
available) 
24h  
(pre-
dose) 
pre-
dose 
pre-
dose 
pre-
dose 
15min 
Window 
(min) 
-30 
± 5  
±5  
± 5  
±10  
±10  
±10  
±30  
±30  
±60  
-30 
-30 
-30 
-30 
± 5  
Blood 
Sampling 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
 
CxDx 
C1D15 
C1D15 
C1D15 
C1D15 
C1D15 
C1D15 
C1D15 
C1D15 
C1D1
6 
C2D1 
C3D1 
C5D1 
C7D1 
C9D1 
NA 
No. 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
NA 
Time 
30min 
1h 
2h 
3h 
4h 
6h 
8h 
12h  
(If 
availab
le) 
pre-
dose 
pre-dose 
pre-
dose 
pre-
dose 
pre-
dose 
pre-
dose 
NA 
Window(mi
n) 
± 5  
± 5  
± 10  
± 10  
± 10  
± 30 
± 30  
± 60  
-30 
-30 
-30 
-30 
-30 
-30 
NA 


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Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
 
Blood 
Sampling 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
NA 
 
Table 7-3: PK blood sampling time for Phase I dose expansion stage and Phase II  
CxDx  
C1D1  
C1D1  
C1D1  
C1D1  
C1D1  
C1D2 
C1D15  
C1D15  
C1D15  
C1D15  
C1D15   
C1D16  
No.  
1  
2  
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Time  
pre-
dose  
2h  
4h 
6h 
8h 
24h 
pre-
dose  
2h  
4h 
6h  
8h 
24h 
Windo
w(min)  
-30  
±10  
±10  
±30  
±30  
±6 0 
-30  
±10  
±10  
±30  
±30   
±60  
Blood 
Sampli
ng  
2mL  
2mL  
2mL  
2mL  
2mL  
2mL  
2mL  
2mL  
2mL  
2mL  
2ml 
2ml 
7.2.2.2 Analytical method 
Plasma samples were analyzed for HH2710 and metabolites using validated liquid 
chromatography-tandem mass spectrometry (LC/MS-MS) methods. Standard pharmacokinetic 
parameters were obtained using Phoenix WinNonlin 6.4 with a noncompartmental method. 
Relationship between dose and exposure was calculated using standard least-squares regression 
analysis. 
7.2.3 Pharmacodynamics Biomarker Assessment 
To confirm on-target and pathway inhibition by HH2710, RSK phosphorylation (pRSK/ total 
RSK) will be examined as a target biomarker in patient whole-blood sample pre-and post- HH2710 
oral dosing in Phase I, Patients will undergo serial blood sampling for PD of HH2710 during cycle 
1, and if applicable, during subsequent dosing cycles. This test will be done in sites that are capable 
of sample collection and processing for Pharmacodynamics. 
Whole-blood sample will be collected on C1D1 and C1D15 (pre-dose, 4, and 24 hours post-dose) 
(time window is the same as related PK sampling time). Then peripheral blood mononuclear cells 
(PBMC) will be isolated and stimulated by PMA, followed by cell lysis and analyzed by ELISA 
for pRSK/RSK. 
Biomarker sample collection information should be captured on sample collection CRF(s) and/or 
Central Laboratory paper requisition form(s). 
Detailed instructions for the collection, handling, and shipping of samples for biomarker 
development are outlined in the HH2710-G101 Laboratory Manual. 


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Protocol No. HH2710-G101 
 
7.2.4 Genetic Biomarkers Assessment 
7.2.4.1 Genetic biomarker assessments in tumor samples during molecular screening 
For the Phase I dose escalation, patients with regardless of MAPK pathway gene alteration status 
can participate clinical screening.  If enrollment eligible patients’ MAPK pathway gene status has 
been determined by local laboratory testing, the gene alteration status information from local test 
reports must be documented in the source files at the sites.   
For Phase I dose expansion, local laboratory test results of MAPK pathway gene alteration status 
will be used to determine the eligibility of patient participating in clinical screening procedure. 
Each enrollment eligible patient must provide adequate archived and/or fresh FFPE tumor samples, 
which will be used for a MAPK pathway gene status determination at a Sponsor Designated 
Central Laboratory (only applicable in China sites). The MAPK pathway gene status from local 
labs should be confirmed and recorded by investigator, and must be documented in the source files 
at the sites (applicable in all sites).  
For Phase II, patients with known MAPK pathway gene mutations from previous local laboratory 
testing can participate in clinical screening procedures. For enrolled patients with a pre-existing 
known MAPK pathway gene status, archived and/or fresh FFPE tumor samples must be provided 
for a confirmatory detection of MAPK pathway gene status by a Sponsor Designated Central 
Laboratory.  
Alternatively, for patients without known MAPK pathway gene mutation, archived and/or freshly 
FFPE tumor biopsy samples must be provided for the MAPK pathway gene mutation pre-screening 
test by the Sponsor Designated Central Laboratory. 
Patients must sign an informed consent form , to allow the collection of available test results of 
local laboratory and/or archived or fresh FFPE tumor tissue samples for the determination of the 
MAPK pathway gene alteration status at a Sponsor-Designated Central Laboratory .  
In order to avoid false negatives in the use of tissue blocks that were archived prior to treatment 
failure, freshly collected or archived after a treatment failure, tissue samples can be collected from  
patients with previous standard treatments, chemotherapy intolerance, or patients who are 
clinically unsuitable for chemotherapy. The detailed instructions for the sample collection, 
handling and shipping are outlined in the (HH2710-G101 Laboratory Manual). 
 
Table 7-4 Biomarker sample collection plan 
Sample Type 
Volume 
Visit 
Time point 
Tumor samples 


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Oncology Clinical Trial Protocol 
 
Protocol No. HH2710-G101 
 
Sample Type 
Volume 
Visit 
Time point 
Mandatory  
Either tumor block or a minimum of 10 
slides from archival paraffin tumor 
tissue, or a freshformalin-fixed tumor 
biopsy 
N/A 
Phase Ib/II:  before Day-28 and 
Day -28 –0 Requires patient’s 
written 
consent 
on 
the 
Additional Biomarker ICF. 
Anytime 
 
Optional  
Fresh FFPE tumor biopsy tissue 
N/A 
Phase Ib/II: anytime when drug 
resistance occurred before Day-
28 and Day -28 –0 
Requires 
patient’s 
written 
consent on the  Additional 
Biomarker ICF. 
Anytime  
 
 
Unscheduled if needed 
Anytime 
Blood samples  
Mandatory 
whole-blood samples 
 (collection of whole-blood sample and 
PBMCs 
to 
measure 
marker 
“pRSK/RSK” to assess PD)  
10 mL 
C1D1 
Pre-dose 
10 mL 
C1D1 
4 hours post-dose  
10 mL 
C1D1 
24 hours post-dose  
10 mL 
C1D15 
Pre-dose 
10 mL 
C1D15 
4 hours post-dose 
10 mL 
C1D15 
24 hours post-dose 
7.2.5 Efficacy assessments 
Screening assessments and each subsequent assessment must include computed tomography (CT) 
scan (with oral/IV contrast, unless contraindicated) or magnetic resonance imaging(MRI) of the 
chest, abdomen, and pelvis. Other known or suspected sites of disease must be included in the 
imaging assessment(neck, brain, ect). Each lesion that is measured at baseline must be measured 
by the same method (either same radiologic/nuclear method or by physical exam) throughout the 
study so that the comparison is consistent. Ultrasound should not be used to measure tumor lesions. 
Assessments of current disease status will be obtained at Screening, Cycle 3–Day 1, and every 2 
cycles thereafter, and will be obtained at EOT visit and Progression Disease follow up 
visit(patients without Progression Disease, approximately every 6 weeks±7  days after the last 
dosing times). All assessments that meet the criteria for partial response (PR) or complete response 
(CR) require a confirmation after approximately 6 weeks (±7  days) to determine PR or CR. 


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CT scans were performed per routine site protocols and assessed by site radiologists; no central 
read assessments were included in this analysis. 
For efficacy endpoint overall survival, collect the information every 3 months by phone calls, or 
registered letters. Lost-to-follow up is defined as no response despite of three documented phone 
calls and three times registered letter being sent. 
Disease relevant assessment criteria should be used according to RECIST v1.1 criteria. Refer to 
the appendices of the protocol for such guidance documents. See Appendix 14.1. Patients with 
LCH/ECD, FDG-PET-CT could be optionally performed at baseline and every 3 to 6 months 
following the initiation of treatment, and the interval between scans can be increased once disease 
has stabilized at investigator’s discretion. Additional examination (brain MR, cardiac MRI or other 
examinations based on organ involvement) which are deemed as appropriate to support tumor 
assessment could be performed at investigator’s discretion. 
8 Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 Definition of Adverse Event（AE） 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent has 
been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events if they induce clinical signs or symptoms, require therapy, require changes in study 
medication(s) and other abnormalities are assessed by the investigator as clinical significance. 
Progression of malignancy should be documented or recorded as a part of efficacy evaluation, but 
not be reported as an adverse event. Adverse events separate from the progression of malignancy 
(example, deep vein thrombosis at the time of progression) will be reported as per usual guidelines 
with proper attribution regarding relatedness to the drug. 
8.1.2 Adverse Events Follow up and Reporting 
Monitoring of adverse event begins when the patient’s signed informed consent has been obtained 
and continued until the subject completes the safety follow-up. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms (e.g. anemia 
instead of low hemoglobin). When a clear diagnosis cannot be identified, each sign or symptom 
should be reported as a separate Adverse Event. When an abnormal laboratory or test result 


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Protocol No. HH2710-G101 
 
corresponds to a sign/symptom of an already reported adverse event, it is not necessary to 
separately record the lab/test result as an additional adverse event. 
The occurrence of adverse events should be sought by non-directive questioning during the 
screening process after taking the study treatment and at each visit during the study. Adverse events 
also may be detected when they are volunteered during the screening process or between visits, or 
through physical examination, laboratory test, or other assessments. 
Once an adverse event is detected, it should be followed until its resolution/baseline or until its 
condition is judged to be stable, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship and action taken to the study 
treatment, the interventions required to treat it, and the outcome. 
8.1.3 Assessment of Adverse Events 
As far as possible, each adverse event should be evaluated to determine the following: 
1. The severity grade (CTCAE Grade 1-5) 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0. If CTCAE grading does not exist for an adverse event, mild, 
moderate, severe, life-threatening and fatal (corresponding to Grades 1 - 5, respectively) will 
be used.  
• 
Grade 1 -Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 -Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). 
• 
Grade 3 -Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting selfcare 
ADL. 
• 
Grade 4 -Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 -Death related to AE. 
Note：A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE 
unless it meets the definition of serious as defined in Section 8.2.1. 
2. 
Its duration (Start and end dates) 
3. 
Its relationship to the study treatment.  
Not related: There is alternative cause for the event which is better plausible to explain the 
event. 
Related: there is a “reasonable possibility” that the drug caused the event. 
To assess the relationship, carefully consider the following points: 
• 
Time interval between AE and study drug administration, including time sequence and 


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reasonability 
• 
Effects of other drugs or therapeutic interventions 
• 
Effect of study indication or co-existent medical conditions 
• 
If AE improved after study drug discontinuation or dose reduction 
• 
If AE re-appeared upon study drug re-administration 
• 
Mechanism of the study drug 
4. 
Action taken with respect to study or investigational treatment due to adverse event (no change, 
dose decreased, dose interrupted, withdrawn, dose increased, not applicable) 
5. 
All adverse events should be treated appropriately, whether medication or therapy was given 
should be recorded on the CRF. (no concomitant medication/non-drug therapy, concomitant 
medication/non-drug therapy) 
6. 
Outcome 
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)  
7. 
Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 . 
8.2 
Serious Adverse Event (SAE) 
8.2.1 Definition of SAE 
An adverse event is considered “serious” if it results in at least one of the following outcomes: 
- Is fatal; 
- Is life-threatening: refers to a reaction in which the patient was at risk of death at the time of 
the reaction; it does not refer to a reaction that hypothetically might have caused death if it 
were more severe; 
- Requires inpatient hospitalization or prolongation of existing hospitalization; 
Note that hospitalizations for the following reasons should not be reported as serious adverse 
events: 
• 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition; 
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent; 
• 
Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition; 
- Results in persistent or significant disability/incapacity; 
- Constitutes a congenital anomaly/birth defect; 
- Is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above; 


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Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. 
8.2.2 Serious Adverse Event Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient 
has provided main informed consent and until completion of the safety follow-up must be reported 
to Haihe Pharmacovigilance team within 24 hours upon the awareness of its occurrence.  
 
Any SAEs experienced after the safety follow-up period should be reported to Haihe 
Pharmacovigilance team only if the investigator suspects a causal relationship to the study 
treatment.  
Information about all SAEs is collected and recorded on HaiHe Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to the study 
treatment, complete the SAE Report Form in English, and send the completed, signed form by e-
mail within 24 hours to the Haihe Pharmacovigilance Team. For SAE causing the death, the 
investigator should provide the Autopsy report or related medical reports if available. 
The e-mail address and contact information of HaiHe Pharmacovigilance Team, are listed in the 
investigator folder provided to each site. The original copy of the SAE Report Form and 
acknowledgement of receipt must be kept with the case report form documentation at the study 
site. 
8.2.3 SAE Follow-up 
Any follow up information to the SAEs should also be sent to Haihe Pharmacovigilance Team by 
using SAE Report Form stating that this is a follow-up to the previously reported SAE and reported 
to Haihe PV team within 24 hours in the same way as initial report. The follow-up information 
should include but not limit to whether the event has resolved or continues, if and how it was 
treated, and whether the patient continued or withdrew from study participation, et al. 
The reported SAEs would be processed and assessed according to Haihe standard procedures by 
Haihe PV team. In order to assess SAE causality accurately, Haihe may require further information 
from the investigator in sending an urgent or a routine follow-up query. The investigator can 


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provide more follow-up information by replying to the query form or updating the SAE report 
form. 
8.2.4 Serious and Unexpected Suspected Adverse Reaction 
If an SAE is assessed by Haihe as unexpected according to the current version of Investigator’s 
Brochure and there is a reasonable possibility that the Haihe study treatment cause the event, the 
case would fulfil the definition of ‘Serious and Unexpected Suspected Adverse Reactions 
(SUSARs)’. All investigators involved in any study with HH2710 as investigational product, 
would be informed about the SUSARs cases, newly identified important safety issues or other 
safety documents, and relevant ethics committees/IRB would also be informed according to 
relevant requirements. 
Haihe will submit Serious and Unexpected Suspected Adverse Reactions (SUSARs) and other 
safety information to the healthy authorities in accordance with national regulatory requirements 
in participating countries. 
8.3 
Reporting of Pregnancy 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to Haihe within 24 hours upon investigator awareness. The pregnancy should be followed 
up to determine outcome, including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy should be recorded on a Haihe Clinical Trial Pregnancy Form and reported by the 
investigator to the Haihe Pharmacovigilance Team. Pregnancy follow-up should be recorded on 
the same form and should include an assessment of the possible relationship to the study treatment. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
The consent from the female partner of male patients should be obtained before any information 
about the pregnancy is collected. 
8.4 
Emergency unblinding of treatment assignment 
This study is an open label study, therefore this section is not applicable. 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator's 
Brochure. Additional safety information collected between IB updates will be communicated in 
the form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 


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8.6 
Steering Committee 
The steering committee (SC) will be established comprising investigators participating in the study. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical study team, the SC will also 
develop recommendations for publications of study results including authorship rules. The details 
of the role of the Steering Committee will be defined in a Steering Committee charter. 
9 Data collection and management 
9.1 
Data confidentiality 
Information about study patients will be kept confidential and managed under the applicable laws 
and regulations. Those regulations require a signed patient authorization informing the patient of 
the following: 
- What protected health information (PHI) will be collected from patients in this study 
- Who will have access to that information and why 
- Who will use or disclose that information 
- The rights of a research patient to revoke their authorization for use of their PHI. 
In the event that a patient revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of patient authorization. 
For patients that have revoked authorization to collect or use PHI, attempts should be made to 
obtain permission to collect follow-up safety information (e.g. has the patient experienced any new 
or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned user 
identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
9.2 
Data collection 
The electronic case report form (eCRF) will be adopted for study data collection and management. 
Investigators shall timely, truthfully, completely record relevant data of each patient in the study. 
Information of all patients who has signed an informed consent shall be collected in the Case 
Report Form. 


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The sponsor or the data management party entrusted by the sponsor will provide the electronic 
data collection (EDC) system to study site. Relevant personnel will apply for corresponding 
account to login the EDC system after training. The investigator will enter the data generated in 
the study and follow the eCRF completion guideline. Finally, the principal investigator or 
personnel authorized shall sign an electronic signature for the confirmed data. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 
During the study, the PK/PD and biomarker specimens were collected by each site and then sent 
to the central laboratory designated by Haihe. Staff of the site will input the information required 
by the protocol in eCRF pages, and in the specimen information form of designated CRO. And the 
CRA (Clinical Research Associate) will review the eCRF to confirm the information is accurate 
and complete. Samples and/or data will be processed centrally and the results will be sent 
electronically to Haihe (or a designated CRO). 
9.3 
Data review 
The CRA will periodically monitor the source data to guarantee the consistency with that recorded 
in the eCRF. The medical monitors will review eCRF data from the medical perspective, and data 
manage personnel will check the integrity and logicality of eCRF data.  
In terms of problems found during the data review, relevant personnel will create data queries to 
sites in the EDC system, and personnel at site will answer the queries and make necessary changes 
to the data. All records of data revision and relevant operations are trailed in the EDC system. 
9.4 
Database locking and archiving 
After all study data are collected cleaned and locking conditions are reached through data review, 
database will be locked. Locked data will be sent to statistical analysts for analysis. 
After the completion of the study, patient eCRF in PDF form shall be generated from EDC and 
saved on CD-ROM which will be submitted to the sponsor and each site. Study documents shall 
be archived and managed in accordance with the requirements addressed in GCP. 
9.5 
Database management and quality control 
For studies using eCRFs, Haihe personnel (or designated CRO) will review the data entered by 
investigational staff for consistency, completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and missing 
values and sent to the investigational site via the EDC system. Designated investigator site staff 
are required to respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 


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system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Samples and/or data will be processed centrally and the results will be sent electronically to Haihe 
(or a designated CRO). 
10 Statistical methods and data analysis 
This section describes the statistical methods and data presentations to be used in the summary and 
analysis of safety, tolerability, pharmacodynamics (PD), pharmacokinetics (PK), and preliminary 
efficacy data for the study drug. Background information is provided for the overall study design 
and objectives. The reader is referred to the previous sections on this protocol for details of study 
conduct and data collection. 
Unless otherwise specified, ‘Phase I’ in this section is referred to as the dose-finding phase of the 
study, in which the BOIN design is used to assess the MTD and/or RP2D of the study drug. ‘Phase 
II’ is referred to as the extension phase where the preliminary efficacy is evaluated for each 
selected patient cohorts. 
10.1 
Study Endpoints 
Study endpoints see Section 3. 
10.2 
Analysis sets 
10.2.1 All-Treated Set 
The All-treated set includes all patients who have received at least one dose of study medication. 
This set will be used for efficacy analysis. 
10.2.2 Safety Set  
The Safety Set (SS) includes all patients who receive at least one dose of study medication. This 
set will be used for safety analysis. 
10.2.3 Pharmacokinetic analysis set 
The pharmacokinetic analysis set (PKS) consists of all patients who receive at least 1 dose of study 
drug and have sufficient, valid PK samples to estimate key parameters for at least 1 of the days of 
sampling. 


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10.2.4 Pharmacodynamics analysis set 
The pharmacodynamics analysis set (PDS) consists of all patients set who receive at least 1 dose 
of study drug and have sufficient, valid PD samples to estimate key parameters for at least 1 of the 
days of sampling. 
10.3 
Covariates and Subgroups 
No covariates will be accounted for in Phase I (dose-finding). In Phase II (cohort extension), 
analyses will be stratified by tumor types and/or genetic mutations in order to evaluate the 
preliminary efficacy. Patient to the request of the sponsor, any further analyses could be conducted 
based on any additional covariates/subgroups. The details of these analyses will be described in 
the statistical analysis plan (SAP). 
10.4 
Sample Size Considerations 
Phase I Dose Escalation Stage 
The planned maximum sample size in Phase I dose escalation stage (ATD + BOIN) is 58 including 
up to 40 subjects for ATD + QD dose escalation cohorts (Part A) and up to 18 subjects for the 
additional BID dose escalation cohorts (Part B). During the ATD, one-patient per cohort is 
required for dose escalation. Once the BOIN design starts, cohorts of 3 patients will be used for 
dose escalation and the maximum number of patients for each dose level should not exceed 15 
patients and 12 patients for BOIN design Part A and Part B, respectively.  
Phase I Dose Expansion Stage 
We plan to recruit up to 15 patients per expansion cohort in the phase I stage of the study. The 
enrolled patients with different cancers must have confirmation of specific MAPK pathway genetic 
alteration. The primary focus of the dose expansion is to further assess the safety and 
pharmacokinetics of HH2710. Preliminary efficacy will also be examined but serve only for an 
exploratory purpose.  
Phase II Dose Extension Stage 
In Phase II, patients will be recruited into the following 4 cohorts at the RP2D level:         
Cohort 1: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, NRAS Q61, 
BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated melanoma;  
Cohort 2: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, NRAS Q61, 
BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated non-small cell lung cancer;  
Cohort 3: Patients with BRAF V600 mutated Langerhans Cell Histiocytosis Syndrome 
(LCH)/ Erdheim-Chester disease (ECD);   


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Cohort 4: Patients with RAS/RAF/MEK/ERK mutated tumors that are not included in other 
cohorts. 
The sample size in Cohort 1 and Cohort 2 is justified according to the Bayesian optimal phase 2 
(BOP2) design [60]. Specifically, let 𝑛 denote the interim sample size and 𝑁 denote the maximum 
sample size. Let 𝑝𝑒𝑓𝑓 denote the probability of efficacy (response rate) and define the null 
hypothesis𝐻0: 𝑝𝑒𝑓𝑓≤0.05, representing that the treatment is inefficacious. We will stop enrolling 
patients and claim that the treatment is not promising if 
𝑃𝑟(𝑝𝑒𝑓𝑓> 0.05|𝑑𝑎𝑡𝑎) < 𝜆(𝑛
𝑁)𝛼, 
where 𝜆=0.75 and 𝛼=0.2 are design parameters optimized to minimize the chance of incorrectly 
claiming that an efficacious treatment is not promising (i.e., type II error) under the alternative 
hypothesis 𝐻1: 𝑝𝑒𝑓𝑓= 0.16, while controlling the type I error rate at 0.1 (i.e., the chance of 
incorrectly claiming that an inefficacious treatment is promising is no more than 10%). Assuming 
a Beta (0.05,0.95) prior distribution for 𝑝𝑒𝑓𝑓, the above decision rule corresponds to the following 
stopping boundaries and yields a statistical power of 0.8201 under 𝐻1: 
Table 10-1 Optimized stopping boundaries for cohort 1 and cohort 2 in Phase II 
# patients treated 
Stop if # responses <= 
23 
1 
36 
3 
Based on Table 10-1, we will perform an interim analysis for the first 23 patients. When at least 
2 patients experience CR or PR or SD (SD≥6 month) events, the study will continue recruiting up 
to 13 more patients in the second stage. When the total number of patients reaches the maximum 
sample size of 36, we reject the null hypothesis and conclude that the treatment is promising if the 
number of responses is greater than 3; otherwise we conclude that the treatment is not promising. 
We plan to recruit a maximum of 9 patients in Cohort 3. Since there are currently no sufficient 
data available (due to the rarity of the disease), we are unable to calculate the sample size provided 
for an acceptable statistical justification. However, at this stage, we think that data from 9 patients 
is considered to be adequate to allow a preliminary investigation of the study objectives for this 
cohort [60].        
Cohort 4 will include a maximum of 27 patients. Patients included in this cohort will have different 
cancer types led by different genetic mutations. Thus, it is difficult to calculate sample size for this 
cohort based on very accurate efficacy goals (e.g. minimum ORR for the alternative hypothesis). 
Therefore, this cohort serves for an exploratory purpose and the number of patients has been based 
on the desire to obtain adequate data whilst exposing as few patients as possible to the study 
procedures. 


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10.5 
Planned Analyses  
10.5.1 Interim Analyses  
There are three planned interim analyses during the study. One is performed for the determination 
of RP2D when Phase I completes. The other two are conducted for futility evaluation for the first 
23 patients in each of cohort 1 and cohort 2 when they have recruited and completed the assessment 
in Phase II. Any additional interim analyses can be conducted as requested by the sponsor for 
safety/efficacy monitoring while the study is ongoing. 
A sponsor-led data review committee will be used to evaluate safety as well as preliminary efficacy 
during the study. In Phase I, safety data will be reviewed by the committee after a minimum of 3 
patients have been enrolled into each dose level and received treatment. Once the dose escalation 
stage completes, the committee will review safety data as well as data from other sources (e.g. 
efficacy, PK/PD) to determine the RP2D for Phase II.   
In Phase II, the efficacy review will be conducted for cohort 1 and cohort 2 by the committee when 
each cohort has recruited and completed the assessment for the first 23 patients. For safety, the 
committee will review the data when every 6 or 12 patients have recruited and received treatments 
in all cohorts. Following the data review, the committee will decide as to whether the cohort may 
continue, whether amendment(s) to the protocol should be implemented, or whether the study 
should be stopped. 
Members of the committee will be internal to the sponsor, which can include employees and study 
investigators. 
Any outcomes of these safety and efficacy reviews that affect study conduct will be communicated 
in a timely manner to the investigators for notification of the Institutional Review Boards/Ethics 
Committees (IRBs/ECs).  
10.5.2 Primary Analysis  
The primary analyses in Phase I focuses on safety endpoints for HH2710 administered alone in 
patients with the advanced and/or refractory tumors. The RP2D will be determined based upon the 
observed DLTs and information from other sources (e.g. pharmacokinetics) as described in the 
protocol. 
In Phase II, the primary analyses will investigate the preliminary efficacy of the ORR and other 
endpoints including DoR, DCR, TTR, TTP, PFS and 1-year OS rate for each tumor type and each 
genetic mutation. 
10.5.3 Final Analysis 
The intended purpose of the final analysis is to provide the up-to-date information on the 
primary/secondary endpoints after patients have completed the follow-ups as described in the 


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protocol. The methods used in the final analyses will be similar as those used in the primary 
analyses. 
10.6 
Planned Methods of Analysis  
10.6.1 General Considerations  
The analysis methods used in the study will be mainly descriptive statistics.  
Unless stated otherwise, the term “descriptive statistics” refers to the number of patients (n), mean, 
median, standard deviation (SD), minimum (min), and maximum (max) for continuous data and 
frequencies and percentages for categorical data. Min and max values will be rounded to the 
precision of the original value, means and medians will be rounded to 1 decimal place greater than 
the precision of the original value, and SDs will be rounded to 2 decimal places greater than the 
precision of the original value. Percentages will be rounded to the nearest whole number (zeroes 
are not displayed) with values of “< 1%” and “> 99%” shown as necessary for values falling near 
the boundaries. 
Unless otherwise noted, all data collected during the study will be included in data listings and 
will be sorted by study (Phase I or Phase II), patient number, and then by date/time for each patient 
number. For Phase I expansion and phase II, patients will additionally be sorted by tumor types 
and genetic mutations. 
Demographic and baseline characteristic data will be summarized with descriptive statistics by 
treatment group and overall for each study part using the All-treated and SS populations. The 
variables include, but not limited to, age (years), gender, race, weight (kg), height (cm), ECOG 
performance status, tumor type, genetic mutation, previous chemotherapy and previous 
immunotherapy.  
All analyses will be conducted using SAS® version 9.2 or higher. 
10.6.2 Primary Efficacy Endpoint 
In Phase I, there is no primary efficacy endpoints.  
In Phase II, the objective response rate (ORR) will be calculated and summarized for each tumor 
type and genetic mutation. If possible, a 95% of confidence interval should be provided for each 
ORR. 
10.6.3 Secondary Efficacy Endpoint(s) 
In Phase I, there is no secondary efficacy endpoints. 
In Phase II, Kaplan-Meier method will be used to analyze the duration of response (DoR), the 
progression-free survival (PFS), time to response (TTR), time to progression (TTP) and 1-year 
overall survival (OS) rate for each tumor type and genetic mutation. If possible, a 95% of 


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confidence interval should be provided for each estimate. The point estimate and its 95% exact 
confidence interval (Clopper Pearson) will be used for analyzing DCR. 
10.6.4 Pharmacokinetic Analysis 
Samples for PK analysis of HH2710 and its metabolite will be obtained from all patients enrolled 
in Phase I dose escalation/expansion and Phase II trial.  
Below is the list of PK parameters that will be calculated after single dose (C1D1)  and steady 
State (C1D15). 
Table 10-2 PK Parameters Description 
PK 
Parameter 
(plasma) 
Description 
Cmax 
Peak plasma concentration determined manually by visual inspection of plasma concentration 
vs. time figures on the untransformed (linear) scale of measurement 
tmax 
Time to reach the peak plasma concentration determined manually by visual inspection of 
plasma concentration vs. time figures on the untransformed (linear) scale of measurement 
AUC0-24 
Area under the plasma concentration-time curve from 0 to 24 hours post-dose, calculated by 
linear/log trapezoidal method 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero to infinity after dosing calculated 
by linear/log trapezoidal method 
%AUCextrap 
Area under the plasma concentration-time curve extrapolated from time t to infinity as a 
percentage of total AUC (%) 
Lambda_z 
(λz) 
Terminal phase rate constant, determined by linear regression of at least 3 points on the terminal 
phase of the log-linear plasma concentration-time curve. The correlation coefficient (r2) for the 
goodness of the fit of the regression line through the data points has to be 0.85 or higher for the 
value to be considered reliable. If the WinNonlin data points are not on the linear portion of the 
terminal slope, the data points will be selected manually prior to calculation of Lambda_z 
t1/2 
Terminal half-life, defined as 0.693 (ln2) divided by Lambda z 
CL/F 
The apparent total body clearance of drug from the plasma (volume x time-1) 
Vz/F 
The apparent volume of distribution during terminal phase (associated with λz)(volume) 
Descriptive statistics [n, arithmetic mean, standard deviation, coefficient of variation (CV), median, 
minimum, maximum, geometric mean, geometric standard deviation geometric CV] will be used 


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to summarize PK parameters by treatment. For t1/2 and tmax, regular descriptive statistics and 95% 
confidence intervals about the arithmetic mean will be calculated, if possible, for each dose. Refer 
to the PK analysis plan for additional details regarding with the PK analyses. 
A listing of blood PK concentrations and parameters will be provided. 
10.6.5 Pharmacodynamics Analysis 
Multiple biomarkers intended to demonstrate inhibition of the molecular target, and mechanism of 
action will be investigated (pRSK and total pRSK) from blood. Additional biomarkers, including 
peripheral blood mononuclear cells (PBMCs) and/or DNA sequence analysis, may be identified 
and measured as appropriate. Descriptive statistics will be provided for pharmacodynamics data 
in a summary table and a listing will present all data or a figure. 
10.6.6 Safety Endpoints 
All safety summaries will be provided for the safety population. 
Summaries for safety variables (physical examinations, vital signs, clinical laboratory analyses, 
ECGs) will be given with descriptive statistics. In addition, all safety variables will be presented 
in by-patient listings, sorted by site and patient identifier. 
Adverse events will be coded using the MedDRA coding dictionary and the severity will be graded 
according to the NCI-CTCAE V5.0. A listing of all events, with seriousness, severity, relationship, 
sequelae and begin and end times will be provided. Narratives for any serious adverse events will 
be provided. Deaths, serious adverse events (SAEs), and AEs leading to discontinuation of study 
medication will be summarized by primary system organ class (SOC) and preferred terms, along 
with the by-patient listing. 
An isotonic regression will be used to estimate the MTD in Phase I. 
10.6.7 Handling of missing values/censoring/discontinuations 
10.6.7.1 
Date Values 
In cases of incomplete dates (e.g., pertaining to AE, concomitant medication, medical history, etc.), 
the missing component(s) will be assumed as the most conservative value(s) possible. For example, 
if the start date has a missing day value, the first day of the month will be imputed for study day 
computations (i.e., treatment-emergent status, etc.). If day is missing for an end date, the last day 
of the month will be imputed. Similar logic will be assumed for missing month and year 
components. 
Date imputation will only be used for computational purposes e.g., treatment-emergent status, etc. 
Actual data values as they appear in the original CRFs will be shown in the data listings. 


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10.6.7.2 
Non-Date Values 
Every effort will be made to obtain the protocol-required data for all study assessments that are 
scheduled for each scheduled visit for all patients who have been enrolled. No data imputation will 
be applied to missing study data except for imputing date values.  
10.6.8 Censoring Rules for Duration of Response (DoR) 
In general, DoR will be censored as described below: 
• 
Patients who do not have documented tumor progression and are still on study at the time of 
analysis will be censored at the date of the last disease assessment documenting absence of 
progressive disease. 
• 
Patients who are removed from study prior to documentation of tumor progression will be 
censored at the date of disease assessment documenting absence of progressive disease. 
11 Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations, 
and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research Ethics 
Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give access 
to all relevant data and records to Haihe monitors, auditors, Haihe Clinical Quality Assurance 
representatives, designated agents of Haihe, IRBs/IECs/REBs and regulatory authorities as 
required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent  
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of the 
procedures described in the protocol). The process of obtaining informed consent should be 


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documented in the patient source documents. The date when a patient’s Informed Consent was 
actually obtained will be captured in their CRFs. 
Haihe will provide to investigators, in a separate document, a proposed informed consent form 
(ICF) that is considered appropriate for this study and complies with the ICH GCP guideline and 
regulatory requirements. Any changes to this ICF suggested by the investigator must be agreed to 
by Haihe before submission to the IRB/IEC/REB, and a copy of the approved version must be 
provided to the Haihe monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order to 
participate in the study they must adhere to the contraception requirement for the duration of the 
study. If there is any question that the patient will not reliably comply, they should not be entered 
in the study. 
Additional consent form 
Sub-studies and studies with an optional Exploratory Biomarker component will have a separate 
consent form covering those studies. This form will be adapted for each Study based on a standard 
template used globally for all Studies. These informed consent forms will be submitted for ethical 
approval together with the Study Protocol and the main informed consent form of the Study. If a 
patient opts not to participate in the optional assessments, this in no way affects the patient’s ability 
to participate in the main research study. 
11.4 
Discontinuation of the study 
Haihe reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions 
for terminating the study are outlined in  
Section 4.4 
11.5 
Publication of study protocol and results 
Upon study completion and finalization of the study report the results of this study will be 
submitted for publication and/or posted in a publicly accessible database of clinical study results. 
11.6 
Study documentation, record keeping and retention of documents 
Each participating site will maintain appropriate medical and research records for this study, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements for 
the protection of confidentiality of patients. As part of participating in a Haihe-sponsored study, 
each site will permit authorized representatives of the sponsor(s) and regulatory agencies to 
examine (and when required by applicable law, to copy) clinical records for the purposes of quality 
assurance reviews, audits and evaluation of the study safety and progress. 


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Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, and patient files and records kept at the pharmacy, at the 
laboratories, and medico-technical departments involved in the clinical study. 
Data collection is the responsibility of the clinical study staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on the 
CRF, that are derived from source documents, should be consistent with the source documents or 
the discrepancies should be explained. All data requested on the CRF must be recorded. Any 
missing data must be explained. Any change or correction to a paper CRF should be dated, initialed, 
and explained (if necessary) and should not obscure the original entry. For electronic CRFs an 
audit trail will be maintained by the system. The investigator should retain records of the changes 
and corrections to paper CRFs. 
The investigator/institution should maintain the study documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than fifteen 
(15) years from the completion of the Clinical Study unless Sponsor provides written permission 
to dispose of them or, requires their retention for an additional period of time because of applicable 
laws, regulations and/or guidelines 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Haihe. Signed informed consent forms and patient enrollment log 
must be kept strictly confidential to enable patient identification at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Haihe or designee or Health Authorities. 


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11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel (according to the local regulation) 
who are directly involved in the treatment or evaluation of patients at the site - prior to study start. 
12 Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Haihe or its agents, if any, monitoring the study to 
request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Haihe and 
approved by the IRB/IEC/REB it cannot be implemented. All significant protocol deviations will 
be recorded and reported in the Clinical study report. 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Haihe, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the investigator 
is expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Haihe should be 
notified of this action and the IRB/IEC at the study site should be informed according to local 
regulations (e.g. FDA requires the notification of urgent safety measures as soon as possible, but 
within 15 days) but not later than 10 working days. 
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[27] Marais, R., et al., Ras recruits Raf-1 to the plasma membrane for activation by tyrosine 
phosphorylation. Embo j, 1995. 14(13): p. 3136-45. 
[28] Marais, R., et al., Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and 
tyrosine kinases. J Biol Chem, 1997. 272(7): p. 4378-83. 
[29] Mason, C.S., et al., Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf 
activation. Embo j, 1999. 18(8): p. 2137-48. 
[30] Xu, S., et al., MEKK1 phosphorylates MEK1 and MEK2 but does not cause activation of 
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[31] Cardone, M.H., et al., Regulation of cell death protease caspase-9 by phosphorylation. 
Science, 1998. 282(5392): p. 1318-21. 
[32] Derijard, B., et al., Independent human MAP-kinase signal transduction pathways defined by 
MEK and MKK isoforms. Science, 1995. 267(5198): p. 682-5. 
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activation by RSK2, a growth factor-regulated CREB kinase. Science, 1996. 273(5277): p. 
959-63. 
[34] Coutant, A., et al., PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation 
whereas MEK/ERK supports both proliferation and survival. Hepatology, 2002. 36(5): p. 
1079-88. 
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[36] Deng, X., et al., Regulation of Bcl2 phosphorylation and potential significance for leukemic 
cell chemoresistance. J Natl Cancer Inst Monogr, 2001(28): p. 30-7. 
[37] Ley, R., et al., Activation of the ERK1/2 signaling pathway promotes phosphorylation and 
proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem, 2003. 
278(21): p. 18811-6. 
[38] Maik-Rachline, G. and R. Seger, The ERK cascade inhibitors: Towards overcoming 
resistance. Drug Resist Updat, 2016. 25: p. 1-12. 
[39] Sullivan, R.J., et al., First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with 
MAPK Mutant Advanced Solid Tumors: Results of a Phase I/II  Dose-Escalation and 
Expansion Study. Cancer Discov, 2018. 8(2): p. 184-195. 
[40] Moschos, S.J., et al., Development of MK-8353, an orally administered ERK1/2 inhibitor, in 
patients with advanced solid tumors. JCI Insight, 2018. 3(4). 
[41] Schubbert, S., K. Shannon, and G. Bollag, Hyperactive Ras in developmental disorders and 
cancer. Nat Rev Cancer, 2007. 7(4): p. 295-308. 
[42] Kanda, M., et al., Presence of somatic mutations in most early-stage pancreatic intraepithelial 
neoplasia. Gastroenterology, 2012. 142(4): p. 730-733.e9. 
[43] Arrington, A.K., et al., Prognostic and predictive roles of KRAS mutation in colorectal cancer. 
Int J Mol Sci, 2012. 13(10): p. 12153-68. 
[44] Hezel, A.F., et al., Phase I/II I study of gemcitabine, oxaliplatin in combination with 
panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder 
cancer. Br J Cancer, 2014. 111(3): p. 430-6. 
[45] Pennycuick, A., et al., Routine EGFR and KRAS Mutation analysis using COLD-PCR in non-
small cell lung cancer. Int J Clin Pract, 2012. 66(8): p. 748-752. 
[46] Dobrzycka, B., et al., Mutations in the KRAS gene in ovarian tumors. Folia Histochem 
Cytobiol, 2009. 47(2): p. 221-4. 
[47] O'Hara, A.J. and D.W. Bell, The genomics and genetics of endometrial cancer. Adv Genomics 
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[48] Khattak, M., et al., Targeted therapy and immunotherapy in advanced melanoma: an evolving 
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[49] Genomic Classification of Cutaneous Melanoma. Cell, 2015. 161(7): p. 1681-96. 
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2002; 417: 949-54). Clin Exp Dermatol, 2013. 38(2): p. 222-3. 
[51] Yao, Z., et al., BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that 
Determine Their Sensitivity to Pharmacologic Inhibition. Cancer Cell, 2015. 28(3): p. 370-83. 


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mutations in melanoma. Nat Genet, 2011. 44(2): p. 133-9. 
[53] Ojesina, A.I., et al., Landscape of genomic alterations in cervical carcinomas. Nature, 2014. 
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[54] Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature, 
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[59] Chapman, P.B., et al., Improved survival with vemurafenib in melanoma with BRAF V600E 
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14 Appendices 
14.1 
Appendix 1 RECIST v1.1 
Statement: this appendix is internal translation material only for reference. Actual operation should 
be based on English version. 
Interpretation 


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At baseline, tumour lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
Measurable lesions 
Tumor lesions: must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
- 10mm by CT scan (CT scan slice thickness no greater than 5 mm) 
- 10mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable) 
- 20mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable lesions 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph nodes 
with ≥10mmto <15mm short axis) as well as truly non-measurable lesions. Lesions considered 
truly non-measurable include: meningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by pharmacological exam that is not measurable by 
reproducible imaging techniques, and cystic lesions. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
- Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance 
of bone lesions; 
- Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above; 
- Blastic bone lesions are non-measurable. 
Cystic lesions: 


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- Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts; 
- “Cystic lesions” thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if noncystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
- Tumour lesions situated in a previously irradiated area, or in an area patiented to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such lesions 
would be considered measurable. 
Specifications by methods of measurements 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
reported lesion at baseline and during follow-up. Imaging based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by colour photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. CT, MRI: CT is the best currently available and reproducible method 
to measure lesions selected for response assessment. This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5mm or less. when CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 


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Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next). If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumour evaluation is 
not advised. However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following complete response or 
surgical resection is an endpoint. 
Tumour markers: Tumour markers alone cannot be used to assess objective tumour response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in complete response. Because tumour markers are disease specific, instructions for 
their measurement should be incorporated into protocols on a disease specific basis. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent 
prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup has 
developed CA-125 progression criteria which are to be integrated with objective tumour 
assessment for use in at least first-line trials in ovarian cancer. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumour types such as germ cell 
tumours, where known residual benign tumours can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumour has met criteria for response 
or stable disease in order to differentiate between response (or stable disease) and progressive 
disease. 
Tumour response evaluation 
Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumour 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable disease at baseline should be included in protocols where objective tumour response 
is the primary endpoint. Measurable disease is defined by the presence of at least one measurable 
lesion. In studies where the primary endpoint is tumour progression (either time to progression or 
proportion with progression at a fixed date), the protocol must specify if entry is restricted to those 
with measurable disease or whether patients having non-measurable disease only are also eligible. 
Baseline documentation of target and non-target lesions 


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When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥ 
15mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short 
axis of the node is the diameter normally used by radiologists to judge if a node is involved by 
solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may 
be axial, saggital or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node which is reported as being 20mm·× 30mm has a short axis of 20mm and qualifies 
as a malignant, measurable node. In this example, 20mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 mm) should be 
considered non-target lesions. Nodes that have a short axis <10mm are considered non-
pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference of baseline diseases. 
All other lesions including pathological lymph nodes should be identified as non-target lesions and 
should also be recorded at baseline. Measurements are not required and these lesions should be 
followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. In addition, it is possible 
to record multiple target lesions involving the same organ as a single item on the case record form 
(e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response Criteria 
This section provides the definitions of the criteria used to determine objective tumour response 
for target lesions. 
Evaluation of target lesions 


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Complete response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have short axis <10 mm. 
Partial response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diameters. 
Progressive disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions 
is also considered progression) 
Stable disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
Special notes on the assessment of target lesions: 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to below 10mm on study. This means that when lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of <10mm. Case report forms or other 
data collection methods may therefore be designed to have target nodal lesions recorded in a 
separate section where, in order to qualify for CR, each node must achieve a short axis <10mm. 
For PR, SD and PD, the actual short axis measurement of the nodes is to be included in the sum 
of target lesions. 
Target lesions that become ‘too small to measure’: While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g. 2mm). However, sometimes lesions or lymph nodes which 
are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being ‘too small to measure’. 
When this occurs, it is important that a value be recorded on the case report form. If it is the opinion 
of the radiologist that the lesion has likely disappeared, the measurement should be recorded as 
0mm. If the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5mm should be assigned. (Note: It is less likely that this rule will be used for lymph nodes 
since they usually have a definable size when normal and are frequently surrounded by fat such as 
in the retro peritoneum; however, if a lymph node is believed to be present and is faintly seen but 
too small to measure, a default value of 5mmshould be assigned in this circumstance as well.) This 
default value is derived from the 5mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 


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error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the ‘coalesced lesion’. 
The table below provides the definitions of the criteria used to determine the tumour response for 
the group of non-target lesions. 
Evaluation of non-target lesions 
Complete response (CR): 
Disappearance of all non-target lesions and normalization of tumour marker level. All 
lymph nodes must be non-pathological in size (<10mm short axis). 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker 
level above the normal limits. 
Progressive disease (PD): 
Unequivocal progression (see comments below) of existing non-target lesions. Notes: 
the appearance of one or more new lesions is also considered progression). 
Special notes on assessment of progression of non-target disease: 
The concept of progression of non-target disease requires additional explanation as follows: When 
the patient also has measurable disease to achieve ‘unequivocal progression’ on the basis of the 
non-target disease, there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of SD or PR in target disease, the overall tumour burden has increased 
sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size of one or more 
non-target lesions is usually not sufficient to quality for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in the face 
of SD or PR of target disease will therefore be extremely rare. 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a response 
may not be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of best overall response. Protocols must specify 
how any new therapy introduced before progression will affect best response designation. The 
patient’s best overall response assignment will depend on the findings of both target and non-target 
disease and will also take into consideration the appearance of new lesions. furthermore, depending 
on the nature of the study, the protocol requirements and confirmatory measurement standard of 


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results. Specifically, in non-randomized trials where response is the primary endpoint, 
confirmation of PR or CR is needed to deem either one the best overall response. 
Time point response 
The table below provides evaluation for patients with target lesions and patients with non-target 
lesions only (no target lesion). 
Time point response: patients with target (+/- non-target) lesions 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = non-
evaluable. 
Time point response: patients with non-target lesions only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
Not evaluated 
Equivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Note: ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease. Since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this category 


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when no lesions can be measured is not advised. For equivocal findings of progression (e.g. very 
small and uncertain new lesions; cystic changes or necrosis in existing lesions), treatment may 
continue until the next scheduled assessment. If at the next scheduled assessment, progression is 
confirmed, the date of progression should be the earlier date when progression was suspected. 
Missing assessments and non-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable 
(NE) at that time point. If only a subset of lesion measurements is made at an assessment, usually 
the case is also considered NE at that time point, unless a convincing argument can be made that 
the contribution of the individual missing lesion(s) would not change the assigned time point 
response. This would be most likely to happen in the case of PD. For example, if a patient had a 
baseline sum of 50mm with three measured lesions and at follow-up only two lesions were 
assessed, but those gave a sum of 80 mm, the patient will have achieved PD status, regardless of 
the contribution of the missing lesion. 
Best overall response 
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response IS NOT 
required: Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be best response, it must 
also meet the protocol specified minimum time from baseline. If the minimum time is not met 
when SD is otherwise the best time point response, the patient’s best response depends on the 
subsequent assessments. For example, a patient who has SD at first assessment, PD at second and 
does not meet minimum duration for SD, will have a best response of PD. The same patient lost 
to follow-up after the first SD assessment would be considered not evaluable. 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). See the following table 
for further information. 
Best Overall Response when Confirmation of CR and PR Required 
Overall 
response 
First time 
point 
Overall 
response 
Subsequent 
time point 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 


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


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14.2 
Appendix 2  ECOG performance status score 
Grade 
Performance Status 
0 
Asymptomatic, fully active, able to carry on all pre-disease activities without restriction. 
1 
Symptomatic but completely ambulatory, restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature. For example, light housework, office work. 
2 
Symptomatic, ambulatory and capable of all self care but unable to carry out any work activities. Up 
and about more than 50% of waking hours, < 50% in bed during the day. 
3 
Symptomatic, capable of only limited self-care, confined to bed or chair 50% or more of waking 
hours, but not bedbound. 
4 
Completely disabled, cannot carry on any self-care, bedbound. 
5 
Death. 
References:  
Am. J. Clin. Oncol.:Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982. 
 
 


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14.3 
Appendix 3  Cockcroft-Gault formula and calculation formula of body surface area 
Serum creatinine concentration (mg/dL): 
Creatinine clearance rate of males (mL/min) = 
(140−Age)×(Body weight)a
(72)×(Serum creatinine)  
Creatinine clearance rate of females (mL/min) = 
(0.85)(140−Age)×(Body weight)a
(72)×(Serum creatinine)
 
Serum creatinine concentration (µmol/L):  
Creatinine clearance rate of males (mL/min) = 
(140−Age)×(Body weight)a
(0.81)×(Serum creatinine)  
Creatinine clearance rate of females (mL/min) = 
(0.85)(140−Age)×(Body weight)a
(0.81)×(Serum creatinine)
 
a 
The unit of age is year and that of body weight is kilogram. 
 
 


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14.4 
Appendix 4  Women of child-bearing age and contraceptive measures 
Women of child-bearing age refer to any women who have experienced menarche, not experienced 
surgical sterilization (hysterectomy or bilateral ovariectomy) and not yet reached menopause. 
Menopause refers to 12-month menostasis of women aged over 45 years in circumstance of lacking 
other biological or physiological causes. In addition, menopause can be confirmed only serum 
follicle-stimulating hormone (FSH) level in women aged below 55 years > 40 mIU/mL. 
- 
Women receiving hormone replacement therapy (HRT) may have artificially inhibited FSH 
levels. Therefore, a wash-out period may be required to reach the physiological FSH level. 
The duration of wash-out period is associated with the functions of HRT. Wash-out duration 
recommended by the guideline is as follows. An investigator shall inspect serum FSH level at 
his or her discretion. If serum FSH level at any time of the whole wash-out period > 40 mIU/ml, 
the woman will be regarded as menopause: 
- 
At least one week of using vaginal hormone products (pessulum, ointment, gel) 
- 
At least four weeks of using transdermal products 
- 
At least eight weeks of using products for oral administration 
Patients (including sexual partners of male patients) of child-bearing potential shall take full 
contraceptive measures and avoid donating eggs and sperms between the date of signing an 
informed consent form and month 6 after the last dose. Contraceptive measures acceptable in the 
study include: absolutely asexual life; intrauterine device (IUDs, e.g. Copper T); cervical cap 
(adding spermicidal cream or gel) plus male condom; diaphragm (adding spermicidal cream or 
gel) plus male condom or other two or more contraceptive measures. Patients will be provided 
with information on relevant acceptable contraceptive measures during patients’ inform consent 
process. 
 
 


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14.5 
Appendix 5  New York Heart Association (NYHA) Functional Classification 
Ⅰ 
Patients have heart disease, but no limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea or angina pectoris. 
Ⅱ 
Patients have heart disease and slight limitation of physical activity. Comfortable at rest. Ordinary physical 
activity results in undue fatigue, palpitation, dyspnea or angina pectoris. 
Ⅲ 
Patients have heart disease leading to marked limitation of physical activity. Comfortable at rest. Less than 
ordinary activity causes undue fatigue, palpitation, dyspnea or angina pectoris. 
Ⅳ 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any 
physical activity is undertaken, discomfort increases. 
 
 
 


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14.6 
Appendix 6  QTc Fridericia's formula 
QTcF = 
𝐐𝐓
√𝑹𝑹
𝒂
 
 
QT refers to the interval from the start of the Q wave to the end of the T wave. 
RR refers to the interval from the occurrence of QRS wave group to the occurrence of the next 
QRS wave. 
 
 


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14.7 
Appendix 7 CYP3A4 inhibitor and inducer 
CYP3A4 inhibitor 
CYP3A4 inducer 
Potent: 
- 
Protease inhibitor 
- 
Ritonavir   
Crizotinib 
- 
Indinavir  
Darunavir  
- 
Nelfinavir   
Delavirdine  
- 
Saquinavir  
Dronedarone 
- 
Danoprevir  
Elvitegravir  
- 
Fosamprenavir   
Amprenavir  
- 
Macrolides antibiotics 
- 
Clarithromycin 
- 
Telithromycin 
- 
Chloramphenicol (antibiotics) 
- 
Azole antifungals 
- 
Ketoconazole 
- 
Itraconazole 
- 
Nefazodone (antidepressant) 
Intermediate: 
- 
Aprepitant (antemetic) 
- 
Calcium channel blockers 
- 
Verapamil 
- 
Diltiazem 
- 
Macrolides antibiotics 
- 
Erythromycin 
- 
Azole antifungals 
- 
Fluconazole 
- 
Bergamottin (grapefruit juice) 
- 
Valerian 
Weak: 
- 
Fluoxetine/norfluoxetine 
- 
Cimetidine (H2-antagonist) 
- 
Anticonvulsants, mood stabilizer 
- 
Carbamazepine 
- 
Phenytoin (anticonvulsants) 
- 
Oxcarbazepine 
- 
Barbiturate 
- 
Phenobarbital  
Modafinil 
- 
Butalbital  
Nafcillin 
- 
Bosentan  
Nevirapine 
- 
Enzalutamide   
Primidone 
- 
Etravirine  
Rifabutin 
- 
Fosphenytoin  
Semagacestat 
- 
Mephenytoin  
Talviraline 
- 
Methylphenobarbital  Thioridazine 
- 
Mitotane  
Vemurafenib 
- 
St John's wort (hypericum perforatum) 
- 
Bactericide 
- 
Rifampicin 
- 
Rifabutin 
- 
Non-nucleoside reverse transcriptase inhibitor 
- 
Efavirenz 
- 
Nevirapine 
- 
Hypoglycemic agents 
- 
Pioglitazone 
- 
Troglitazone 
- 
Glucocorticoid 
(glucose 
increased, 
immunosuppression) 
- 
Modafinil (stimulant) 


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CYP3A4 inhibitor 
CYP3A4 inducer 
- 
Buprenorphine (analgesic) 
- 
Cafestol (unfiltered coffee) 
- 
Orphenadrine 
 
Sensitive Substrates of CYP2C8, CYP2C9, and CYP2C19 
CYP2C8 
CYP2C9 
CYP2C19 
Repaglinide 
Tolbutamide, warfarin 
Lansoprazole, omeprazole 
 
 
 


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14.8 
Appendix 8 Examples of P-gp inhibitor 
Amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and 
ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, verapamil 
Source: http//www.fda.gov/drug/drug-interactions-labeling 
 

SAP_001.pdf: 
Product:  HH2710 
Statistical Analysis Plan: 2.0 
Dated: 16May2023 
Page 1 
 
 STATISTICAL ANALYSIS PLAN 
 
 
A First-in-Human, Open Label, Phase I/II Study to Evaluate 
the Safety, Tolerability and Pharmacokinetics of HH2710 in 
Patients with Advanced Tumors 
 
ClinicalTrials.gov ID: NCT04198818 
 
 
                                
 
 
 
Sponsor: 
Haihe Biopharma Co., Ltd 
Protocol Number: 
HH2710-G101 
Version: 
Version 2.0 
Date: 
16 May 2023 
Author: 
Yin Huang 
 


Product:  HH2710 
Statistical Analysis Plan: 2.0 
Dated: 16May2023 
Page 2 
 
Signature Page  
 
 
A First-in-Human, Open Label, Phase I/II Study to Evaluate 
the Safety, Tolerability and Pharmacokinetics of HH2710 in 
Patients with Advanced Tumors 
 
Protocol Number: 
HH2710-G101 
Version: 
Version 2.0 
 
 
Author 
 
 
____________________________  
 
        Date: ______________   
            Yin Huang 
 
Title: Statistician 
            Tigermed Consulting Co., Ltd. 
Reviewer 
 
 
 
____________________________  
 
          Date: ______________   
            Joe Yao 
 
Title: Review Statistician 
            Tigermed Consulting Co., Ltd. 
 
 
Approver 
 
__________________________ 
 
                      Date_____________   
           Meng Li 
           Title: Statistician  
            Haihe Biopharma Co., Ltd 
 


Product:  HH2710 
Statistical Analysis Plan: 2.0 
Dated: 16May2023 
Page 3 
 
 
Amendment History 
Version 
Date 
Author 
Description 
0.7 
2021-06-10 
Bruce Hu 
 
1.0 
2023-05-09 
Yin Huang 
1. Remove phase Ⅱ exploratory objective and 
exploratory endpoint since it was 
not planned currently in protocol summary and 
section 3 
2. Update the sample size 
3. Remove the “and safety analysis set” in section 
8.3 
4. Update the definition of TEAE in section 8.8.1 
5. Remove “24 hour…” from Urinalysis in 
section 8.8.3 
6. Add pulse in section 8.8.4 and Table 3 
7. Add “The HH2710 program…” in section 7 
planned analyses 
 
2.0 
2023-05-16 
Yin Huang 
1. Update “all-treated” to “full analysis” in section 
8.2, 8.7 
2. Update “Incidence Rate ≥ 5%” to “Incidence 
Rate ≥ 10%” in section 8.8.1  
3. Add censoring rule for TTR, TTP in section 10 
 
 
 
 
 


Product:  HH2710 
Statistical Analysis Plan: 2.0 
Dated: 16May2023 
Page 4 
 
TABLE OF CONTENTS 
Page 
Table of Abbreviations ............................................................................................. 6 
1. 
Introduction .................................................................................................... 7 
2. 
Objectives ...................................................................................................... 7 
2.1 
Primary ............................................................................................... 7 
2.2 
Secondary ........................................................................................... 7 
2.3 
Exploratory .......................................................................................... 7 
3. 
Study Overview .............................................................................................. 7 
3.1 
Study Design ....................................................................................... 7 
3.2 
Sample Size ........................................................................................ 9 
4. 
Study Endpoints and Covariates ..................................................................... 11 
4.1 
Study Endpoints .................................................................................. 11 
4.2 
Planned Covariates ............................................................................. 12 
5. 
Hypotheses and/or Estimations ....................................................................... 12 
6. 
Analysis Sets ................................................................................................. 12 
6.1 
Full Analysis Set (FAS) ........................................................................ 12 
6.2 
Safety Analysis Set (SAS) .................................................................... 12 
6.3 
Pharmacokinetic Analysis Set (PKS) ..................................................... 12 
6.4 
Pharmacodynamics analysis set (PDS) ................................................. 12 
6.5 
Subgroup Analyses ............................................................................. 12 
7. 
Planned Analyses .......................................................................................... 13 
7.1 
Interim Analysis and Early Stopping Guidelines ..................................... 13 
7.2 
Primary Analysis ................................................................................. 13 
8. 
Statistical Methods of Analysis ........................................................................ 14 
8.1 
General Principles ............................................................................... 14 
8.2 
Major Protocol Deviations .................................................................... 15 
8.3 
Demographic and Baseline Characteristics ............................................ 15 
8.4 
Medical history .................................................................................... 15 
8.5 
Prior and Concomitant Medications/Procedures ..................................... 16 
8.6 
Study Drug Exposure .......................................................................... 16 
8.7 
Efficacy Analyses ................................................................................ 17 
8.7.1.1 
Best Overall Response .......................................... 17 
8.7.1.2 
Analysis of Primary Efficacy Endpoint ..................... 17 
8.7.1.3 
Analysis of Secondary Efficacy Endpoint ................. 17 
8.7.1.4 
Analysis of Exploratory Efficacy Endpoint ............... 17 


Product:  HH2710 
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8.8 
Safety Analyses .................................................................................. 18 
8.8.1.1 
Adverse Events .................................................... 18 
8.8.1.2 
Dose Limiting Toxicity (DLT ) ................................ 19 
8.8.1.3 
Laboratory Test Results ........................................ 19 
8.8.1.4 
Vital Signs ........................................................... 20 
8.8.1.5 
Physical Examination ............................................ 21 
8.8.1.6 
Analysis of 12-lead ECG ........................................ 21 
8.8.1.7 
Analysis of ECOG ................................................. 21 
8.9 
Pharmacokinetic Analysis .................................................................... 21 
8.10 
Pharmacodynamics Analysis ................................................................ 22 
8.11 
Exploratory Biomarker Endpoints Analysis ............................................. 22 
8.12 
Changes From Protocol-specified Analyses ........................................... 22 
9. 
Literature Citations / References ...................................................................... 24 
10. 
Appendices .................................................................................................... 25 
10.1 
Appendix A Censor rule for PFS, DoR ................................................... 25 
10.2 
Appendix B Censor rule for TTR ........................................................... 25 
10.3 
Appendix C Censor rule for TTP ........................................................... 26 
10.4 
Appendix D. Laboratory Grading and Notable Vital Sign Values .............. 26 
10.5 
Appendix E  Definitions ........................................................................ 28 
 
List of Tables 
Table 2.  Grading of Select Laboratory Parameters .................................................... 27 
Table 3.  Notable Abnormalities of Vital Signs ........................................................... 27 
 


Product:  HH2710 
Statistical Analysis Plan: 2.0 
Dated: 16May2023 
Page 6 
 
Table of Abbreviations 
Term or Abbreviation 
Description 
ATD  
Accelerated Titration Designs 
CRF 
Case Report Form 
DLT 
Dose Limiting Toxicity 
DoR 
duration of response 
ECG 
Electrocardiogram 
EOI 
Event Of Interest 
E-R 
Exposure-Response 
IBG 
Independent Biostatistics Group 
IPD 
ORR 
Important Protocol Deviation 
Objective Response Rate 
OS 
overall survival 
KM 
Kaplan-Meier  
MedDRA 
Medical Dictionary for Regulatory Activities 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SMC 
Safety Monitoring Committee 
PD 
Pharmacodynamic or pharmacodynamics 
PFS 
progression-free survival 
PK 
Pharmacokinetic or Pharmacokinetics 
t1/2 
plasma elimination half-life 
TEAE 
treatment-emergent adverse event 
tmax 
peak time 
WHODRUG 
World Health Organization Drug dictionary 
 


Product:  HH2710 
Statistical Analysis Plan: 2.0 
Dated: 16May2023 
Page 7 
 
1. 
Introduction 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study HH2710 Protocol-EN-
V2.0-final dated 21Mar2022 and CRF HH2710-G101-CRF 2022-05-11. The scope of 
this plan includes the interim analysis, the primary analysis and final analysis that are 
planned and will be executed by the Biostatistics and data sciences department of 
Tigermed Consulting Co., Ltd.. This SAP follows the ICH Good Clinical Practice 
guidance including ICH E9 and other related guidelines. 
2. 
Objectives 
2.1 
Primary 
Phase I: 
To evaluate the safety and tolerability of HH2710 administered orally in patients with 
advanced tumors; 
To identify the Maximum Tolerated Dose (MTD) and/or Recommended Phase II 
dose (RP2D). 
Phase II: 
To evaluate efficacy of HH2710 in patients with advanced tumors with MAPK 
signaling pathway genetic alterations, at the recommended phase 2 dose (RP2D). 
2.2 
Secondary 
Phase I: 
To characterize the pharmacokinetic profile of HH2710 and selected metabolites 
when administered orally in patients with advanced tumors. 
Phase II: 
To evaluate the efficacy of HH2710 in advanced tumor patients with MAPK 
signaling pathway genetic alterations. 
To evaluate the safety of HH2710. 
2.3 
Exploratory 
Phase I: 
To assess the preliminary efficacy of HH2710. 
To explore the changes of the pharmacodynamics (PD) markers of HH2710. 
3. 
Study Overview 
3.1 
Study Design 
This is an open-label, multicenter, first-in-human Phase I/II study which is composed of a 
Phase I dose escalation stage, phase I dose expansion stage and a Phase II dose extension 
stage.  
3.1.1       Phase I: Dose escalation 


Product:  HH2710 
Statistical Analysis Plan: 2.0 
Dated: 16May2023 
Page 8 
 
The accelerated titration (ATD) incorporated with Bayesian optimal interval (BOIN) 
design will be used to assess the safety and tolerability, and furthermore, to help find the 
maximum tolerated dose (MTD), and/or to establish the recommended phase 2 dose 
(RP2D) combined with data from other sources. 
A maximum sample size is 58 patients for the dose escalation (ATD + BOIN). The total 
number of patients will depend upon the number of dose escalations actually needed. 
Accelerated titration part: 
One patient per cohort will be assigned to receive HH2710. The first three patients will 
take HH2710 once daily(QD) in cycle 1 day 1 for the single dose PK testing, from the 
second day, HH2710 will be administered orally on a continuous twice daily (BID). 
The proposed dose level in accelerated titration stage is 25mg, 50mg and 100mg twice 
daily (BID). It may be adjusted according to the available data. 
BOIN design part:  
When there is an adverse event of grade≥2 occurs, the dose escalation process will shift 
to a BOIN design, in which at least 3 patients per treatment cohort will be assigned (ATD 
+ BOIN design details please see Protocol Section 6.2.3) 
The provisional dose levels are planned different doses (25mg, 50mg, and 100mg BID, 
300mg QD, 400mg (BID/QD), 600mg (BID/QD), and 800mg (BID/QD)) (See details in 
Protocol Section 6.2.2). Dosing frequency and dose level may be adjusted based on 
available pharmacokinetic and safety data. 
When 800mg QD escalation cohort and 600mg QD expansion cohort suspended due to 
safety concerns, 300mg QD dose level has been added to explore before or while 
proceeding with further dose escalation. In addition, an alternative BID dosing regimen 
starting from 200mg is also reinitiated to better understand the safety, tolerability and PK 
of HH2710 in dose escalation stage. 
After the escalation is completed, select the MTD based on the isotonic regression as 
specified in [1]. Specifically, select the MTD for which the isotonic estimate of the 
toxicity rate is closest to the target toxicity rate. If there are ties, select the higher dose 
level when the isotonic estimate is lower than the target toxicity rate and select the lower 
dose level when the isotonic estimate is greater than or equal to the target toxicity rate. 
Dose expansion stage: 
An additional 15 patients per cohort may be included in order to further evaluate the 
safety, pharmacokinetics and anti-tumor activities among biomarker-selected patients. 
One or more dose levels may be expanded based on the available data. Patients enrolled 
could have different tumor types but must be confirmed with specific MAPK pathway 
genetic alteration (the same requirement as in phase II). The total number of patients will 
depend upon the number of dose expansions necessary. 
3.1.2     Phase II Dose extension: 
This is an open-label, multicenter, dose extension stage at RP2D to explore the response 
of patients with particular tumor types harboring MAPK genetic alteration. A maximum 
of 108 patients will be enrolled. 


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Patients enrolled will be divided into four cohorts once RP2D is defined and each of them 
focuses on specific tumors with specific genetic alteration, which NGS (next generation 
sequencing) will be used to detect, described as follows:  
- Cohort 1: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, NRAS 
Q61, BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated melanoma; 
- Cohort 2: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, NRAS 
Q61, BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated non-small cell 
lung cancer; 
- Cohort 3: Patients with BRAF V600 mutated Langerhans Cell Histiocytosis 
Syndrome (LCH)/ Erdheim-Chester disease (ECD); 
- Cohort 4: Patients with RAS/RAF/MEK/ERK mutated tumors that are not included in 
other cohorts. 
The overall study design is described in the following study flow chart. 
Figure 1 Study Flow Chart 
 
 
 
 
 
3.2 
Sample Size 
Phase I Dose Escalation Stage: 
The planned maximum sample size in Phase I dose escalation stage (ATD + BOIN) is 58 
including up to 40 subjects for ATD + QD dose escalation cohorts (Part A) and up to 18 
subjects for the additional BID dose escalation cohorts (Part B). During the ATD, one-
patient per cohort is required for dose escalation. Once the BOIN design starts, cohorts of 
3 patients will be used for dose escalation and the maximum number of patients for each 
dose level should not exceed 15 patients and 12 patients for BOIN design Part A and Part 
B, respectively.  


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Phase I Dose Expansion Stage: 
We plan to recruit 15 evaluable patients per expansion cohort in the phase I stage of the 
study. The enrolled patients with different cancers must have confirmation of specific 
MAPK pathway genetic alteration. The primary focus of the dose expansion is to further 
assess the safety and pharmacokinetics of HH2710. Preliminary efficacy will also be 
examined but serve only for an exploratory purpose.  
Phase II Dose Extension Stage: 
In Phase II, patients will be recruited into the following 4 cohorts at the RP2D level:         
Cohort 1: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, 
NRAS Q61, BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated 
melanoma;  
Cohort 2: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, 
NRAS Q61, BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated 
non-small cell lung cancer;  
Cohort 3: Patients with BRAF V600 mutated Langerhans Cell Histiocytosis 
Syndrome (LCH)/ Erdheim-Chester disease (ECD);   
Cohort 4: Patients with RAS/RAF/MEK/ERK mutated tumors that are not 
included in other cohorts. 
Cohort 1-2 will utilize the Bayesian Optimal design for phase II trials (BOP2). The null 
hypothesis of the response rate is 0.05, and the alternative hypothesis is 0.16. The design 
controls the type I error rate at 0.1 and yields the power of 0.8201 under H1. 
Table 3-1 Optimized stopping boundaries for cohort 1 and cohort 2 in Phase II 
# patients 
treated 
Stop if # responses 
<= 
23 
1 
36 
3 
Based on Table 3-1, we will perform an interim analysis for the first 23 patients. When at 
least 2 patients experience CR or PR or SD(SD≥6 weeks) events, the study will continue 
recruiting up to 13 more patients in the second stage. When the total number of patients 
reaches the maximum sample size of 36, we reject the null hypothesis and conclude that 
the treatment is promising if the number of responses (CR or PR or SD(SD≥6 weeks)) are 
greater than 3; otherwise we conclude that the treatment is not promising. 
We plan to recruit a maximum of 9 patients in Cohort 3. Since there are currently no 
sufficient data available (due to the rarity of the disease), we are unable to calculate the 
sample size provided for an acceptable statistical justification. However, at this stage, we 
think that data from 9 patients is considered to be adequate to allow a preliminary 
investigation of the study objectives for this cohort.        
Cohort 4 will include a maximum of 27 patients. Patients included in this cohort will 
have different cancer types led by different genetic mutations. Thus, it is difficult to 
calculate sample size for this cohort based on very accurate efficacy goals (e.g. minimum 
ORR for the alternative hypothesis). Therefore, this cohort serves for an exploratory 


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purpose and the number of patients has been based on the desire to obtain adequate data 
whilst exposing as few patients as possible to the study procedures. 
 
4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints 
Primary Endpoint 
Phase I: 
Safety and Tolerability: The incidence, type, and severity of adverse events (AEs) 
assessed according to the National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) V5.0, physical examination findings,  clinical laboratory 
values, vital signs and Electrocardiograms (ECGs)  
The MTD, if any, and RP2D for HH2710 will be determined based on safety, tolerability, 
PK, preliminary efficacy, and other available data. 
Phase II: 
Tumor objective response rate (ORR) based on RECIST version 1.1. 
Secondary Endpoints  
Phase I: 
Peak plasma concentration (Cmax), peak time (tmax), area under the plasma 
concentration-time curve from time 0 to time (t) (AUC0-t), plasma elimination half-life 
(t1/2), plasma clearance rate constant (λz), apparent clearance (CL/F), apparent volume 
of distribution (Vz/F). 
Phase II: 
the duration of response (DoR), progression-free survival (PFS), disease control rate 
(DCR), time to response (TTR), time to progression (TTP), and 1-year overall survival 
(OS) rate. 
The incidence, type, and severity of adverse events (AEs) assessed according to the 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-
CTCAE) V5.0, physical examination findings, clinical laboratory values, vital signs and 
Electrocardiograms (ECGs). 
Exploratory Endpoints 
Phase I: 
ORR, DoR, DCR, PFS and TTR. 
Changes in PD markers of HH2710 efficacy including phosphorylation of RSK (pRSK) 
and total RSK. 


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4.2 
Planned Covariates 
No covariates will be accounted for in Phase I (dose-finding and dose expansion). In 
Phase II (cohort extension), analyses will be analyzed by subgroups of tumor types and/or 
genetic mutations in order to evaluate the preliminary efficacy. 
5. 
Hypotheses and/or Estimations 
Phase I: 
No hypothesis for this phase since the primary endpoint are safety profile, MTD and 
RP2D. 
Phase II for Cohort 1 and Cohort 2: 
In Cohort 1 and Cohort2, the null hypothesis of the response rate is 0.02, and the 
alternative hypothesis is 0.16. The design controls the type I error rate at 0.1 and yields 
the power of 0.8201 under H1. 
We will perform an interim analysis for the first 23 patients. When at least 2 patients 
experience CR or PR or SD (SD≥6 weeks) events, the study will continue recruiting up to 
13 more patients in the second stage. When the total number of patients reaches the 
maximum sample size of 36, we reject the null hypothesis and conclude that the 
treatment is promising if the number of responses (CR or PR or SD(SD≥6 weeks)) are 
greater than 3; otherwise we conclude that the treatment is not promising. 
No hypothesis for cohort 3 and cohort 4 of phase II since both cohorts are served as 
preliminary investigation or exploratory purpose. 
6. 
Analysis Sets 
6.1 
Full Analysis Set (FAS) 
The Full Analysis Set includes all patients who have received at least one dose of study 
medication. This set will be used for efficacy analysis. 
6.2 
Safety Analysis Set (SAS)  
The Safety Analysis Set (SAS) includes all patients who receive at least one dose of 
study medication. This set will be used for safety analysis. 
6.3 
Pharmacokinetic Analysis Set (PKS) 
The pharmacokinetic analysis set (PKS) consists of all patients who receive at least 1 
dose of study drug and have sufficient, valid PK samples to estimate key parameters for 
at least 1 of the days of sampling. 
6.4 
Pharmacodynamics analysis set (PDS) 
The pharmacodynamics analysis set (PDS) consists of all patients set who receive at least 
1 dose of study drug and have sufficient, valid PD samples to estimate key parameters for 
at least 1 of the days of sampling. 
6.5 
Subgroup Analyses 
Subgroup analyses will be performed to explore the consistency of the treatment effect 
when the sample sizes allows for meaningful interpretation. The following subgroup may 
be used to examine efficacy:  


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 
 Sex (female vs. male) 
 Age (<65 vs  ≥65)  
 Race 
 Tumor type 
 Genetic mutation 
7. 
Planned Analyses 
The HH2710 program is stopped and this study is terminated ahead of time with a limited number 
of subjects treated than planned.  As the result, many planned analyses will have insufficient data 
to render the planned analyses feasibly, meaningful or interpretable. Therefore, many of the 
planned analyses described in this SAP may not be conducted, depending on data availability or 
maturity, and purpose of the analysis. 
 
7.1 
Interim Analysis and Early Stopping Guidelines 
There are three planned interim analyses during the study. One is performed for the 
determination of RP2D when Phase I completes. The other two are conducted for futility 
evaluation for the first 23 patients in each of cohort 1 and cohort 2 when they have 
recruited and completed the assessments in Phase II. Additional or administrative interim 
analyses may be conducted as necessary by the sponsor for safety/efficacy monitoring 
while the study is ongoing. 
A Safety Monitoring Committee (SMC) will be used to evaluate safety as well as 
preliminary efficacy during the study. In Phase I, safety data will be reviewed by the 
committee after a minimum of 3 patients have been enrolled into each dose level and 
received treatment. Once the dose escalation stage completes, the committee will review 
safety data as well as data from other sources (e.g. efficacy, PK/PD) to determine the 
RP2D for Phase II.   
In Phase II, the efficacy review will be conducted for cohort 1 and cohort 2 by the 
committee when each cohort has recruited and completed the assessments for the first 23 
patients. For safety, the committee will review the data when every 6 or 12 patients have 
recruited and received treatments in all cohorts. Following the data review, the committee 
will decide as to whether the cohort may continue, whether amendment(s) to the protocol 
should be implemented, or whether the study should be stopped. 
Members of the committee will be internal and external to the sponsor, which can include 
employees of the Sponsor and study investigators. 
7.2 
Primary Analysis 
The primary analyses in Phase I focuses on safety endpoints for HH2710 administered 
alone in patients with the advanced and/or refractory tumors. The RP2D will be 
determined based upon the observed DLTs and information from other sources (e.g 
pharmacokinetics) as described in the protocol. 
In Phase II, the primary analyses will investigate the preliminary efficacy of the ORR and 
other endpoints including DoR, DCR, TTR, TTP, PFS and 1-year OS rate, and by  tumor 


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type and  by genetic mutation if warranted. The RP2D might be adjusted based on the 
phase II data. 
8. 
Statistical Methods of Analysis 
8.1 
General Principles 
TFLs will be displayed by treatment groups, which are the dose levels for phase I study 
and cohort levels for phase II study. If necessary, the same dose level may be combined 
and analyzed across phase I and II studies. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), median, minimum 
value (min), and maximum value (max). The number of subjects (n) will represent the 
number with non-missing data on the continuous variable under consideration. The 
precision of the measurement for each continuous variable will be used to determine the 
number of decimal places to present in tables, figures, and derived listings. Unless 
otherwise specified, min and max values will be reported with the same decimal as the 
units of measure; the mean, median will be reported to 1 greater decimal place, the SD 
will be reported to 2 greater decimal place, all of them will not be greater than 4 decimal 
place. Any values that require transformation to standard units (metric or International 
System [SI]) will be converted with the appropriate corresponding precision. 
Categorical variables will be summarized using counts and percentages (95% 
confidence interval of percentage if necessary). Percentages will be presented to 1 
decimal place unless otherwise specified.  
Treatment group indicates the dose level of HH2710 (such as 25 mg BID) and total (if 
more than one dose level) for phase I and cohort in Phase II.  
Baseline value, unless otherwise specified, will be defined as the last non-missing 
measurement (scheduled or unscheduled) collected prior to the initial administration of 
study drug. For example, if an assessment was performed at screening and Day 1 prior to 
initial dosing of study drug, then Baseline is the Day 1 measurement if the Day 1 value is 
not missing; if the Day 1 value is missing, then the screening value is Baseline, and so 
forth.  
Change (absolute change) from baseline will be calculated as post-baseline value - 
baseline value. 
Unscheduled visits: Subject data for safety or efficacy assessments (such as unscheduled 
labs) will be incorporated into the cycle windows appropriate to the scheduled visits. For 
summary by visit tables and figures, only scheduled visits will be included in the analysis. 
Incomplete/missing data: Unless otherwise specified, for efficacy and safety analysis, 
no imputation will be used.  If a partial dates need to be imputed for computational 
purposes, conservative conventions will be used as far as possible.  
All statistical analyses will be performed using SAS 9.4 (SAS Institute, Cary, North 
Carolina, USA). 


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8.2 
Major Protocol Deviations 
Major Protocol Deviations (MPDs) categories are defined by the study team before the 
first subject’s visit and updated during the MPD reviews throughout the study prior to 
database lock.  These definitions of MPD categories, sub-category codes and descriptions 
will be used during the course of the study.  
For phase I and phase II, a summary of the number and percentage of subjects with a 
major protocol deviation by type of deviation will be provided using the full analysis set. 
Individual subject listings of protocol deviations will be provided. 
8.3 
Demographic and Baseline Characteristics 
For phase I and phase II, demographic (ie, age, age group [<65, ≥65], sex and race) and 
baseline disease characteristics will be summarized using descriptive statistics for the full 
analysis set. Though different names, these two sets have the same definition and subjects. 
The baseline characteristics to be summarized include: 
Weight (kg) 
Height (cm) 
Body mass Index (kg/m**2) 
ECOG performance status 
Tumor Histology and pathology type 
Tumor Stage 
Genetic mutation type 
Number of metastases at baseline 
Location of metastases at baseline 
Subject received any prior systemic anti-tumor therapy: Number of prior lines or 
regimens of therapy, Best overall response 
Received radiotherapy for Tumor 
Received surgery for Tumor 
8.4 
Medical history 
For phase I and phase II, medical history will be coded according to MedDRA (version 
23.0 or higher).  
The number and percentage of subjects experiencing a medical history will be 
summarized by the MedDRA System Organ Class and Preferred Term. Subjects 
reporting more than one condition/diagnosis within a System Organ Class will be counted 
only once for that System Organ Class. 
For phase I, medical history will be based on the safety analysis set; and for phase II, 
medical history summaries will be based on the full analysis set. 


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8.5 
Prior and Concomitant Medications/Procedures  
For phase I, medication/procedure summaries will be based on the safety analysis set; and 
for phase II, medication/procedure summaries will be based on the full analysis set. All 
medications will be coded using WHOdrug global B3, 201903 or higher.  
Medications used in the study will be classified in two parts:  
1.   Prior medication: medication that ended before the first dose of study drug, regardless 
of when dosing of the medication started. 
2.   Concomitant medication: medications ended after or on the first dose of study drug or 
medication with missing stop date, regardless of when dosing of the medication started. 
The following medication categories will also be summarized by ATC2 and preferred 
term. 
1. Prior Anti-tumor Medication 
2. Prior Non-Anti-tumor Medication 
3. Post-Treatment Anti-tumor Medication 
Missing or partial dates will be imputed for medication. Algorithm for missing or partial 
start date is: 
Missing day: first day of the month is imputed; 
Missing month: January is imputed; 
Missing year: not imputed. 
Algorithm for missing or partial end date is: 
Missing day: last day of the month is imputed; 
Missing month: December is imputed (31 December if day is also missing); 
Missing year: not imputed. 
Missing data algorithms will be reviewed to ensure the algorithm works. For example, 
end date will not be before the start date after the imputation. 
8.6 
Study Drug Exposure  
Total number of cycles is defined as the maximum number of treatment cycles that a 
subject receives. Total cumulative dose (mg) is the sum of the actual doses that the 
subject receives across cycles. Total planned dose (mg) is the sum of the planned doses.  
Actual exposed weeks = (Last dosing day – first dosing day +1)/7; 
Total planned Dose (mg) = Planned dose* (Last dosing day – first dosing day +1); 
Planned exposed weeks = 21*number of cycles/7; 
Relative dose intensity is defined as follows: 
Relative dose intensity = (total cumulative dose/actual exposed weeks)/ (Total planned 
/planned exposed weeks) *100%  


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The total number of cycles, total cumulative dose (mg), total planned dose (mg), relative 
dose intensity and categorized as < 80%, 80% - 120%, >120% will be summarized for 
each component of the dosing regimen for phase I and phase II. 
A dose reduction, dose interruption, dose withdrawn and their reasons will be 
summarized by treatment group for phase I and phase II. 
The study drug exposure will be summarized based on the safety analysis set.  
8.7 
Efficacy Analyses  
The efficacy analysis will be based on full analysis set. 
8.7.1.1 
Best Overall Response 
Best Overall Response (BOR) is defined as the best overall response recorded from the 
start of treatment until disease progression or initiation of alternative therapy or end of 
study. A summary of subjects achieving a best overall response in a given category (CR, 
PR, SD, PD, NE, and Missing) will be provided.  
In phase II, BOR will be summarized by investigator. 
8.7.1.2 
Analysis of Primary Efficacy Endpoint 
Objective response rate (ORR) will be calculated and summarized by treatment group, 
along with the 95% of confidence interval calculated by the Clopper-Pearson method.  
8.7.1.3 
Analysis of Secondary Efficacy Endpoint 
If the sample size or the number of responders allow for meaningful interpretation, 
Kaplan-Meier method will be used to analyze the duration of response (DoR), the 
progression-free survival (PFS), time to response (TTR) and time to progression (TTP) 
for each tumor type, genetic mutation and other factors required by sponsor. If possible, a 
95% of confidence interval band should be provided for each estimate.  
For all the time-to-event endpoints (DoR, PFS, TTR and TTP), the survival curve will be 
estimated by the Kaplan-Meier estimate, and the first percentile, the median survival, the 
third percentile and their 95% CI will be provided.  
For Time to Response (TTR) and Duration of Response (DoR), only subjects with BOR 
is CR/PR during the study treatment will be calculated.  
DCR and 1-year overall survival (OS) rate will be estimated and analyzed by the same 
methods as those in ORR. 
The listing of all the time-to-event endpoints will be provided.  
See Appendix , B, C and E for detailed rule of Censor date for PFS and other time-to-
event endpoints. 
8.7.1.4 
Analysis of Exploratory Efficacy Endpoint 
If there exsits exploratory efficacy endpoints analysis, it will be included in separate 
analysis documents. 


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8.8 
Safety Analyses 
8.8.1.1 
Adverse Events 
AEs will be coded according to MedDRA (version 23 or higher). The severity of adverse 
events will be judged in accordance with NCI CTCAE 5.0. The number and percentage 
of subjects experiencing an AE will be summarized by System Organ Class and Preferred 
Term. AEs will be classified as pretreatment or treatment-emergent. 
Treatment-emergent AEs (TEAEs) are defined as AEs that were reported or worsened 
on or after the start of study drug dosing and up to the safety follow-up.  
For any SAE that occurs after the safety follow-up and was related to study drug, it will 
be considered to a TEAE.     
Missing or partial dates will be imputed for AE. Algorithm for missing or partial start 
date is: 
Missing day: if month/year equal to month and year of first dose date, then impute to 
date of the first dose; else impute to first day of the month.  
Missing month: if year equal to year of first dose date, then impute to date of the first 
dose; else impute to Jan01 of the year. 
Missing year: impute to first dose date if first dose date<AE end date, else impute to 
ICF date. 
Algorithm for missing or partial end date is: 
Missing day: last day of the month is imputed; 
Missing month: impute to 31 December  
Missing year: not imputed. 
Missing data algorithms will be reviewed to ensure the algorithm works. For example, 
end date will not be before the start date after the imputation. 
Only TEAEs will be summarized in tables. 
The overall TEAE summary will include the following: 
 All TEAEs (regardless of relationship to study drug) 
Grade ≥ 3 TEAEs  
Treatment related TEAEs  
Treatment related Grade ≥ 3 TEAEs  
Serious TEAEs 
Treatment related serious TEAEs 
TEAEs leading to dose reduced 


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TEAEs leading to dose interrupted 
TEAEs leading to study drug withdrawn  
TEAEs leading to Death 
Treatment related TEAEs leading to dose reduced 
Treatment related TEAEs leading to dose interrupted 
Treatment related TEAEs leading to study drug withdrawn 
Treatment related TEAEs leading to Death 
The TEAEs, TEAEs related to study drug, TEAEs leading to study drug withdrawn, 
Treatment related TEAEs leading to study drug withdrawn, Grade ≥ 3 TEAE, Treatment 
related Grade≥ 3 TEAEs, TEAE by worst CTCAE Grade, Treatment related TEAEs by 
worst CTCAE Grade, Serious TEAEs,  Treatment related serious TEAEs, TEAE leading 
to dose reduced, Treatment related TEAEs leading to dose reduced, TEAE leading to 
dose interrupted, Treatment related TEAEs leading to dose interrupted, TEAEs leading to 
death, Treatment related TEAEs leading to death, TEAEs with an Incidence Rate ≥ 10% 
and Treatment related TEAEs with an Incidence Rate ≥ 10% summary will be presented 
by MedDRA system organ class and preferred term using frequency counts and 
percentages in descending order of frequency separately.  
The number and percentage of subjects with death and the primary cause will 
summarized and listed for subjects in the Safety Analysis Set. 
All AEs, Serious AEs and AEs leading to Death will be listed in an individual subject 
data listing. 
8.8.1.2 
Dose Limiting Toxicity (DLT ) 
The listing for dose limiting toxicity will be provided. 
8.8.1.3 
Laboratory Test Results 
Hematology, blood biochemistry and urinalysis will be conducted in the screening period, 
treatment period and follow-up period according to study process, and examination 
frequency will be increased according to clinical indications. 
Specific evaluation items include: 
● Hematological test: red blood cell count, hemoglobin, hematocrit, reticulocyte count, 
platelet count and absolute leukocyte differential count (neutrophil, lymphocyte, 
eosinophils, monocyte, basophils); 
● Blood biochemical test: Total protein, albumin, total bilirubin, direct bilirubin, ALT, 
AST, Gamma-glutamyl transferase, Creatine phosphokinase, Alkaline phosphatase, 
Lactate dehydrogenase, Blood urea nitrogen, Urea, Creatinine, Uric acid, Blood glucose, 
Chloride, Sodium, Potassium, Calcium, Phosphate, Amylase, Lipase and CKMB.  
● Urinalysis: specific gravity, urine glucose, protein, white blood cell (qualitative) and 
red blood cell (qualitative).; 


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● Coagulation function test: prothrombin time, activated partial thromboplastin time and 
international normalized ratio; 
● Pregnancy test (applicable to non-menopausal women); 
An observed value and change from baseline in laboratory by visit descriptive table will 
be provided by treatment group.  
For serum chemistry, hematology and urinalysis data, a shift table between the worst 
post-baseline clinical significance and baseline clinical significance will be provided by 
treatment group.  
For liver safety, summaries of the liver chemistry elevations will be presented in the table 
according to Table .  
Table 1 Liver Chemistry Elevations 
Test 
Categary 
ALT  or AST increased 
>= 3 * ULN 
 
>= 5 * ULN 
 
>= 10 * ULN 
 
>= 20 * ULN 
 
 
ALT increased 
>= 3 * ULN 
 
>= 5 * ULN 
 
>= 10 * ULN 
 
>= 20 * ULN 
 
 
AST increased 
>= 3 * ULN 
 
>= 5 * ULN 
 
>= 10 * ULN 
 
>= 20 * ULN 
 
 
TBIL increased 
>= 1.5 * ULN 
 
>= 2 * ULN 
 
 
ALP increased 
>= 1.5 * ULN 
In additional, ALT or AST >=3 * ULN and TBIL>= 2 * ULN and ALP < 2*ULN, ALT 
or AST >=3 * ULN and TBIL>= 2 * ULN, ALT and AST >=3 * ULN and TBIL>= 1.5 * 
ULN will also presented in this table. 
The listing for abnormal findings in laboratory data will be provided. 
8.8.1.4 
Vital Signs 
An observed value and change from baseline in vital sign by visit descriptive table will 
be provided by dose group. 
The number and percentage of subjects with abnormal changes (defined in Appendix D) 
in systolic blood pressure, diastolic blood pressure, pulse/heart rate, respiratory rate and 


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temperature will summarized for subjects in the safety analysis set. A shift table between 
the worst post-baseline notable abnormalities and baseline notable abnormalities will be 
provided by treatment group. 
A vital sign data listing will be provided.  
8.8.1.5 
Physical Examination 
General physical examination: including General appearance, Skin, Neck, Eyes, Ears, 
Nose, Throat, Lungs, Heart, Abdomen, Back, Lymph nodes, Extremities, Vascular, 
Neurological and other. 
For each general physical examination, a shift table between the worst post-baseline 
clinical significance and baseline clinical significance will be provided by dose group.  
The listing for abnormal PE findings will be provided. The listing for abnormal 
ophthalmological examinations will be provided in another listing.  
8.8.1.6 
Analysis of 12-lead ECG 
12-lead ECG: Including heart rate, PR interval, QRS interval, QT interval, QTcF interval 
and diagnosis.  
An observed value and change from baseline in ECG by visit descriptive table will be 
provided by dose group. 
A shift in Clinical Evaluation table from baseline to worst post-baseline value will be 
presented.  
A 12-lead ECG listing will be provided for all subjects in the Safety analysis Set. 
8.8.1.7 
Analysis of ECOG 
A shift table between the worst post-baseline ECOG Performance Status and baseline 
ECOG Performance Status will be provided by dose group.  
8.9 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be determined with non-compartmental analysis method 
with PK Analysis Set. 
Samples for PK analysis of HH2710 and selected metabolites will be obtained from all 
Phase I/II patients during their first cycle of treatment (Cycle 1). PK samples will also be 
obtained from additional patients in Phase II depending on the outcome of initial PK 
analysis.  
Below is the list of various PK parameters that will be calculated after Dose 1 (Day 1) 
and at Steady State (Day 22). 
Table 2 PK parameters Description 
PK 
Parameter 
(plasma) 
Description 
Cmax 
Peak plasma concentration determined manually by visual inspection of plasma 
concentration vs. time figures on the untransformed (linear) scale of 
measurement 


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tmax 
Time to reach the peak plasma concentration determined manually by visual 
inspection of plasma concentration vs. time figures on the untransformed (linear) 
scale of measurement 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 12 hours postdose, 
calculated by linear/log trapezoidal method 
AUC0-last 
Area under the plasma concentration-time curve from time 0 to time of last 
observation after dosing calculated by linear/log trapezoidal method 
Lambda_z 
(λz) 
Terminal phase rate constant, determined by linear regression of at least 3 points 
on the terminal phase of the log-linear plasma concentration-time curve. The 
correlation coefficient (r2) for the goodness of the fit of the regression line 
through the data points has to be 0.85 or higher for the value to be considered 
reliable. If the WinNonlin data points are not on the linear portion of the terminal 
slope, the data points will be selected manually prior to calculation of Lambda_z 
t1/2 
Terminal half-life, defined as 0.693 (ln2) divided by Lambda z 
CL/F 
The total body clearance of drug from the plasma (volume x time-1) 
Vz/F 
The apparent volume of distribution during terminal phase (associated with 
λz)(volume) 
Descriptive statistics [n, arithmetic mean, standard deviation, coefficient of variation 
(CV), median, minimum, maximum, geometric mean, geometric standard deviation 
geometric CV] will be used to summarize PK parameters by treatment. For t1/2 and tmax, 
regular descriptive statistics and 95% confidence intervals about the arithmetic mean will 
be calculated, for each dose.  
A listing of blood PK concentrations and parameters will be provided. 
8.10 
Pharmacodynamics Analysis 
Pending for medical confirmation. 
8.11 
Exploratory Biomarker Endpoints Analysis 
If there exists exploratory biomarker endpoints analysis, it will be included in separate 
analysis documents. 
8.12 
Changes From Protocol-specified Analyses 
1 year survival rate instead of 1 year overall survival time will be summarized in SAP.   
 
Percentages will be presented to 1 decimal place unless otherwise specified in SAP.  
 
For baseline characteristics, SAP will present Previous Anti-tumor Therapy Type: 
medication, surgery and radiotherapy instead of previous chemotherapy and previous 
immunotherapy. 
 
Updated Safety Set to Safety Analysis Set and All-Treated Set to Full analysis set and 
keep the algorithm the same as protocol. 
 
Members of the review committee will be internal and external to the sponsor. 
 
Remove “Final Analysis section”. By default, primary analyses are final analysis.   
 


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Remove “Percentages will be rounded to the nearest whole number (zeroes are not 
displayed) with values of “< 1%” and “> 99%” shown as necessary for values falling near 
the boundaries” from general principles section. 
 
 
 


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9. 
Literature Citations / References 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol. 2007;25:579-586. 
Clopper CJ and Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial, Biometrika. 1934; 26(4):404-413. 
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 
1979;35:549-556. 
Liu S, et al., Bayesian Optimal Interval Designs for Phase I/II  Clinical Trials. Journal of 
the Royal Statistical Society. 2015, 64(3): 507-523 


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10. 
Appendices 
10.1 
Appendix A Censor rule for PFS, DoR 
No. Situation 
Events or 
Censor 
Analysis date* 
1 
No baseline assessment 
Censor 
First dose date 
2 
No post-baseline assessment, 
no Death 
Censor 
First dose date 
3 
PD during the study (except 
#5, #7) 
Events 
(PD) 
PD date 
4 
Any kind of Death (except #5, 
#7) 
Events 
(Death) 
Death date 
5 
PD or Death after missed two 
consecutive assessment 
Censor 
Last assessment date before the 
missed two consecutive assessment 
6 
Have at leatest one post-
baseline assessment, no PD, 
no Death 
Censor 
Last assessment date 
7 
Initiating alternative anti-
cancer therapy 
Censor 
Last assessment date before 
initiating alternative anti-cancer 
therapy 
* If there are multiple assessment date on one tumor assessment, choose the earliest 
assessment date when overall response is PD, and choose the latest assessment date 
when overall response is CR/PR/SD. 
 
 
10.2 
Appendix B Censor rule for TTR  
No. Situation 
Events or 
Censor 
Analysis date* 
1 
CR, PR before PD, Death, 
alternative anti-cancer therapy 
or missed two consecutive 
assessment. 
Events 
First CR, PR date 
2 
No CR/PR/ alternative anti-
cancer therapy/ missed two 
consecutive 
assessment/PD/Death  
Censor 
Last assessment date 
3 
No CR/PR, have PD or Death 
Censor 
First date of PD or Death 
4 
No CR/PR before alternative 
anti-cancer therapy 
Censor 
Last assessment date before 
initiating alternative anti-cancer 
therapy 
5 
No CR/PR before missed two 
consecutive assessment 
Censor 
Last assessment date before the 
missed two consecutive assessment 
* If there are multiple assessment date on one tumor assessment, choose the earliest 
assessment date when overall response is PD, and choose the latest assessment date 
when overall response is CR/PR/SD. 
 


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10.3 
Appendix C Censor rule for TTP  
No. Situation 
Events or 
Censor 
Analysis date* 
1 
No baseline assessment 
Censor 
First dose date 
2 
No post-baseline assessment, 
no Death 
Censor 
First dose date 
3 
PD during the study (except 
#5, #7) 
Events 
(PD) 
PD date 
4 
Any kind of Death (except #5, 
#7) 
Censor 
Death date 
5 
PD or Death after missed two 
consecutive assessment 
Censor 
Last assessment date before the 
missed two consecutive assessment 
6 
Have at leatest one post-
baseline assessment, no PD, 
no Death 
Censor 
Last assessment date 
7 
Initiating alternative anti-
cancer therapy 
Censor 
Last assessment date before 
initiating alternative anti-cancer 
therapy 
* If there are multiple assessment date on one tumor assessment, choose the earliest 
assessment date when overall response is PD, and choose the latest assessment date 
when overall response is CR/PR/SD. 
 
10.4 
Appendix D. Laboratory Grading and Notable Vital Sign Values 
Laboratory Values 
Safety laboratory values below a distinct limit (eg. detection limit, documented as 
“< [limit]”) will be substituted by half of the limit and values above a distinct limit 
(documented as “> [limit]”) will be substituted by the limit itself for all analyses. 
A Grade (based on CTC AE version 5.0 [v5.00: November 27, 2017]) will be assigned to 
each laboratory result as detailed in Table 2. Depending on the toxicity definition, the 
same result may be assigned to two grading for deviations towards higher or lower 
values. In case no lower limit of normal is provided for the absolute lymphocyte, 
neutrophils or leukocyte counts it will not be differentiated between grade 1 and grade 0 
results for these parameters. Values not meeting any of the criteria will be assigned a 
grade 0. 


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Table 1.  Grading of Select Laboratory Parameters 
Laboratory 
Parameter 
[Unit] 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Lymphocytes 
[G/L] 
0.8 -  < LLN 
0.5 - < 0.8 
0.2 - < 0.5 
< 0.2 
Neutrophils  
[G/L] 
1.5 - < LLN 
1.0 - < 1.5 
0.5 - < 1.0 
< 0.5 
Leukocytes 
[G/L] 
3.0 - < LLN 
2.0 - < 3.0 
1.0 - < 2.0 
< 1.0 
Platelets [G/L] 
75 - < LLN 
50 - < 75 
25 - < 50 
< 25 
Hemoglobin 
[g/L]* 
100 - < LLN  
80 - < 100 
< 80 
not defined 
Albumin [g/L] 
30 - < LLN 
20 - < 30 
< 20 
not defined 
AST* 
> ULN – 3*ULN 
> 3*ULN – 5*ULN 
> 5*ULN – 20*ULN 
> 20*ULN 
ALT * 
> ULN – 3*ULN 
> 3*ULN – 5*ULN 
> 5*ULN – 20*ULN 
> 20*ULN 
GGT  
> ULN – 
2.5*ULN 
>2.5*ULN – 5*ULN 
> 5*ULN – 20*ULN 
> 20*ULN 
Bilirubin 
> ULN – 
1.5*ULN 
>1.5*ULN – 3*ULN 
> 3*ULN – 10*ULN 
> 10*ULN 
Fibrinogen^ 
%change of BL 
<25%  
decrease  or 
0.75*LLN - < 
LLN 
25%- <50%  
decrease of BL 
  or  
< 75*LLN – 
0.5*LLN 
50% -  <75% 
decrease of BL  
or 
< 0.5* LLN – 
0.25*LLN 
>= 75% 
decrease of 
BL or < 
50mg/dL or 
< 0.25*LLN 
Calcium 
[mmol/L]* 
2.0 - < LLN 
1.75 - < 2.0 
1.5 - < 1.75 
< 1.5 
Potassium 
[mmol/L]* 
not defined 
3.0 - < LLN 
2.5 - < 3.0 
< 2.5 
Lipase 
> ULN – 
1.5*ULN 
> 1.5*ULN – 
2.0*ULN 
> 2.0*ULN – 5.0*ULN 
> 5.0*ULN 
Amylase  
> ULN – 
1.5*ULN 
> 1.5*ULN – 
2.0*ULN 
> 2.0*ULN – 5.0*ULN 
> 5.0*ULN 
BL: baseline value, LLN: Lower limit of normal, ULN: Upper limit of normal 
*: Clinical criteria from CTC AE 5.0 grading were not considered in order to assign grades 
^: In case of conflicting criteria the higher grade will be assigned, % change only used when 
baseline is <LLN  
Vital Signs 
Notable values for vital signs are defined according to the following table: 
Table 2.  Notable Abnormalities of Vital Signs 
Vital Sign 
 
Notable Abnormalities 
Pulse rate/Heart rate 
(bpm) 
 
>100 
<60 
Respiratory Rate (bpm) 
 
>24 


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Vital Sign 
 
Notable Abnormalities 
<12 
Blood pressure (mmHg) 
Systolic 
160 
90 
 
Diastolic 
105 
50 
Weight (kg) 
 
change from baseline >10% (in both 
directions) 
Body temperature (°C) 
 
> 39 
 
 
 
10.5 
Appendix E  Definitions 
ORR  
Objective response rate is defined as the percentage of patients who have at least one 
confirmed response of CR or PR defined by RECIST 1.1 prior to any evidence of 
progression.  
DoR 
Duration of response will be defined as the time from the date of first documented 
response, (that is subsequently confirmed) until date of documented progression or death 
in the absence of disease progression, the end of response should coincide with the date 
of progression or death from any cause used for the PFS endpoint. The time of the initial 
response will be defined as the latest of the dates contributing towards the first visit 
response of PR or CR.  
DCR 
Disease control rate is defined as the proportion of subjects with advanced tumors among 
whom achieve a best overall response CR/PR/SD after treatment with HH2710.   
PFS 
PFS is defined as the time from date of first dosing until the date of objective disease 
progression as defined by RECIST 1.1 or death (by any cause in the absence of 
progression) regardless of whether the subject withdraws from HH2710 treatment or 
receives another anticancer therapy prior to progression. 
Overall Survival  
Overall survival is defined as the interval between the date of first dose and the date of 
patient death due to any cause. Patients who have not died at the time of the statistical 
analysis will be censored at the time they were last known to be alive.  
TTR 


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TTR is defined as the duration from the first day of study treatment until the first 
documented response (CR or PR). 
TTP 
TTP is defined as the duration from the first day of study treatment until the first 
documented progression (PD). 
Baseline 
For data analyses, baseline will be defined as the value measured on day 1 of the start of 
HH2710. The protocol specifies that all study procedures on day 1 should be completed 
before the initiation of HH2710 which will be the assumption in the analysis unless the 
time of the assessment is recorded.  If a day 1 value is not available, the latest value 
before the day of the start of HH2710 may be used. 
End of Treatment Date 
The end of HH2710 therapy date is the date the decision was made to end investigational 
product reported on the end of investigational product administration CRF.   
End of Study  
For a subject: a subject ends the study when they die, consent is withdrawn, or they are 
lost to follow-up. The end of study date will be captured on the end of study CRF. 
For the study as a whole: the end of study as a whole is defined as a minimum of 80% of 
patients in the Phase II stage have died, have been lost to follow-up, or have been 
followed for survival for minimum 12 months after the first dose of study treatment. 
Treatment-emergent Adverse Event 
TEAE are defined as AEs that were reported or worsened on or after the start of study drug 
dosing and up to the safety follow-up.